World Health Organization Classification of Tumours

WHO
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~~ '1-1~ lff~
~~
OMS

lnternational Agency for Research on Cancer (IARC)

4th Edition

WHO Classification of
Head and Neck Tumours

Edited by

Adel K. El-Naggar
John K.C. Chan
Jennifer R. Grandis
Takashi Takata
Pieter J. Slootweg

1nternational Agency for Research on Cancer

Lyon, 2017
World Health Organization Classification of Tumours

Series Editors Fred T. Bosman, MD PhD

Elaine S. Jaffe, MD
Sunil R. Lakhani, MD FRCPath
Hiroko Ohgaki, PhD

WHO Classification of Head and Neck Tumours

Editors Adel K. El-Naggar, MD , PhD

John K.C. Chan, MBBS
Jennifer R. Grandis, MD
Takashi Takata, DOS, PhD
Pieter J. Slootweg, MD , DMD, PhD

Project Assistants Asiedua Asante

Anne-Sophie Hameau

Technical Editor Jessica Cox

Database Alberto Machado

Delphine Nicolas

Layout Julia Brinkmann

Printed by Maestro
38330 Saint-lsmier, France

Publisher lnternational Agency for

Research on Cancer (IARC)
69372 Lyon Cedex 08, France
The WHO Classification of Head and Neck Tumours presented in this book reflects the views
of a Working Group that convened for a Consensus and Editorial Meeting at the lnternational
Agency for Research on Cancer,
Lyon, 14-16 January 2016.

Members of the Working Group are indicated

in the list of contributors on pages 285-292.
 Publ ished by the lnternational Agency for Research on Cancer (IARC) ,
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First print run (10 000 copies)

Format far bibliographic citations:

El-Naggar A.K., Chan J.K.C , Grandis J.R , Takata T., Slootweg P.J. (Eds):
WHO Classification of Head and Neck Tumours (4th edition) .
IARC: Lyon 2017

IARC Library Cataloguing in Publication Data

WHO classification of head and neck tumours / edited by Adel K. El-Nagg ar, John K.C. Chan,
Jennifer R. Grandis, Takashi Takata , Pieter J. Slootweg. - 4th edition.

(World Health Organization classification of tumours)

1. Head and neck neoplasms - genetics 2. Head and neck neoplasms - pathology
3. Odontogenic tumou rs - genetics 4. Odontogenic tumours - pathology

l. E\-Naggar, Adel K. JI. Series

ISBN 978-92-832-2438-9 (N LM Classification WE 707)

Contents
Tumours of the nasal cavity, paranasal sinuses and 11 lntroduction 65
skull base Nasopharyngeal carcinoma 65
WHO and TNM classifications 12 Nasopharyngeal papillary adenocarcinoma 70
lntroduction 14 Salivary gland tumours 71
Carcinomas 14 Adenoid cystic carcinoma 71
Keratinizing squamous cell carcinoma 14 Salivary gland anlage tumour 71
Non-keratinizing squamous cell carcinoma 15 Benign and borderline lesions 72
Spindle ce ll (sarcomatoid) squamous cell carcinoma 17 Hairy polyp 72
Lymphoepithelial carcinoma 18 Ectopic pituitary adenoma 72
Sinonasal undifferentiated carcinoma 18 Craniopharyngioma 73
NUT carcinoma 20 Soft tissue tumours 74
Neuroendocrine carcinoma 21 Nasopharyngeal angiofibroma 74
Adenocarcinoma 23 Haematolymphoid tumours 75
lntestinal-type adenocarcinoma 23 Notochordal tumours 76
Non- intestinal-type adenocarcinoma 24 Chordoma 76
Teratocarcinosarcoma 26
Sinonasal papillomas 28 3 Tumours of the hypopharynx, larynx, !rachea and 77
Sinonasal papilloma, inverted type 28 parapharyngeal space
Sinonasal papil loma, oncocytic type 29 WHO and TNM classifications 78
Sinonasal papilloma, exophytic type 30 lntroduction 81
Respiratory epithel ial lesions 31 Malignan! surface epithelial tumours 81
Respiratory epithelial adenomatoid hamartoma 31 Conventional squamous cell carcinoma 81
Seromucinous hamartoma 32 Verrucous squamous cell carcinoma 84
Salivary gland tumours 33 Basaloid squamous cell carcinoma 85
Pleomorphic adenoma 33 Papillary squamous cell carcinoma 87
Malignan! soft tissue tumours 34 Spindle cell squamous cell carcinoma 87
Fibrosarcoma 34 Adenosquamous carcinoma 89
Undifferentiated pleomorphic sarcoma 35 Lymphoepithelial carcinoma 90
Leiomyosarcoma 35 Precursor lesions 91
Rhabdomyosarcoma 36 Dysplasia 91
Angiosarcoma 38 Squamous cell papilloma & squamous cell papillomatosis 93
Malignan! peripheral nerve sheath tumour 39 Neuroendocrine tumours 95
Biphenotypic sinonasal sarcoma 40 Well-differentiated neuroendocrine carcinoma 95
Synovi al sarcoma 41 Moderately differentiated neuroendocrine carcinoma 96
Borderline / low-grade malignan! soft tissue tumours 43 Poorly differentiated neuroendocrine carcinoma 97
Desmoid-type fibromatosis 43 Salivary gland tumours 99
Sinonasal glomangiopericytoma 44 Adenoid cystic carcinoma 99
Solitary fibrous tumour 45 Pleomorph ic adenoma 99
Epithelioid haemangioendothelioma 46 Oncocytic papillary cystadenoma 99
Benign soft tissue tumours 47 Soft tissue tumours 100
Leiomyoma 47 Gran ular cell tumour 100
Haemangioma 47 Liposarcoma 100
Schwannoma 48 lnflammatory myofibroblastic tumour 101
Neurofibroma 49 Cartilage tumours 102
Other tumours 50 Chondroma and chondrosarcoma 102
Meningioma 50 Haematolymphoid tumours 104
Sinonasal ameloblastoma 51
Chondromesenchymal hamartoma 51 4 Tumours of the oral cavity and mobile tangue 105
Haematolymphoid tumours 52 WHO and TNM classifications 106
Overview 52 lntroduction 108
Extranodal NK/T-cell lymphoma 52 Malignan! surface epithelial tumours 109
Extraosseous plasmacytoma 54 Squamous cell carcinoma 109
Neuroectodermal / melanocytic tumours 56 Oral potentially malignan! disorders & oral epithelial dysplasia 112
Ewing sarcoma/primitive neuroectodermal tumours 56 Oral potentially malignan! disorders 112
Olfactory neuroblastoma 57 Oral epithel ial dysplasia 112
Mucosa! melanoma 60 Prol iferative verrucous leukoplakia 113
Papil lomas 115
2 Tumours of th e nasoph arynx 63 Squamous cell papilloma 115
WHO and TNM classifications 64 Condyloma acuminatum 116
 Verruca vulgaris 117 lntroduction 162
Multifocal epithelial hyperplasia 117 Malignant tumours 163
Tumours of uncertain histogenesis 119 Mucoepidermoid carcinoma 163
Congenital granular cell epulis 119 Adeno id cystic carcinoma 164
Ectomesenchymal chondromyxoid tumour 119 Acinic cel l carc inoma 166
Soft tissue and neural tumours 121 Polymorphous adenocarcinoma 167
Granular cell tumour 121 Clear cell carcinoma 168
Rhabdomyoma 122 Basal cel l adenocarcinoma 169
Lymphangioma 122 lntraductal carcinoma 170
Haemangioma 123 Adenocarcinoma, NOS 171
Schwannoma and neurofibroma 123 Salivary duct carcinoma 173
Kaposi sarcoma 124 Myoep ithelial carcinoma 174
Myofibroblastic sarcoma 125 Epithelial- myoepithelial carcinoma 175
Oral mucosa! melanoma 126 Carcinoma ex pleomorphic adenoma 176
Salivary type tumours 127 Secretory carcinoma 177
Mucoepidermoid carcinoma 127 Sebaceous adenocarcinoma 178
Pleomorphic adenoma 127 Carcinosarcoma 179
Haematolymphoid tumours 128 Poorly differentiated carcinoma 180
Overview 128 Lymphoepithelial carcinoma 181
CD30-positive T-cell lymphoproliferative disorder 129 Squamous cell carcinoma 182
Plasmablastic lymphoma 129 Oncocytic carcinoma 182
Langerhans cell histiocytosis 130 Sialoblastoma 183
Extramedu llary myeloid sarcoma 131 Beni gn tumours 185
Pleomorphic adenoma 185
5 Tumours of the oropharynx 133 Myoepithelioma 186
(base of tangue, tonsils, adenoids) Basal cell adenoma 187
WHO and TN M c lassifications 134 Warthin tumour 188
lntroduction 136 Oncocytoma 189
Squamous cell carcinoma 136 Lymphadenoma 190
Squamous cell carcinoma, HPV-positive 136 Cystadenoma 191
Squamous cell carcinoma, HPV-negative 138 Sialadenoma papi lliferum 192
Salivary gland tumours 139 Ouctal papillomas 192
Pleomorphic adenoma 139 Sebaceous adenoma 193
Adenoid cystic carcinoma 139 Canalicular adenoma and other ductal adenomas 194
Polymorphous adenocarcinoma 140 Non-neoplastic epithelial lesions 195
Haematolymphoid tumours 141 Sclerosing polycystic adenosis 195
lntroduction 141 Nodular oncocytic hyperplasia 195
Hodgkin lymphoma 141 Lymphoepithelial si aladenitis 196
Burkitt lymphoma 142 lntercalated duct hyperplasia 197
Follicular lymphoma 143 Benign soft tissue lesions 198
Mantle cell lymphoma 144 Haemang ioma 198
T-lymphoblastic leukaemia/lymphoma 144 Lipoma/sialol ipoma 198
Follicular dendritic cell sarcoma 145 Nodular fasci itis 199
Haematolymphoid tumours 200
6 Tumours and tumour-like lesions 147 Extranodal marginal zone lymphoma of mucosa-
of the neck and lymph nades associated lymphoid tissue (MALT lymphoma) 201
WHO classification 148
lntroduction 148 8 Odontogenic and maxillofacial bone tumours 203
Tumours of unknown origin 150 WHO classification 204
Carcinoma of unknown primary 150 lntroduction 205
Merkel cell carcinoma 151 Odontogenic carcinomas 206
Heterotopia-associated carcinoma 152 Ameloblastic carcinoma 206
Haematolymphoid tumours 154 Primary intraosseous carcinoma, NOS 207
Cysts and cyst-like lesions 155 Sclerosing odontogenic carcinoma 209
Branchial cleft cyst 155 Clear cel l odontogenic carcinoma 210
Thyroglossal duct cyst 156 Ghost cell odontogenic carcinoma 211
Ranu la 156 Odontogenic carcinosarcoma 213
Oermoid and teratoid cysts 157 Odontogenic sarcomas 214
Benign epithelial odontogenic tumou rs 215
7 Tumours of salivary glands 159 Ameloblastoma 215
WHO and TNM classifications 160 Amelob lastoma, unicystic type 217
 Amelob lastoma, extraosseous/peripheral type 218 9 Tumours of the ear 261
Metastasizing ameloblastoma 218 WHO classification 262
Squamous odontogenic tumour 219 lntroduction 263
Calcifying epithelial odontogenic tumour 220 Tumours of the externa! auditory canal 263
Adenomatoid odontogenic tumour 221 Squamous cell carcinoma 263
Benign mixed epithelial & mesenchymal odontogenic tumours 222 Ceruminous adenocarcinoma 264
Amelob lastic fib roma 222 Ceruminous adenoma 265
Pri mord ial odontogenic tumour 223 Tumours of the middle and inner ear 266
Odontoma 224 Squamous cell carcinoma 266
Dentinogenic ghost cell tumour 226 Aggressive papillary tumour 266
Benign mesenchymal odontogenic tumours 228 Endolymphatic sac tumour 267
Odontogenic fibroma 228 Otosclerosis 268
Odontogenic myxoma/myxofibroma 229 Cholesteatoma 269
Cementoblastoma 230 Vestibular schwannoma 270
Cemento-ossifying fibroma 23 1 Mening ioma 271
Odontogenic cysts of inflammatory origin 232 Middle ear adenoma 272
Radicular cyst 232
lnflammatory col lateral cysts 233 1O Paraganglion tumours 275
Odontogenic and non-odontogenic developmental cysts 234 WHO classification 276
Dentigerous cyst 234 1ntrod uction 276
Odontogen ic keratocyst 235 Carotid body paraganglioma 277
Lateral periodontal cyst and botryoid odontogenic cyst 236 Laryngeal paraganglioma 281
Gingival cysts 238 Middle ear paraganglioma 282
Glandular odontogenic cyst 238 Vagal paraganglioma 283
Calcifying odontogenic cyst 239
Orthokeratinized odontogenic cyst 241 Contributors 285
Nasopalatine duct cyst 241 Declaration of interests 292
Malignan! maxillofacial bone and cartilage tumours 243
IARC/WH O Committee far ICD-0 293
Chondrosarcoma 243
Mesenchymal chondrosarcoma 244 Sources of figures 294
Osteosarcoma 244 Sources of tables 297
Benign maxillofacial bone and cartilage tumours 246 References 298
Chondroma 246 Subject index 340
Osteoma 246
List of abbreviations 347
Melanotic neuroectodermal tumour of infancy 247
Chondroblastoma 248
Chondromyxoid fibroma 249
Osteoid osteoma 249
Osteoblastoma 249
Desmoplastic fibroma 250
Fibro-osseous and osteochondromatous lesions 251
Ossifying fibroma 251
Fami lia! gigantiform cementoma 253
Fibrous dysplasia 253
Cemento-osseous dysplasia 254
Osteochondroma 255
Giant cell lesions and simple bone cyst 256
Central giant cell granuloma 256
Peripheral giant cell granuloma 257
Cherubism 257
Aneurysmal bone cyst 258
Simple bone cyst 259
Haematolymph oi d tumours 260
Solitary plasmacytoma of bone 260
 CHAPTER 1

Tumours of the nasal cavity, paranasal

sinuses and skull base
Squamous cell carcinomas
Lymphoepithelial carcinoma
NUT carcinoma
Neuroendocrine carcinomas
Adenocarcinomas
Teratocarcinosarcoma
Sinonasal papillomas
Respiratory epithelial lesions
Salivary gland tumours
Malignant soft tissue tumours
Borderline / low-grade malignant
soft tissue tumours
Benign soft tissue tumours
Haematolymphoid tumours
Neuroectodermal / melanocytic tumours
WHO classification of tumours of the nasal cavity,
paranasal sinuses and skull base

Carcinomas Borderline/low-grade malignant soft tissue tumours

Keratinizing squamous cell carcinoma 8071 /3 Desmoid-type fibromatosis 8821 / 1
Non-keratinizing squamous cell carc inoma 8072/3 Sinonasal glomangiopericytoma 9150/ 1
Spindle cell squamous cell carcinoma 8074/3 Solitary fibrous tumour 8815/1
Lymphoepithelial carcinoma 8082/3 Epithelioid haemangioendothelioma 9133/3
Sinonasal undifferentiated carcinoma 8020/3
NUT carcinoma 8023/3* Benign soft tissue tumours
Neuroendocrine carcinomas Leiomyoma 8890/0
Small cell neuroendocrine carcinoma 8041/3 Haemangioma 9120/0
Large cell neuroendocrine carcinoma 8013/3 Schwannoma 9560/0
Adenocarcinomas Neurofibroma 9540/0
lntestinal-type adenocarcinoma 8144/3
Non- intestinal-type adenocarcinoma 8140/3 Other tumours
Meningioma 9530/0
Teratocarcinosarcoma 9081/3 Sinonasal amelob lastoma 9310/0
Chondromesenchymal hamartoma
Sinonasal papillomas
Sinonasal papilloma, inverted type 8121 / 1 Haematolymphoid tumours
Sinonasal papilloma, oncocytic type 8121 / 1 Extranodal NK/T-cell lymphoma 9719/3
Sinonasal papilloma, exophytic type 8121/0 Extraosseous plasmacytoma 9734/3

Respiratory epithelial lesions Neuroectodermal / melanocytic tumours

Respiratory epithelial adenomatoid hamartoma Ewing sarcoma / primitive neuroectodermal
Seromucinous hamartoma tumour 9364/3
Olfactory neuroblastoma 9522/3
Salivary gland tumours Mucosa! melanoma 8720/3
Pleomorphic adenoma 8940/0

Malignant soft tissue tumours

Fibrosarcoma 8810/3
Undifferentiated pleomorphic sarcoma 8802/3
Leiomyosarcoma 8890/3
Rhabdomyosarcoma , NOS 8900/3
Embryonal rhabdomyosarcoma 8910/3
The morphology codes are from the lnternational Classification of Diseases
Alveolar rhabdomyosarcoma 8920/3 for Oncology (ICD-0) {776A}. Behaviou r is coded /0 for benign tumours;
Pleomorphic rhabdomyosarcoma , adult type 8901 /3 /1 for unspecified , borderline, or uncertain behaviou r; /2 for carcinoma in
Spindle cell rhabdomyosarcoma 8912/3 situ and grade 111 intraepithelial neoplasia; and /3 for mal ignan! tumours.
The classification is modified from the previous WHO c lassifi cation, taking
Angiosarcoma 9120/3 into account changes in our understand ing of these lesions.
Malignant peripheral nerve sheath tumour 9540/3 ·r hese new codes were approved by the IARC/WHO Committee for ICD-0.
Biphenotypic sinonasal sarcoma 9045/3*
Synovial sarcoma 9040/3

12 Tumours of the nasal cavity, paranasal sinuses and skull base

TN M classification of carcinomas of the nasal cavity and
paranasal sinuses

TNM classification•·b N - Regional lymph nodes (i.e. the cervical nodes)

T - Primary tumour NX Regional lymph nades cannot be assessed
TX Primary tumour cannot be assessed NO No regional lymph node metastasis
TO No evidence of primary tumour N1 Metastasis in a single ipsilateral lymph node, ~ 3 cm in
Tis Carcinoma in situ greatest dimension
N2 Metastasis as specified in N2a, N2b, m N2c below
Maxillary sinus N2a Metastasis in a single ipsilateral :ymph node, > 3 cm but
T1 Tumour limited to the antral mucosa, with no erosion or ~ 6 cm in greatest dimension
destruction of bone N2b Metastasis in multiple ipsi lateral lympll nodes, ali ~ 6 cm
T2 Tumour causing bone erosion or destruction, including in greatest dimension
extension into hard palate and/or middle nasal meatus, N2c Metastasis in bi lateral or contralateral lymph nades, all
except extension to posterior wal l of maxillary sinus and ~ 6 cm in greatest dimension
pterygoid plates N3 Metastasis in a lymph node > 6 cm in greatest dimension
T3 Tumour invades any of the following : bone of posterior
Note: Midline nades are considered ipsilateral nades.
wal l of maxillary sinus, subcutaneous tissues, floor or
medial wall of orbit, pterygoid fossa, ethmoid sinuses
T4a Tumour invades any of the following: anterior orbital M - Distant metastasis
contents, skin of cheek, pterygoid plates, infratemporal MO No distan! metastasis
fossa, cribriform plate, sphenoid or frontal sinuses M1 Distant metastasis
T4b Tumour invades any of the following: orbital apex , dura,
brain, middle cranial fossa, cranial nerves other than max- Stage grouping
illary division of trigeminal nerve (V2), nasopharynx, clivus Stage O Tis NO MO
Stage 1 T1 NO MO
Nasal cavity and ethmoid sinus Stage 11 T2 NO MO
T1 Tumour limited to one subsite of nasal cavity or ethmoid Stage 111 T1- 2 N1 MO
sinus, with or without bony invasion T3 N0- 1 MO
T2 Tumour involves two subsites in a single site or extends to Stage IVA T1-3 N2 MO
involve an adjacent site within the nasoethmoidal T4a N0-2 MO
complex, with or without bony invasion Stage IVB T4b Any N MO
T3 Tumour extends to invade the medial wall or floor of the Any T N3 MO
orbit, maxillary sinus, palate, or cribriform plate Stage IVC Any T Any N M1
T4a Tumour invades any of the following: anterior orbital
contents , skin of nose or cheek, minimal extension to
ªAdapted from Edge et al. {625A} - used with pernission of the American
anterior cranial fossa, pterygoid plates, sphenoid or
Joint Committee on Cancer (AJCC), Chicago, lllinois; the original and prima-
frontal sinuses ry source far this information is the AJCC Cancer Scaging Manual , Seventh
T4b Tumour invades any of the following: orbital apex , dura, Edition (2010) published by Springer Science+Busi1ess Media - and Sobin
brain, middle cranial fossa, cranial nerves other than V2, et al. {2228A}.
nasopharynx, clivus bA help desk far specific questions about TNM classification is available at
http://www.uicc.org/resources/tnm/helpdesk.

TNM classification of carcinomas of the nasal cavity and pararasal sinuses 13

Tumours of the nasal cavity, paranasal
sinuses and skull base
lntroduction
Slootweg P.J.
Chan J.K.C.
Stelow E.B.
Thompson L.D .R .
The sinonasal tract (i.e. the nasal cav-
ity and associated paranasal sinuses)
is the site of origin for a wide variety of
neoplasms. The entities included in this
chapter meet one of three inclusion crite-
ria: (1) they occur exclusively in the sino-
nasal tract, (2) they occur at other head
and neck sites but show a predilection
for the sinonasal tract, or (3) they are im -
portant in the sinonasal tract for differen -
tial diagnostic reasons. The first group is
discussed extensively and the other two
more concisely, with the reader referred
to other chapters for additional informa-
tion . This edition includes NUT carcino-
ma and biphenotypic sinonasal sarcoma
as well-defined new entities. HPV-related
Carcinomas
Keratinizing squamous ce//
carcinoma
Bishop J.A.
Bell D.
Westra W.H.
Definition
Sinonasal keratinizing squamous cell
carcinoma (KSCC) is a malignant epi -
thelial neoplasm arising from the surface
epithelium lining the nasal cavity and
paranasal sinuses and exhibiting squa-
mous differentiation .
ICD-0 code 8071 /3
14 Tumours of the nasal cavity, paranasal sinuses and skull base
carcinoma with adenoid cystic-like fea-
tures is provisionally listed as a subtype
of non-keratinizing squamous cell carci-
noma, with additional data needed to jus-
tify full recognition as a unique entity. Tu-
mours of bone and cartilage , which were
included in both the jaw and sinonasal
tract chapters in the previous edition , are
in this edition discussed exclusively in
Chapter 8 (Odontogenic and maxillofacial
bone tumours, p. 203) - a more appropri -
ate approach given their morphological
overlap with sorne odontogenic tumours.
The role of immunohistochemical and
genetic features in tumour characteriza-
tion is reported with a balance between
worldwide global application and the use
of more expensive diagnostic methods
not everywhere available, in an effort to
ensure a more universal applicability of
the classification.
lt is noted that sorne tumours may consti-
tute a spectrum of entities, such as high-
grade non- intestinal-type adenocar-
cinoma and sinonasal undifferentiated
Synonym
Epidermoid carcinoma
Epidemiology
Sinonasal KSCCs are rare, and the sino-
nasal tract is the least common head and
neck subsite involved by squamous cell
carcinoma (SCC) {82}. KSCC most often
affects patients in their sixth to seventh
decades of life, and men are affected
twice as often as women {82 ,2065 ,2438}.
Etiology
Cigarette smoking increases risk, al-
though less dramatically than in other
head and neck sites {271 ,960,1458,
2688}. Wood dust, leather dust, and other
carcinoma, and that there may be sorne
overlap between tumours, such as be-
tween sorne sinonasal undifferentiated
carcinomas and high -grade neuroendo-
crine carcinomas. More data are needed
before recommendations can be made
on how best to classify tumours within
these categories. In the meantime, we
have tried to remain consisten! with pre-
vious classification systems of tumours
both at this site and at others (e.g. the
classification of high-grade neuroendo-
crine carcinomas of the lung).
Within the sinonasal tract, CT is primarily
used to evaluate mass effect on adjacent
osseous structures, whereas MRI is bet-
ter for distinguishing mucosa! thickening
and fluid resulting from a pathological
mass process. Th us, these imaging mo-
dalities are complementary techniques.
However, in general, cross-sectional im-
aging findings are not unique or tumour-
specific; therefore , information regarding
imaging findings is included only when it
is of specific diagnostic value .
. ... ..
__... . ;¡ . •; ·
.A.... ~, .. , t
Fig. 1.01 Sinonasal keratinizing squamous cell
carcinoma consisting of small nests of neoplastic cells
with numerous squamous pearls within a desmoplastic
stroma.
industrial exposures are linked to sinona-
sal KSCC, although the association is
not as strong as with intestinal -type ade-
nocarcinoma {940,1490,1627). High-risk
HPV is most frequently associated with
non-keratinizing squamous cell carci-
noma (see Non-keratinizing squamous
ce// carcinoma, p. 15) \199,636,1335).
Sorne sinonasal papillomas (2-10%) un-
dergo malignant transformation, usually
into KSCC and less frequently into non-
keratinizing squamous cell carcinoma
\1750).

Localization
The maxillary sinus is most frequently af-
fected, followed by the nasal cavity and
ethmoid sinus. Primary carcinomas of the
sphenoid and frontal sinuses are rare \82 ,
1999,2065,2342, 2438).

Clinical features
Presenting symptoms are generally non-
specific and include nasal obstruction ,
epistaxis, and rhinorrhoea. Facial pain
and/or paralysis, diplopia, and proptosis
are indicative of more-advanced tumour
growth {1458). lmaging determines ex-
tent of disease.

Macroscopy
The tumour is exophytic or endophytic ,
with various degrees of ulceration , ne-
crosis, and haemorrhage.

Cytology
Aspirates of metastases are cellular, with
sheets and small clusters of malignant
squamous cells with intracellular and
.....
Fig. 1.02 Sinonasal non-keratinizing squamous cell carcinoma. A lnterconnecting squamous ribbons invading the
stroma with a broad, pushing border. B lnvasion takes the form of thick, anastomosing ribbons of tumour cells with
extracellular keratinization. Mixed inflam- a smooth stromal interface and no desmoplastic reaction. C Non-keratinizing squamoid cells with nuclear atypia,
mation and necrosis can be present. numerous mitotic figures, and peripheral palisading of tumour nuclei.

Histopathology similar to that of its counterpart in the oro- Non-keratinizing squamous

KSCC exhibits histological features iden-
tical to those of conventional squamous
cell carcinoma of other head and neck
sites, with irregular nests and cords of
eosinophilic cells demonstrating kerati -
nization and inducing a desmoplastic
stromal reaction. Grades include well,
moderately, and poorly differentiated.
See Chapter 3 (Tumours ofthe hypophar-
ynx, larynx, trachea and parapharyngeal
space, p. 77) for further detail.
Genetic profile
The genetic profile is similar to that of
KSCC of other upper aerodigestive tract
sites, whereas the genetic profile of non-
keratinizing squamous cell carcinoma is
pharynx {447,1458,1474). ce// carcinoma
Prognosis and predictive factors Bishop J.A.
The 5-year overall survival rate for sino- Brandwein-Gensler M.
nasal squamous cel l carcinoma is approx- Nicolai P
imately 50-60%, and is stage-depend- Steens S.
ent {2065 ,2397,2438). Carcinomas of Syrjanen S.
the nasal cavity have a better prognosis Westra W.H.
than carcinomas arising in the paranasal
sinuses {82,617,2397,2438). This differ-
ence is likely in part because sinus carci - Definition
nomas present later and at higher stage; Non-keratinizing squamous cell carcino-
it is unclear whether there is a stage-for- ma (NKSCC) is a squamous cell carcino-
stage survival difference. Regional lymph ma (SCC) characterized by a distinctive
node metastasis is uncommon {1458). ribbon-like growth pattern with absent to
limited maturation .

Carcinomas 15
ICD-0 code 8072/3
Synonyms
Schneiderian carcinoma; transitional cell
carcinoma; cylindrical cell carcinoma
Epidemiology
NKSCC accounts for approximately 10-
27% of sinonasal SCC. lt affects adults in
their sixth to seventh decades of lite, and
men more frequently than women {199 ,
636,1784,1999}.
Etiology
In general, NKSCC has similar risk fac-
tors to keratinizing squamous cell car-
cinoma, but 30-50% of cases harbour
transcriptionally active high -risk HPV
(199 ,636 ,1335). Sorne sinonasal papil-
lomas (2-10%) undergo malignan! trans-
formation, usually into keratinizing squa-
mous cell carcinoma and less frequently
into NKSCC {1750).
Localization
NKSCC arises most frequently from the
maxillary sinus or nasal cavity (82,1402,
2065,2438l.
Fig. 1.04 HPV-related carcinoma with adenoid cystic-like features . A Many examples demonstrate foci of squamous dysplasia in the overlying surface epithelium.
B Transcriptionally active high-risk HPV is demonstrated within the neoplasm by RNA in situ hybridization.
16 Tumours of the nasal cavity, paranasal sinuses and skull base
Clinical features
Presenting signs and symptoms include
nasal obstruction , discharge, epistaxis ,
facial pain or fullness, nasal mass or
ulcer, and eye-related symptoms in ad-
vanced cases (1458}. Patients with para-
nasal sinus neoplasms present later and
at a higher stage than do patients with
nasal cavity carcinomas (82,2438). lm-
aging determines extent of disease.
Macroscopy
The tumours are variably exophytic and/
or inverted in growth, and often friable ,
with necrosis and/or haemorrhage.
Cytology
Aspirates of metastases are cellular, with
clusters of basaloid cells showing cyto-
logical features typical of malignancy,
with nuclear atypia and increased mitotic
figures. Mixed inflammation and necrosis
can be present.
Histopathology
NKSCC characteristically grows as ex-
panding nests or anastomosing ribbons
of cells in the submucosa, with a smooth
stromal interface and a pushing border
eliciting minimal or no desmoplasia. This
pattern is reminiscent of urothelial carci-
noma (hence the synonym "transitional
cell carcinoma") and may be difficult
to recognize as invasive, particularly in
small biopsies. Papillary features can
be seen within the tumour or at the mu-
cosa! surface. NKSCC has an immature
appearance, with minimal or no kerati-
nization; tumour nuclei are oval and the
N:C ratio is high. Basal/superficial cel-
lular polarity is often apparent: basal-
type cells often demonstrate peripheral
palisading, whereas superficial cells are
more flattened. Scattered mucinous cells
are occasionally present. The degree of
nuclear atypia varies, but mitotic figures
are typically numerous, and necrosis is
common. There is no established role for
tumour grading in this variant.
There is a broad differential diagnosis;
the growth pattern of NKSCC can mimic
that of a sinonasal papilloma with malig-
nan! transformation . However, this would
require confirmation of metachronous
or synchronous sinonasal papilloma.
Sinonasal undifferentiated carcinoma,
neuroendocrine carcinoma, the solid
variant of adenoid cystic carcinoma,
and SMARCB1-deficient carcinomas
should be considered in the differential
diagnosis. The presence of so-called
abrupt keratinization should raise the
possibility of NUT carcinoma.
NKSCC is diffusely positive for cytokerat-
ins (including high -molecular-weight
forms such as CK5/6) and for p63 and
p40. lt retains nuclear express ion of
SMARCBi (INli) and is negative for neu -
roendocrine markers, S100, and NUTi.
HPV-related SCCs are diffusely pi 6-
positive by immunohistochemistry and
pos itive for HPV by in situ hybridization
and PCR.
Genetic protile
The distinctive mutational profi les of
HPV-positive and HPV-negative sinona-
sal SCC are similar to those of their coun -
terparts in other head and neck siles,
such as the oropharynx 1447,i458,i474).
Prognosis and predictive tactors
The 5-year overall survival rate of sino-
nasal SCCs as a group is approximately
60%; it is unclear whether the survival rate
of NKSCC differs from that of keratiniz-
ing squamous cell carcinoma {82,i999,
2065,2397,2438) HPV positivity may be
associated with improved survival, al -
though the prognostic significance is not
as clearly defined as it is in the oropha-
rynx {199 ,i335}. Sorne studies have dem -
onstrated improved survival in sinonasal
SCC harbouring high-risk HPV or overex-
pressing EGFR {i99,i335,2342}.
The newly recognized sinonasal tract
HPV-related carcinoma with adenoid
cystic-like features is a distinctive HPV-
related carcinoma of the sinonasal tract,
with histological and immunophenotypic
features of both surface-derived and sali -
vary gland carcinoma - the latter show-
ing the appearance of a high-grade ad -
enoid cystic carcinoma. Among the few
cases of HPV-related carcinoma with ad -
eno id cystic- like features that have been
reported to date, the female-to-male ratio
is 7:2 and the patient age range is 40-
75 years {i99,202,1065) The presence
of a high-risk HPV type suggests a viral
etiology 1202,1065). Most cases present
with nasal obstruction and/or epistaxis,
with a tan-white, fleshy mass undermin-
ing normal -looking mucosa. The tumour
consists of highly cellular proliferations of
basaloid cells growing in various sizes ,
separated by thin collagen ized fibrous
bands. The growth pattern is predomi -
nantly salid, but cribriform structures are
frequently encountered. The basaloid
cells align around cylindromatous micro-
cystic spaces and have hyperchromatic
and slightly angulated nuclei with a high
N:C ratio . In contras! to typical NKSCC,
true ductal cells are also present (al-
though less conspicuous), often sur-
rounded by a peripheral layer of basaloid
to clear myoepithelial cel ls. When this
bilayered pattern is we ll developed, it im-
parts an appearance li ke that of epithe-
lial-myoepithelial carcinoma. Although
overt squamous differentiation is not typi -
cally present in the invasive component,
the surface ep ithelium may show various
degrees of dysplasia. Mitotic rates are
usually high, and necrosis may be seen . Etiology
The basaloid cells show myoepithelial sesee is associated with smoking and
differentiation (e.g . S100, calponin, p63, radiation exposure {1398,2396). HPV has
and actin), and the ductal cells are KIT- been negative in the few cases tested
positive. Cytokeratins tend to be more 1199}
strongly expressed in the ductal rather
than myoepithelial cells. Both cell types Localization
are pi 6-positive and harbour high -risk sesee arises in the nasal cavity and/
HPV as detected by in situ hybridization. or maxillary or frontal sinuses 1787,9i2,
No MYB translocations (typically seen in 1032,i035).
about 50% of adenoid cystic carcinomas)
have been identified 1202) To date, with Clinical teatures
only a limited number of cases reported, Patients present with nasal obstruction,
local recurrence has been seen, but no epistaxis , and/or f9.cial swelling, with
regional or distant metastases or tumour- masses apparent on CT or MRI {787,896,
related deaths 1202). 9i 2,1032,1035).
Macroscopy
Spindle ce// (sarcomatoid) Sorne SCSCCs grow as a polypoid mass
squamous ce// carcinoma with an ulcerated surface, sim ilar to the
more common laryngeal examples {896 ,
Bishop J.A. 9i2}.
Lewis J.S.
Cytology
See Spindle ce// squamous ce// carcino -
Definition ma section (p. 87) ir Chapter 3.
Spindle cell squamous ce ll carcinoma
(SCSCC) is a variant of squamous cell Histopathology
carcinoma characterized by predomi - For histology and cifferential diagnosis,
nan! malignan! spindle and/or pleomor- see Spindle ce// sq'..lamous ce// carcino-
phic cells . ma section (p. 87) ir Chapter 3.
ICD-0 code 8074/3 Prognosis and predictive tactors
No specific featurEs are described for
Synonym the sinonasal tract region.
Sarcomatoid carcinoma
Epidemiology
sesee presents most commonly in el-
derly men {i56 ,i330,2396}. This variant
is rare in the sinonasal tract , accounting
for < 5% of sinonasal squamous ce ll car-
cinomas 1199,787,896,9i2,i032,1035}.
Carcinomas i7
Lymphoepithelial carcinoma
Bishop JA
Gaulard P
Gillison M.
Definition
Lymphoepithelial carcinoma (LEC) is a
squamous cell carcinoma morphologi-
cally similar to non-keratinizing naso-
pharyngeal carcinoma, undifferentiated
subtype.
ICD-0 code 8082/3
Synonym
Lymphoepithelioma-like carcinoma
Epidemiology
Sinonasal LEC is rare, with only about 40
reported cases ¡1125, 2034, 2584, 2733}
lt most frequently affects men in their
fifth to seventh decades of life (median
patient age: 58 years) !381,1125 ,2034,
2584,2733). Most reported cases have
been in patients from Asia, where EBV-
related malignancies are endemic.
Etiology
In the sinonasal tract, most cases
(> 90%) of LEC harbour EBV {1125 ,1392,
2034,2584,2733).
Localization
Sinonasal LEC arises in the nasal cav-
ity more frequently than in the paranasal
sinuses !2034,2584,2733). For an LEC
to be considered truly primary to the
sinonasal region, spread from a nearby
nasopharyngeal carcinoma must be ex-
cluded on clinical , radiographical , and/or
pathological grounds.
18 Tumours of the nasal cavity, paranasal sin uses and skull base
Clinical features
Patients present with nasal obstruction,
nasal discharge, and/or epistaxis. Pa-
tients may also have eye symptoms or
cranial nerve palsies as a result of local
tumour invasion {1125 ,2034,2584,2733}.
Macroscopy
The tumours are irregular or polypoid ,
tan -white, bulky masses that may be
haemorrhagic {1155,2034,2347)
Cytology
The cytological findings are the same as
those for non-keratinizing nasopharyn-
geal carcinoma , undifferentiated subtype
(see Nasopharyngeal carcinoma, p. 65.)
Histopathology
LEC is defined by its resemblance to
non-keratinizing nasopharyngeal carci -
noma, undifferentiated subtype (see Na-
sopharyngeal carcinoma, p. 65).
By immunohistochemistry, LEC is dif-
fusely positive for pancytokeratin, CK5/6 ,
p63, and p40, and is negative far lym-
phoid and melanocytic markers. Sino-
nasal LEC is usually positive for EBV-
encoded small RNA (EBER) by in situ
hybridization.
Sinonasal LEC must be distinguished
from lymphoma and melanoma (potential
mimics), as well as from sinonasal undif-
ferentiated carcinoma, a neoplasm that
lacks the syncytial growth pattern of LEC ,
is consistently EBER -negative, and lacks
CK5/6, with limited to absent p63.
Prognosis and predictive factors
According to the SEER database, sinon-
asal LEC has a 5-year disease-specific
survival rate of approximately 50% ;
patients with localized disease, aged
< 60 years, and of White ethnicity have
significantly improved survival ¡381}.
Sinonasal LEC metastasizes to regional
lymph nades \ess frequently than does
nasopharyngeal carcinoma, and tends
to be radiosensitive even in the presence
of nodal disease !381 ,1125,2034,2584,
2733).
Sinonasal undifferentiated
carcinoma
Lewis J.S .
Bishop JA
Gillison M.
Westra W.H.
Yarbrough W.G.
Definition
Sinonasal undifferentiated carcinoma
(SNUC) is undifferentiated carcinoma of
the sinonasal tract without glandular or
squamous features and not otherwise
classifiable.
Table 1.01 Differential diagnosis of sinonasal
undifferentiated carcinoma
Lymphoma
Non-keratinizing squamous cell carcinoma (including
HPV-related carcinoma with adenoid cystic-like
features)
Basaloid squamous cell carcinoma
High-grade neuroendocrine carcinoma
Olfactory neuroblastoma
NUT carcinoma
Alveolar rhabdomyosarcoma
Ewing sarcoma I primitive neuroectodermal tumour
Adenoid cystic carcinoma, solid-type (grade 111)
Mela noma

ICD-0 code 8020/3
Epidemiology
SNUC is rare, with about 0.02 cases
per 100 000 people, accounting for only
about 3-5% of all sinonasal carcinomas
(1458} lt occurs in patients of a wide
range of ages, from teenagers to the el-
derly (average patient age: 50-60 years) .
Approximately 60- 70% of patients are
Caucasian males {371,1974)
Etiology
No consisten! etiology of SNUC has been
identified. Sorne patients are smokers
but many are not (365}. lf EBV or HPV is
detected, the diagnosis of SNUC should
be questioned {199,365,885,2518}.
Localization
Tumours arise most frequently in the na-
sal cavity and ethmoid sin uses, and most
present as very large masses involving
multiple siles. As many as 60% of cases
have spread beyond the sinonasal tract
to adjacent sites such as the orbital apex,
skull base, and brain (1974) Nodal me-
tastases are relatively uncommon (occur-
ring in 10-15% of cases) despite large
primary tumour size {416,885,1974}.
Clinical features
Patients present with nasal obstruction,
epistaxis, headache, and diplopia or
other visual symptoms (2656}. Proptosis
and periorbital swel ling can be seen as
well, features reflecting frequent orbital
involvement.
Macroscopy
Tumours are usually large (> 4 cm) at
presentation, with a 1ungating endoscop-
ic appearance and poorly defined mar-
gins radiographicall¡r (1883}.
Cytology
Aspirates of metastatic SNUC are cel-
lular, with cohesive groups, single large
malignant cells, and background necrotic
debris. Numerous mitotic figures and ap-
optotic bodies can be seen. Neuroendo-
crine features are typically not prominent,
and squamous or glandular features are
not seen.
Histopathology
SNUC consists of sheets, lobules, and
trabeculae of overtly malignant cells with
moderately large rcound nuclei, varying
amounts of cytoplasm, and well -defined
cell borders. Nuclei •;ary from hyperchro-
matic to vesicular, but most tumours have
open ch romatin with prominent nucleoli.
Apoptosis , mitoses, and necrosis are
frequent. Despite their high-grade ap-
pearance, SNUCs characteristically have
tumour nuclei of relatively consistent size
and lack of pleomorphism. By definition ,
there is no squamm,s or glandular differ-
entiation , although adjacent carcinoma in
situ has been described.
By immunohistochemistry, the tumour
is positive for pancytokeratin (A E1 /AE3)
and simple cytokeratins such as CK7,
CK8, and CK18 , but is negative for
CK5/6. The tumour cells are variably pos-
itive for p63, but consistently negative for
its more squamous-specific isoform, p40
{2186}. The cells are consistently positive
for neuron-specific enolase. Very focal,
patchy staining for chromogranin and
synaptophysin may be seen {365,416},
but does not qualify a tumour as a neu-
roendocrine carcinc ma in the absence
0
of supporting histological features. The
tumours are negative for carcinoembry-
onic antigen, 8100, CD45, and calretinin
(2635}. The tumours are consistently
p16-positive, regardless of HPV status
{885,2518).
The differential diagnosis is lengthy
(Table 1.1), but most importantly includes
lymphoma, non-keratinizing squamous
cell carcinoma, basaloid squamous cell
Carcinomas 19
carcinoma, and neuroendocrine carcino-
ma. Squamous cell carcinoma has areas
of histological squamous differentiation
and is consistently ::iositive for CK5/6,
p63 , and p40. Neuroendocrine carcino-
mas have speckled chromatin and other
histological features such as rosette
formation and palisading , and are con-
sistently reactive w1th neuroendocrine
markers. NUT carcinoma has evidence
of squamous differentiation (at least fo-
cally) , is consistently diffusely positive
for p63 and p40, and strongly expresses
the NUT protein by immunohistochemis-
try. Recently, a subset of undifferentiated
carcinomas with rhabdoid features and a
lack of SMARCB1 (INl1) protein by immu-
nohistochemistry has been reported. lt is
unclear whether these tumours constitute
a distinct entity {198}
Genetic profile
No specific genetic alterations have been
identified in SNUC {813) The SOX2gene is
amplified in one third of tumours !2102). KIT
(CD117) is frequently strongly expressed,
but no activating mutations or gene amplifi-
cations have been identified !416).
Prognosis and predictive factors
The prognosis of SNUC is poor, although
it seems to have improved in recent
years, likely dueto the use of aggressive
trimodality therapy !371) Systemic che-
motherapy is associated with particularly
high response rates 1243). A large analy-
sis of SEER data showed a median over-
all survival of 22.1 months and 3-, 5-, and
10-year survival rates of 44.3%, 34.9%,
and 31.3%, respectively !371} A recent
meta-analysis had similar findings !1974).
Patient survival is sign ificantl y better with
primary surgical resection !1974,2685).
NUT carcinoma
French CA
Bishop J.A.
Lewis J.S.
Muller S.
Westra WH.
Definition
NUT carcinoma is a poorly differentiated
carcinoma (often with evidence of squa-
mous differentiation) defined by the pres-
ence of nuclear protein in testis (NUT)
gene (NUTM1) rearrangement.
20 Tumours of •he nasal cavity, paranasal sinuses and skull base
-
Fig. 1.09 NUT carcinoma. A Sheets of moderate-sized monomorphic poorly differentiated epithelioid cells have pale
to clear glycogenated cytoplasm; the intervening stroma is sean!, and necrosis and mitoses are invariably present.
B Abrupt keratinization can appear as a discrete island within a sea of poorly differentiated cells. C FISH demonstrates
NUT rearrangement when red and green probes flanking the NUT locus are split apart; the red and green signals
together are the normal NUT allele. D Diffuse, nuclear immunohistochemical staining with the NUT antibody is
diagnostic of NUT carcinoma; the speckled pattern is characteristic but not always this distinct.
ICD-0 code 8023/3 Clinical features
NUT carcinoma presents with non -
Synonyms specific symptoms caused by a rapidly
NUT midline carcinoma; t(15;19) carci- growing mass. In the sinonasal tract,
noma; midline carcinoma of children and this manifests as nasal obstruction, pain,
young adults with NUTrearrangement epistaxis , nasal discharge, and frequent-
ly eye-related symptoms such as prop -
Epidemiology tosis !205,692). lmaging studies revea!
NUT carcinoma is a rare tumour in the extensive local invasion into neighbour-
upper aerod igestive tract !159,393, ing structures such as the orbit or brain
2234). Oue to its rarity, the true incidence !205,692). In approximately 50% of cas-
is unknown. In the largest series report- es, NUT carcinoma presents with lymph
ed (n = 40), the median patient age was node involvement or distant metastatic
21.9 years, but people of ali ages were disease !159).
affected (range: 0.1-82 years). A slight
predominance of females was seen , with Macroscopy
55% of the cases occurring in females Few tumours are resected, due to early
!393). disease spread . No consistent macro-
scopic features have been described.
Etiology
The etiology is unknown. There is no as- Cytology
sociation with HPV, EBV, other viral in - Aspirates of metastases are cellular, with
fection; smoking; or other environmental variably sized clusters of malignant cells
factors. and single malignan! cells . Mitotic figures
and apoptotic bodies are seen. Squa-
Localization mous differentiation may be observed.
Most cases (65%) in the head and neck
are in the nasal cavity and paranasal si - Histopathology
nuses, but rare cases involve the orbital The diagnosis of NUT carcinoma is es-
region, nasopharynx, oropharynx, lar- tablished by demonstration of NUT re -
ynx, epiglottis, and majar salivary glands arrangement, rather than by histology.
!159,508,763,2032). The tumours are An unequivocal diagnosis can be made
generally midline. by demonstration of diffuse (> 50%)

BRD4-NUT N
BRD3-NUT N
PWWP
1 PHD
SET 11
C/Hrich
- Bromo
- Acidicdomainl
Fig. 1.10 NUT carcinoma. Schematic illustration of !he various translocations !ha! occur in NUT carcinoma between
NUT genes and BRD4, BRD3, and WHSC1 L1 (also called NSD3) ; !he arrows indicate breakpoints. Nearly the entire
NUT transcript is preserved in every known translocation. PWWP, PWWP domain; PHD, plan! homeodomain; SET,
SET domain; C/H rich , Cys/His-rich domain; NLS, nuclear localization signal sequence; NES, nuclear export signa\
sequence; Bromo, bromodomain; ET, extraterminal domain.
nuclear staining with the NUT monoclo-
nal antibody C52, which has a sensitiv-
ity of 87% {916). Other diagnostic tools
include FISH, RT-PCR, conventional cy-
togenetics, and targeted next-generation
sequencing approaches.
The histology is that of an undifferenti-
ated carcinoma or poorly differentiated
squamous cell carcinoma. NUT carcino-
ma consists of sheets of cells with mod-
erately large, round to oval nuclei. The
chromatin is vesicular with distinct nucle-
oli. Cytoplasm varies from scant to mod-
erate, and can be clear. Mitotic activity is
brisk and necrosis is often present. Hall-
mark features include monomorphism
and the presence of so-called abrupt
foci of keratinization. Occasional tumours
have more extensive squamous differen-
tiation (764). lntratumoural acute inflam-
mation can be brisk and is frequently
present. Glandular and mesenchymal
differentiation, although described, is in-
frequent (566). Markers other than NUT
that are commonly positive include p63,
p40, and cytokeratins {2265). NUT carci-
noma occasionally (in 55% of cases) ex-
presses CD34 (764). Occasional positiv-
ity for neuroendocrine markers, p16, and
TTF1 has also been described.
Due to the non-specific, poorly differenti-
ated nature of NUT carcinoma, it is often
confused with poorly differentiated squa-
mous cell carcinoma, Ewing sarcoma,
sinonasal undifferentiated carcinoma,
leukaemia, germ cell tumour, and even
olfactory neuroblastoma (763). A provi-
sionally defined entity included in the dif-
ferential diagnosis is SMARCB1-deficient
Chromosome 15q14
Chromosome 19p13.1
Chromosome 9q34.2
Chromosome Bpll.23
Acidicdomain 2
NLS
NES
ET
carcinoma. However, unlike NUT carci-
nomas, SMARCB1-deficient sinonasal
carcinomas do not exhibit focal kerati-
nization. lnstead, the basaloid cells
demonstrate various degrees of rhab-
doid or plasmacytoid features. Be-
cause SMARCB1-deficient sinonasal
carcinomas have biallelic inactivation of
SMARCB1 (IN/1) , immunohistochemi-
cal staining for SMARCB1 consistently
demonstrates loss of nuclear expres-
sion, an important finding for distinguish-
ing SMARCB1-deficient carcinoma from
NUT carcinoma.
Genetic profile
NUT carcinoma is genetically defined by
rearrangements of the nuclear protein
in testis (NUT) gene (NUTM1). In most
NUT carcinomas , most of the coding
sequence of NUTM1 on chromosome
15q14 is fused with BR04 (in 70% of
cases), BR03 (in 6%), or WHSC1L1 (also
called NSD3), creating chimeric genes
that encode NUT fusion proteins {159 ,
764,765 ,766,767,2318). In the remaining
cases, referred to as NUT-variant carci-
noma, NUTM1 is fused toan unknown part-
ner gene. To date, no other oncogenic
mutations have been identified in NUT
carcinoma.
Prognosis and predictive factors
Prognosis is poor, with a median overall
survival of 9.8 months (393). Sorne evi-
dence suggests that patients with NUT-
variant carcinoma may have a longer
survival than do BRD-NUT carcinoma
patients (159,763).
Neuroendocrine carcinomas
Thompson L.D.R.
Bell D.
Bishop J.A.
Definition
Sinonasal neuroendocrine carcinoma is
a high-grade carcinoma with morpholog-
ical and immunohistochemical features
of neuroendocrine differentiation.
ICD-0 codes
Small cell neuroendocrine
carcinoma (SmCC) 8041/3
Large cell neuroendocrine
carcinoma (LC NEC) 8013/3
Synonyms
Poorly differentiated neuroendocrine
carcinoma; high-grade neuroendocrine
carcinoma
Epidemiology
Sinonasal neuroendocrine carcinomas
are rare, accounting for about 3% of
sinonasal tumours, but are more com-
mon in middle-aged to older men. The
mean patient ages are 49-65 years for
LCNEC and 40-55 years for SmCC (370 ,
1831 ,1853,2222}.
Etiology
There is rare association with transcrip-
tionally active high-risk HPV (199,1323}
and previous irradiation (2535), but no
strong smoking association {2296).
Localization
The most common location is the ethmoid
sinus , followed by the nasal cavity and
the maxillary and sphenoid sinuses
(1631,2222,2296}.
Clinical features
Many patients present with non-spe-
cific symptoms (e.g. nasal obstruction,
discharge, and sinusitis) and have ad -
vanced local disease (pT3 or T4) , with re-
gional or distant metastases (to lung , liv-
er, or bone) (114,1428 ,1631,1853}. Rarely,
paraneoplastic syndromes are reported
(1 14,1207,2018,2482}.
Macroscopy
The tumours are large and destructive,
with haemorrhage and necrosis.
Carcinomas 21
 .. . .) .
.......
"' ~ ~""l . .... , • • '};
~ .:O- ~ 1 :a . Qo_ - ~QJ ... -" ~ t - . -~ •
Fig. 1.11 Sinonasal neuroendocrine carcinoma. A Coronal CT demonstrates a midline destructive mass. B Small cells with nuclear moulding , even chromatin distribution, and
inconspicuous nucleoli are characteristic for a small cell neuroendocrine carcinoma; apoptotic figures and mitoses are apparent. C The neoplastic cells are large and have a high
N:C ratio, with small nucleoli and salt-and-pepper nuclear chromatin distribution in a large cell neuroendocrine carcinoma. DA strong and diffuse, cytoplasmic dot-like (perinuclear)
reaction with pancytokeralin in a small cell neuroendocrine carcinoma.

Cytology chromogranin , neuron-specific enolase, light-m icroscopic features of neuroendo-

Aspirates of metastases are identical to
those of SmCC and LCNEC sampled
elsewhere. Malignant cells show less co-
hesion than seen in other epithelial malig-
nancies and are more fragile, displaying
more crush artefact. Mitotic figures and
apoptotic bodies are frequent.
Histopathology
Sinonasal neuroendocrine carcinoma is
histologically identical to its counterparts
in lung and other head and neck sites;
for a detailed description, see Poorly dif-
ferentiated neuroendocrine carcinoma
(p. 97) The tumours are highly infiltrative,
with frequent perineural and lymphovas-
cular invasion {1853,2222).
LCNEC contains large cells that show
light microscopic neuroendocrine fea-
tures; for a detailed description of these
features , see Poorly differentiated neuro-
endocrine carcinoma (p. 97).
SmCC and LCNEC are strongly immu-
nopositive for cytokeratins (e.g. CAM5.2
and AE1/AE3) and EMA , frequently
showi ng a perinuclear or dot-like pattern
{1587). Neuroendocrine differentiation
can be confirmed by staining with at least
one neuroendocrine marker, such as syn-
aptophysin (most sensitive and specific),
or CD56 (\east specific) {486l, although
neuron-specific enolase is less common
in LCNEC {114 ,2568). In SmCC, 8100
protein staining (when positive) is diffuse
rather than sustentacular {2222). SmCC
and LCNEC are positive for p16 (which
is negative in sinonasal undifferentiated
carcinoma); focally, they may be weak\y
positive for p63 . The tumours are rare\ y
reactive with calretinin and are consist-
ently negative for CK5/6, EBV-encoded
smal\ RNA (EBER), and CK20 (378 ,390,
2635\ ASCL1 (also called hASH1), which
is a master gene for neuroendocrine dif-
ferentiation , shows a higher degree of
expression in SmCC and LCNEC than
in olfactory neuroblastoma or rhabdo-
myosarcoma {486 ,2331\. Nuclear immu-
nohistochemistry for p53 correlates with
TP53 mutations {758) .
Rare examples of sinonasa\ neuroendo-
crine carcinoma combined with either
squamous ce\\ carcinoma (in situ or in-
vasive) or adenocarcinoma have been
reported {114 ,758 ,1320\. However, squa-
mous cell carcinoma or adenocarcinoma
should not be regarded as sinonasal
neuroendocrine carcinoma based solely
on the presence of focal neuroendo-
crine immunoreactivity in the absence of
crine differentiation .
The differential diagnosis frequently in-
cludes olfactory neuroblastoma, sinona-
sa\ undifferentiated carci noma, and NUT
carcinoma. High-grade olfactory neu -
roblastoma may retain a focal \obular
architecture with a variable presence of
peripheral sustentacular cells demon-
strated by immunohistochemistry; cy-
tokeratins , if expressed , tend to be focal
rather than diffuse. Sinonasal undifferen-
tiated carc inomas occasionally express
neuroendocrine markers , but lack the
morphological features of LCNEC {773 ,
1034,2568}. NUT carci noma does not
show neuroendocrine differentiation, and
typically shows diffuse expression of
CK5/6 and p63 {692)
Prognosis and predictive factors
The 5-year disease-free survival rate is
about 50-65% overa\\, and is better for
sphenoid sinus tumours (-80%) than
for maxillary or ethmoid sinus tumours
(-33%), in particular when managed by
combination su rgery and/or neoadjuvant,
concu rrent, or adjuvant chemoradiother-
apy, with neoadjuvant therapy possibly
yielding a better outcome (especially
for LCNEC) {770,1428 ,1631,1831,2462}

22 Tumours of the nasal cavity, paranasa\ sinuses and skull base

Data are limited, but LCNECs tend to Epidemiology
have a better prognosis than do SmCCs Sinonasal ITACs are uncommon, with
{1587,1631,2016,2462}. Advanced-stage an overall incidence of < 1 case per
disease is associated with poor progno - 1 million person -years. However, inci -
sis (1831}. dence varies drastically across popula-
tions, and the tumours are as much as
500 times as prevalent among people
lntestinal-type adenocarcinoma who work for prolonged periods in wood
or leather-working industries as they are
Stelow E.B. in the general population {9} . Men are
Franchi A. 3-4 times as likely to develop these tu-
Wenig B.M. mours as women, which is thought to be
due to differences in occupational ex-
posure rates (139,1238,2063}. Although
Definition the patient age range is reportedly wide,
Sinonasal intestinal-type adenocarci- most patients are older, with mean and
noma (ITAC) is an adenocarcinoma of median reported patient ages at diagno-
the sinonasal tract morphologically simi- sis in the sixth to seventh decades of life.
lar to adenocarcinomas primary to the
intestines. Etiology
Many ITACs are secondary to wood dust
ICD-0 code 8144/3 or leather dust exposure {9,10,918,1238}.
Formaldehyde and textile dust exposures
may also increase the risk of these tu -
Synonyms mours (1490}.
Colloid-type adenocarcinoma; colonic-
type adenocarcinoma; enteric-type Localization
adenocarcinoma ITACs typically develop near the lateral
.l
Fig. 1.12 Sinonasal intestinal-type adenocarcinoma. A This well-differentiated tumour shows papillary growth with numerous goblet and Paneth cells. B This tumour is
moderately differentiated, with cribriform growth and areas of necrosis. C This tumour is composed of abundan! extracellular mucus with occasional strips of malignan! epithelium.
D Sorne tumours are composed of signet-ring cells.
nasal wall, near the middle turbinate (139,
2063}. lt is estimated that 40% of cases
develop in the ethmoid sinuses, 28% in the
nasal cavity, and 23% in the maxillary sinus.
Clinical features
Patients with ITACs typically present with
unilateral nasal obstruction, epistaxis,
and/or rh inorrhoea (139,2063} . Less
common symptoms include pain, facial
contour changes, a1d diplopia. The tu-
mours present as soft tissue densities
within the sinonasal tract (139}. Destruc-
tion of surrounding bone occurs in nearly
half of ali patients. Patients most often
present with multiple sites of involvement
(139} . Osseous destruction with local
spread into surrounding tissues, includ-
ing the orbit and brain, is frequently seen.
Macroscopy
In vivo, ITACs are polypoid, papillary,
nodular, and fungating (139,2063} They
are usually friable, sometimes ulcerated
or haemorrhagic, and uncommonly ge-
latinous or mucoid .
Carcinomas 23
Cytology
Aspirates of rare metastatic lesions show
findings identical to those seen with colo-
rectal adenocarcinomas.
Histopathology
ITACs show a morphological spectrum
similar to that of adenocarcinomas of
the intestines (139,1238,2063). They
are often exophytic with a papillary and
tubular growth (in approximately 75%
of cases) or may be mucinous or com -
posed predominantly of signet ring cells.
The degree of differentiation varies from
extremely well differentiated to poorly
differentiated. Papillae and tubules are
lined by a single layer of columnar epi-
thelial cells that show differentiation and
cytological features similar to those seen
in intestinal adenocarcinomas. Most cells
appear columnar with eosinophilic, mu-
cinous cytoplasm . Paneth cells, goblet
cells, and endocrine cells are typically
also present in variable proportions. Al-
though atypia may be difficult to appreci-
ate, nuclear changes that appear at least
adenomatous are the rule. Thus , nuclei
are cigar-shaped, hyperchromatic , and
enlarged, and lose basement membrane
localization. Mitotic figures are frequent.
Necrosis is usually present, typically
within the tubular and folded spaces,
similar to what is seen in intestinal adeno-
carcinomas. As these tumours become
more poorly differentiated, tubular and
papillary structures are replaced by nest-
ed , cribriform , and solid growth patterns.
A minority of cases show abundant mu-
cus production (139,12381 These cases
are similar to sorne primary intestinal
adenocarcinomas and consist of small
to medium-sized cystic spaces (alveoli)
partially lined by (and containing strips of)
attenuated neoplastic epithelium rich in
goblet cells. The strips often float like rib-
bons within mucus lakes and sometimes
form small cribriform structures. The indi -
vidual neoplastic cells have atypical and
hyperchromatic nuclei and abundant mu-
cinous cytoplasm. Less commonly, the
neoplastic cells are mostly sing le, with
a large amount of intracytoplasmic mu-
cus that compresses the nucleus (signet
ring cells). Finally, sorne tumours have a
mixed pattern of growth, appearing pap-
illary and tubular in sorne areas and more
mucinous in others.
ITACs are invasive (often extensively in-
filtrating the submucosa) and may show
perineural and osseous invasion (139).
24 Tumours of the nasal cavity, paranasal sin uses and skull base
Stromal tissues are loose and fibrovas-
cular, often containing abundant chronic
inflammatory cells. Histological similarity
to primary gastrointestinal tract tumours
necessitates exclusion of a metastatic
tumour.
Proposed grading schemas are rather
complicated, given the rarity of these tu -
mours (139 ,1238). Tumours that are pre-
dominately papillary can be graded as
well, moderately, or poorly differentiated
(papillary tubular cylinder cell 1, 11, and
111; or papi llary, co lonic, and solid). Mu-
cinous tumours are either moderately dif-
ferentiated (alveolar) or poorly differenti -
ated (signet ring cell). Mixed tumours are
typically \Nell to moderately differentiat-
ed. Overall survival rates at 3 years have
been shown to vary depending on grade.
Histochemical staining shows intracyto-
plasmic, intralum inal , and/or extracellu-
lar material that is mucicarmine-positive
and gives a diastase-resistant positive
periodic acid-Schiff (PAS) reaction
(1391. Neoplastic cells express pancy-
tokeratins , are variably reactive with CK7
and carcinoembryonic antigen, and are
mostly CK20-positive (1213,15731. Most
tumours also express the markers CDX2,
MUC2, and villin (358,12131 There may
be variable expression of neuroendo-
crine markers (1573,1928).
Genetic profile
KRAS mutations occur in 6- 40% of cas-
es, whereas BRAF mutations occur in
< 10% (755 ,1926,2037,23271. Tumours
are microsatellite-stable and do not lose
expression of mismatch repair proteins
(1546,18541. EGFR mutations are infre-
quent and amplifications are uncommon
(755 ,1926). Expression of p53 is aber-
rant in more than half of ali cases, and
41 % have be en shown to have TP53
mutations (757). CDKN2A (also called
P16) is frequently altered, due either to
promoter methylation or to loss of hete-
rozygosity at 9p21 (1857). Variable beta-
catenin expression has been reported ,
with sorne studies showing > 30% of
cases with aberrant nuclear expression
(757,18541.
Prognosis and predictive factors
The grading systems described above
predict survival and recurrence , although
results have not been universal (139,754,
760,1238). Low-grade papillary tumours
have the best outcomes , with > 80% of
patients surviving 3 years and > 60% of
patients being disease-free at 5 years.
Grade 2 and 3 papillary tumours have
3-year survival rates of 54% and 36%,
respectively. Mucinous tumours with al-
veolar growth and mixed or transitional
tumours have prognoses similar to that
of grade 2 papillary tumours, whereas
tumours showing signet ring morphology
behave the most aggressively. Locally
advanced tumours that invade into the
orbit, skin, sphenoid or frontal sinuses, or
brain have a significantly worse progno -
sis. Local disease is the most common
cause of mortality. About 8% of patients
have lymph node metastases and 13%
have distan! metastases (1391.
Non-intestinal-type
adenocarcinoma
Stelow E.B.
Brandwein-Gensler M.
Franchi A.
Nicolai P.
Wenig B.M.
Definition
Sinonasal non-intestinal-type adeno-
carcinoma (non-ITAC) is an adenocar-
cinoma of the sinonasal tract that does
not show the features of a salivary gland
neoplasia and does not have an intesti-
nal phenotype. Although these tumours
are morphologically heterogeneous, this
category may include sorne specific enti-
ties that are morpholog ically unique (e.g.
renal cell-like carcinoma).
ICD-0 code 8140/3
Synonyms
Terminal tubulus adenocarcinoma; tubu-
lopapillary low-grade adenocarcinoma;
low-grade adenocarcinoma; seromuci-
nous adenocarcinoma; renal cell-like
carcinoma
Epidemiology
Sinonasal low-grade non-intestinal-type
adenocarcinomas (LG non -ITACs) are
very uncommon. There is no sex predi-
lection (967,1139,1721). Patients have
ranged in age from 9 to 89 years, with
a mean age at presentation in the sixth
decade of life. High-grade non- intestinal-
type adenocarcinomas (HG non-ITACs)
are rare, affect men more frequently,
and occur over a wide age range , with a
mean patient age at presentation in the
sixth decade of life {967,2266).

Etiology
There is no known etiology for LG non-
ITACs or HG non-ITACs . Rare HG non-
ITACs have been associated with high -
risk HPV or sinonasal papillomas {2266}.

Localization
Most LG non-ITACs (64%) arise in the Fig. 1.13 Sinonasal low-grade non- intestinal-type adenocarcinoma. Endoscopic view of the right nasal fossa (A) and
nasal cavities (frequently the middle tur- coronal turbo spin echo T2-weighted MRI (B). The tumour (T) is centred on the superior meatus and laterally displaces
binate), and 20% arise in the ethmoid si - the ethmoidal complex (asterisks); the point of origin was on the upper par! of the septum. LW, lateral wall; MT, middle
nuses {967,1139). The remaining tumours turbinate; NS, nasal septum.
involve the other sinuses or multiple lo-
cations throughout the sinonasal tract.
Approximately half of all HG non-ITAC
cases are locally advanced at presenta-
tion and involve both the sinuses and the
nasal cavity {967,2266). Approximately
one third involve the nasal cavity only.

Clinical features
Most patients with LG non-ITACs present
with obstruction {1721,2193). Other symp -
toms include epistaxis and pain. Patients
with HG non-ITACs present with obstruc-
tion , epistaxis, pain , deformity, and prop-
tosis {967). On imaging, LG non-ITACs
present as solid masses, filling the nasal
..c.;.:=-::............... -- -e·-. ""'
cavity or sinuses. HG non-ITACs show Fig. 1.14 Sinonasal low-grade non- intestinal-type adenocarcinoma. Tubules grow back-to-back as they infiltrate the
more destructive growth , with osseous underlying stroma.
involvement and invasion into surround-
ing structures (e.g. the orbit).

Macroscopy
Low-grade non-ITACs may appear red
and polypoid or raspberry-like and firm
{1237).

Histopathology
Low-grade non-ITACs have predomi-
nately papillary and/or tubular (glandular)
features with complex growth, including
back-to-back glands (cribriform) with lit-
tle intervening stroma {967,1139,1237). A
single layer of uniform mucinous cuboi-
dal to columnar epithelial cells lines the
structures. These cells have eosinophilic
cytoplasm and uniform, basally located
nuclei. Mitotic figures are rare and necro-
sis is not seen. lnvasive growth , includ-
ing within the submucosa as well as into
bone , may be present. Calcispherules
are rarely seen {967). Occasional tu-
mours have more dilated glands {1237,
1721).
HG non-ITACs show much more diver-
sity in their histology {967,2266}. Many
have a predominately solid growth with
occasional glandular structures and/
or individual mucocytes. Sorne have a
nested growth and are infiltrative. Numer-
ous mitotic figures are seen wi th necrosis
(individual-cell and confluent), as well as
infiltrative growth with tissue destruction
and osseous invasion.
Occasional cases are composed pre-
dominately of clear cells , reminiscent of
metastatic renal cell carcinoma {2287}.
These tumours have been referred to
as sinonasal renal cell-like carcino-
mas. The tumours are composed of
monomorphous cuboidal to columnar
glycogen-rich clear cells that lack mucin
production. The cellular cytoplasm may
be crystal clear or slightly eosinophilic.
Perineural invasion, lymphovascular in-
vasion, necrosis, and severe pleomor-
phism are absent, and the overall histo-
logical impression is that of a low-grade
neoplasm.
In most LG non-ITACs and HG non-
ITACs, intraluminal mucin or material
that gives a diastase-resistant positive
reaction with periodic acid-Schiff (PAS)

Carcinomas 25
Fig. 1.16 Sinonasal high-grade non-intestinal-type adenocarcinoma.
mostly solid, with focal tubular formation.
can be identified. In HG non-ITAC, cells
with intracytoplasmic mucin or diastase-
resistant PAS positivity may be pres-
ent. The tumours express cytokeratins
(typically CK7 and infrequently limited
CK20) (2266). Squamous antigens, such
as p63, are typically not expressed orare
expressed only focally (2193} Markers of
intestinal differentiation, such as CDX2
and MUC2, are also not expressed or
are expressed only focally (358 ,2266).
Sorne authors have reported expres-
sion of DOG1, SOX10, and S100 {1933) .
HG non-ITACs can focally express
Teratocarcinosarcoma
Definition
Sinonasal teratocar::;inosarcoma is a
malignant sinonasal neoplasm with com-
bined histological features of teratoma
and carcinosarcoma, lacking malignant
germ cell components.
ICD-0 code
Synonyms
Malignant teratoma; blastoma; teratocar-
cinoma; teratoid carcinosarcoma
Epidemiology
Teratocarcinosarcoma is a rare tumour
affecting adults (median patient age: 60
years), with a strong male predilection.
Localization
The tumour most commonly involves the
26 Tumours of the nasal cavity, paranasal sinuses and skull base
neuroendocrine antigens (2266). Renal
cell-like carcinomas express CAIX and
CD10 , but do not express PAX8 or renal
cell carcinoma marker (2156). Beta-cat-
enin and mismatch repair protein expres-
sion is wildtype (2679). Overexpression
of p53 may occur as well {2193)
Genetic profile
Only rare LG non-ITACs have been stud-
ied for molecular abnormalities. RAS mu-
tations are not seen (755). Rare BRAF
mutations have been found (755).
nasal cavity, followed by the ethmoid si-
nus and the maxillary sinus (1628). lntrac-
ran ial extension occurs in approximately
20% of cases {1628).
Clinical features
The most common presenting symptoms
9081/3 are nasal obstruction and epistaxis. lm-
aging studies show a nasal cavity mass
with opacification of paranasal sinuses
and frequent bone destruction.
Macroscopy
Tumou r tissue is firm to friable, with a
variegated reddish-purple to brown appear-
ance. When present, the surface mucosa
is often ulcerated, and areas of necrosis
and haemorrhage are evident at the cut
surface.
Prognosis and predictive factors
Approximately 25% of LG non-ITACs
recur, and only 6% of patients die from
their tumours , usually as a result of loss
of local control (967,1139,1721). Patients
with HG non-ITAC fare much worse (967);
most die from the disease within 5 years
of diagnosis. Occasional HG non-ITACs
metastasize locally and distally. The re-
ported cases of renal cell-like carcinoma
have neither recurred nor metastasized
{2156).
Franchi A.
Wenig B.M.
Histopathology
Teratocarcinosarcoma is composed of
an admixture of epithelial , mesenchy-
mal, and neuroepithelial elements. The
epithelial components include kerati-
nizing and non-keratinizing squamous
epithelium, pseudostratified columnar
ciliated epithelium, and glandular/duct-
al structures. An important diagnostic
feature is the presence of nests of
immature squamous epithelium with clear
so-called fetal-appearing cells {966).
The most-represented mesenchymal ele-
ments are spindle cells with features of
fibroblasts or myofibroblasts, but areas
with rhabdomyoblastic, cartilaginous, os-
teoblastic, smooth-muscle, or adipocytic
differentiation can be seen, with appear-
ances ranging from benign to frankly ma-
lignant. The neuroepithelial component
consists of a proliferation of immature
round to oval cells either in solid nests
or within a neurofibrillary background,
sometimes with rosette formation .
The immunohistochemical profile matches
that of the tumour components , including
epithelial, mesenchymal, and neuroepi-
thelial components. PLAP, alpha-fetopro-
tein, hCG, and CD30 are negative.
Cell of origin
The favoured hypothesis is origin from
somatic pluripotent stem cells of the
neuroepithelium related to the olfactory
membrane (1801,2054).
Genetic profile
There are limited reports in the literature
on the cytogenetic abnormalities. These
abnormalities include extra copies of
chromosome 12p in a subpopulation of
neoplastic cells in a hybrid case that also
exhibited foci of yolk sac elements (2380}
in addition to teratocarcinosarcoma fea-
tures, thus not completely meeting the
definition that excludes malignant germ
cell components , and the presence of tri-
somy 12 with a subclone of cells showing
loss of 1p in one case (2516}. In another
study, no amplification of 12p was found
in any of 3 cases {2054).
Prognosis and predictive factors
Teratocarcinosarcoma is an aggressive
tumour, with frequent lymph node and
distant metastasis. Reported survival
rates range from 50% to 70% in different
series, with an average follow-up of 40
months (1628).
Teratocarcinosarcoma 27
Sinonasal papillomas
Sinonasal papilloma,
inverted type
Hunt J.L.
Bell D.
Sarioglu S
Definition
Sinonasal inverted pap ill oma is a surface
mucosa! lesion of the sinonasal tract that
usually shows inverted growth and has
multilayered epithelium with mucocytes
and transmigrating neutrophils.
ICD-0 code 8121/1
Synonyms
lnverting papilloma; inverted Schneide-
rian papilloma; Schneiderian papilloma,
inverted type
Epidemiology
lnverted papi llomas are the most fre -
quent papi llomas of the sinonasal region,
arising from the sinonasal epithelial lin -
ing . An estimated 0.74-2.3 new cases
may be expected per 100 000 population
annually (294,1750). The tumour is most
frequent in the fifth and sixth decades of
life (patient age range: 6-84 years) and is
2.5-3 times as common in males as in fe -
males (141,1224,2511). Recurrences are
frequent and malignant transformation
28 Tumours of the nasal cavity, paranasal sinuses and skull base
has been reported in 1.9-27% of cases
in different series; most malignancies
were synchronous tumours (1750) .
Etiology
Exposure to organic solvents seems to be
a risk factor for inverted papilloma devel -
opment (505), whereas no such associa-
tion for smoking or alcohol consumption
has been shown. Varying rates of HPV
detection have been reported. In a meta-
analysis including 760 inverted papilloma
cases, 38 .5% of the cases were HPV-
positive by either in situ hybridization or
PCR (2323). Low-risk HPV (HPV 6 and
11) is 2.8 times as frequent as high -risk
HPV (HPV 16 and 18) in inverted papil -
loma. However, high -risk HPV is more
frequent in cases with high -grade dys-
plasia and carcinoma (1352). E6 and E7
mRNAs, associated with transcriptionally
active high-risk HPV infection, were de-
tected in al l cases in a series of 19 in -
verted papillomas; however, this expres-
sion was seen in on ly 1% of the tumour
cells in 58% of the cases, and HPV DNA
was positive in only 2 cases. Expression
of p16, which is an accepted surrogate
biomarker for high -risk HPV infection in
oropharyngeal carcinoma, is controver-
sia! in inverted papilloma; in sorne series,
no correlation between p16 and HPV was
seen {420,2283).
Localization
The nasal cavity and the maxillary sinus
are the most common locations of invert-
ed papilloma, with the medial wall being
the most common site of origin in the
maxillary sinus. Other locations as site
of primary origin are more rare, includ -
ing the ethmoid sinus, frontal sinus, and
nasal septum. About 30% of cases origi -
nate from multiple sites. lnverted papil-
loma may rarely be bilateral and may
originate from multiple extrasinonasal
sites, including the nasopharynx, phar-
ynx, lacrimal sac, middle ear, temporal
bone, and neck (75,1224,2147).
Clinical features
Patients may present with non-specific
symptoms such as nasal obstruction,
polyps, epistaxis, rhinorrhoea, hyposmia,
and headache of long duration. Rarely,
sensorineural and auditory symptoms
are described. Both CT and MRI are val-
uable; CT may provide information about
the site of origin of the tumour, and MRI
shows the extent of the disease. On MRI,
the lesion characteristically has a septate
striated appearance {75). Severa! staging
systems have been proposed for invert-
ed papilloma (75,1224} One commonly
used staging system (1283) depends
on the extent of disease, considering
both radiological and endoscopic find-
ings. The American Joint Committee on
Cancer (AJCC) staging system is also
commonly used.
Macroscopy
lnverted papilloma is covered with a grey,
undulating surface resembl ing a mulber-
ry. Because of their cellular density, the
lesions do not transilluminate.
Histopathology
Multiple inversions of the surface epi-
thelium into the underlying stroma, com-
posed of squamous and/or respiratory
cells and lined by a distinct and intact,
continuous basement membrane, is the
typical morphology of inverted papilloma.
Non-keratinizing squamous or transition -
al epithelium, 5-30 cells thick, frequently
predominates, and is covered by a layer
of ciliated columnar cells . lnfiltration of
the epithelium by neutrophils (so-called
transmigrating neutrophils) is frequently
seen. Mitoses are sparse and confined
to the basal layers (141,2002,2075).
There is usually a loss of underlying se-
romucinous glands (2075). The stroma
may be either loose or dense, and may
be inflamed. Cells showing squamous
and columnar differentiation are positive
for cytokeratins (e.g . CK10, CK10/13, and
CK1/2/10/11) (2106).
Premalignant and malignant features,
dysplasia, carcinoma in situ, and inva-
sive carcinoma can be seen arising in
inverted papilloma. Sampling should be
thorough, and evidence of malignant
transformation should be sought during
histopathological evaluation . There is no
consensus about the grading of dyspla-
sia in inverted papilloma, and the diag-
nosis of malignant transformation may be
challenging. Keratinizing squamous cell
carcinoma, non-keratinizing squamous
Fig. 1.19 Sinonasal oncocytic papilloma. A The lesion shows inverted growth and markedly thickened epithelium; the cells have an oncocytic appearance. B Neutrophilic microcysts
and transmigrating neutrophils can be seen, as well as the oncocytic nature of the epithelial cells.
cell carcinoma, mucoepidermoid car-
cinoma, sinonasal undifferentiated car-
cinoma, and verrucous squamous cell
carcinoma can all be seen in malignant
transformation. Lymphovascular inva-
sion, atypical mitoses, desmoplasia,
bone invasion, decreased transmigrating
neutrophils, paradoxical maturation, dys-
keratosis, increased Ki-67 expression,
and p53 expression in > 25% of cells are
among the most important features of
malignancy (1750).
Genetic profile
lnverted papillomas are neoplastic and
monoclonal proliferations, as shown by
X chromosome analysis. However, the
chromosomal LOHs at arms 3p, 9p21,
11q13, 13q11, and 17p13 that occur fre-
quently during neoplastic transformation
of the upper respiratory tract have not
been detected (315). In one small series
of 7 cases, at least one epigenetic event
of aberrant DNA hypermethylation was
observed, suggesting a role of epigenet-
ics in inverted papilloma development
(2276). Furthermore, from a small num -
ber of cases studied, it appears that acti-
vating mutations in the EGFR gene have
a high prevalence in inverted papillomas
and in concurrent squamous cell carci -
nomas arising from inverted papilloma
(2442A)
Prognosis and predictive factors
In one large series, cases originating from
the nasal cavity had a significantly lower
recurrence rate (1224). The ratio of low-
risk HPV (HPV 6 and 11) to high-risk HPV
(HPV 16 and 18) was 1.1 :1 in inverted pap-
illoma with high-grade dysplasia, versus
4.8:1 in the rest of the cases, suggesting
an association between high-risk HPV and
• ••
malignant transformation (1352). However,
no correlation was found between E6/E7
transcriptional activity and progression,
recurrence, or malignant transformation
(2283). In one series, malignant :transfor-
mation in inverted papilloma was identified
more frequently in smokers (in 24.6% of
cases) than in non-smokers (in 2.8%), and
the odds ratio of malignancy for smoking
vvas 12.7 {1020). Type of surger-y is also an
important prognostic factor for recurrence
{962).
Sinonasal papilloma,
oncocytic type
Hunt J.L.
Chiosea S.
Sarioglu S.
Definition
Sinonasal oncocytic papilloma is a papil-
loma derived from the sinonasal epithe-
lium composed of both exophytic fronds
and endophytic invaginations lined by
multiple layers of columnar cells with
oncocytic features . lntraepithelial micro-
cysts containing mucin and neutrophils
are characteristic.
ICD-0 code 8121/1
Synonyms
Oncocytic Schneiderian papilloma; cylin-
drical cell papilloma; columnar cell papil-
loma
Epidemiology
Oncocytic papilloma is equally distribut-
ed between the sexes, and most patients
are aged > 50 years {2511 }.
Sinonasal papillomas 29
Etiology
Unlike in exophytic and inverted papillo-
mas, HPV has not been identified in on-
cocytic papillomas {792).
Localization
Oncocytic papilloma almost always oc-
curs unilaterally on the lateral nasal wall
or in the paranasal sinuses (usually the
maxillary or ethmoid). lt may remain lo-
calized, involve both areas, or (if neglect-
ed) extend into contiguous areas.
Clinical features
Patients present with nasal obstruction
and/or intermittent epistaxis.
Macroscopy
Oncocytic papilloma is a fleshy , pink,
tan , or reddish-brown polypoid growth.
Histopathology
Oncocytic papilloma exhibits both exo-
phytic and endophytic growth. The epi-
thelium is multilayered, 2-8 cells thick,
and composed of columnar cells with
swollen, finely granular cytoplasm . The
high content of cytochrome c oxidase
and ultrastructural presence of numerous
mitochondria establish the papilloma's
oncocytic nature {145). The nuclei are
either small, dark, and uniform or slightly
vesicu lar with barely discernible nucleoli.
Cilia in various stages of regression may
be observed in the outermost cells . The
epithelium usually contains small cysts
fi lled with mucin or neutrophils (microab-
scesses). These cysts are not present in
the stroma, which helps distinguish this
lesion from rhinosporidiosis. The stroma
varíes from oedematous to fibrous , and
may contain modest numbers of lympho-
cytes , plasma cells, and neutrophils, but
few eosinophils. Seromucinous glands
are sparse to absent. Oncocytic pap-
illoma may rarely undergo malignant
transformation. lt is also occasionally
confused with low-grade papillary ade-
nocarcinoma {1403} . The presence of in-
tact basement membranes and absence
of infiltrative growth are features that in-
dicate a benign lesion. In addition , the
presence of intraepithelial mucin-filled
cysts and microabscesses and the strati-
fied oncocytic epithelium of a papilloma
are rarely seen in low-grade adenocarci-
noma.
Prognosis and predictive factors
The clinical behaviour parallels that of
30 Tumours of the nasal cavity, paranasal sinuses and skull base
inverted papilloma. lf inadequately ex-
cised, especially using mucosal strip-
ping, at least 25-35% of cases recur,
usually within 5 years {962) . Smaller tu-
mours can be resected endoscopically.
About 4-17% of all oncocytic papillomas
harbour a carcinoma (1201,1441,2511}.
Most of these are squamous, but mu-
coepidermoid, small cell, and sinonasal
undifferentiated carcinomas have also
been described (2370,251 1}. Prognosis
depends on the histological type, the
degree of invasion, and the extent of tu -
mour. In sorne instances, the carcinoma
is in situ and of little consequence to the
patient, whereas other cases are locally
aggressive and may metastasize.
Sinonasal papilloma,
exophytic type
Hunt J.L.
Lewis J.S.
Richardson M.
Sarioglu S.
Syrjanen S.
Definition
Sinonasal exophytic papilloma is a papil-
loma derived from the sinonasal mucosa,
composed of papillary fronds with deli-
cate fibrovascular cores covered by mul-
tilayered epithelium.
ICD-0 code 8121/0
Synonyms
Schneiderian papilloma, exophytic type;
fungiform papilloma; everted papilloma;
transitional cell papilloma; septal papil-
loma; Ringertz tumour
Epidemiology
Exophytic papil lomas are 2-10 times as
common in men as in women, and typi-
cally occur in individuals aged 20-50
years (reported range: 2-87 years) (441).
Etiology
There is increasing evidence to suggest
that exophytic papillomas may be etio-
logically related to HPV. In a large meta-
analysis, exophytic papillomas were as-
sociated with HPV in 63.5% of cases ,
predominantly with the low-risk types 6
and 11 , and rarely with types 16 and 57b
{2323}.
Localization
Exophytic papillomas usually arise on
the lower anterior nasal septum. As they
enlarge, they may secondarily involve the
lateral nasal wall , but only infrequently
originate from this location. lnvolvement
of the paranasal sinuses is practically
non-existent. Bilateral lesions are ex-
ceptional. Benign keratinizing cutaneous
tumours of nasal vestibule origin do not
constitute sinonasal exophytic papilloma.
Clinical features
The typical presenting symptoms are
epistaxis, unilateral nasal obstruction,
and the presence of an asymptomatic
mass.
Macroscopy
The lesions present as papillary or
warty; grey, pink, or tan; non-translucent
growths attached to the nasal septum by
a relatively broad base.
Histopathology
Exophytic papillomas are typically as
large as about 2.0 cm. Microscopically,
they are composed of papillary fronds
with fibrovascular cores covered by
a multilayered epithelium that is 5-20
cells thick. The epithelium varies from
squamous to ciliated pseudostrati -
fied columnar (respiratory), or may be
transitional between the two. Scat-
tered mucocytes are common . Surface
keratinization is absent or scant, unless
the lesion has been irritated by trauma
or exposure to the drying effects of air.
Mitoses are rare and are not usually
atypical. Unless infected or irritated, the
stroma contains few inflammatory cells .
Respiratory epithelial lesions
Respiratory epithelial
adenomatoid hamartoma
Wenig B.M.
Franchi A
RoJY
Definition
Sinonasal respiratory epithelial adenom-
atoid hamartoma (REAH) is a ben ign ac-
quired overgrowth of indigenous glands
of the sinonasal trae! arising from the sur-
face epithelium .
Synonym
Glandular hamartoma
Epidemiology
The lesions predominantly occur in adult
patients, with a distinct male predomi-
nance ¡1367,2588}. Patients range in
Malignant change in exophytic papillo-
ma is extremely rare (157,441). Exophytic
papillomas must be distingu ished from
keratinizing cutaneous squamous cell
papillomas, which are much more com -
mon in the nasal vestibule. The absence
of extensive surface keratinization, pres-
ence of mucocytes, and presence of cili -
ated and/or transitional epithel ium help
to confirm the diagnosis of exophytic
papilloma. The presence of seromuci-
nous glands and septal cartilage further
indicate that the lesion is of mucosal
rather than cutaneous origin.
age from the third to ninth decades of
life, with a median patient age in the sixth
decade ¡1367 ,2588} .
Localization
The majority occur in the nasal cavity,
in particular the posterior nasal septum
(2588}. lnvolvement of other intranasal
sites occurs less often, and may be iden-
tified along the lateral nasal wall, middle
meatus, and inferior turbinate . Uncom-
monly, the lesions may occur in the na-
sopharynx, ethmoid sinus, and frontal si-
nus. Most lesions are unilateral but sorne
are bilateral (2588}
Clinical features
Patients present with nasal obstruction,
stuffiness, epistaxis, and chronic (recur-
ren!) rhinosinusitis occurring over the
course of months to years {2588}.
Prognosis and predictive factors
Complete surg ical excision is the treat-
ment of choice. lnadequate excision
(rather than multiplicity of lesions) proba-
bly accounts for the local recurrence rate
of 22-50% {441). Exceptionally, carc ino-
mas have been seen arising in exophytic
papillomas, with reported cases including
squamous cell carcinoma; mucoepider-
moid carcinoma (1750}; and low-grade
non-intestinal, non - salivary gland ad -
enocarcinoma (220}. HPV status has not
been clearly shown to correlate with re-
currence risk or carcinoma development.
Macroscopy
REAHs are polypoid or exophytic lesions
with a rubbery consistency. They are tan-
white to reddish-brown and measure as
much as 6 cm in greatest dimension.
Histopathology
Histopathology shows a glandular pro-
liferation composed of widely spaced ,
small to medium-sized glands separated
by stromal tissue. The glands arise in
direct continuity with the surface epithe-
lium, which invaginates downwards into
the submucosa (1852,2588} . The glands
are round to oval and composed of multi -
layered ciliated respiratory ep ithelium, of-
ten with admixed mucin-secreting (gob-
let) cells; glandular dilatation distended
with mucus can be seen . A characteristic
finding is the presence of envelopment of
the glands by a thickened, eosinophilic
basement membrane (2588}. Atrophic
Respiratory epithelial lesions 31
glandular alterations may be present,
lined by a single layer of flattened to
cuboidal-appearing epithelium. Small re-
active-appearing seromucinous glands
are present among the glandular prolif-
eration. Additional coexisting findings
may include sinonasal inflammatory pol-
yps , surface epithelial hyperplasia and/
or squamous metaplasia, and osseous
and/or chondroid metaplasia. Rarely, the
lesions may be associated with sinona-
sal inverted papilloma or solitary fibrous
tumour {2588) . The occasional pres-
ence of both REAH and seromucinous
hamartoma suggests a spectrum from
pure REAH to seromucinous hamartoma
{1218}.
The glands are immunoreactive for cy-
tokeratins such as AE1/AE3, CAM5.2,
and CK7 but negative for CK20 and
CDX2 . Myoepithel ial/basal cell markers
(including p63) are typically present but
may be absent; the absence of markers
for myoepithelial/basal cells does not
confer a diagnosis of adenocarcinoma
{1794).
Genetic profile
The reported increased fractional allelic
loss of 31 % is unusually high for a non-
neoplastic entity, raising the possibility
that REAH may in fact be a benign neo-
plasm rather than a hamartoma {1796}.
Prognosis and predictive factors
Complete surgical excision is curative.
32 Tumours of the nasal cavity, paranasal sinuses and skull base
Seromucinous hamartoma
RoJY
Franchi A.
Definition
Sinonasal seromucinous hamartoma
(SH) is a ben ign overgrowth of indige-
nous seromucinous glands of the nasal
cavity and paranasal sinuses.
Synonyms
Epithelial hamartoma; glandular hamarto-
ma; microglandular adenosis of nose {445)
Epidemiology
SHs are extremely rare {1218} . They oc-
cur predominantly in adults , with a male-
to-female ratio 3:2. The patient age range
is 14-85 years (mean : 56 years).
Etiology
SH has no association with any specific
etiological agent, but it often arises in the
setting of inflammatory polyps.
Localization
SH usually occurs at the posterior nasal
septum or nasopharynx , and is rarely de-
scribed on the lateral nasal wall or in the
paranasal sinuses {2567).
Clinical features
The typical symptoms are nasal obstruc-
tion and epistaxis. The lesions are often
found incidental ly, and are sometimes
associated with other medical condi-
tions, such as rheumatoid arthritis , Par-
kinson disease, and chronic sinusitis.
Physical examination reveals a polypoid
mass without other aggressive features.
Macroscopy
SHs are typically polypoid or exophytic ,
typically with a rubbery consistency and
a tan -white to reddish-brown appear-
ance . They measure 0.6-6 cm in grea-
WWtest dimension.
Histopathology
SH is a polypoid mass covered by respira-
tory epitheli um , and contains small to large
glands and ducts lined by a single layer of
cuboidal or flattened epithelial cells with
bland, oval to round nuclei and ampho-
philic to eosinophilic cytoplasm. Mitoses
are absent. The surrounding fibrous stro-
ma often contains a lymphoplasmacytic
infiltrate {125,1044). Eosinophilic secretion
can be seen in the lumen, and goblet or
clear cells may be observed. The tubular
glands may be encircled by thick base-
ment membrane material. The proliferat-
ing tubules intermingle with the pre-ex-
isting seromucinous acini or invaginated
respiratory epithelium forming glands or
cysts, similar to features of respiratory epi-
thelial adenomatoid hamartoma, support-
ing the possibility that SH and respiratory
epithelial adenomatoid hamartoma con-
stitute a spectrum of lesions, often seen
together {2565,2567}
lmmunohistochemistry shows positiv-
ity for CK17, CK19 , EMA, lysozyme, and
S100, with an absence of myoepithe-
lial (basal) cells around the seromuci-
nous glands {731) . The stroma around
tubules is positive for calponin, SMA,
and desmin , indicating myofibroblastic /
smooth muscle differentiation {1564).
Prognosis and predictive factors
Conservative but complete surgical ex-
cision is curative. With follow-up avail-
able from 4 months to 10 years (mean: 6
years), all patients are alive and well after
surgical removal , with no documented
cases of metastasis and only one report
of recurrence {731 }.
Salivary gland tumours Bell D.
Bullerdiek J.
Gnepp D.R.
Hunt J.L

Pleomorphic adenoma
Definition
Pleomorphic adenoma (PA) is a benign
tumour with variable cytomorphological
and architectural manifestations. The
identification of epithelial and myoepithe-
lial/stromal components is essential for
the diagnosis of PA.
See also the P/eomorphic adenoma
section (p 185) in Chapter 7 (Tumours of
salivary glands).

ICD-0 code 8940/0

Synonym
Benign mixed tumour

Epidemiology
Most intranasal PAs present in the third to
..;
sixth decades of life, with a slight female
preponderance (8,477,2109 ,2257)

Localization
, ' '
•'
~'
r ~
~ ..., .,
: •,,
fa.. I •

The tumour generally (in about 80% of

cases) arises in the nasal septal mucosa,
despite the fact that the seromucinous
-.... . .
/'
I ~ r

glands are mainly located in the lateral

wall and turbinates (8,1286,2109). ...
•
,,, .....
... '
/I
. ..
. ~ "': t"~....• -...:
.• - ..
Clinical features ·~ ...,._ j ' /

The most common presenting symptom • ' • 1

is unilateral nasal obstruction. Epistaxis 4* ~ • \. • '

and sinusitis can occur secondary to , • ~ ... ~ .JL..~~-..:!'T'.

extension into the maxillary sinus (2109).
Affected patients present within 1 year of
the onset of symptoms (2109)
Macroscopy
The range of tumour size is 0.5-7 cm,
and the tumours are described as exo-
phytic or polypoid (with a broad base),
oval, dome-shaped, firm, and grey
(8,2109) . No destruction of surrounding
tissue is seen.
Fig. 1.23 Pleomorphic adenoma. A These mixed tumours have greater cellularity and a more dominan! epithelial
componen! (vs chondroid, myxoid, and collagenous stromal components) than are seen in pleomorphic adenomas of
the major salivary glands. B Higher magnification showing myoepithelial and ductal elements.
Histopathology Prognosis and predictive factors
In the nasal cavity, these neoplasms Complete surgical excision is the treat-
display a more dominan! epithelial com- ment of choice. The recurrence rate is
ponen! (vs stromal components) than is lower than that of parotid PA. Malignan!
seen in PAs of the major salivary glands transformation of PA of the nasal cavity
(8,2109) has been reported in 2.4-10% of cases
(8,451,2109).

Salivary gland tumours 33

Malignant soft tissue tumours
Fibrosarcoma
Franchi A.
Flucke U.
Thompson L.D.R.
Definition
Fibrosarcoma is a malignant spindle
cell tumour with fascicular architecture
and variable collagen matrix production,
showing fibroblastic/myofibroblastic dif-
ferentiation. lt is a diagnosis of exclusion.
ICD-0 code 8810/3
Synonym
Adult-type fibrosarcoma
Epidemiology
Sinonasal fibrosarcoma is a rare tumour
(accounting for < 3% of all non-epithelial
tumours), but is the second most com-
mon head and neck sarcoma. lt affects
adults (mean age: 55 years), with no sig-
nifican! sex predilection {1829}.
Etiology
The etiology is uncertain, but sinonasal
radiation-induced fibrosarcomas have
been reported {314}.
Localization
The maxillary sinus is the most common
site of involvement, followed by the nasal
cavity {1829).
Clinical features
The most common presentations are na-
sal obstruction, epistaxis, and a nasal
mass, usually with short symptom dura-
tion {780}.
Macroscopy
The tumour presents as a polypoid, poor-
ly circumscribed, white, firm, and pedun-
culated or fungating mass projecting into
the lumen, with frequent infiltration of the
adjacent bone. Haemorrhage and necro-
sis are present in high-grade examples.
34 Tumours of the nasal cavity, paranasal sinuses and skull base
Histopathology
Fibrosarcomas are moderately to highly
cellular proliferations of spindle cells ,
arranged in intersecting fascicles, often
with a herringbone or chevron pattern,
and with a variable amount of collagen
production . There is moderate cellular
atypia, but profound pleomorphism is
usually lacking. Tumours with signifi -
can! pleomorphism and storiform areas
are better categorized as undifferentiat-
ed pleomorphic sarcoma. Mitotic activ-
ity is variable. The tumour borders are
poorly defined and there is invasion of
the sinonasal mucosa and bone. Histo-
logical grading, with distinction of low-
grade and high-grade tumours , is per-
formed on the basis of cellularity, atypia,
mitotic activity, and tumour necrosis.
Because the histological appearance
of the tumour is non-specific, diagno-
sis requires the exclusion of other enti-
ties, including sarcomatoid carcinoma,
synovial sarcoma, leiomyosarcoma,
spindle cell rhabdomyosarcoma, spin-
dle cell melanoma, malignant periph-
eral nerve sheath tumour, biphenotypic
sinonasal sarcoma , glomangiopericy-
toma, desmoid fibromatosis, and fibro-
blastic osteosarcoma. An appropriate
immunohistochemical panel is neces-
sary to rule out these other neoplasms,
with the addition of selected molecular
studies as necessary. By convention,
the tumour is reactive with vimentin and
occasionally with actins, but negative
for epithelial markers, S100 protein,
SOX10, HMB45, beta-catenin, desmin,
myogenin, and CD34. Electron mi-
croscopy can confirm the fibroblastic
differentiation of the tumour, demon-
strating the presence of abundant cy-
toplasmic rough endoplasmic reticulum
cistern ae and excluding the presence
of epithelial, muscle, and melanocytic
differentiation.
Genetic profile
The genetic profile of sinonasal fibrosar-
coma has not been specifically investi-
gated, but soft tissue fibrosarcomas in
general show a complex karyotype, with
several numerical and structural chromo-
somal abnormalities.
Prognosis and predictive factors
The disease-specific survival rate is
about 75%, with better survival among
patients treated with surgery (with or
without adjuvant radiotherapy) than
among those treated with radiotherapy
alone (1829). The rate of recurrence is
high (-60%), and recurrence is usually
identified befare metastatic disease (to
lung or bone), which occurs in about
15% of patients. The prognosis is worse
for male patients, and in cases of large
tumours, multisite involvement, high his-
tological grade, and positive margins
{156,780,965,1263).
Undifferentiated
pleomorphic sarcoma
Flucke U.
Franchi A.
Thompson L.D.R.
Definition
Undifferentiated pleomorphic sarcoma is
a high-grade soft tissue sarcoma with no
line of differentiation. lt is a diagnosis of
exclusion.
ICD- 0 code 8802/3
Synonym
Malignant fibrous histiocytoma
Epidemiology
This sarcoma occurs in adults, and
sinonasal examples are rare. However,
undifferentiated pleomorphic sarcoma is
the third most frequently reported histo-
type in the sinonasal tract, after rhabdo -
myosarcomas and fibrosarcomas (2326,
2534).
Etiology
Radiation therapy contributes to the risk
of developing an undifferentiated pleo-
morphic sarcoma (2294,2534).
Localization
Lesions are generally evenly distributed
among the sinonasal tract (i .e. maxillary
sinus, nasopharynx, and nasal cavity),
upper aerodigestive system, and parotid
region (2294,2326,2534} The mass is
usually subcutaneous or submucosal in
location, regardless of the affected site,
but may also arise in bone (2294).
Clinical features
There are non-specific signs and symp -
toms, including a painless mass, nasal
obstruction , proptos is, diplopia, and
epistaxis. Very rarely, undifferentiated
pleomorphic sarcoma presents with re-
gional or distan! metastasis (2294).
Macroscopy
The tumours consist of a multilobulated
greyish-white fleshy mass. Cut surface
often shows haemorrhagic, myxoid, and/
or necrotic changes. Most neoplasms
appear circumscribed , but extension into
adjacent structures may be seen (2578}.
Histopathology
The tumour is composed of an admixture
of spindle and pleomorphic cells set in a
variably collagenized extracellular matrix.
Cellularity varies. Pleomorphism, numer-
ous mitoses, atypical mitoses, areas of
tumour necrosis, histiocyte-like cells , and
foamy cells, as well as giant tumour cells
with enlarged, polylobulated nuclei are
commonly observed .
lmmunohistochemically, there are sorne
limited foci of SMA reactivity, whereas
h-caldesmon, desmin , S100 protein, and
epithelial markers are usually not ex-
pressed . Histiocytic antigens are of no
utility.
Ultrastructurally, many tumour cells show
features of fibroblasts, myofibroblasts, or
histiocytes.
Undifferentiated pleomorphic sarcoma is
a diagnosis of exclusion. Other potential
mimics must be ruled out, including car-
cinomas, melanoma, lymphoma, and sar-
comas (including rhabdomyosarcoma,
leiomyosarcoma, malignan! peripheral
nerve sheath tumour, dedifferentiated
and pleomorphic liposarcoma, and high-
grade myxofibrosarcoma) (902}.
Genetic profile
There are complex genetic aberrations
(902}.
Prognosis and predictive factors
The 5-year survival rate is 60-70%
(2326,2529). Surgery seems to be es-
sential regardless of the margin status,
and radiation therapy seems to be nec-
essary for local control (2326). Previous
radiation has been reported as an ad-
verse prognostic factor for disease-free
survival {2534).
Leiomyosarcoma
Flucke U.
Franchi A.
Definition
Leiomyosarcoma is defined as sarcoma
with smooth muscle differentiation.
ICD- 0 code 8890/3
Epidem iology
Smooth muscle tumours of the sinona-
sal tract are very rare. Most cases arise
in adults. Children are rarely affected
{538,606,902,1047).
Etiology
Radiation therapy contributes to the risk
of developing a leiomyosarcoma {778}.
Localization
The nasal cavities , nasopharynx, and
paranasal sinuses may be involved
{778,1312,2326} Tumours can also
arise in the oral cavity or perioral region
(606,2104}
Clinical features
The tumours present as a polypoid soft
tissue mass. Symptoms depend on the
site of involvement and include pain,
nasal obstruction, and epistaxis. The
lesions can also affect the craniofa-
cial bone, either primarily or secondar-
ily. Leiomyosarcomas metastasize to the
lung, liver, brain, other soft tissue sites, or
bone. Lymph node metastases are rarely
reported {606,778,1312 ,2326,2664}. Me -
tastasis from other siles (e.g. the uterus)
should be excluded {606 ,2104}
Malignan! soft tissue tumours 35

Fig. 1.26 Leiomyosarcoma. These tumours consist of long intersecting fascicles of pleomorphic cells with eosinophilic
cytoplasm.
Macroscopy
The tumours are polypoid , firm , and ei-
ther poorly defined or well circumscribed
but unencapsulated. On sectioning , they
are whorled and whitish or tan-grey, with
areas of haemorrhage, cystic degenera-
tion, and necrosis !538,778,1590}.
Histopathology
The tumours show infiltrative growth or
sharply demarcated borders. They are
composed of sp indl e cells arranged in in-
terlacing fascicles. Storiform architecture
can be focally present. The tumour cell
nuclei are oval to elongate and frequently
blunt-ended. There is variable atypia,
with enlarged nuclei and hyperchroma-
sia. Nucleoli are sometimes obvious. The
eosinophilic cytoplasm often shows small
perinuclear vacuoles. Epithelioid cyto-
morphology is rarely seen. Osteoclastic
and pleomorphic giant cells may occur.
Tumours with a myxoid background must
not be confused with spindle cel l myoepi -
thelioma. Scattered inflammatory cells
are seen in sorne cases. Rarel y, dys-
trophic or psammomatous calcification
has been reported . The French Fédéra-
tion Nationale des Centres de Lutte Con-
tre le Cancer (FNCLCC) grading criteria
depend on mitotic activity, necrosis, and
resemblance to normal tissue {467,538,
606,902,1312,1590,1607}
lmmunohistochem icall y, smooth muscle
differentiation is demonstrated by diffuse
stain ing for desmin, h-caldesmon , SMA,
and MSA, with positivity for at least two of
these markers {467,1312 ,1607).
Genetic profile
There is a complex genomic profile,
with a variety of genes involved in the
36 Tumours of the nasal cavity, paranasal sinuses and skull base
pathob iology of leiomyosarcomas, inclu-
ding TP53, FANCA, ATM, RB1, CDK2NA ,
PTEN, MYOCD, ROR2, and MED 12
{902,1607,1961}.
Prognosis and predictive factors
Clinical behaviour depends mainly on
tumour location , with sinonasal tumours
being more agg ressive due to thei r close
proximity to both orbital and cerebral cav-
ities. Surgery is the treatment of choice ,
but wide resection is often impossible.
Radiotherapy can be given. One third of
ali patients die of their tumour, as a re-
sult of either distant metastases or un-
controlled local recurrence involving vital
head and neck structures. Complete sur-
gical excision seems to be an important
predictor of disease-free survival. Mor-
pholog ically high-grade sarcomas seem
to be more aggressive ¡467,606,778,902,
1607, 2294,2326).
Rhabdomyosarcoma
Franchi A.
Flucke U.
Thompson L.D.R.
Definition
Rhabdomyosarcoma is a malignant mes-
enchymal tumour with skeletal muscle
differentiation. Embryonal , alveolar, pleo-
morphic, and spindle-cell subtypes are
recogn ized.
ICD- 0 codes
Rhabdomyosarcoma, NOS
Embryonal rhabdomyosarcoma
Alveolar rhabdomyosarcoma
Pleomorphic rhabdomyosarcoma,
adult type 8901/3
Spindle cell rhabdomyosarcoma 8912/3
Synonyms
Rhabdosarcoma ; myosarcoma;
malignant rhabdomyoma
Epidemiology
Sinonasal rhabdomyosarcoma is a rare
tumour, with an overall annual incidence
of 0.034 cases per 100 000 population
!2066). lt is the most common sinona-
sal sarcoma in both children and adults
{317,983 ,2326}. The peak incidence is in
,,., patients in the first decade of life, with no
significant sex predilection !2066}.
Etiology
Rare examples of radiation-induced
sinonasal rhabdomyosarcoma have
been reported {1191 }.
Localization
The most commonly involved sites are
the paranasal sinuses , followed by the
nasal cavity {2066}.
Clinical features
Symptoms include nasal obstruction ,
pain , facial swelling , proptosis, and
epistaxis {317,779 }.
Macroscopy
Most lesions present as polypoid, poorly
circumscribed masses with smooth sur-
faces , often extending into the adjacent
structures. They are fleshy, gelatinous le-
sions with a tan to grey cut surface. Bot-
ryoid rhabdomyosarcoma presents with
multiple grape-like polypoid masses. The
spindle -cell variant is tan-white with a
firm consistency.
Histopathology
In the sinonasal tract, embryonal rhab-
domyosarcoma (including the botryoid
variant) is the most frequent histological
subtype in young patients. lt consists
of primitive round to spindle cells , with
scant cytoplasm and hyperchromatic
nucle i. Scattered rhabdomyoblasts with
brightly eosinophilic eccentric cytoplasm
are observed. Their number increases
in tumours treated with chemotherapy.
Botryoid rhabdomyosarcoma typically
has a polypoid architecture, and pre-
8900/3 sents linear aggregates of tumour cells
8910/3 close to the surface epithelium (cambium
8920/3 layer), yielding a gradient of cellularity.
Sinonasal alveolar rhabdomyosarcoma
is more frequent in the adult population
{2326), and typically presents fibrovas-
cular septa separating nests of round ,
small to medium-sized neoplastic cells,
which tend to coalesce in the centre
with dyscohesion at the periphery. Giant
ce ll s with multiple peripheral nuclei may
be present. The salid variant of alveolar
rhabdomyosarcoma lacks the fibrovas-
cular septa , and the tumour cells grow in
sheets. The spindle-cell subtype is very
rarely observed in the sinonasal region
{1707); it consists of a fasciculated pro-
liferation of spindle cells with elongated
nuclei and pale indistinct cytoplasm, with
interspersed spindled or polygonal rhab-
domyoblasts with abundan!, brightly eo-
sinophilic cytoplasm.
lmmunohistochemically, the most use-
ful myogenic markers are desmin and
MYF4 (myogenin), which are expressed
in ali tumours . Compared with alveolar
rhabdomyosarcomas, in which there
is MYF4 staining in almos! 100% of the
nuclei, embryonal rhabdomyosarcomas
stain for MYF4 in a more heterogeneous
fashion , which provides a clue as to their
subclassification !1819). MYOD1, fast
myosin, myoglobin, and MSA are also
positive, but less specific. SMA is pos i-
tive in about 10% of cases !983) Rhab-
domyosarcoma, in particular the alveolar
subtype, may coexpress non-myogenic
markers, including cytokeratins (in 5- 8%
of cases), EMA , CD56, chromogranin ,
synaptophysin, C020, and CD99, and
this may be a source of diagnostic con -
fusion with carcinomas, neuroendocrine
tumours , and haematolympho id tumours
!1707,2671).
Ultrastructurally, rud imentary sarcom -
eric structures, consisting of alternating
thin and th ick filaments with Z band-
like structures , are recognized in the
cytoplasm.
Genetic profile
Most alveolar rhabdomyosarcomas (70-
80%) harbour a PAX3-FOX01 fusion,
and the PAX7-FOX01 fusion is less fre -
quently detected. ldentification of these
gene fusions is particularly useful for the
diagnosis of tumours arising in unusual
clinical settings (e.g. in older adults) and/
or with atypical morphology and immu-
nohistochemical profiles !2671). To date,
no specific recurren! genetic abnormality
has been identified in embryonal rhab -
domyosarcoma. Most of these tumours
have allelic losses in various chromo-
some 11 loci. Paediatric spindle cell
rhabdomyosarcoma shows a consisten!
NCOA2 rearrangement !1661 ).
Genetic susceptibility
Rhabdomyosarcoma can arise in chil-
dren affected by genetic syndromes,
including Li-Fraumeni syndrome (asso-
ciated with an inactivating mutation of
TP53), Costello syndrome (also called
faciocutaneoskeletal syndrome; HRAS
mutation), neurofibromatosis type 1 (in -
activating mutation of one allele of the
NF1 gene), and Beckwith-Wiedemann
syndrome (mutation or deletion of the
11p15.5 chromosomal region) !506).
Prognosis and predictive factors
Overall, rhabdomyosarcoma carries arel-
atively poor prognosis among sinonasal
Malignan! soft tissue tumours 37
sarcomas, with a 5-year survival rate of
40-45% {2326,2645,2648). Patient age
< 18 years and female sex are associ -
ated with better survival {2066,2381}.
Patients with alveolar rhabdomyosarco -
mas present more often with regional and
distant metastases and have a higher re-
currence rate and poorer survival {2381}
than do patients with the embryonal or
botryoid subtype. lnfiltration of the skull
base and the presence of a residual tu-
mour after primary therapy have also
been associated with an unfavourable
clinical course {2648).
Angiosarcoma
Bullerdiek J.
Flucke U.
Franchi A.
Thompson L.D.R.
Definition
Angiosarcoma is a malignan! neoplasm
of vascular origin.
ICD-0 code 9120/3
Synonyms
Epithelioid haemangioendothelioma; ma-
lignan! haemangioendothelioma; malig-
nan! angioendothelioma; haemangiosar-
coma; haemangioblastoma
The use of these synonyms is discour-
aged , particularly given that epithelioid
haemangioendothelioma is a unique entity.
38 Tumours of the nasal cavity, paranasal sinuses and skull base
and neck, but sinonasal angiosarcoma
accounts for < 0.1% of all head and neck
malignancies and < 1% of ali sinona-
sal malignancies {107,1540,1706,1718).
Sinonasal angiosarcomas can develop
in patients of any age (reported range:
8-82 years), with peak incidence in
the fifth decade of life (mean patient
age: 47 years) , younger than the cor-
responding age for skin and soft tissue
angiosarcomas of the head and neck
{107,1508,1540). There is a male predi-
lection , with a male-to-female ratio of 3:2
{777,1718,2419,2613,2626).
Etiology
Environmental exposure to radiation
{1472,1508,1706), vinyl chloride {2613),
and coal dust are rarely reported risk
factors.
Localization
A single site of involvement within the
sinonasal tract is more common than
multiple siles; the nasal cavity and max-
illary sinus are most frequently affected
{777,1718,2419,2613 ,2626}.
Clinical features
The presenting signs and symptoms,
wh ich are non-specific and usually of
short duration (mean: 9.8 months), are
most commonly recurrent epistaxis and
obstruction {1718} along wi th nasal dis-
charge, enlarging mass, sinusitis, epi-
phora, pain, diplopia, and headaches.
Sinonasal angiosarcomas are infiltrative
tumours , often associated with bone
erosion . The tumours show contras!
enhancement or a bright signal on T2-
weighted MRI. Angiography reveals
tumour extent and feeder vessel(s) ,
, . _.........,,,....,
Fig. 1.29 Sinonasal angiosarcoma. Neolumen formation
is seen within this angiosarcoma, where there is only mild
nuclear pleomorphism; vascular channels are apparent
throughout.
fac ilitating pre-surgical embol ization
{1718 ,2419}. Staging is not applied to
sinonasal angiosarcoma, but lymph node
and distan! metastasis are not common
at initial presentation.
Macroscopy
The tumours can be as large as 8 cm
(mean: 3.9 cm); paranasal sinus tumours
are typically larger than sinonasal cav-
ity tumours (6.8 vs 2.2 cm). The tumours
are nodular to polypoid , soft, friable,
purple to red , and often ulcerated, with
associated haemorrhage and necrosis
{777,1718,2419 ,2613 ,2626).
Histopathology
The tumours develop below an intact,
uninvolved epithelium, with vasoforma-
tive neoplastic cells expanding into soft
tissue and bone, frequently accompa-
nied by necrosis and haemorrhage. The
tortuous, irregular, freely anastomosing
vascular channels create cleft-like spac-
es, ru dimentary vessels, capillary-sized
vessels, and/or large cavernous spaces
filled with erythrocytes and lined by
plump, enlarged , atypical , spindled or
epithelioid endothelial cells protrud ing
into the vascular spaces in multiple layers
or papillae. lntracytoplasmic lumina (of-
ten containing erythrocytes) are patho-
gnomonic. Enlarged pleomorphic nuclei
show coarse, heavy nuclear chromatin
distribution , irregular nuclear contours ,
and prominent nucleoli. Mitotic figures,
including atypical forms, are easily iden-
tified throughout {1718,2419 ,2613,2626).
The tumours are diffusely immunoreac-
tive with vimentin , CD34, CD31, claudin 5,
ER G, FLl1 , 02-40, and factor Vlll-related
antigen, and focally reactive with keratin
(in particular the epithelioid variant) and
actin {1609 ,1718,2626) Grading is not
applied to sinonasal angiosarcoma.
Genetic profile
There are no specific cytogenetic find-
ings (2626).
Prognosis and predictive factors
Although recurrences are com-
mon (occurring in -40% of cases),
the overall survi val rate for angio-
sarcoma is still approximately 60%
(777,1706,1718,2419,2613,2626). Meta-
static disease occurs most commonly
to the lung, liver, spleen , and bone
(marrow) (1718). 8pecific etiological fac-
tors are associated with shorter survival
{2613,2675) .
Malignant peripheral
nerve sheath tumour
Flucke U.
Franchi A.
Thompson L.D.R.
Definition
Malignan! peripheral nerve sheath tu-
mours (MPN8Ts) are malignan! soft tis-
sue neoplasms that arise from peripheral
nerves or benign nerve sheath tumours
with variable differentiation towards one
of the cellular components of the nerve
sheath (i.e. 8chwann cells , fibroblasts , or
perineurial cells).
ICD-0 code 9540/3
Synonyms
Malignant schwannoma; neurofibrosar-
coma; malignant neurilemmoma
Epidemiology
About 20% of ali MPN8Ts develop in the
head and neck, with 25-30% of cases
associated with neurofibromatosis type
1 (NF1). MPN8Ts occur mainly in adults,
with a wide patient age range and a
mean patient age in the fifth decade of
life (965,972). Cases associated with NF1
tend to occur in younger patients, with a
mean patient age in the third to fourth
decade (613). More rarely, MPN8Ts de-
velop during childhood {2398).
Etiology
MPN8T develops in the setting of NF1
and infrequently in patients who have
been irradiated (2005).
Fig. 1.30 Sinonasal malignan! peripheral nerve sheath
tumour. Coronal T2-weighted MRI demonstrates a large,
heterogeneously enhancing mass filling the maxillary
sinus.
Localization
Cranial nerves are involved , with the
vestibular and vaga! nerves being most
commonly affected (613,1626).
Clinical features
The tumours arise de novo, commonly in
a major nerve trunk or from a pre-existing
neurofibroma, and rarely from schwan-
noma. Patients may present with a painful
and/or rapidly enlarging mass, with asso-
ciated neurological deficits (2398}.
Macroscopy
The tumours may be within or attached to
a nerve trunk or neurofibroma with a fusi-
form appearance. They tend to be white,
solid, and fleshy, sometimes with myxoid
change and frequent necrosis and haem-
orrhage (965,2398).
Fig. 1.31 Sinonasal malignan! peripheral nerve sheath tumour. Moderate pleomorphism can be seen in this interlacing
fascicular arrangement of a malignan! peripheral nerve sheath tumour; note the area of necrosis (lower right).
H istopathology
MPN8Ts are usually unencapsulated ,
highly infiltrative tumours with a range
of cell morphologies (including spin-
dle, epithelioid, pleomorphic, and small
round cell) . Common growth patterns
include a marbled effect with alternating
cellular and myxoid areas, perivascular
cuffs, poorly defined nuclear palisad-
ing, and neuroid whorls . A rosette-like
appearance with hyaline bands is less
common. Tumours often show multiple
patterns within the same lesion, including
pleomorphic or small -cell areas. 8pindle
cell MPN8Ts are often arranged in long
fascicles or a herringbone pattern. The
cells have elongated, tapered , buckled ,
or wavy nuclei and scant amphophilic cy-
toplasm. The nuclei may be hyperchro-
matic or may be vesicular with coarse
chromatin . Mitoses, haemorrhage, and
necrosis are frequent. Heterologous (e.g.
osteoid , cartilage, striated muscle, oran-
giosarcoma) elements are seen in about
15% of cases (613,965,2005,2398). Ma-
lignant triton tumour shows MPN8T with
rhabdomyosarcoma (965). Glandular
MPN8T may have goblet cells , with be-
nign or malignan! glands present. The
tumours are classified as low-grade or
high-grade on the basis of mitotic index,
atypical mitoses, pleomorphism, and ne-
crosis {2005 ,2398}.
There is no diagnostic immunoprofile,
but neoplastic cells show nuclear and
cytoplasmic 8100 protein and nuclear
80X10 immunoreactivity {1608) . Epithe-
lioid MPN8Ts show strong 8100 protein
expression and loss of 8MARCB1 (INl1)
(in 70% of cases), whereas only scat-
tered cells are reactive with 8100 protein
Malignant soft tissue tumours 39
in spindle cell MPNSTs in which INl1 is
retained. Nestin shows strong cytoplas-
mic staining and is useful in combination
with other markers. Cytokeratins, EMA ,
and CD34 may be positive, but their ex-
pression has not been described in the
epithelioid variant {1138 ,2398}.
Genetic profile
The most frequent gene alterations in-
clude loss of NF1on17q11 and of TP53on
17q13. lnactivation of the NF1 tumour sup-
pressor gene can occur both in sporadic
cases and in patients with NF1 {2398).
Genetic susceptibility
The tumours are associated with NF1.
Prognosis and predictive factors
MPNSTs are aggressive tumours. Worse
prognosis is associated with large tu-
mours (> 5 cm), NF1 association, high tu-
mour grade, trunca! location, high mitotic
index (> 6 mitoses per 10 high-power
fields), and incomplete resection . The
recurrence rate is as high as 40%, and
approximately two third of cases metas-
tasize , usually haematogenously to the
lungs and bone {965 ,972,2398}.
most frequently characterized by a recur-
rent PAX3-MAML3 gene fusion.
ICD- 0 code
Synonym
Low-grade sinonasal sarcoma with neu-
ral and myogenic features
Epidemiology
BSNS predominantly affects females,
with a female-to-male ratio of 2:1. The re-
ported patient age range is 24-85 years
(mean: 52 years) {1051 ,1409,1913).
Localization
BSNS typically involves multiple siles
in the sinonasal tract, in particular the
superior aspect of the nasal cavity and
ethmoid sinus. Tumour may also extend
to the orbit or cribriform plate.
9045/3
Clinical features
The symptoms, which are relati vely non -
specific and reflect the presence of a
sinonasal mass, include difficulty breath-
ing through the nose, facial pressure,
and congestion.
Macroscopy
The gross specimen usually presents as
multiple polypoid fragments of somewhat
firm , reddish -pink to tanor grey tissue, as
large as approximately 4 cm in greatest
aggregate dimension.

Biphenotypic sinonasal
sarcoma
Lewis J.E.
Oliveira A.M.
w .
\~ ." 'J ,
Definition
' -· ()
"'í \\~'\
. . . ......-~......- .....'--,M.l\)~.
Biphenotypic sinonasal sarcoma (BSNS) Fig. 1.33 Biphenotypic sinonasal sarcoma. A Uniform, elongate spindle cells arrayed in long intersecting fascicles;
is a low-grade spindle cell sarcoma with !he nuclei show pale chromatin and punctate nucleoli without significan! pleomorphism. B Focal rhabdomyoblastic
distinctive histological, immunohisto- differentiation is seen in a minority of biphenotypic sinonasal sarcomas. C S100 immunostaining often shows a spotty
chemical , and molecular features . lt is or patchy staining pattern. D lnfiltration of sinonasal bones is a frequent finding .

40 Tumours of the nasal cavity, paranasal sinuses and skull base

Histopathology A 2
B
The tumour is characterized by a cel- Q

~ "~
lular submucosal spindle-cell prolifera- 00<(4)
tion, composed of elongated spindle PAX3 •-1'° •• i'~ l-o
cells arranged in medium-length to long p ¡¡
8
intersecting fascicles. A herringbone
~
¡:¡ •1 ¡MAML3
~
;¡
MAML3 •-l_-~1~·¡~·~-----•
- o

pattern, which resembles the histology

of synovial sarcoma , is frequently seen.
l ¡PAX3 ~
' "' u
'11PAX3! ! ! ! ! !i! ! 9-'
;-!-l PAX3-MAML3
PAX3-MAML3 _ _ •~•-!~•~-----~·-
•-1 '
Tumours are unencapsulated and infil -
trative, including into bone. There is a
scant, delicate collagen matrix. Nuclei 60

are slender and relatively uniform in ap- PAX3-MAML3

f
pearance, without significant pleomor- 1iol
phism or hyperchromasia. Mitotic activity e D
~
~
40

is sparse (1051 ,1409,1913}. Most tumours ~

¡:;¡
show a striking concomitant proliferation e

of the covering epithelium , the invagi-

nations of which are intimately admixed
f
u
u
20

with neoplastic spindle cells. Squamous
or oncocytic metaplasia of the epithe-
lial proliferation can resemble that seen
in sinonasal papillomas. Other frequent
findings include haemangiopericytoma-
tous vascular pattern and the presence
of scattered small lymphocytes. A minor-
ity of cases (11%) show focal rhabdo-
myoblastic differentiation , a histological
feature that may be associated with an
alternate fusion partner (1051 ).
lmmunohistochemical features are also
distinctive. Ali tumours show at least fo-
cal positivity for 8100 and most (96%)
also stain with either SMA or MSA. 8100
zand actin staining patterns may be fo -
cal , patchy, or diffuse. Focal and/or weak
reactivity for CD34 , desmin , MYOD1, my-
ogenin , EMA , and cytokeratin has been
noted in several cases (1051,1409).
Genetic profil e
At the cytogenetic and molecular levels,
BSNS is characterized by the chromo-
somal translocation t(2;4)(q35;q311),
which results in an in-frame fusion of
exon 7 of the transcription factor PAX3
to exon 2 of MAML3, a coactivator of
the Notch signal ling pathway. The fu-
sion transcript is highly expressed and
may contribute to the unusual phenotype
of this tumour (2545) . PAX3-MAML3 is
found in most examples, but a subset of
cases harbour alternate PAX3 or MAML3
fusion genes, including PAX3-FOX01
and PAX3-NCOA 1, the same fusion tran-
scripts found in alveolar rhabdomyosar-
coma (1051,2305,2628).
Prognosis and predictive factors
The natural history of BSNS is character-
ized by slowly progressive growth with
~
Control PAX3- PAX3 PAX3-
MAML3 FOX01
Fig. 1.34 Biphenotypic sinonasal sarcoma. Structure and transactivation potential of the PAX3-MAML3 fusion protein.
A,B The 1(2;4) translocation !uses exons 1-7 of PAX3 to exons 2- 5 of MAML3 to create a novel PAX3-MAML3 fusion
protein that retains the DNA-binding domains of PAX3 but lacks the Notch-binding site of MAML3; the arrows along the
chromosomes indicate the transcription orientation of PAX3, MAML3, and PAX3-MAML3. C Fusion-signal FISH shows
the juxtaposition of the 5' PAX3 (red) locus to the 3' MAML3 (green) locus; the location of these probes is shown in
panel A. D Transient transcription assays demonstrate the poten! transactivation potential of PAX3-MAML3. PD, paired
domain; HD, homeodomain; TAO, transactivation domain . Reprinted from Wang X et al. {2545).
invasion of local structures. Nearly 50% sarcomas in children , adolescents , and
of patients with follow-up in the original young adults, with a mean patient age at
series experienced local recurrence , as first diagnosis in the third to fourth dec-
long as 9 years after initial treatment. ade of life {1215).
Neither metastatic disease nor death
from disease has been reported (1409). Etiology
Specific predictive factors have not been Synovial sarcomas are exception -
defined. ally associated with prior radiotherapy
(568 ,629,2459).
Synovial sarcoma Localization
The sinonasal tract and skull are rare
Bullerdiek J. localizations.
Bell D.
Clinical features
There are palpable, deep-seated swell -
Definition ings, with or without associated pain or
Synovial sarcoma is a mesenchymal tu - tenderness.
mour that displays a variable degree of
epithelial differentiation, including gland Macroscopy
formation , and has a specific chromo- Lesions are yellow or grey to white , and
somal translocation t(X;18)(p11 ;q11) that well circumscribed when slow-growing .
leads to formation of an SS18-SSX fusion
gene (735). Histopathology
Severa! monophasic subtypes (i.e. spin-
ICD-0 code 9040/3 dle-cell, calcifying/ossifying , myxoid ,
and poorly differentiated) and biphasic
Synonyms subtypes with glandular or solid epithe-
Synovial cell sarcoma; synovioma lial cells can be distinguished. Poorly
differentiated tumours may contain ar-
Epidemiology eas with frequent mitoses and necrosis
Synovial sarcomas are the most com - (726,2399). There is TLE1 nuclear immu -
mon non-rhabdomyosarcoma soft tissue noreactivity in as many as 95% of cases;

Malignant soft tissue tumours 41

variable positivity for C099, BCL2, and
CD56; and patchy to focal reactivity with
epithelial markers (EMA), cytokeratins
(CK7), and BerEP4. The tumours are usu-
ally negative for 8100 and WT1.

Genetic profile
The chromosomal translocation t(X;18)
(p11;q11), likely acting as driver mutation ,
is a specific genetic alteration in synovial
sarcomas {2436), and is also described
among skull base and sinonasal tract tu -
mours {181,450 ,835,2299}. lt results in a
gene fusion between SS18 (also called
SYT) and one of three SSX genes {454) .
The fusion can be detected by classic
Fig. 1.35 Biphasic synovial sarcoma. High-power micrograph of a tumour of !he skull base showing a biphasic
cytogenetics , quantitative RT-PCR {903), appearance, with spindled and glandular cells.
or FISH {827). Variant translocations ex-
ist, and a considerable percentage of
synovial sarcomas do not show these
aberrations.

Prognosis and predictive factors

The prognosis varies depending on stag -
ing, grading , resectability, use of radia-
tion therapy, site of primary tumour, and
presence of metastases {2507). Clinically
aggressive behaviour, apparently deter-
mined early during tumorigenesis , is as-
sociated with more-complex genomes Fig. 1.36 Biphasic synovial sarcoma. A lmmunoreactivity with a pancytokeratin cocktail. B Nuclear immunoreactivity
and upregulation of AURKA and K!F18A with TLE1 .
{1930) .

42 Tumours of the nasal cavity, paranasal sinuses and skull base

Bord erline / low-grade malignant
soft tissue tu mours
Desmoid-type fibromatosis
Wenig B.M.
Flucke U.
Thompson L.D.R.
Definition
Desmoid-type fibromatosis is a locally in -
filtrative, non-metastasizing, cytologically
bland (myo)fibroblastic neoplasm.
ICD-0 code
Synonyms
Desmoid tumour; aggressive fibroma-
tosis; infantile fibromatosis (desmoid
variant)
Epidemiology
About 10-15% of cases occur in the
head and neck {528,1556,2532). As
many as 30% of cases occur in children
{551,738,1018,1847). There is no sex
predilection.
Etiology
There is an association with Gardner
syndrome (familia! colorectal polyposis)
{463), including familia! adenomatous
polyposis {472,2094). Surgery-related
trauma may be a contributory factor.
Fig 1.37 Desmoid-type fibromatosis of the neck. A This example is characterized by a moderately cellular proliferation composed of bland-looking spindle cells with associated
collagenized stroma; the spindle cells are uniform, and nuclear atypia, increased mitotic activity, and associated necrosis are absent. B Diffuse and strong nuclear beta-catenin
immunoreactivity is a valuable finding for rendering a diagnosis of desmoid-type fibromatosis.
Localization
Soft tissues of the neck are most com-
monly affected {155,551}, whereas
the maxillary sinus , nasopharynx, and
oral cavity are infrequently involved
{753,780,856) . Multifocality may be seen
in syndromic cases.
Clinical features
Symptoms include an enlarging painless
neck mass, as well as nasal obstruction
and epistaxis in the sinonasal tract. Fa-
8821/1 cial deformity, proptosis, and dysphagia
may occur with disease progression.
Macroscopy
Desmoid-type fibromatosis presents as
a firm, tan-white, poorly delineated or
infiltrating lesion of variable size, with a
trabecular or whorled appearance on cut
section.
Histopathology
Histopathology shows a poorly circum -
scribed, infiltrative (to muscle and/or
bone) , fascicular growth of moderate
cellularity composed of spindle-shaped
cells with tapering to plump vesicular
nuclei, small nucleoli, and indistinct cyto-
plasm, separated by abundant collagen.
Mild nuclear pleomorphism and rare mi-
totic figures may be identified; atypical
mitoses and necrosis are absent. The
stroma is variably collagenized , may
v .
Borderline/low-grade malignant soft tissue tumours
focally be myxoid or mucoid-appearing,
and may be characterized by keloid -like
collagen. Vascularity varies, consisting
of compressed vessels that tend to be
evenly spaced . Lesiona! cells are reac-
tive for vimentin, nuclear beta-catenin (in
70-75% of cases) , actins, and occasion-
ally desmin {184 ,335,1818,2400).
Genetic profile
Cytogenetic abnormalities on chromo -
somes 8 and 20 support a monoclonal
neoplastic nature {269). Germline mu-
tations of the APC gene are primarily
identified in the setting of Gardner-type
familia! adenomatous polyposis, where-
as mutations in the beta-catenin gene
(CTNNB1) are identified in as many as
85% of sporadic cases {738,1059 ,1355),
with T41A , S45F, and S45P mutations be-
ing the most frequent {1059 ,1355).
Genetic susceptibility
Patients with Gardner syndrome {463) or
Gardner-type familia! adenomatous poly-
posis are at increased risk {472,2094) .
Prognosis and predictive factors
In general, the prognosis is good {1193),
with positive surgical margins associated
with recurrence, usually < 2 years after
surgery {1050). Young patient age and
CTNNB1 S45F mutation may be indepen-
dent risk factors for recurrence {473,2457).
1
~ ~
~
~
~ "a i_:&."r.,.
43
Sinonasa/
glomangiopericytoma
Thompson L.D.R.
Flucke U.
Wenig B.M.
Definition
Sinonasal glomangiopericytoma is a
sinonasal tumour demonstrating a perivas-
cular myoid phenotype.
ICD- 0 code
Synonym
Sinonasal haemangiopericytoma-like
tumour
Epidemiology
Glomangiopericytomas account for
< 0.5% of ali sinonasal tract neoplasms
{356,476,2389}, with a slight female pre-
dilection anda peak incidence in the sev-
enth decade of lite, although individuals
of any age may be affected.
Localization
The tumour is nearly always unilateral
(only 5% are bilateral) , affecting the na-
sal cavity alone and frequently extending
into paranasal sinuses. lsolated parana-
sal sinus involvement has also been re -
ported {189,356,476,640,2389).
Clinical features
Most patients present with nasal obstruc-
tion and epistaxis, with other non-specific
findings present for an average duration
of < 1 year {2389). Associated severe on -
cogenic osteomalacia has been reported
{257,356).
. .
Fig. 1.38 Nasal glomangiopericytoma. A The surface respiratory epithelium is uninvolved by the patternless proliferation of spindled neoplastic cells; there is well-developed
peritheliomatous hyalinization. B Spindled cells with ovoid nuclei in a syncytial arrangement; numerous eosinophils and mas! cells are apparent.
44 Tumours of the nasal cavity, paranasal sinuses and skull base
Macroscopy
The tumou rs are generally polypoid, non-
translucent, beefy red to pink , soft, and
fleshy to friable, with an average size of
3.0cm.
Histopathology
The unencapsulated tumour is identified
below an intact epithelium , although fric-
tion surface erosion may be seen in large
tumours. There is a so-called patternless
diffuse architecture, frequently effacing or
enve loping normal tissue. The cells may
9150/1 be arranged in short fascicles ; in stori -
form , whorled , meningothelial, or reticu -
lar arrangements; or in short palisades
of closely packed cells. The cells are
separated by a vascu lar plexus rang ing
from capillaries to large patulous spaces.
Prominent, th ick, acellular, perithel ioma-
tous hyalinization is a characteristic fea-
ture . There is a syncytial architecture to
the closely packed, uniform, oval to elon-
gate cells, with indistinct cell borders . The
nuclei are oval to spindle-shaped , vesic-
ular to hyperchromatic , and surrounded
by nondescript cytoplasm. Mitoses are
limited (< 3 per 10 high-power fields),
and nuclear pleomorphism is absent to
mi ld. Mast cells, eosinophi ls, and extrav-
asated erythrocytes are variably present.
Tu mour giant cells are rarely identified ,
but an aggregation of degenerating tu-
mour cells, similar to those of symplas-
tic glomus tumou r, may be seen {657) .
lnfrequently, fibrosis or myxoid change
may be identified. Rarely, glomangio-
pericytoma may contain mature adipose
tissue (lipomatous) or extramedullary
haematopoiesis (742, 904, 1732, 2389}.
Concurren! co ll ision tumours, most
often solitary fibrous tumours, have
been reported {17,822,2389}. Malignant
'·... .
glomangiopericytomas show pro-
found pleomorphism, necrosis, and
increased mitoses (2389). By immuno-
histochemical analysis, glomangiopericy-
tomas usually show diffuse reactivity with
actins (SMA > MSA), nuclear beta-
caten in, cyclin 01 , factor Xllla, and vi-
mentin , and lack significant expression
of C034, C031 , C0117, STAT6 , BCL2,
cytokeratin, EMA, desmin, or S100 pro-
te in (17,356,630,1274,1339,2389)
Genetic profile
Somatic, single-nucleotide-substitution,
heterozygous mutations in the beta-
catenin gene (CTNN81), specifically in
the GSK3beta region (codons 32, 33,
37, 41, and 45 encoded by exon 3) have
been identified in glomangiopericytoma
(923,1339). Accumulation of beta-catenin
results in nuclear translocation, wh ich
has been shown to upregulate cycl in 01
and lead to its oncogenic activation. Ac-
tivation of beta-catenin and the resu lting
cyclin 0 1 overexpression are important
pathogenetic events (1339}. In the dif-
ferential diagnosis it is importan! to note
that NAB2-STAT6 gene fusion in solitary
fibrous tumours (603}, MIR143-NOTCH
fusion in glomus tumours {1660} and
- . - ,.;
ACTB-GL/1 fusion in pericytoma {514)
are not seen in glomangiopericytoma.

Prognosis and predictiva factors

Glomangiopericytoma is an indolent tu-
mour with an excellent survival rate. Re-
currence (which occurs in as many as 40%
of cases) is usually a result of inadequate
surgery {356 ,640,2389). Aggressi ve (ma-
lignant) behaviour is suggested by tumour
size > 5 cm , bone invasion , profound
nuclear pleomorphism, high mitotic rate
(> 4 mitoses per 10 high-power fields),
and necrosis {356,476,1274 ,2389).

Solitary fibrous tumour

Flucke U.
Thompson L.D.R.
Wenig B.M.

Definition
Sol itary fibrous tumour is a fusion gene-
associated tumour of fibroblastic pheno-
type, with a branching vasculature.

ICD-0 code 8815/1

Synonyms
Haemangiopericytoma; giant cell
angiofibroma

Epidemiology
Solitary fibrous tumours are rare, account-
ing for < 0.1% of all sinonasal neoplasms
{151). Adults are mainly affected, with no
sex predilection {17,564,861,2620,2735).
Localization
Tumours affect the nasal cavity {2620 ,
2735).
Clinical features
Patients experience nasal obstruction
and epistaxis, among other non-specific
findings {151,2620,2735)
Macroscopy
Tumours are polypoid , firm , and
white, and are usually small due to the
confined space of the sinonasal tract
{151 ,2620,2735).
Fig. 1.40 Solitary fibrous tumour. A Note !he patternless architecture of the fibroblastic cells; there is a collagenous
background, and sinonasal mucosa is seen in the upper par! of the field . B Nuclear STAT6 expression is the most
specific immunohistochem ical marker.
Histopathology Genetic profile
Tumours are submucosal , pseudoen- NAB2-STAT6 gene fusion seems to be
capsu lated, and variably cellular, con- specific {33,511 ,565,1634).
sisting of bland spindle-shaped cells
arranged in a haphazard architecture. Prognosis and predictiva factors
Multinucleated giant cells may be pre- Complete surgical resection is usu-
sent. The vessels are stellate to stag- ally curative. Patient age > 55 years ,
horn -li ke in shape. There is a variable tumour size > 15 cm, necrosis, and > 4
collagenous background that includes mitoses per 10 high-power fields prob-
ropey, keloidal, or amianthoid collagen ably suggest more aggressive behaviour
bundles. lmmunohistochemically, the {564 ,1297,2659).
cells show a specific reaction with STAT6
(nuclear) and CD34 , but are non-reactive
with desmin , S100 protein , actins, and
nuclear beta-catenin {489 ,563 ,603,923,
2620,2683,2735).

Borderline/low-grade malignant soft tissue tumours 45

Epithelioid
haemangioendotheHoma
Flucke U.
Franchi A.

Definition
A malignant neoplasm of low- to inter-
mediate-grade, composed of neoplastic
cells that have an endothelial phenotype,
epithelioid morphology, and a hyalinized ,
chondroid , or basophilic stroma.

ICD-0 code 9133/3

Epidemiology
There is a wide patient age distribu-
tion, with children rarely being affected
{280 ,2579).

Localization
Occurrence in the head and neck is rare .
Epithelioid haemangioendothelioma may
arise in soft tissue, skin , and bone. The
neck, oral cavity, salivary glands , and
jawbones may be affected . Very rarely,
a lymph node may be the primary site
{422,662,739,1886).

Clinical features
Epithelioid haemangioendotheliomas
are classically slow-growing , infiltrative,
and (rarely) metastasizing lesions {280).
Symptoms are mostly non-specific.
Pain and tenderness may be present
{1589,2579) There is a propensity for
lymph node metastasis (739}.
Macroscopy
The (multi)nodular mass typically shows
a pale , solid cut surface, sometimes with
sorne haemorrhage {280).
Histopathology
The epithelioid- and histiocytoid-ap-
pearing endothelial cells are arranged in
short cords and strands in a myxohyaline
stroma. They show subtle intracytoplas-
mic lumina and an abundant hyaline cy-
toplasm. Striking nuclear atypia is seen in
approximately 30% of cases. Mitotic ac-
tivity is usually low. Multicellular vascular
channels are present in individual cases
{574 ,739,1589,2579).
Endothelial markers are expressed, with
CD31 , ERG, and FLl1 being the most
sensitive. Cytokeratin expression is seen
in about 30% of cases , which may as a
result be confused with carcinomas or
myoepithelial tumours (739,1589). There
is nuclear positivity for CAMTA1 in cases
with WWTR1-CAMTA1 fusion. There is
nuclear expression of TFE3 in cases with
YAP1-TFE3fusion , but this marker should
be used with caution due to the possibil-
ity of unspecific staining (662,739,2161).
Genetic profile
WWTR1-CAMTA1 fusion is present in
most of the cases. A small subset of
tumours harbour a YAP1-TFE3 fusion
(85,662 ,739,2351}
Prognosis and predictive factors
Most cases behave in an indolent man-
ner. A progressive clinical course with tu-
mour-related fatality has been document-
ed in sorne instances (574,1589,2579).
A proposal for risk stratification showed
that > 3 mitoses per 50 high-power fields
and tumour size > 3 cm are associated
with higher mortality, irrespective of local -
ization, atypia, cell spindling, or necrosis
(574).

46 Tumours of the nasal cavity, paranasal sinuses and skull base

Benign soft tissue tumours
Leiomyoma
Definition
Leiomyomas are benign tumours with
smooth muscle differentiation (and
vascular differentiation in the case of
angioleiomyoma).
ICD-0 code
Epidemiology
Leiomyomas are extremely rare in the
head and neck region, accounting far
< 1% of all leiomyomas {2488) . Adults are
most commonly affected, with an equal
sex distribution {1047,2488} lt seems that
most sinonasal tract examples are angio-
leiomyomas {20,1047,1607}
Localization
The most common site of leiomyoma
in the head and neck region is the lips,
followed by the tangue, cheeks, pal-
ate, gingiva, and mandible {2488) . The
tumours are extraordinarily rare in the
sinonasal tract, with involvement of the
nasal cavity in most of the cases and
more rarely of the paranasal sinuses {20,
778,1047).
Clinical features
The tumours are clinically indistinct
and present as longstanding polypoid
masses with nasal obstruction, epistaxis,
and pain {20,778,1047,2488).
:a! ._
Fig. 1.42 Sinonasal leiomyoma. A An intact surface overlies a proliferation of smooth muscle that is intimately associated with vessels. B A loosely arranged spindled cell population
of smooth muscle cells surrounds vascular spaces.
Macroscopy
Lesions are polypoid, nodular, and usual-
ly sharply demarcated, with a white to tan
trabecular cut surface {20,1047,2488) .
Histopathology
Tumours are subepithelial with infre-
quent mucosal ulceration . Spindled tu -
8890/0 mour cells are arranged in intersecting
fascicles. The nuclei are oval to elongate
and cigar-shaped, without atypia. There
is eosinophilic fibrillary cytoplasm. Un-
like in leiomyosarcoma, mitotic figures
are absent. Angioleiomyoma, the most
common smooth muscle tumour in this
region, shows a prominent vasculature
surrounded by smooth muscle cells with
which the vessels are intimately associat-
ed. Calcification, ossification, fatty meta-
plasia, or myxohyaline degeneration may
be seen and may suggest regression in
longstanding lesions {20,606,778,1047,
1606). A fatty component is more com-
mon in males and older patients {20).
lmmunohistochemical ly, lesions express
smooth muscle markers (alpha-SMA,
MSA, desmin, and caldesmon) but are
negative far HMB45, SOX10, and S100
{20,1047,1606} .
Genetic profile
Angioleiomyomas show loss of 22q11.2
and low-level amplification of Xq {1741}.
Prognosis and predictive factors
The prognosis is excellent {20,1047).
~ <;~ ·~
. . ·;,: ·~
Thompson L.D .R .
Bullerdiek J.
Flucke U.
Franchi A.
Haemangioma
Definition
Haemangioma is a benign neoplasm of
vascular phenotype.
ICD-0 code 9120/0
Synonyms
Lobular capillary haemangioma; pyogen-
ic granuloma; capillary haemangioma;
cavernous haemangioma
Epidemiology
Mucosal haemangiomas account far
about 10% of head and neck haeman-
giomas and about 25% of non-epithelial
sinonasal tract neoplasms {777,1620,
1936,2221). Haemangiomas occur in
patients of ali ages (median: 40 years).
There are incidence peaks among boys
and adolescent males and among preg-
nant women, with an equal sex distribu -
tion in patients aged > 40 years {644,
777,963,1174,1620,2221 }.
Etiology
Lobular capillary haemangioma is associ-
ated with injury, hormonal factors (pregnan-
cy and oral contraceptive use) {559,1292,
1936), and drugs (vemurafenib) {2061).
Localization
The anterior septum is most frequently
affected, followed by turbinates and
sinuses {644,1620,1936,2221)
Ben ign soft tissue tumours 47
A
Fig. 1.43 Lobular capillary haemangioma.
surrounding a central penetrating vessel.
Clinical features
Presenting symptoms include epistaxis
and obstruction, usually of short duration
{559,1620,1936,2221 ) lmaging studies
show an intensely enhancing tumour sur-
rounded by a hypoattenuated peripheral
rim, often with bony remodelling {1174,
1360,2669).
Macroscopy
The mean size is < 1.0 cm, but examples
as large as 8 cm have been reported
{1936 ,2221). The gross appearance
ranges from that of a diffuse, flat mass
to that of a bulging , polypoid nodule. The
lesions are soft and usually have surface
epithelial ulceration {644,777,963,1174,
1620).
Histopathology
Haemangiomas in the sinonasal tract
are divided primarily into capillary and
cavernous types {1174,1620,1936,1956,
2221}. Other variants are reported rarel y.
Lobular capillary haemangioma is a cir-
cumscribed proliferation of capillaries
with plump endothelial cells surrounded
by pericytes in a fibromyxoid stroma, ar-
ranged in one or more lobules (which may
show high cellularity). Each lobule has a
large central vein surrounded by small
capillaries, with an overlying collarette of
epithelium (often ulcerated or atrophic).
Mitoses are often identified , without atyp-
ical forms . Cavernous haemangiomas
are composed of multiple, large, cystic,
thin-walled, blood -filled spaces lined by
endothelial cells and separated by scant
connective tissue stroma. The neoplastic
cells react with FLl1 , CD34, CD31, and
factor Vlll-related antigen, with variable
48 Tumours of the nasal cavity, paranasal sinuses and skull base
expression of estrogen and progesterone
receptors.
Genetic profile
A single case had a clonal del(21)
(q21.2q22.12) {2425).
Genetic susceptibility
Associations with Sturge-Weber syn-
drome (encephalotrigeminal angiomato-
sis) and von Hippel-Lindau disease have
been reported.
Prognosis and predictiva factors
Recurrences , which occur in as many
as 42% of cases , are usually identified
in older patients. Pregnancy-related re-
gression occurs after parturition {134,
559,1936,2221). Angiosarcomas arise de
novo {1718)
Schwannoma
Definition
Schwannoma is a benign tumour of
Schwann-cell phenotype.
ICD-0 code 9560/0
Synonyms
Neurilemmoma; benign peripheral nerve
sheath tumour
Epidemiology
Less than 4% of schwannomas involve the
nasal cavity and paranasal sinuses {929,
952,994,2170}, developing in middle-
aged adults (mean patient age: 50 years ;
range: 17-81 years) with an equal sex dis-
tribution {747,1594,2170,2314).
Localization
Sinonasal schwannomas arise from the
branches of the cranial nerves (V and IX-
XI I) and autonomic nervous system, af-
fecting (in descending order of frequen-
cy) the ethmoid and maxillary sinuses,
nasal cavity, and sphenoid and frontal
sinuses {952,994,1866,2170,2314}
Clinical features
The most common presenting symp-
toms are headache, nasal obstruction,
facial pain, and Horner syndrome (ocu-
losympathetic palsy), followed by other
non-specific findings {929 ,1866,2170,
2314). lmaging shows an inhomogene-
ous, low-density soft tissue mass, with
bone erosion occasionally noted {1230,
1866,2170,2314). Tumours may expand
into the orbit, nasopharynx, and cranial
cavity {1866,2170).
Macroscopy
Sinonasal schwannomas can reach 7 cm
in size (mean: 2.5 cm). They are well-
circumscribed, globular, firm to rubbery,
yellowish-tan tumours with a solid to myx-
oid and cystic cut surface, frequently with
haemorrhage.
Histopathology
Schwannomas are unencapsulated tu-
mours composed of Antoni A cellular
areas with nuclear palisading alternating
with hypocellular, myxoid Antoni B areas.
The tumour cells are fusiform with elon-
gated cytoplasmic extensions imparting a
wavy to spindled appearance. The nuclei
are wavy and tapered , with heterochro-
matin. In Antoni B areas, a perivascular
hyalinization is characteristic. Mitoses are

scant and necrosis is absent. Extensive
degeneration may result in a narrow rim
of recognizable tumour at the periphery
(300,952}. Epithelioid variants and hybrid
tumours (i.e. neurofibroma and perineuri-
oma) are rare in the sinonasal tract (109}.
lmmunophenotype
The neoplastic cells are strongly and
diffusely reactive with 8100 protein and
SOX10, with C034-positive fibroblasts
in the Antoni B areas. Focal GFAP and
AE1/AE3 immunoreactivity has been de-
scribed , but neurofilament protein (NFP)
and actin are negative (1608}.
Prognosis and predictive factors
Schwannomas exceptionally undergo
malignan! transformation (972,1575,1626,
2422}, but otherwise have a very low re-
currence potential.
Fig. 1.45 Nasal neurofibroma. A An intact squamous mucosa overlies a proliferation of Schwann cells, perineurial cells, and fibroblasts blended with collagen fibres . B Nerve fibre
twigs are interspersed among Schwann cells, perineurial cells, and collagen fibres; mast cells are also present
Neurofibroma
Definition
Neurofibroma is a benign peripheral
nerve sheath tumour composed of mixed
Schwann cells, perineural-like cells, and
intraneural fibroblasts.
ICD-0 code
Synonym
Fibroneuroma
Epidemiology
Neurofibromas are exceptional in the
sinonasal tract. They show no sex pre-
dilection. The mean patient age is in the
fifth decade of life overall, and 35 years
among patients with neurofibromatosis
type 1 (109}.
Localization
Sinonasal neurofibromas arise most com-
monly at the nasal vestibu le, followed by
.• ~ "I
B Loose fascicles of
the maxillary sinus (109,281}; the majority
are unilateral (2 11 ,1308}.
Clinical features
Non-specific symptoms include a mass,
obstruction, epistaxis, and pain (81,109,
1866}.
9540/0 Macroscopy
Tumours are firm , glistening , fusiform,
and sometimes polypoid, with a mean
size of 3.1 cm (81 ,109,998}.
Histopathology
Neurofibromas are unencapsulated
tumours intimately associated with nerve
twigs. Lesiona! cells (modified Schwann
cells, intraneural fibroblasts, and perineu-
rial hybrid cells) intermix with coarse col-
lagen bundles and mast cells within a mu-
copolysaccharide-rich stroma. There are
ovoid to spindled cells with undulating ,
pointy nuclei with thin cytoplasmic pro-
cesses extending into the stroma, often
Benign soft tissue tumours 49
with a centripetal gradient of cellularity.
lncreased cellularity, a storiform growth
pattern, and pleomorphism may be seen,
but fascicular growth or increased mi-
toses (in particular atypical mitoses) sug-
gest malignant change (109,994,1866).
Plexiform neurofibroma and composite
tumours (i.e. schwannoma and perineu -
rioma) are exceptional (109,1026,1308),
and the diffuse type has not been report-
ed. The subpopulations of neurofibroma
Other tumours
Meningioma
Ro J.Y.
Bell D.
Nicolai P.
Thompson LD.R .
Definition
Meningioma is a neoplasm composed of
meningothelial cells .
ICD-0 code 9530/0
Synonym
Sinonasal tract meningioma
Epidemiology
Primary extracranial (i.e. ectopic or ext-
racalvarial) meningiomas of the sinona-
sal tract are rare, accounting for 0.1% of
primary sinonasal neoplasms , 2% of all
meningiomas, and 24% of all primary ex-
tracranial meningiomas. Direct extension
50 Tumours of the nasal cavity, paranasal sinuses and skull base
are highlighted with S100 protein, GFAP,
CD34, and BCL2, with SOX10, NFP, and
calretinin highlighting the axons specifi-
cally (109,719).
Genetic profile
Neurofibromatosis type 1-related neu-
rofibromas have associated biallelic inac-
tivation by germline mutations of the NF1
gene (17q11.2) {6 ,1836)
is much more common, with 20% of men-
ingiomas showing extracranial extension
(772,1867,2029,2388}. By consensus, a
diagnosis of primary sinonasal menin-
gioma should not be rendered when a
detectable intracranial mass is present
{1666,2029}. Sinonasal meningiomas af-
fect women and men equally (with a ra-
tio of 1:1), and have a mean patient age
of 48 years (range: 13-88 years) (2160,
2388)
Etiology
Radiation exposure and sex hormones
are unproven etiological factors {772,
1006,1039}.
Localization
Sinonasal meningiomas involve the nasal
cavity most commonly, followed by the
paranasal sinuses (most commonly the
frontal sinus), with multiple sites frequent-
ly affected. Most tumours are left-sided
{772,1006,1867,2029,2388}.
Genetic susceptibility
About 10% of sinonasal neurofibromas
arise within neurofibromatosis type 1
(109,2001,2453).
Prognosis and predictive factors
Neurofibromas are benign, with a 5% re-
currence rate due to incomplete excision
{1866 ,2001}. Malignant transformation is
exceptional {1866}.
Clinical features
Symptoms are non-specific, present for a
long duration (mean : 4 years), and most
commonly include a mass or polyp and
nasal obstruction {772,823,1006,1867,
2388}. The imaging findings are non-
specific, revealing opacification, some-
times with bone erosion or hyperosto-
sis. In most cases , direct extension by
permeative growth from an intracranial
primary can be documented; the intrac-
ranial primary may be a small en plaque
meningioma {1666 ,2388}.
Macroscopy
The tumours are often polypoid , covered
by an intact epithelium , and expanding
into bone. They can reach 8.0 cm in size
(mean: 3 cm).
Histopathology
Sinonasal meningiomas, often blended
with surface squamous or respiratory
epithelium, are arranged in lobules of
whorled syncytial meningothelial cells.
Nuclei are bland and round to oval, with
small nucleoli and occasional intranu-
clear cytoplasmic inclusions (2388).
Psammoma bodies are occasionally
present.
Of the 15 histological types of menin-
gioma, the most common in the sinona-
sal tract are meningothelial, transitional,
metaplastic, and psammomatous, and
most are grade 1 tumours {1858,1859).
Grade 2 and 3 meningiomas are rare
(2388).
Meningiomas typically react with EMA,
CK18, and vimentin. Rare tumours may
react with pancytokeratin and CK7 (in a
pre-psammomatous pattern), CD34 (fi-
brous and atypical types), and S100 pro-
tein (fibrous type), whereas GFAP, STAT6,
and SMA are non-reactive {2160). Pro-
gesterone and estrogen receptor reactiv-
ity is present {2388).
Genetic susceptibility
Neurofibromatosis type 2 association is
not significant in sinonasal meningiomas.
Prognosis and predictive factors
The prognosis of sinonasal meningiomas
is good. Although recurrences develop
in about 30% of cases (due to incom-
pletely excised tumours), metastasis and
malignant transformation have not been
reported (1006,1858,1867,2388).
Sinonasal ameloblastoma
Wenig B.M.
Definition
Sinonasal ameloblastoma is a locally ag-
gressive, primarily gnathic (jaw) tumour
with a high propensity far recurrence.
lt originates wholly within the sinonasal
tract, without connection to gnathic sites,
arising from sinonasal epithelium and
showing histological features identical to
those of its counterpart originating in the
jaw.
ICD-0 code 9310/0
Epidemiology
Sinonasal ameloblastomas are un-
common tumours . There is a decided
male predilection and the mean patient
age at presentation is 59.7 years (ap-
proximately 15-25 years older than far
ameloblastoma occurring in the jaws)
{2090}
Localization
The tumours may involve the nasal cav-
ity only, the paranasal sinuses only, or
both the nasal cavity and the paranasal
sinuses {2090)
Clinical features
Patients usually present with a mass le-
sion and nasal obstruction; symptom
duration ranges from 1 month to several
years {2090}. Unlike gnathic ameloblas-
tomas, which have a characteristic mul-
tilocular and radiolucent presentation ,
sinonasal ameloblastomas are described
radiographically as salid masses or
opacifications {2090). Bone destruction,
erosion, and remodelling (with remnant
of bony shell delimiting the lesion as it
grows) may be present {2090}.
Histopathology
Histologically, sinonasal ameloblastomas
are similar in appearance to their gnath-
ic counterparts. In the sinonasal tract,
ameloblastomatous proliferation can be
seen arising in direct continuity with the
intact sinonasal surface mucosal epithe-
lium, a finding that in conjunction with the
absence of continuity with gnathic sites
confirms primary sinonasal origin.
Prognosis and predictive factors
Overall treatment success correlates with
complete surgical eradication performed
in conjunction with thoroughly detailed
radiographical imaging.
The tumour may recur, which generally
happens within 1-2 years of the initial
procedure but may occur years after the
surgery {2090). No tumour deaths, me-
tastases, or instances of malignant trans-
formation have been reported .
Chondromesenchymal
hamartoma
Toner M.
Hunt J.L.
Definition
Chondromesenchymal hamartoma is a be-
nign, locally destructive, tumour-like growth
containing mixed mesenchymal elements.
Synonyms
Nasal chondromesenchymal hamarto-
ma; mesenchymoma
Epidemiology
This rare lesion occurs predominantly in
infants, but occasionally in older children
and adults, with a male predominance.
Localization
The most common sites are the parana-
sal sinuses, nasal cavity, and orbit. lntra-
cranial and skull base extension may oc-
cur {1568) .
Clinical features
This is a slow-growing expansile lesion
that can be locally destructive. Patients
may present with nasal congestion or
symptoms related to a polypoid mass.
Radiological findings may appear de-
ceptively aggressive, with bone erosion
and intracranial extension.
Other tumours 51
Macroscopy
The tissue is typ ically firm and white, re-
sembling cartilage.
Histopathology
Histopathology shows a lobular prolifera-
tion of mature and immature hyaline car-
tilage in a variably cellular fibrous back-
ground {1568). The stromal component
may be highly cellular, and mitoses may
be present. The stromal and cartilaginous
elements may be admixed with bony tra-
beculae or may surround bony islands
{1795) The cartilaginous areas are S100-
positive; the stromal cells are SMA-posi-
tive and cytokeratin -negative {1795) .
Genetic susceptibility
There is an association with the pleuro-
pulmonary blastoma-associated DICER1
familia! tumour susceptibility syndrome ,
Haematolymphoid tumours
Overview
Chuang S.-S.
Ferry JA
Definition
Nearly all haematolymphoid tumours
arising from the nasal cavity or paranasal
sinuses are non-Hodgkin lymphomas,
although extramedullary plasmacytomas
and rare myeloid and histiocytic neo-
plasms also occur {116 ,1027,1830,1888).
Epidemiology
Sinonasal lymphoma accounts for 12-
15% of all head and neck cancers. lt is
the third most common sinonasal malig-
nancy, after squamous cell carcinoma
and adenocarcinoma {484,1012) In the
USA, the frequency decreased in the
early 21st century, probably reflecting
a reduction in HIV-associated lympho-
mas due to antiretroviral therapy (484).
However, extranodal NK/T-cell lym-
phoma, nasal-type (ENKTL), which has
a predilection for East Asians and Latín
Americans (86,446 ,607,1349), is increas-
ing in the USA , with an average annual
increase in incidence of approximately
52 Tumours of the nasal cavity, paranasal sinuses and skull base
'
""
Fig. 1.48 Chondromesenchymal hamartoma. Fibrovascular stroma with cellular lobules of cartilage that surround bony
trabeculae.
in wh ich chondromesenchymal hamar- Prognosis and predictive factors
toma may be the presenting lesion After surgical removal , the recurrence
{2281) . rate is generally low {1554).
9% between 2000 and 2011 (607). myeloid sarcoma, and histiocytic neo-
plasm {484,500 ,1012).
Localization
ENKTL has a predilection for the nasal Prognosis and predictive factors
cavity and may also arise from paranasal Modern therapies have significantly
sinuses {86,446,607,1349). Diffuse large improved the prognosis of sinonasal
B-cell lymphoma (DLBCL) most com- DLBCL. lnvolvement of multiple sinuses
monly arises from the paranasal sinuses is a negative prognostic indicator (1169).
but may arise from the nasal cavity (1169).
Clinical features Extranodal NK/T-cell Jymphoma
Patients with nasal tumours present with
nasal obstruction, epistaxis, and/or a de- Chuang S.-S.
structive mass involving nose, nasal sep- Gaulard P
tum, palate, orbit, or facial skin. Patients Jaffe E.S.
with paranasal tumours present with Ko Y. -H.
symptoms of chronic paranasal sinusitis
and soft tissue or bony destruction. B
symptoms (e.g. fever, night sweats, and Definition
weight loss) occur in about 20% and 10% Extranodal NK/T-cell lymphoma, nasal-
of patients, respecti vely, with sinonasal type (ENKTL) is an extranodal lymp homa
ENKTL and DLBCL. with a cytotoxic phenotype and a univer-
sal association with EBV.
Histopathology
In addition to DLBCL and ENKTL there ICD-0 code 9719/3
have been rare cases of other sinona-
sal haematolymphoid tumours, such as Synonyms
sinonasal Burkitt lymphoma, peripheral Angiocentric lymphoma; lethal midline
T-cell lymphoma, MALT lymphoma, extra- granuloma; malignant midline reticulosis;
osseous plasmacytoma, extramedullary polymorphic reticulosis

Fig. 1.49 Extranodal NK/T-cell lymphoma, nasal-type. A Right nasal tumour with obstruction, ecchymosis of !he nasal
side wall and facial skin, and invasion to !he right nasal ala with tumour formation. B Postcontrast CT of !he same case
shows a homogeneously enhancing soft tissue mass in !he right nasal cavity involving !he right nostril, nasal ala, and
perinasal facial skin, and destruction of the anterior lower aspee! of the nasal septum.
Epidemiology
Extranodal NK/T-cell lymphoma is more
prevalen! among East Asians and the
indigenous populations of Mexico and
Central and South America than in other
populations {86,446 ,1349,1940l
Etiology
The precise etiology is unknown, al-
though EBV is crucial in pathogenesis.
Lifestyle and environmental factors such
as being a farmer, pesticide use, and liv-
ing near incinerators might be risk factors
{2657).
Localization
ENKTL occurs most commonly in the
upper aerodigestive tract (in 70- 85% of
cases), mainly in the nasal cavity, para-
nasal sinuses, and Waldeyer ring (pha-
ryngeal lymphoid ring), with sorne cases
occurring in the skin, gastrointestinal
tract, soft tissue, and other extranodal
sites {1132,1229,1909,23171.
Clinical features
Patients with nasal tumours present with
nasal obstruction and/or epistaxis. Nasal
tumours may cause perforation of the
nasal septum or palate and may spread
to the skin or orbit with ecchymosis or
ulcerative tumours. Paranasal tumours
may mimic chronic paranasal sinusitis.
Most cases present with stage 1 or 11 dis-
ease, with as many as 10-20% of cases
spreading to skin , gastrointestinal tract ,
testis , or distan! nodal regions.
Histopathology
ENKTL infiltrates nasal tissue in a diffuse
pattern, frequently with an angiocentric/
angioinvasive growth pattern, leading to
geographical tumour necrosis. In rare
instances, multiple biops ies might be
needed to identify tumours showing ex-
tensive necrosis with few viable cells. The
neoplastic cells vary in size and have ir-
regularly folded nuclei, granular chroma-
tin, and small nucleoli. Small cells might
mimic a benign infiltrate but exhi@it cel -
lular atypia such as irregular nuclear con-
tours and mitoses.
lmmunohistochemically, the tumour cells
express CD3, cytotoxic markers (i.e. TIA1,
granzyme B, or perforin), and frequently
CD56 {1132,1909}. They rarely express
CD4, CD5, or CDS . Examples with large-
cell morphology often express CD30.
CD57 is nearly always negative {1132} .
The tumours are mainly derived from
NK cells, with a minority (10-40%) hav-
ing T-cell lineage (gamma delta or more
rarely alpha beta) {102,1132,1418,1909l.
CD56 is more frequently expressed in
tumours of NK-cell origin, whereas CD5
expression usually indicates a T-cell lin-
eage {1132 ,1909} ENKTL is positive for
EBV-encoded small RNA (EBER) in the
majority of cells by in situ hybridization
{443,444,2322). LMP1 is usually weak or
negative. Cases showing a similar phe-
notype but EBV negativity are consid-
ered peripheral T-cell lymphoma, NOS
{1108,2322).
Genetic profile
ENKTL shows complex genetic alter-
ations, with numerous chromosomal
gains and losses {1695j. The commonly
deleted chromosomal region at 6q21 -23
contains several candidate tumour sup-
pressor genes, including PRDM1, ATG5,
AIM1, HACE1, and FOX03 {1091,1189,
1289). ENKTL has a distinctive genetic
signature shared by cases with NK-cell
and T-cell origin {1053l . The JAK/STAT
pathway is activated in most cases, by
genetic alterations of JAK3, STAT3, or
PTPRK {406,485 ,1053,1272,1370). Re-
current mutations are frequent in tumour
suppressor genes, including TP53 (in
20- 60% of cases) {1941} and DDX3X
(in 20% of cases) {1134). EBV infection

Fig. 1.50 Extranodal NK/T-cell lymphoma, nasal-type. A Prominent geographical tumour necrosis. B Diffuse lymphoid infiltrate beneath ulcerative nasal mucosa.

Haematolymphoid tumours 53
 ~--
Fig. 1.51 Extranodal NK!T-cell lymphoma, nasal-type. A The metastalic tumour in !he subcutis shows angioinvasion (left) and subcutaneous infiltration mimicking panniculitis.
B Small to medium-sized cells with irregular nuclear contours surrounding a secretory gland. C lmmunohistochemical staining showing expression of CD3.
severely deregulates host microRNA pro-
files; downregulation of miR-146a and
miR-15a promotes cell proliferation and
predicts poor prognosis in ENKTL {1266,
1802).
Genetic susceptibility
The strong EBV association and ethnic
predisposition suggest a genetic defect
in the host immune response to EBV in-
fection (534,535). The lymphotoxin alpha
gene (LTA) +252 (AG) polymorphism is
associated with increased risk of ENKTL
{409).
Prognosis and predictive factors
Prognostication of ENKTL traditionally
depends on clinicopathological param-
eters, including stage {1364,2431). How-
ever, the amount of EBV DNA in plasma
is a surrogate biomarker of lymphoma
load , with diagnostic and prognostic
54 Tumours of the nasal cavity, paranasal sinuses and skull base
...,, -. .....
significance {1221 ,1319,2431 ). EBV DNA
and PET findings have been integrated
into prognostic algorithms {1226) . With
current regimens, durable remission can
be achieved in 70-80% of stage 1/11 cas-
es, and as many as 50% of stage 111/IV
cases {1318,2431).
Extraosseous plasmacytoma
Feldman A.L.
Ott G.
Definition
Extraosseous plasmacytoma is a mass-
forming proliferation of monoclonal plas-
ma cells with extraosseous (extramed-
ullary) presentation, in the absence of
underlying multiple myeloma. Extraosse-
ous plasmacytomas in the nasopharynx
. .,,
and other soft tissues in the head and
neck must be distinguished from B-cell
lymphomas with plasmacytic/plasmab-
lastic differentiation, in particular MALT
lymphoma and plasmablastic lymphoma.
ICD-0 code 9734/3
Synonyms
Extramedu llary plasmacytoma;
plasmacytoma
Epidemiology
The median patient age is 60 years and
there is a male predominance, with a
male-to-female ratio of 3-41 {46,1617).
Localization
About 80% of extraosseous plasmacyto-
mas involve the upper respiratory tract,
most commonly the nasal cavity and
paranasal sinuses , followed by the na-
sopharynx, oropharynx , and larynx {46,
1617). Less common primary sites in the
head and neck include the hypophar-
ynx, salivary and thyroid glands, cervical
lymph nodes, trachea, and oesophagus.
Cervical lymph nodes are involved sec-
ondarily in about 15% of cases {1586).
Clinical features
Extraosseous plasmacytomas are typi-
cally solitary, and examples occurring in
the head and neck most commonly (in
80% of cases) presentas a mass {161 7).
Additional findings at presentation in-
clude airway obstruction, epistaxis, lo-
cal pain, proptosis, rhinorrhoea, cervical
lymphadenopathy, and cranial nerve pal-
sies. A minority of patients (< 25%) have
a monoclonal serum paraprotein (M pro-
tein), typically of lgA type {2245). By defi-
nition , diagnostic features of plasma cell
myeloma are absent {1476).
Histopathology
Microscopic evaluation typically shows

Fig. 1.53 Plasmacytoma. A diffuse monotonous infiltrate of plasma cells is present beneath an intact stratified
squamous epithelium.
diffuse infiltration by sheets of plasma
cells, which may be well , moderately, or
poorly differentiated {1617,2316) Amy-
loid deposits may be present {2316,
2616} Moderately and well- differentiated
extraosseous plasmacytomas must be
distinguished from B-cell lymphoma, in
particular from MALT lymphoma with ex-
tensive plasmacytic differentiation {584,
1062). Poorly differentiated extraosseous
plasmacytomas must be distinguished
from plasmablastic lymphoma {2316);
sorne cases may be anaplastic to the
point that plasma-cell differentiation is
not apparent, prompting consideration of
poorly differentiated non-haematological
neoplasms {1172).
lmmunophenotype
The neoplastic cells often express mark-
ers of plasmacytic differentiation, such
as CD138, CD38, VS38, and MUM1/IRF4
{232). They variably express CD79a ,
only rarely express CD20, and are typi-
cally negative for PAX5. Extraosseous
plasmacytomas may express EMA. Cyc-
lin 01 has been reported to be negative.
CD56 is expressed less frequently than
in plasma cell myeloma, and the Ki-67 in-
dex is lower than in plasma cell myeloma
¡¡
Fig. 1.54 Plasmacytoma. Monotonous infiltrate of
plasma cells.
{1278). Monotypic immunoglobulin light
chains can typically be demonstrated by
immunohistochemistry or in situ hybridi-
zation. Staining for heavy chains may
reveal expression of lgA or lgG , whereas
staining for lgM should raise suspicion
for B-cell lymphoma. EBV has been re-
ported to be positive in 15% of cases
{26}, but the presence of EBV should also
prompt consideration of plasmablastic
lymphoma.
Genetic profile
Sorne genetic features are similar to
those of plasma cell myeloma {232},
but differences have been reported, in
particular different IGH translocation
partners {193}.
Prognosis and predictive factors
The prognosis of extraosseous plasma-
cytoma is much better than that of plas-
ma cell myeloma, and most patients are
treated with local radiation therapy {504,
583). Regional recurrence or spread to
other extraosseous siles may occur, and
about 15% of patients develop multiple
myeloma {46).
Haematolymphoid tumours 55
Neuroectodermal I melanocytic tumours
Ewing sarcoma/primitive
neuroectodermaltumour
Wenig B.M.
Flucke U.
Thompson L.D.R.
Definition
Ewing sarcoma/ primitive (peripheral)
neuroectodermal tumours are high-grade
primitive small round cell sarcomas with
variable neuroectodermal differentiation ,
characterized by the presence of trans-
locations between the EWSR1 gene on
chromosome 22 and a member of the
ETS family of transcription factors.
ICD-0 code
Synonyms
Peripheral neuroectodermal tumour; pe-
ripheral neuroepithelioma; peripheral
neuroblastoma; adult neuroblastoma
Epidemiology
Ewin g sarcoma and primitive neuroec-
todermal tumour primarily occur in non-
head and neck siles, with only 2-10%
developing in the head and neck {49}.
The tumours are slightly more common in
males \49,921), and occur predominant-
ly (but not exclusively) in children and
young adults \921,1017,1036,1331 ,2601 ,
._
Fig. 1.56 Sinonasal Ewing sarcoma / primitive neuroectodermal tumour. A Hypercellular neoplasm with diffuse growth composed of uniform small cells with round to oval nuclei,
fine-appearing nuclear chromatin, and paleto vacuolated cytoplasm. B Neoplastic cells show diffuse and strong membranous CD99 staining in nearly ali cases; CD99 is sensitive but
not specific for the diagnosis of Ewing sarcoma I primitive neuroectodermal tumour.
56 Tumours of the nasal cavity, paranasal sinuses and skull base
2617}; older patients may occasionally
be affected {921 ,2617}.
Localization
The most common head and neck siles
include the skull and jaws \49 ,2601}; less
common siles include the sinonasal tract
(most commonly the maxillary sinus or
nasal fossa) \921 ,1036,1331,2617}, orbit,
and various mucosal sites. Extension to
dura, orbit, or brain may be present \921).
Clinical features
Symptoms include pain , mass lesion ,
and nasal obstruction, which often de-
velop rapidly (within months) {2617}
Macroscopy
9364/3 Sinonasal tract tumours may appear
polypoid or multilobular, greyish-white,
and glistening, with associated haemor-
rhage; ulceration is often present.
Histopathology
The tumour is markedly cel lular with dif-
fuse (sheet-like) or lobular growth ; the ap-
pearance may occasionally be trabecu-
lar or cord-like . The tumour is composed
of uniform small cells with round to oval
nuclei, fine-appearing (powdery) nuclear
chromatin , a distinct nuclear membrane,
inconspicuous to small nucleoli, scant
paleto vacuolated (clear) cytoplasm, and
indistinct cell borders. Mitotic activity is
- )'. -- ( · ·=------~~L...J<~.-...im.-..ir;.&:.__..-.----
variable, with 5-10 mitoses per 1O high-
power fields. Prominent intratumoural
thin-walled vessels are present, which
may be compressed and obscured by
the cellular proliferation. A minimal stro-
mal componen! is present, which may
include thin fibrous strands separating
tumour lobules. Pseudorosettes (Hom-
er Wright rosettes) are present in most
cases; less often, true neural rosettes
(Flexner-Wintersteiner rosettes) may be
identified . Histological variants include
atypical or large-cell , clear-cell , haeman-
gioendothelioma-like, adamantinoma-
like, spindled , and sclerosing forms {197,
743}.
lntracytoplasmic material that gives a
diastase-sensitive positive reaction with
periodic acid-Schiff (PAS) is present.
Neoplastic cells strongly and diffusely
express membranous CD99 in nearly all
cases. Nuclear FLl1 is seen in a large
percentage of cases; those with EWSR1-
FL/1 fusion show strong nuclear reactions
with the C-terminus of FL/1 \1506 ,2411 ,
2544}. Vimentin is positi ve. Cytokeratins
show strong , focal to diffuse staining with
a dot-li ke pattern in as many as one third
of cases , and in particular in adamanti-
noma-like tumours {197,894,921}. There
is reactivity for at least one neural marker
(e.g. neuron-specific enolase, S100 pro-
tein, synaptophysin , chromogranin , NFP,
or GFAP). KIT (CD117) expression is
.....-

Fig. 1.57 Ewing sarcoma/primitive neuroectodermal tumour. On EWSR1 dual-colour break-apart FISH, Ewing
sarcoma cells that have the chromosomal rearrangement show a red signal distanced from a green signal, indicating
a translocation involving one EWSR1 allele, whereas the second allele is intact, as shown by red and green signals
that overlap.
present in approximately 25% of cases
{743). Rarely, desmin staining is present,
but myogenic and haematolymphoid
markers are typically absent.
Genetic profile
There is consisten! reciproca! translo-
cation between chromosome 11 and
chromosome 22 (present in 90-95% of
cases). The most common translocation
involves the EWSR1 gene (on chromo-
some 22) and the FL/1 gene (on chromo-
some 11), resulting in an EWSR1- FLl1 fu -
sion transcript. C!C-DUX4 fusion, a result
of a t(4;19) or t(10;19) translocation, may
be identified in EWSR1 fusion-negative
cases {1101}. CIC-DUX4 fusion-positive
tumours occur mainly in young adult
men, most frequently in the soft tissues of
extremities. They show a higher degree
of heterogeneity in nuclear morphol-
ogy and have variable C099 expres-
sion (membranous, not diffuse) than do
EWSR1 fusion-positive cases, raising the
possibility that C!C-DUX4 fusion tumour
may be outside the scope of Ewing sar-
coma {2246).
Genetic susceptibility
Heritable retinoblastoma may predispose
patients to Ewing sarcoma and perhaps
to a subset of poorly differentiated neu-
roectodermal tumours in the sinonasal
region that may be related to olfactory
neuroblastoma {1236}.
Prognosis and predictive factors
The 5-year survival rate for sinonasal Ew-
ing sarcoma / primitive neuroectodermal
tumour is 50-75% , reflecting a better
overall prognosis at this site compared
with cases at other siles {49,921 }. The
5-year survival rate for patients with ad-
vanced disease is < 25% {2617). Local
recurrence and distant metastases may
occur with in 2 years, even in patients with
localized disease. When metastases oc-
cur, the most common sites include the
lungs and bone; lymph node metastasis
is less common , occurring in approxi-
mately 20% of cases.
Prognosis has been found to be linked
to tumour stage as determined by the
lntergroup Rhabdomyosarcoma Study
Group (IRSG) staging system {126}, tu-
mour size (with size > 8 cm associated
with adverse behaviour) {127,2601}, TP53
alteration (which appears to define a clin-
ical subset with a markedly poorer out-
come) {1592}, the presence of the type 1
EWSR1-FLl1 fusion transcript (thoug ht
to suggest a better prognosis than other
fusion transcripts) {542}, and poor his-
tological or radiological response at the
site of primary tumour and incomplete
radiological rem ission of lung metasta-
ses after primary chemotherapy (associ-
ated with adverse behaviour) {31,49,127).
There is an increased incidence of radia-
tion-induced sarcomas later in life among
surviving patients {1838).
Neuroectodermal/melanocytic tumours
Olfactory neuroblastoma
Bell O.
Franchi A.
Gillison M.
Thompson L.D.R.
Wenig B. M.
Definition
Olfactory neuroblastoma (ONB) is a ma-
lignant neuroectodermal neoplasm with
neuroblastic differentiation, most often
localized in the superior nasal cavity.
ICD-0 code 9522/3
Synonyms
Aesthesioneuroblastoma; aesthesioneu-
rocytoma; aesthesioneuroepithelioma;
olfactory placode tumour
Epidemiology
ONB has an estimated annual incidence
of 4 cases per 10 million population, and
accounts for approximately 3% of ali
sinonasal tumours {273) . Patients range
in age from 2 to 90 years. Although a
bimodal age distribution was initiall y re-
ported, recen! data support an even dis-
tribution across ali ages, with a peak in
the fifth and sixth decades of life {273,
1130,1903}. Males are affected slightly
more often than females (male-to-female
ratio: 1.2:1). There is no reported ethnic or
familia! predilection.
Localization
The anatomical distribution of ONB is
confined to the cribriform plate, the su-
perior turbinate (nasal concha), and the
superior half of the nasal septum. The
vomeronasal organ (also called Jacob-
son's organ) , sphenopalatine ganglion ,
olfactory placode, and the terminal nerve
(also called the ganglion of Loci) are in-
cluded in the areas of proposed origin.
Ectopic tumours within the paranasal si-
nuses (other than the ethmoid sinuses)
are vanishingly rare (except in recurrent
cases), and the diagnosis of ONB with no
involvement of the cribriform plate is a di-
agnosis of exclusion {1619,2383)
57

Fig. 1.58 Olfactory neuroblastoma. lmaging studies
show a dumbbell-shaped tumour.
Fig. 1.59 Olfactory neuroblastoma. The gross
appearance is that of a polypoid reddish-grey mass, with
hypervascular cut surface.
Clinical features
Clinically, ONBs often have a subtle pre-
sentation mimicking that of benign inflam-
matory/infectious diseases, and delay in
diagnosis is frequent. Nasal obstruction
and epistaxis are typical early manifes-
tations; headaches, pain, excessive lac-
rimation, rhinorrhoea, and visual distur-
bances are uncommon. Anosmia occurs
in < 5% of patients . Paraneoplastic syn -
dromes (i.e. ectopic adrenocorticotropic
hormone syndrome or syndrome of in-
appropriate antidiuretic hormone secre-
tion) are detected in about 2% of patients
1789). Physical examination and flexible
fibre-optic endoscopic evaluation, com -
plemented with CT and MRI , are useful in
the diagnostic work- up.
The classic imaging findings include
a dumbbell-shaped mass extending
across the cribriform plate, with the waist
at the cribriform plate. MRI better deline-
ates sinonasal and intraorbital or intracer-
ebral extension. ONB is T1-hypointense
and T2- isointense or T2- hyperintense to
grey matter, with avid homogeneous en -
hancement with contras!. Bone erosion
is better demonstrated by CT, with care -
ful evaluation for erosion of the lamina
papyracea, cribriform plate, and fovea
ethmoidalis. Peripheral tumour cysts and
58 Tumours of the nasal cavity, paranasal sinuses and skull base
speckled calc ifications are characteristic
of ONB.
Severa! staging systems have been
proposed , with no single system univer-
sally accepted . The first staging system
proposed, and the one most commonly
applied, is that of Kadish 11162), which
stages local disease only; it distingu ish-
es tumours that involve the nasal cav-
ity only (Kadish stage A), from those
that extend into the paranasal sinuses
(Kadish stage B), and those that extend
beyond the paranasal sinuses (Kadish
stage C) 11162) Morita 11650) modified
the Kadish system by adding a stage O,
defined by the presence of metastases
(either regional nodal disease or distant
metastasis) . The TNM staging system for
paranasal sinus tumours can potentially
be applied 1626); however, the Kadish
system and Morita modification are more
applicable , dueto the biologically unique
behaviour of ONB compared with other
sinonasal tumours.
Macroscopy
The tumours are usually unilateral, poly-
poid, glistening, soft, reddish-grey mass-
es with an intact mucosa; the cut surface
appears greyish -tan to pinkish - red and
hypervascularized. The tumours range
from < 1 cm in size to large masses in-
volving the nasal cavity and intracranial
region. They frequently expand into the
adjacent paranasal sinuses, orbit, and
cranial vault 12383}
Cytology
Aspirates of metastatic lesions show cy-
tological findings most similar to those
seen in low-grade neuroendocrine car-
cinoma aspirates , w ith nests of some-
what monomorph ic, fragile epithelioid
cells with delicate chromatin and cyto -
plasm. Aspirates of high -grade tumours
may show features similar to those seen
A "t*-.;,_,/
.;'.,.l!U!
Fig. 1.60 Olfactory neuroblastoma. A Tumour lobules separated by a vascularized stroma; pseudorosettes and an in
situ componen! are present. B The cells are small to medium-sized, set in a richly vascularized fibrovascular stroma;
the nuclei are round, with delicate salt-and-pepper chromatin distribution and small nucleoli .
Table 1.02 Olfactory neuroblastoma staging systems
proposed by Kadish and Morita; reprinted from Ow TJ
et al. (1789)
Kadish stage
A Tumour confined to the nasal cavity
Tumour involvement of the nasal
B
cavity and paranasal sinuses
Tumour extends beyond the nasal
e cavity and paranasal sinuses
Morita modification
A Tumour confined to the nasal cavity
Tumour involvement of the nasal
B
cavity and paranasal sinuses
Tumour extends beyond the nasal
e cavity and paranasal sinuses
Presence of metastases (regional
D
or distan!)
in smal l cell neuroendocrine carcinoma
aspirates.
Histopathology
Low-grade ONBs form submucosal,
sharply demarcated nests, lobules, or
sheets of cells , often sep arated by richly
vascular or hyalinized fibrous stroma.
Pseudorosettes (Homer Wright rosettes),
with neoplastic cells pal isading or cuffed
around the central delicate fibrillar neu -
ra l matrix, may be seen. The cells are
often uniform, with sparse cytoplasm
and round or ovoid nuclei with punctate
salt-and-pepper chromatin and nucleoli
that are either small or absent. ONB is
characterized by fibrillary cytoplasm and
interdig itating neuronal processes (neu-
ropil), created by a syncytium of cells.
Higher-grade tumours show tumour
necrosis, pleomorphism, increased mi-
toses, decreased to absent neurop il, and
a less overt lobular growt h pattern . The
cells can be arranged in gland - like rings
or tight annular formations with a true
lumen (Flexner-Wintersteiner rosettes).
Table 1.03 Olfactory neuroblastoma staging systems. Key features and criteria for Hyams grades 1-IV and corresponding histopathological H&E slides
Key feature/criterion
Architecture
Mitotic activity
Nuclear polymorphism
Fibrillary matrix
Rosettes Homer Wright rosettes
Necrosis
H&E
Rosettes alone are not diagnostic of
ONB, although the Homer Wright rosettes
are nearly pathognomonic in the nasal
cavity when containing true neuropil.
Perivascular pseudorosettes (like those
seen in ependymomas) are non-specific.
The mitotic rate is variable, but is usually
low, especially in lower-grade tumours.
Calcifications (concretion-like or psam-
momatous) may be seen, less frequently
as the grade increases. Melanin pig-
ment, ganglion cells, rhabdomyoblasts,
divergent differentiation as islands of true
epithelium (squamous pearls or gland
formation), and clear-cell change may
occasionally be encountered in ONB
{149,694,1457,1632)
The most widely used grading system
for ONB was developed by Hyams et
al. {950}. This system divides the spec-
trum of ONB maturation into four grades,
ranging from most differentiated (grade 1)
to least differentiated (grade IV), on the
basis of tumour architecture, mitotic ac-
tivity, nuclear pleomorphism, fibrillary
matrix and rosettes, necrosis, gland pro-
liferation , and calcifications . This grading
scheme has been independently vali-
dated in relation to prognosis {802,1203,
2036,2336}.
The typical immunohistochemical pro-
file includes diffuse staining for neuron-
specific enolase {2424}, synaptophysin,
chromogranin A, CD56 (NCAM) and
Hyams grade
11
Lobular Lobular
Absent Present
Absent Moderate
Prominent Pres en!
Homer Wright rosettes
Absent Absent
beta-tubulin, as well as variable 8100
protein reactivity, which is typically in a
sustentacular cell pattern highlighting
only cells at the periphery of the nests,
often limited in higher-grade tumours.
Sustentacular cells may also be posi-
tive for GFAP. Calretinin staining (nuclear
and cytoplasmic) has been reported
in ONB {2635} but can also be seen in
other sinonasal tumours. As many as one
third of ONBs may also stain focally for
cytokeratin (CAM5.2, CK18) {1014,1619}
Negative markers include CD45RB,
CD99, p63, and FLl1. Proliferation mark-
er studies reveal a variable Ki-67 prolif-
eration index (2-50%) {1619,2383}, and
BCL2 expression increases with tumour
grade. Rare desmin or myogenin reactiv-
ity is seen in ONB with rhabdomyoblastic
differentiation {203}.
Genetic profile
ONB demonstrates numerous chromo-
somal aberrations, deletions, and gains,
but with no consistent pattern {221,907,
1015,1983} In one study, a specific dele-
tion on chromosome 11 and gain on chro-
mosome 1p were associated with metas-
tasis anda worse prognosis {221}. Gains
have been shown to be more frequent
than losses , and high-stage ONBs show
more alterations than low-stage tumours .
Gains in 20q and 13q may be impor-
tant in the progression of this neoplasm;
111 IV
Variable Variable
Prominent Marked
Prominent Marked
Minimal Absent
Flexner-Wintersteiner rosettes Flexner-Wintersteiner rosettes
+/- present Common
these regions may harbour genes with
functional relevance in ONB. The detec-
tion of PTCH1, GL/1, and GL/2 in 70%,
70%, and 65%, respectively, of human
ONB specimens suggests that the SHH
signalling pathway may be involved in the
pathogenesis of th is neoplasm {1534}.
The OMP and RICBB genes have been
found to be expressed in ONBs {875}.
Prognosis and predictive factors
In addition to staging, histological grade
is useful in prognostication and manage-
ment of ONB {174,1203,1519,2468}. High-
grade tumours tend to have a poorer
outcome {174,616,1130,1519}. A single in -
stitutional retrospective review found that
high tumour grade was significantly asso-
ciated with poor outcome, but advanced
stage was not {174}. Metastatic ONB is
associated wi th significantly worse over-
all survival , and high -grade ONB with
significantly worse disease-free survival.
High Hyams grade (111/IV) is associated
with more aggressive locoregional dis-
ease {1519} and is a predictor of worse
disease-free survival {174). lt is yet to be
determined whether histopathological
grading alone is a sufficient stratifica-
tion tool and an independent predictor
of overall survival {616 ,802,1203,2036,
2336 ,2468).
Neuroectodermal / melanocytic tumours 59
Mucosa/ me/anoma
Williams M.O.
Speight P.
Wenig B.M.

Definition
Mucosal melanoma is a malignant neo-
plasm arising from melanocytes in the
mucosa.
ICD-0 code
Epidemiology
Sinonasal mucosal melanomas con-
stitute 1% of all melanomas and about
4% of all sinonasal tumours (796,1645).
Th ere is a wide patient age range, with
an incidence peak in the seventh decade
of lite (2395) There is no sex predi lection
(2395).
Etiology
Mucosa! melanomas are biologically dis-
tinct from cutaneous melanomas. Etio-
logical factors, including melanocytosis,
remain speculative.
Fig. 1.61 Sinonasal mucosal melanoma. T2-weighted
axial MRI of sinonasal mucosal melanoma of !he nasal
8720/3 septum (arrow).
Localization
Sinonasal mucosal melanomas most fre-
quently arise in the nasal cavity or sep-
tum, and rarely in the nasopharynx or
maxillary sinuses (1645,2395).
Clinical features
Patients may present with non-specif-
ic symptoms of epistaxis or sinonasal
congestion.
Macroscopy
Sinonasal mucosa! melanomas are
often polypoid, and range from deeply
Fig. 1.62 Sinonasal mucosal melanoma. A polypoid
slightly pigmented mass distends the submucosa.
pigmented (black) and friable to tan or
grey and firm.
Cytology
Aspirates of metastatic lesions show the
diversity of features discussed within the
histopathology section below, similar to
the features seen in aspirates of meta-
static dermal melanoma. The diagnosis
must be considered wi thin the differential
for any aspirate showing a malignancy
that is not obviously epithelial.
Histopathology
Solid sheets or nests of epithelioid cells

-.. .......""""" .... - ...

Fig. 1.63 Sinonasal mucosal melanoma. The histological features vary from (A) clear, non-pigmented, slightly spindled cells to (B) pigmented epithelioid cells with prominent nucleoli.
The histological spectrum of melanoma includes (C) spindled, fasciculated growth pattern and (D) rhabdoid proliferation.

60 Tumours of the nasal cavity, paranasal sinuses and skull base

 ·.~
Fig. 1.64 Sinonasal mucosa! melanoma. A Epithelioid cells with prominent nucleoli and frequent mitoses (arrows).
surrounding a fibrovascular core.
with variable N:C ratios infiltrate the sub -
mucosa. Surface ulceration is often pre -
sent, but with intact surface epithelium,
pagetoid and/or surface spread may
be present. Variable cel lular morphol -
ogy is present from case to case and
within individual cases, ranging from
epithelioid/undifferentiated cells to spin-
dled, plasmacytoid, and rhabdoid cells ,
with or without prominent nucleoli . In
neoplasms with a prominent spindle-
cell component, fascicular to storiform
growth can be seen. Mitoses are read-
ily identified and atypical forms are often
present. Discohesion leads to cuffin g of
endothelial cells (resulting in a pseudo -
papillary or peritheliomatous pattern). As
many as 50% of lesions are amelanotic,
resulting in a broader differential diagno-
sis at this site, including small blue cell
tumours (olfactory neuroblastoma and
rhabdomyosarcoma), high -grade carci-
nomas (sinonasal undifferentiated car-
cinoma, poorly differentiated squamous
Table 1.04 Molecular alterations in melanomas vary by site of origin
Frequency by site of origin
Molecular alteration Mucosal {2708}
BRAF mutationsª < 6%
NRAS 15-20%
K/T mutation/
25% (10-37%)
amplifi cationb
BAP1mutation Unknown
GNAQ 0%
GNA11 Rare
Treatment and clinical trials are on -going for:
ªBRAF inhibitors (cutaneous) and
blmatinib (mucosa!; most patients develop resistance).
lmmunotherapy trials are also underway; evaluation in ali subsites will be critica! for determ ining efficacy.
cell carcinoma, NUT carcinoma, and
SMARCB1 -deficient carcinoma), neu-
roendocrine carcinomas, diffuse large
B-cell lymphoma, and Ewing sarcoma/
primitive neuroectodermal tumour.
lmmunohistochemical evaluation is
necessary, particularly in amelanotic
tumours. 8100 protein and melanocytic
markers (HMB45, tyrosinase, melan-A,
MITF, and SOX10) show variable sensi -
tivity depending on morphological type.
S100 protein highlights > 95% of epithe-
lioid/undifferentiated mel anomas, versus
85% of spind led mucosa! melanomas
(1917,2395). Similar variability has been
noted for melanocytic markers, which
highlight 75- 80% of melanomas with epi -
the lioid morphology versus 65-70% of
spindle cell melanomas (2395l
Genetic profile
The molecular profile is distinct from those
of cutaneous and uveal melanomas, with
higher rates of K/Tmutations, fo llowed by
Cutaneous {1} Ocular (uveal) {2467}
50% 0%
30% <5%
6-8% < 1%
3% 50% (metastases)
2% 50%
4% 36%
Monosomy of chromosome
Neuroectodermal/melanocytic tumou rs
NRAS mutations and rare BRAF muta-
tions (Table 1.04) (1,2467,2708).
Genetic susceptibility
Sinonasal mucosa! melanomas have a
possible association with melanocytosis,
which is strongly associated with uveal
melanomas.
Prognosis and predictive factors
Distinguishing mucosa! from cutaneous
origin and excluding metastasis to the
sinonasal region are importan! for stag-
ing and prognosis. The seventh edition of
the American Joint Committee on Cancer
(AJCC) cancer staging manual added
head and neck mucosa! melanoma stag-
ing: ali tumours are T3-4, associated
with poor overall survival (< 30%) at 5
years {117,530,1495). Metastatic disease
(stage IV) and advanced patient age
are the most important prognostic fac-
tors. K/T-mutant tumours have shown re-
sponse to KIT inhibitor therapy; however,
the response is not durable {1009,2439)
Future therapeutic development requires
trials specifically evaluating mucosa!
melanomas; findings in cutaneous mela-
nomas may not be applicable, dueto the
different genetic profile {1354) Cutane-
ous melanoma prognostic factors (e.g .
Clark level of invasion and Breslow tu-
mour thickness) do not apply.
61
¡
l
11
 CHAPTER 2

Tumours of the nasopharynx

Nasopharyngeal carcinoma
Nasopharyngeal papillary adenocarcinoma
Salivary gland tumours
Benign and borderline lesions
Soft tissue tumours
Haematolymphoid tumours
Notochordal tumours
WHO classification of tumours of the nasopharynx

Carcinomas Soft tissue tumours

Nasopharyngeal carcinoma Nasopharyngeal angiofibroma 9160/0
Non-keratin izing squamous cell carc inoma 8072/3
Keratinizing squamous cell carcinoma 8071/3 Haematolymphoid tumours
Basaloid squamous cell carcinoma 8083/3 Diffuse large B-cell lymphoma 9680/3
Nasopharyngeal papillary adenocarcinoma 8260/3 Extraosseous plasmacytoma 9734/3
Extramedullary myeloid sarcoma 9930/3
Salivary gland tumours
Adenoid cystic carcinoma 8200/3 Notochordal tumours
Salivary gland anlage tumour Chordoma 9370/3

Benign and borderline lesions

Hairy polyp The morphology codes are from the lnternational Classification of Diseases
for Oncology (ICD-0) {776A}. Behaviour is coded /O for benign tumours;
Ectopic pituitary adenoma 8272/0 /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in
Craniopharyngioma 9350/1 situ and grade 111 intraepithelial neoplasia; and /3 for malignant tumours .
The classification is modified from the previous WHO classification , taking
into account changes in our understanding of these lesions.

TNM classification of carcinomas of the nasopharynx

TNM classification•·b M - Distant metastasis

MO No distant metastasis
T - Primary tumour M1 Distant metastasis
TX Primary tumour cannot be assessed
TO No evidence of primary tumour Stage grouping
Tis Carcinoma in situ Stage O Tis NO MO
T1 Tumour confined to nasopharynx, or extends to Stage 1 T1 NO MO
oropharynx and/or nasal cavity Stage 11 T1 N1 MO
T2 Tumour with parapharyngeal extension (which denotes T2 N0-1 MO
posterolateral infiltration of tumour) Stage 111 T1 -2 N2 MO
T3 Tumour invades bony structures of skull base and/or T3 N0-2 MO
paranasal sinuses Stage IVA T4 N0-2 MO
T4 Tumour with intracranial extension and/or involvement of Stage IVB Any T N3 MO
cranial nerves, infratemporal fossa, hypopharynx, orbit, or Stage IVC Any T Any N M1
masticator space

ªAdapted from Edge et al. {625A} - used with permission of the American
N - Regional lymph nodes (i.e. the cervical nodes)
Joint Committee on Cancer (AJCC), Chicago, lllinois; the original and prima-
NX Regional lymph nodes cannot be assessed ry source for this information is the AJCC Cancer Staging Manual, Seventh
NO No regional lymph node metastasis Edition (2010) published by Springer Science+Business Media - and Sobin
N1 Unilateral metastasis in cervical lymph node(s), and/ et al. {2228A}.
ºA help desk for specific questions about TNM classification is available at
or unilateral or bilateral metastasis in retropharyngeal
http://www.uicc.org/resources/tnm/helpdesk.
lymph nodes, s; 6 cm in greatest dimension, above the ' The supraclavicular fossa is the triangular region defined by three points:
supraclavicular fossa ( 1) the superior margin of the sternal end of the clavicle, (2) the superior mar-
N2 Bilateral metastasis in cervical lymph node(s), s; 6 cm in gin of the lateral end of the clavicle, and (3) the point where the neck meets
greatest dimension, above the supraclavicular fossa the shoulder; this includes caudal portions of levels IV and V.
N3 Metastasis in cervical lymph node(s), > 6 cm and/or in the
supraclavicular fossa
N3a > 6 cm in greatest dimension
N3b In the supraclavicular fossaº

Note: Midline nodes are considered ipsilateral nodes.

64 WHO and TNM classification of tumours of the nasopharynx

lntroduction Chan J.K .C.
Slootweg P.J.

A broad range of neoplasms can arise
in the nasopharynx, from epithelial to
mesenchymal , lymphoid, and neuro-
ectodermal. The most common is na-
sopharyngeal carcinoma, which shows
remarkable geographical differences in
incidence. In this chapter, only the more
common tumour types and site-specific
tumour types are described in detail.
Other tumour types that can occur in the
nasopharynx are covered in other chap-
ters, incl uding Chapter 1 (Tumours of
the nasal cavity, paranasal sinuses and
skull base, p. 11), Chapter 3 (Tumours
of the hypopharynx, larynx, trachea and
parapharyngeal space, p. 77) , Chapter 4
(Tumours of the oral cavity and mobíle
tangue, p. 105), and Chapter 5 (Tumours
of the oropharynx, p. 133).

Nasopharyngeal carcinoma Petersson B.F. Lewis J.S.

Bell D. Nadal A.
El-Mofty S.K. Nicolai P.
Gillison M. Wenig B.M.

Definition
Nasopharyngeal carcinoma (N PC) is a
carcinoma arising in the nasopharyngeal
mucosa that shows light microscopic or
ultrastructural evidence of squamous dif-
ferentiation . The term encompasses non-
keratinizing, keratinizing , and basaloid
squamous cell carcinoma.
ICD-0 codes
Non -keratinizing squamous cell
carcinoma 8072/3
Keratin izing squamous cell
carcinoma 8071 /3
Basaloid squamous cell
carcinoma 8083/3
Synonyms
Lymphoepithelial carcinoma; undiffer-
entiated carcinoma with lymphoid stro-
ma; squamous cell carcinoma (WHO
grade 1); non -keratin izing carcinoma
(WHO grade 2); undifferentiated carci-
noma (WHO grade 3)
Epidemiology
NPC is an uncommon tumour among
Caucasians , with an age-adjusted an-
nual incidence of less than 1 case per
100 000 population. The annual inci-
dence in North America is 0.3-0.7 cases
per 100 000 population !1124) NPC is
common among sorne ethnic groups,
including the lnuit, Northern Africans , Table 2.01 Structures involved by local infiltration of
nasopharyngeal carcinoma; MRl data of 308 patients,
and Chinese from south-eastern Asia. Pamela Youde Nethersole Eastern Hospital, Hong Kong.
Sorne of the highest incidences of NPC
Structures involved Frequency
have been observed in Hong Kong SAR,
China, with 2012 age-standardized inci- Adjacent soft tissues
dences of 12.5 cases and 4.1 cases per Nasal cavity 87%
100 000 males and females , respective- Oropharyngeal wall, soft palate 21 %
ly ¡363}. The an nual incidence of NPC
Parapharyngeal space, carotid space 68%
in southern China is 15-50 cases per
100 000 population {1004). The rates in Pterygoid muscle (medial, lateral) 48%
men are commonly double or triple those Prevertebral muscle 19%
in women. NPC affects predominantly Bony erosion I paranasal sinus
adults, but rare cases are seen in the
Nasal septum 3%
paediatric population. In high-risk popu-
lations, NPC incidence rises after the age Pterygoid plate(s), pterygomaxillary
27%
of 30 years , peaks at 40-60 years, and fissure, pterygopalatine fossa
then declines {1822}. In Chinese who mi- Maxillary antrum 4%
grate to North America, the incidence of Ethmoid sinus 6%
NPC declines , but remains significantly
Sphenoid sinus; sphenoid bone;
higher than in the general North Ameri- 38%
foramina lacerum, ovale, and rotundum
can population {296).
Clivus 41 %
The age-standardized incidences of
NPC have decreased over the past dec- Petrous bone, petra-occipital fissure 19%
ades, particu larly among Chinese in Jugular foramen , hypoglossal canal 4%
Hong Kong SAR {826,2693). Pituitary fossa/gland 3%
Extensive/intracranial extension
Etiology
Causative carcinogens have not yet Cavernous sinus 16%
been definitively identified , but tobacco Cerebrum, meninges, cisterns 4%
smoking and alcohol consumption are lnfratemporal fossa 9%
likely contributing factors for keratiniz-
Orbit, orbital fissure(s) 4%
ing NPC (K-NPC); and a high cdnsump-
tion of salted and fermented foods with Hypopharynx 2%

Nasopharyngeal carcinoma 65
 generally absent in K-NPC, especially in
non -endemic regions {1542,1731} EBV
infection is necessary but not sufficient
for tumorigenesis.
Oncogenic (high-risk) HPV types may
play a role in a subset of NPCs, espe -
cially in non -endemic regions. Like in the
oropharynx, HPV-related NPCs most fre-
quently show non-keratinizing histology
¡2000' 2273}.
Localization
The pharyngeal recess (fossa of Rosen-
müller) is the most common site of ori -
gin (1010,1011). The next most common
site is the superior posterior wall of the
nasopharynx.

C linical features
Most patients present with locoregionally
advanced disease, commonly with cervi-
1984 1986 988 1990 1992 1994 1996 1998 2 cal lymph node metastases {1040,2508)
The presenting symptoms are related
Yez
to the presence of a mass in the naso-
Fig. 2.01 Age-standardized incidence rates (per 100 000 population) of malignan! neoplasm of nasopharynx by sex in
Hong Kong SAR, China, 1983-2000; compiled based on the World Standard Population specified by Ahmad OB et al. pharynx (e.g. epistaxis, obstruction, and
{29). Note: Data from 1996 onwards are based on population estimates using !he residen! population approach rather blood -stained postnasal drip), Eustachi -
!han the extended de facto approach. The Hong Kong Population Census conducted in June to August 2011 provides an tube dysfunction (e.g. hearing impair-
a benchmark for revising population figures compiled since !he 2006 Hong Kong Population By-census. Classification ment, tinnitus, and serous otitis media),
of diseases and causes of death is based on the lnternational Statistical Classification of Diseases and Related Health skull base involvement with impairment
Problems, 1Oth Revision (ICD-1 O) from 2001 onwards; figures from 2001 onwards may no! be comparable with figures of the fifth and sixth cranial nerves (e.g.
for previous years, which were compiled based on ICD-9. Reprinted from Hong Kong Cancer Registry {363).
headache, diplopia , facial pain, numb-
ness , and paraesthesia), and painless
Table 2.02 Common presenting symptoms and signs of high nitrosamine content has been im- neck mass dueto lymph node metastasis
nasopharyngeal carcinoma; data from 722 consecutive plicated in non -keratinizing NPC (NK- {1358). Distant metastasis at presentation
patients treated al Pamela Youde Nethersole Eastern NPC) in populations where that histologi- has been reported in approximately 5% of
Hospital , Hong Kong SAR, China, in 1994- 2001 .
cal subtype is endemic. NK-NPC has a patients {2368}, and 10% of patients with
Presenting features Frequency multifactorial etiology, including genetic NPC are asymptomatic. In endemic are -
Symptoms susceptibility, EBV infection, and pos- as, 12% of patients with dermatomyositis
Neck mass 42% sibly consumption of salted fish {96 ,97,
1003, 1005, 1740, 2693, 2694, 2695, 2696).
Nasal (postnasal drip, discharge, 46%
Salted fi:::h contains volatile carcinogenic
bleeding, obstruction)
nitrosamines or their precursors, as well
Aural (tinnitus, discharge, earache, 42% as EBV-activating substances (1045 ,
deafness) 1046,2144,2734). The importance of ex-
Headache 16% posure ir early life is indicated by studies
Double vision, squint, blindness 6% showing that low-risk ethnic groups born
5%
in high-risk areas have higher risk of NPC
Facial numbness
{1120,1121) . In low-incidence regions
Speech/swallowing problem 2% like northern China, the consumption of
Weight loss 4% salted fish still carries an adjusted rela- Fig. 2.02 MRI of nasopharyngeal carcinoma (NPC). A
Physical signs tive risk as high as 5.6 {295). Other envi- 40-year-old woman presented with a 2-month history
ronmental factors, such as occupational of tinnitus, followed by neck masses, nasal symptoms,
Enlarged neck node(s) 72%
exposure to wood dust, formaldehyde , headache, and diplopia. Physical examination revealed
Bilateral neck nades 35% heat, smoke, dust, and chemical fumes left sixth nerve palsy and bilateral upper-middle cervical
Neck nades extending to supraclavicular 12% have also been proposed as possible lymph nades. Endoscopy revealed tumour in !he
fossa contributing or causative factors {98, nasopharynx extending to the posterior nasal cavity.
Biopsy confirmed undifferentiated carcinoma. MRI
Cranial nerve palsy 10% 1740,2693}. showed NPC with extensive local infiltration of adjacent
Deafness 3% Most studies show that NK-NPC has a soft tissues, erosion of skull base / paranasal sinuses,
strong association with EBV, especially and intracranial extension, together with bilateral
Dermatomyositis 1%
in endemic regions; conversely, EBV is retropharyngeal and cervical nades.

66 Tumours of the nasopharynx

have NPC as an underlying malignancy
{1848), whereas only 1% of patients with
NPC have dermatomyositis {2367)
Tumour spread
NPC is notorious for its highly malignant
behaviour, with extensive locoregional in-
filtration and early lymphatic spread, ero-
sion of skull base and paranasal sinuses ,
intracranial spread, infiltration of cranial
nerves, and extension to adjacent struc-
tures (e.g. infratemporal fossa, orbit, and
hypopharynx). Given the rich lymphatic
plexus in the nasopharynx, lymphatic
spread occurs early in the course of dis-
ease. In cases staged by imaging, about
20% of patients have no enlarged nodes,
and about half have retropharyngeal
node involvement {2140) The jugulodi-
gastric node is the most commonly pal-
pable node at presentation , and involve-
ment of the posterior cervical chain is
more frequent than with other head and
neck cancers. The most common sites of
distant metastasis (in descending order
of frequency) are bone, lung, liver, and
distant nodes {2369).
TNMstaging
The main differences between the sixth
and seventh editions of the AJCC can-
cer staging manual are that (1) tumours
classified in the sixth edition as T2a (i.e.
tumour extending to oropharynx and/or
nasal cavity without parapharyngeal ex-
tension) are classified in the seventh edi -
tion as T1 and (2) retropharyngeal lymph
node(s), regardless of unilateral or bilat-
eral location , are considered N1 in the
seventh edition.
Serology
EBV serology is positive in most patients
with NK-NPC {917). lgA antibod 1{ against
EBV viral capsid antige n and lgG/lgA
against EBV early antigens are the most
extensively used diagnostic tools, with
detection rates of 69- 93% {383,525).
Another approach is to test for elevated
levels of circulating EBV DNA or RNA,
using techniques for detecting the
BamHl-W region of the EBV genome,
EBV-encoded small RNAs (EBERs), or
EBNA1 in the plasma or serum, with re-
ported sensitivity in NPC as higr as 96%
{382,1433,1463,2168).
Macroscopy
The tumour can present as a smooth
bulge in the mucosa, a discrete raised
nodule with or without surface ulceration,
or a frankly infiltrative fungating mass. In
sorne cases , there is no grossly visible le-
sion {1468).
Cytology
Aspirates of metastatic K-NPCs and NK-
NPCs show findings similar to those at
other sites. Aspirates often show a back-
ground of lymphocytes and plasma cells,
with irregular clusters of large cells with
overlapping vesicular nuclei and large
nucleoli {384,1265). The cytoplasm of
these cells is often fragile and barely
visible. There are commonly many na-
ked nuclei {1636) . The diagnosis can be
readily confirmed by immunostaining for
cytokeratin and in situ hybridization for
EBER.
Histopathology
Non-keratinizing squamous ce//
carcinoma
NK-NPC exhibits a variety of architec-
tural patterns, frequently mixed within the
Nasopharyngeal carcinoma 67
~
~
11
..
•
;•
,,
~
Fig. 2.06 A Metastatic nasopharyngeal carcinoma in lymph nade. Fine-needle aspiration smear shows light clusters of tumour cells among small lymphocytes. B,C Morphological
spectrum of non-keratinizing nasopharyngeal carcinoma, undifferentiated subtype. (B) The cells exhibit a syncytial quality and have vesicular nuclei , prominent nucleoli, and
amphophilic cytoplasm. (C) Focally, there can be cells with more distinct cell borders and a moderate amount of eosinophilic cytoplasm.
same tumour mass, ranging from solid
sheets to irregular islands, trabeculae ,
and discohesive sheets of malignant
cells intimately intermingled with variab le
numbers of lymphocytes and plasma
cells.
The undifferentiated subtype, wh ich is
more common, is characterized by large
tumour cells with a syncytial appearance,
round to oval vesicu lar nuclei , and large
central nucleoli. The nuclei can be chro-
matin-rich rather than vesicular and the
neoplastic cells generally have scant am-
phophilic or eosinophilic cytoplasm. The
malignant cells can assume spindle-cell
features in fascicular arrangements.
The differentiated subtype exhibits cel-
lular stratification and pavementing , of-
ten with plexiform growth; occasional
keratinized cells may be present. Com-
pared with those in the undifferentiated
subtype, the neoplastic cells are often
slightly smaller, the N:C ratio is lower,
the nuclei are often more chromatin-rich,
and the nucleoli are usually less promi-
nent. Focally, intercellular bridges may
be present.
However, subclassification into undiffer-
entiated and differentiated subtypes has
no clinical or prognostic value.
The density of lymphocytes and plasma
cells within the tumour cell aggregates is
68 Tumours of the nasopharynx
highly variable. When abundant, the in-
flammatory cells break up the tumour into
tiny clusters or single cells, making it dif-
ficult to recognize the epithelial nature of
the neoplasm . Sorne cases may demon-
strate abundant eosinophils , neutrophils,
or epithelioid granulomas {399,781 ,1379,
1471). A desmoplastic stromal reaction is
uncommon.
lsolated or scattered groups of tu-
mour cells may appear shrunken , with
smudged nuclei and dense amphophilic
or eosinophilic cytoplasm . In as many as
10% of cases, there are interspersed in-
tra- or extracellular small spherical amy-
loid globules {1919}. Uncommon features
include papillary frond formation , clear-
cell change , accumulation of extracellular
oedema fluid or mucosubstances, and
presence of intracytoplasmic mucin in
very rare cells {1109,1302}.
In cervical lymph node metastases,
malignant cells within the lymph nodes
may be arranged in various patterns. In
particular, neoplastic cells may display
Reed-Sternberg cell- like features in a
mixed inflammatory background, mim-
icking Hodgkin lymphoma {329,1384).
Epithelioid granulomas (sometimes ne-
crotizing) are present in approximately
20% of cases {1384). A cystic appear-
ance of NK-NPC metastases to lymph
nodes may simulate a metastasis from
the oropharynx.
Keratinizing squamous ce// carcinoma
K-NPCs are a group of invasive carci-
nomas showing obvious squamous dif-
ferentiation at the light microscopic level ,
in the form of intercellular bridges and/or
various degrees of keratinization, accom-
panied by a desmoplastic stroma, akin to
that seen in squamous cell carcinoma at
other head and neck sites. K-NPC can
arise de novo or (more rarely) secondary
to radiotherapy {398} .
Basaloid squamous ce!! carcinoma
This tumour is morphologically identical
to analogous tumours more commonly
occurring in other head and neck sites ,
and has infrequently been reported to
occur as a primary tumour of the naso-
pharynx (132,133,1672,1839,2528). EBV
may be positive, especially in high-inci-
dence ethnic groups (1672,2528).
lmmunohistochemistry
NPC stains strongly for p63, pancy-
tokeratin , and high-molecular-weight cy-
tokeratins , with often patchy expression
of low-molecular-weight cytokeratins and
EMA. CK7 and CK20 are negative (756).
EBV detection
NK-NPC is associated with EBV in almost
all cases. The most reliable way to dem-
onstrate EBV is in situ hybridization for
EBER (1037,1066,1085,1904,2428). This
test is helpful in the evaluation of cervi-
cal lymph nodes harbouring undifferen-
tiated or poorly differentiated squamous
cell carcinoma of unknown origin, with
a positive resu lt strongly suggesting the
possibility of NPC.
lmmunostaining for LMP1 is not a sensi -
tive or reliable method for demonstrating
the presence of EBV {908 ,1833,1904).
PCR for EBV is not reliable either, be-
cause even a few bystander EBV-positive
lymphocytes can give rise to a positive
result (2428).
Genetic profile
Deletions on 3p and 9p are early events
in NPC (442), and the chromosomal re-
gions that most frequent show gain and
loss are on chromosome 12 and 3p. Ar-
ray comparative genomic hybridization
studies have identified frequent copy-
number gains of MYCL (1p34.3), TERC
(3q26.3), ESR1 (6q251), and PIK3CA
(1056). Genomic sequencing reveals a
distinctive mutational signature, with nine
significantly mutated genes (1431}. The
significance of these genes in pathogen-
esis, prognosis , and response to therapy
has yet to be determined.
Genetic susceptibility
The risk of developing NPC is linked to
genes coding for certain tissue antigens
(i.e. HLA genes). In Chinese populations,
HLA-A*02 alleles and HLA-8*46 alleles
are associated with a high ri sk of NPC
{864 ,1042) High-resolution genotyping
has shown a consistent association be-
tween NPC and the HLA-A*0207 allele,
which is common in Chinese populations
{990) . Genetic polymorphisms in genes
coding for metabolic enzymes (CYP2E1
and GSTM1) and DNA repair enzymes
(OGG1 and XRCC1) have also been as-
sociated with increased risk of NPC (989 ,
991 }. Linkage studies have suggested
that susceptibility loci for NPC are pres-
ent on chromosomes 3, 4, and 14 {700 ,
2654). Familia! clustering of NPC is well
reported {1003 ,1133,1157,2609). The
relative risk in first-degree relatives of
patients with NPC varies from 6.3 to 21.3
(397,1362,2692,2722). There are no clini-
cal characteristics that separate sporadic
from familia! cases.
Prognosis and predictive factors
The most powerful prog nostic factor of
NPC is stage at presentation. A study us-
ing the 2002 TNM staging system found
that the 5-year disease-specific survival
rate for stage 1 disease was 98%; for
stage llA-B, 95%; for stage 111, 86%; and
for stage IVA-B, 73%. lncreasing tumour
volume is a negative prognostic factor,
with an estimated 1% increase in risk of
local failure per 1 cm 3 increase in vol-
ume (386 ,2330}. Circulating plasma/se-
rum levels of EBV DNA are substantially
elevated in patients with active disease
(in particular distant metastasis); drop to
very low titres upon remission (374,1462 ,
1728,2 168); and correlate with advanced
stage {1463) and survival {374 ,1462).
Other unfavourable prognostic factors
are fixation of involved neck nodes, male
sex, patient age > 40 years, cranial nerve
palsy, and ear symptoms at presentation
(1851 ,2139,2368).
The issue of histopathological type
(keratinizing vs non-keratinizing) in rela-
tion to prognosis is complex . Compared
with NK-NPC, K-NPC shows a greater
propensity for locally advanced tumour
growth (which occurs in 76% vs 55% of
cases , respectively) (1966} and a lower
propensity for lymph node metastasis
(which occurs in 29% vs 70% of cases,
respectively) {1715). Sorne studies have
suggested that K-NPC is less respon-
sive to radiation therapy and has a worse
prognosis than NK-NPC {1023 ,1715,
1966,2142), but other studies have not
found any differences in biological be-
haviour (375,737)
The significance of the presence of high-
risk HPV is not well established. Several
studies have suggested that HPV-related
tumours have a worse prognosis than do
EBV-related cases , but perhaps a bet-
ter outcome than do cases negative for
both viruses {592,1435,1460,1561 ,2000,
2273).
With improved treatment protocols, the
development of a second malignant tu -
mour becomes significant. Squamous
cell carcinoma and various sarcomas
Nasopharyngeal carcinoma 69
are most common. The annual incidence
of postradiation squamous cell carci-
noma has been reported to be 0.55-1%
{1270,2531}; in one study, the mean la-
tency period was 10.5 years (range:
Nasopharyngeal papillary
adenocarcinoma
Definition
Nasopharyngeal papillary adenocarci-
noma is a low-grade adenocarcinoma
with predominately papillary architecture,
found in the nasopharynx.
ICD-0 code 8260/3
Synonym
Thyroid-like low-grade nasopharyngeal
papillary adenocarcinoma
Epidemiology
Nasopharyngeal papillary adenocarcino-
mas account for < 1% of nasopharyngeal
malignancies. They can occur in patients
of any age (reported range: 9-64 years)
{1894 ,2590} No sex predilection has
been shown .
Localization
Nasopharyngeal papillary adenocarci-
nomas can involve any part of the naso-
pharynx {2590}.
Clinical features
Patients typically present with nasal ob-
struction {1894 ,2590}. Subsets of pa-
tients present with rhinorrhoea , epistaxis,
otitis media, or hearing problems.
70 Tumours of the nasopharynx
6.4-15.8 years) {380} Postradiation
squamous cell carcinoma may occur at
uncommon siles, such as the externa!
auditory canal , middle ear, and temporal
bone {1430,1461 ,1752,2364}.
Macroscopy
Nasopharyngeal papillary adenocarcino-
mas are exophytic and appear papillary,
polypoid, or nodular. They may be soft or
gritty {2590}.
Histopathology
Nasopharyngeal papillary adenocarcino-
mas are composed of complex, arboriz-
ing papillae with hyalinized fibrovascular
cores and glands {1894 ,2590}. The le-
sions are invasive and typically involve
the surface epithelium , focally merging
with non-neoplastic epithelium. Papillae
are lined by a single layer of cuboidal
to columnar cells that have a moder-
ate amount of eosinophilic cytoplasm .
Similar to those seen in papillary thyroid
carci nomas, the nuclei vary from round
to oval and have moderate membrane
irregularity with vesicular to clear chro-
matin. Psammomatoid calcifications are
seen in about one third of cases. Mitotic
figures are uncommon and necrosis is
rare . Perineural and angiolymphatic inva-
sion are not seen.
The tumours express EMA, CK5/6, and
often CK7 {1894,2590} The subset of
cases positive for CK19 and TTF1 {342}
has been referred to as thyroid-like
Many prognostic molecular and immuno-
histochemical markers have been stud-
ied, but only that of plasma/serum levels
of EBV DN A {2717} has been incorporat-
ed into clinical practice.
Stelow E.B .
Bell D.
Wenig S.M.
-
Fig. 2.09 Nasopharyngeal papillary adenocarcinoma.
Papillae are lined by a single !ayer of bland cuboidal
cells.
low-grade nasopharyngeal papillary ad-
enocarcinoma, but thyroglobulin is nega-
tive. 8100 protein expression is seen fo-
cally in many cases.
Genetic profile
BRAFmutations have not been identified
{1768,1870}.
Prognosis and predictive factors
Most patients with nasopharyngeal papil-
lary adenocarcinoma have been treated
with surgery alone, although sorne have
also recei ved radiation therapy {1894 ,
2590}. No patients have developed re-
currences or metastases.
Salivary gland tumours
Adenoid cystic carcinoma
Stelow E.B.
Bell D.
Seethala R.
Stenman G.
Definition
Adenoid cystic carcinoma is a slow-
growing and relentless salivary gland
mali gnancy composed of epithelial and
myoepithelial neoplastic cells that form
various patterns, including tubular, cribri -
form, and solid forms .
ICD-0 code 8200/3
Epidemiology
Approximately 2-8% of adenoid cystic
carc inomas involve the nasopharynx
{1709,i864l. The tumours are the most
common salivary gland malignancy af-
fecting the area and account for almost
one quarter of all adenocarcinomas found
at the site {1894). The mean patient age
at presentation is 45 years, and men and
women are equally affected {1894,2391l .
Localization
Adenoid cystic carcinoma can involve
the nasopharynx either in isolation or
through spread from the sinonasal tract.
Clinical features
Patients most often present with epistax-
is, nasal obstruction, and tinnitus {1447).
Most patients present with advanced-
stage disease {325,2391l
Histopathology
The histological and immunohistochemical
findings are similar to those for adenoid
cystic carcinomas found elsewhere
{2391 l. They are described in detail in
the Adenoid cystic carcinoma section
in Chapter 7, p. 164. The tumours are
mostly submucosal, but sorne may show
mucosa! extension .
Genetic profile
The adenoid cystic carcinoma- specific
t(6;9) chromosomal translocation, result-
ing in a MYB-NFIB gene fusion, has been
detected in tumours at this site {987,1862,
2391).
Prognosis and predictive factors
The reported 5-year disease-free and
overall survival rates are 30- 65% and
54- 70%, respectively {325,1447).
Salivary gland anlage tumour
Chiosea S.
Seethala R.
Skálová A.
Definition
Salivary gland anlage tumour is a mid -
line nasopharyngeal lesion with biphasic
epithelial and myoepithelial components
{979l
Synonym
Congenital pleomorph ic adenoma {554,
937}
Epidemiology
Approximately 35 examples of salivary
gland anlage tumour have been reported
{554, 816, 978, 979,1537, 1633, 1945, 2282,
B Complex squamous proliferation intermixed with myoepithelial
2406,2516). The affected patients are
infants (diagnosed by 3 months of age),
and there is a male predilection . A case
suspected to have developed in utero
has been reported {1945l.
Localization
Salivary gland anlage tumours occur in
the posterior nasal septum or the poste-
rior nasopharyngeal wall.
Clinical features
Patients present with respiratory distress
due to nasal airway obstruction {979). Be-
fare birth, salivary gland anlage tumour may
be associated with polyhydramnios {1945l
Macroscopy
The typical appearance is that of a poly-
poid to pedunculated smooth tan -brown
mass with solid to microcystic cut sur-
face {979) .
Histopathology
Salivary gland anlage tumours display
a complex polypo id configuration , with
a submucosal network of tubules and
ducts with variable keratinization that are
continuous with the surface squamous
epithelium. The spindle cell component
varies from hypocellular to more cellular
myoepithelial nodules in the centre of the
polyp. Cellular atypia and mitoses are
absent {979) . The epithelial components
are positive for cytokeratins and EMA,
and the myoepithelial nodules express
SMA and cytokeratins .
Prognosis and predictive factors
No recurrences after excision have been
reported.
Salivary gland tumours 71
Benign and borderline lesions
Hairypolyp
Definition
Hairy polyp is a benign polypoid lesion
with a suspected developmental origin ,
composed of ectoderm and mesoderm.
Synonyms
Teratoid polyp; dermoid polyp
Epidemiology
Hairy polyp occurs primarily in neonates
and older infants , and extremely rarely in
adults (364,888). There is a female pre-
dominance, with a female-to-male ratio of
6:1 189,622,1210}.
Localization
The most common location is the lateral wall
of the nasopharynx (accounting for 60% of
cases), but hairy polyp may also occur in
the oropharynx, palate, tonsil, tangue, lip,
and middle ear (622,1210,1223}
Clinical features
The presentation includes a peduncu-
lated mass that may be associated with
cough , dyspnoea, vomiting, and difficulty
in swallowing. Rarely, it is associated with
other congenital malformations , such as
cleft palate or Dandy-Walker syndrome
1106,2359}.
Macroscopy
The polyp has a skin-like surface and
can be as large as 6 cm in greatest di-
mension, with an attachment to the lateral
wall of the nasopharynx 11623).
Histopathology
The polyp is covered by keratinized
squamous epithelium containing pi-
losebaceous units. The core consists
of fibroadipose tissue. Skeletal muscle,
cartilage, and bone may be present.
Meningothelial remnants have been iden-
tified (1770). Hairy polyp is differentiated
from teratoma by a lack of endodermal
components.
Prognosis and predictive factors
Surgical excision is curative 12359).
72 Tumours of the nasopharynx
Ectopic pituitary adenoma
Definition
Ectopic pituitary adenoma is a benign
anterior pituitary gland neoplasm that
does not involve the sella turcica.
ICD-0 code 8272/0
Synonyms
Extrasellar pituitary adenoma; extracra-
nial pituitary adenoma
Epidemiology
Pituitary adenomas account for < 3% of
tumours of the sphenoid sinus or naso-
pharynx 1683,1782,2392}. Patient age
at presentation varies widely (range:
2-84 years; mean: 54 years).
Females are affected slightly more than
males, with a female-to-male ratio of 1.3:1
(2392}
Localization
Ectopic pituitary adenomas occur most
frequently in the sphenoid sinus/bone
(301 ,1459,1959,2392,2417}, followed by
the nasopharynx, with rare cases re-
ported in the nasal cavity, ethmoid sinus,
temporal bone, and nasal bridge 187,
1959}
Clinical features
Symptoms include obstruction , sinusi-
tis, rhinorrhoea, discharge, headache,
and pain. Visual disturbances and
nerve changes are uncommon (2392}.
Sorne patients present with endocrino-
pathic manifestations, such as Cush-
ing syndrome (hypercortisolism), acro-
megaly, amenorrhoea, or galactorrhoea
1468,483,1030,1932,2175).
Asymptomatic presentation occurs in
about 10% of cases. lmaging studies are
required to exclude direct extension from
the sella. Bone destruction is often pres-
ent 1873,958,2207,2668}.
Macroscopy
Macroscopically, ectopic pituitary ade-
nomas are polypoid tumours measuring
0.8-8 cm (mean: 3.4 cm) (1459,2166}.
Katabi N.
Hunt J.L.
Thompson LD.R.
Wenig B.M.
Histopathology
Ectopic pituitary adenoma is a submu-
cosal epithelioid neoplasm with solid, or-
ganoid , and trabecular growth patterns.
The epithelioid cells have round nuclei,
with a dispersed chromatin pattern and
granular eosinophilic cytoplasm. Plas-
macytoid-appearing cells may be pres-
ent. Gland-like spaces may be seen,
but there is no squamous differentiation.
There is mild to moderate nuclear varia-
tion (so-called endocrine atypia). Scat-
tered mitotic figures may be present, but
not atypical mitoses or necrosis. Cal-
cifications and psammoma-like bodies
may be identified 11459,1493,2166} The
stroma is usually richly vascularized and
often heavily collagenized.
The tumour cells express cytokeratins
(often in a perinuclear dot-like pattern)
and neuroendocrine markers (e.g. syn-
aptophysin, CD56, and chromogranin).
S100 protein may be positive, but the
sustentacular pattern of olfactory neuro-
blastoma is absent. Reactivity with two
or more pituitary hormones is seen in as
many as 50% of cases. About one third
of all cases express a single hormone,
most commonly prolactin. Approximately
20% of ectopic pituitary adenomas are
null cell adenomas - lacking expression
of any hormone marker. The diagnosis
of null cell adenoma is preferably sup -
ported by the demonstration of pituitary
transcription factors (e.g. PIT1 , TPIT, SF1 ,
ER-alpha, GATA2, and alpha subunits)
Fig. 2.11 Ectopic pituitary adenoma. Strong and diffuse
granular cytoplasmic immunoreactivity for prolactin, one
of the peptides most commonly identified in ectopic
pituitary adenoma.

Fig. 2.12 Ectopic pituitary adenoma. A Organoid growth pattern with rich vascularity. B Marked sclerosing fibrosis associated with compressed neoplastic cells. C Rosettes and
pseudorosettes. D Profound nuclear pleomorphism can frequently be seen in pituitary adenoma; there is a spicule of bone noted, as bone destruction may be seen.
{87,1459) Ectopic pituitary adenoma
must be distinguished from other neu-
roendocrine neoplasms.
Prognosis and predictive factors
Surgical resection can be curative, but
recurrences are not uncommon .
Craniopharyngioma
Definition
Craniopharyngioma is a benign epithelial
tumour thought to derive from the Rathke
cleft.
ICD-0 code
Synonym
Pituitary adamanti noma
Localization
Craniopharyngioma can occur extra-
cranially in the nasopharynx {1622), and
exceptionally in the sinonasal tract {1064,
1748,2716).
Clinical features
Nasopharyngeal involvement is associ-
ated with headache, impaired vision, and
nasal obstruction.
Macroscopy
Most craniopharyngiomas have a cystic
component containing brown (so called
machine-oil) fluid {2697) .
9350/1 Histopathology
The adamantinomatous type shows
cords of basaloid cells with peripheral
palisading surrounding loose stellate-
" ..L -- ' ~- '
type cells. In addition, so-called wet kera-
tin (composed of eosinophilic keratinized
cells with ghost nuclei) and associated
calcification is present. The papillary
type includes sheets of dyscohesive
squamous epithelium that form pseudo-
papillae with anastomos ing fibrovascular
stroma {1905,2333)
Genetic profile
The adamantinomatous type harbours
CTNNB1 (beta-catenin) mutations and
the papillary type harbours BRAFV600E
mutations {263,1547).
Prognosis and predictive factors
Treatment includes surgery with or with-
out radiation {2697) Craniopharyngioma
may be associated with long -term mor-
bidity and recurrence {1948).
Benign and borderline lesions 73
Soft tissue tumours
Nasopharyngealangiofibrorna
Definition
Nasopharyngeal angiofibroma is a locally
aggressive, variably cellular fibrovascular
neoplasm arising in the nasopharynx of
young males.
ICD-Ocode 9160/0
Synonyms
Angiofibroma; juvenile angiofibroma;
juvenile nasopharyngeal angiofibroma
Epidemiology
Nasopharyngeal angiofibroma is rare,
constituting < 0.5% of all head and neck
tumours (230,2700}. lts incidence is
0.4 cases per million in the general popu-
lation and 3.7 per million in the at-risk
population (i .e. 10- to 24-year-old males)
(845}. The tumour develops almost exclu-
sively in adolescent and young males (av-
erage patient age: 17 years) (230,1716,
2621}. Female patients should be evalu-
ated for underlying testicular feminization .
Etiology
There is evidence of hormonal depend-
ency of nasopharyngeal angiofibroma.
Tumour growth is associated with pu-
berty in boys , and tumour cells frequently
express androgen receptor (1063,1716,
2621}.
Fig. 2.13 Nasopharyngeal angiofibroma. 30 reconstruction
of CT angiography of a 15-year-old boy with a hypervascular
left nasal mass centred in the sphenopalatine foramen
and extending into the pterygopalatine fossa, with
supply from an enlarged left intemal maxillary artery
(arrow), which is a branch of !he externa! carotid artery
(arrowhead}.
74 Tumours of the nasopharynx
Prasad M.L.
Franchi A.
Thompson L.D.R.
,: .
-~
"\. ·º' ..,.'
·. .• .
·· ~ .
#.•
,.
'
_¿'"• . ...
Fig. 2.14 Nasopharyngeal angiofibroma. A A richly vascular tumour underlying the nasopharyngeal respiratory-type
mucosa, showing variously sized blood vessels in a cellular fibroblastic stroma. The vascular componen! ranges
from capillaries to large dilated vessels. B The vascular componen! is variable, ranging from !hin, slit-like branching
capillaries supported only by endothelial cells to dilated vessels; the stroma shows dense collagen with spindled to
stellate fibroblasts. C In this area, !he stroma is loase and myxoid, and contains stellate fibroblasts. The blood vessel
walls range from !hin (supported only by endothelium) to unevenly thick, due to the variable mural smooth muscle
content. D Nuclear localization of beta-catenin is seen in stromal cells only; in endothelial cells, the expression remains
membranous and cytoplasmic.
Localization cranial fossa) is seen in 10-30% of cases
Nasopharyngeal angiofibroma arises in {230,1388,1559,1716}. Angiography is
the nasopharynx or posterolateral nasal diagnostic, identifies the feeding vessel
cavity wall (230,1716,2700}. (usually the interna! maxillary artery), and
is essential for pre-surgical embolization
Clinical features {219). Due to the characteristic imaging
Patients present with the classic triad appearance, diagnostic biopsy (which
of nasal obstruction , epistaxis, and na- carries a risk of life-threatening haemor-
sopharyngeal mass {230,1222}. Other rhage) is often unnecessary.
symptoms include nasal discharge, si-
nusitis, facial deformity, deafness, otitis, Macroscopy
diplopía, proptosis, headache, and pain The average tumour size is 4 cm, but tu-
{1716,2700). Radiological imaging fre- mours as large as 22 cm have been re-
quently shows a tumour in the nasophar- ported. The neoplasm is polypoid and
ynx and nasal cavity with sinus opacity lobulated and often takes the shape of
and bone destruction. Anterior bowing of surrounding structures.
the posterior wall of the maxillary antrum
(called the Holman-Miller sign or the an- Histopathology
tral sign) is typical (1716,2700}. Large tu- The tumour has two components: vascu-
mours can extend into maxillary, ethmoid , lar and stromal. The blood vessels are of
and sphenoid sinuses; pterygopalatine various sizes, shapes , and thicknesses,
and infratemporal fossa; and orbit. lntrac- ranging from slit-like capillaries to ir-
ranial extension (usually into the middle regularly dilated and branching vessels.
The vessel wal ls may be thin (support-
ed only by endothelial cells) or may be
ensheathed focally or continuously by
smooth muscle of varying thickness. No
elastic tissue is identified except in feed-
ing arteries.
The stroma consists of bipolar or stellate
fibroblastic cells with plump, vesicular,
spindled nuclei, and the cells may ap-
pear to be arranged around the blood
vessels. Nucleoli are indistinct and mi-
toses are usually absent. Scattered multi-
nucleated stellate stromal giant cells may
be seen . The stroma varies from loose,
oedematous , and cellular to densely col-
lagenous and paucicellular; mast cells
are frequently present. Tumours treated
with embolization show areas of necrosis
and intravascular foreign material. Tu-
mours treated with the androgen recep-
tor blocker flutamide are hypocellular,
with increased stromal collagen {815).
CD31 and CD34 immunohistochemistry
Haematolymphoid tumours
Definition
Haematolymphoid tumours of the na-
sopharynx are neoplasms of lymphoid,
plasma cell, or myeloid origin arising in
the nasopharynx.
ICD-0 codes
Extraosseous plasmacytoma 9734/3
Extramedullary myeloid sarcoma 9930/3
Diffuse large B-cell lymphoma 9680/3
Epidemiology
Nasopharyngeal lymphomas account
far about 15% {37,666,934} of ali head
and neck lymphomas and for 9% {1372)
to 35% {682} of Waldeyer ring (pharyn-
geal lymphoid ring) lymphomas. Diffuse
large B-cell lymphoma is the most com-
mon type {37,50,682,2652). NK-cell and
T-cell lymphomas occur more frequently
in Asia than in western countries (1054).
Adults and (rarely) children are affected
{50,432,1635). The average patient age
and male-to-female ratio vary by type of
lymphoma. Far example, extranodal NK/
T-cell lymphoma (see Extranodal NK/T-
cel/ !ymphoma, p 52) {1108,2322) affects
highlights the endothelium of blood ves-
seis , and SMA highlights the smooth
muscle in the vessels . The stromal cells
show nuclear expression of androgen
receptor and beta-catenin - the latter in
> 90% of tumours {5,1063}. The stromal
cells occasionally express SMA, espe-
cially at the periphery of the tumour, but
are negative for desmin and S100 pro-
tein. Expression of estrogen receptor,
progesterone receptor, and KIT (CD117)
has been reported {1452 ,1641 ,1978).
Genetic profile
Nasopharyngeal angiofibroma is charac-
terized by chromosomal gains {282} . Loss
of the Y chromosome with gain of the
X chromosome is frequently document-
ed {2092). Somatic mutation in exon 3 of
the beta-catenin gene (CTNNB1) is seen
in 75% of the tumours, although nuclear
localization of beta-catenin is seen in
> 90% of cases {5}.
slightly younger patients, with a higher
male-to-female ratio, than does diffuse
large B-cell lymphoma (see Diffuse large
B-cell lymphoma) {2652). Burkitt lym-
phoma is a common type among children
{2642).
Nasopharyngeal extraosseous plasma-
cytoma accounts for 10-16% of ali head
and neck extraosseous plasmacyto-
mas {116,494 ,2078). Nasopharyngeal
myeloid sarcoma is rare {433,1957).
Etiology
Most lymphomas, plasmacytomas, and
myeloid sarcomas arise sporadically.
EBV contributes to the pathogenesis of
NK/T-cell lymphoma. Sorne patients with
high-grade B-cell lymphoma or classical
Hodgkin lymphoma are immunocompro-
mised {1939,2228).
Localization
Lymphoma forms an often bulky, usually
symmetrical lesion, commonly with inva-
sion of adjacent structures {432,2652).
Stage at presentation varies by type of
lymphoma, but most lymphomas involve
Genetic susceptibility
There have been isolated reports of na-
sopharyngeal angiofibroma arising in
association with familia! adenomatous
polyposis {712,832,2454).
No germline mutations of APC, CTNNB1 ,
or any other gene have been reported in
sporadic nasopharyngeal angiofibroma.
Prognosis and predictive factors
One or more recurrences occur in 5-25%
of patients {230,1222,1388). Prognosis
depends on the size and extent of the
tumour, the presence of multiple feeding
vessels (including bilateral vascularity),
and the completeness of surgical resec-
tion {1559,2227).
Sarcomatous transformation has been
reported in association with radiotherapy,
as has metastasis {2621}. Spontaneous
regression alter puberty can rarely occur
{2621).
Ferry J.A.
Ko Y. -H.
cervical lymph nodes at presentation,
and more-distant spread is not uncom-
mon (37,50,432,1054,1635).
Clinical features
Patients present with nasal obstruction,
epistaxis, hearing loss, headache, dysp-
noea, and/or cervical lymphadenopathy.
A minority have constitutional symptoms
(50,1054,2228,2652)
Histopathology
Diffuse large B-cell lymphoma is most
common, followed by NK/T-cell lym-
phoma and peripheral T-cell lymphoma,
NOS {50,432,1054,1372,2652). Other
lymphomas include MALT lymphoma
{50,1372,2652}, follicular lymphoma
{50,432,1372}, Burkitt lymphoma {2228,
2652}, and mantle cell lymphoma
{2652}, as well as the rare anaplastic
large cell lymphoma {1054,2652}, B-
and T-lymphoblastic lymphomas {1054,
1473}, and classical Hodgkin lymphoma
{1143,1939}.
Haematolymphoid tumours 75
Notochordal tumours Baumhoer D.
Bullerdiek J.
Nicolai P.

.. .. .
... .·-
•

-- .._ ..
..
-- ' · ...: , ~'IL.. .. is' • -.D . •
Fig. 2.15 Chordoma. A Nests of epithelioid cells with eosinophilic and vacuolated cytoplasm showing osteodestruclive growth. B lmmunohistochemical double-stain with CK19 (red,
staining of cytoplasm) and brachyury (brown, staining of nuclei).

Chordoma
Definition
Chordoma is a malignant tumour with no-
tochordal differentiation.
ICD-0 code
Epidemiology
The annual incidence of chordoma is
0.8 cases per 100 000 population, with
32-42% arising in cranial sites , mainly in
the base of the skull.
There is a male predominance, with a
male-to-female ratio of 1.6:1. lndividu-
als of any age can be affected, although
chordoma is rare in childhood ¡372,
2224).
Localization
The clivus is most commonly involved.
The nasopharynx and nasal cavity can
be involved by local extension, but
primary occurrence at these sites is ex-
ceedingly rare !2665).
Clinical features
Chordomas present with headache, cra-
nial nerve palsy, or brain stem compres-
9370/3 sion, depending on the anatomical struc-
tures compromised.
Macroscopy
The tumours generally show bone-de-
structive growth; the cut surface is gelati-
nous or cartilage-like.
Histopathology
Chordomas consist of cords and lobules
of cells in a myxoid stroma , separated
by thin fibrous septa. The characteristic
cells are physaliphorous , with abundant
and highly vacuolated (bubbly) cyto-
plasm, but many tumour cells are non-
descriptly epithelioid in appearance .
The nuclei are uniform and round , with
variable pleomorphism. Necrosis is fre-
quently present. Chordoma typically
shows expression of cytokeratins, EMA,
8100, and brachyury !1610,2517). Vari-
ants include chondroid chordoma, which
shows matrix reminiscent of hyaline car-
tilage , and dedifferentiated chordoma ,
which is a biphasic tumour with classic
chordoma juxtaposed to high-grade un-
differentiated sarcoma.
Genetic susceptibility
In rare familia! cases, a duplication of
the T (brachyury) gene can be found
!2670).
Prognosis and predictive factors
The most important prognostic factor is
complete surgical resection, which can
be achieved only rarely in cranial sites
!2259). The 3- , 5-, and 10-year overall
survival rates are 80.9%, 73.5%, and
58 .7%, respectively ¡372).

76 Tumours of the nasopharynx

 CHAPTER 3

Tumours of the hypopharynx, larynx,

trachea and parapharyngeal space
Malignant surface epithelial tumours
Precursor lesions
Neuroendocrine tumours
Salivary gland tumours
Soft tissue tumours
Cartilage tumours
Haematolymphoid tumours
WHO classification of tumours of the hypopharynx, larynx,
trachea and parapharyngeal space

Malignant surface epithelial tumours Salivary gland tumours

Conventional sq uamous cell carcinoma 8070/3 Adenoid cystic carcinoma 8200/3
Verrucous squamous cell carcinoma 8051/3 Pleomorphic adenoma 8940/0
Basaloid squamous cell carcinoma 8083/3 Oncocytic papi llary cystadenoma 8290/0
Papi llary squamous cell carcinoma 8052/3
Spindle cell squamous cell carcinoma 8074/3 Soft tissue tumours
Adenosquamous carcinoma 8560/3 Granular cell tumour 9580/0
Lymphoepithel ial carcinoma 8082/3 Li posarcoma 8850/3
lnflammatory myofibroblastic tumour 8825/1
Precursor lesions
Dysplasia, low grade 8077/0 Cartilage tumours
Dysplasia, high grade 8077/2 Chondroma 9220/0
Squamous cell papi lloma 8052/0 Chondrosarcoma 9220/3
Squamous cell papi llomatosis 8060/0 Chondrosarcoma, grade 1 9222/1
Chondrosarcoma , grade 2/3 9220/3
Neuroendocrine tumours
Well-differentiated neuroendocrine carcinoma 8240/3 Haematolymphoid tumours
Moderately differentiated neuroendocrine
carcinoma 8249/3
The morphology codes are from the lnternational Classification of Diseases
Poorly differentiated neuroendocrine carcinoma for Oncology (I CD-0) {776A}. Behaviour is coded /O for benign tumours;
Small cel l neuroendocrine carcinoma 8041/3 / 1 for unspecified , borderline, or uncertain behaviour; /2 for carcinoma in
Large cell neuroendocri ne carcinoma 8013/3 situ and grade 111 intraepithel ial neoplasia; and /3 for malignant tu mours.
The classification is modified from the previous WHO classification , taking
into account changes in our understanding of these lesions.

78 WHO classification of tumours of the hypopharynx, larynx, trachea and parapharyngeal space
TN M classification of carcinomas of the larynx

TNM classificationª·º T3 Tumour limited to larynx, with vocal cord fixation

T - Primary tumour
TX Primary tumour cannot be assessed
TO No evidence of primary tumour
Tis Carcinoma in situ
Supraglottis
T1 Tumour limited to one subsite of supraglottis, with normal
vocal cord mobility
T2 Tumour invades mucosa of more than one adjacent
subsite of supraglottis or glottis or region outside the
supraglottis (e.g. mucosa of base of tangue, vallecula, or
medial wall of pyriform sinus), without fixation of the larynx
T3 Tumour limited to larynx with vocal cord fixation and/or in-
vades any of the fol lowing: postcricoid area, pre-epiglottic
space, paraglottic space, inner cortex of thyroid cartilage
T4a Tumour invades through the thyroid carti lage and/or
invades tissues beyond the larynx; far example, !rachea,
soft tissues of neck including deep/extrinsic muscle of
tangue (geniog lossus, hyoglossus, palatoglossus, and
styloglossus), strap muscles, thyroid, oesophagus
T4b Tumour invades prevertebral space or mediastinal struc-
tures, or encases carotid artery
T4a Tumour invades cricoid or thyroi d cartilage and/or
invades tissues beyond the larynx; far example, !rachea,
soft tissues of neck including deep/extrinsic muscle of
tangue (genioglossus, hyog lossus, palatog lossus, and
styloglossus), strap muscles, thyroid, oesophagus
T4b Tumour invades prevertebral space or mediastinal
structures, or encases carotid artery
N - Regional lymph nodes (i.e. the cervical nodes)
NX Regional lymph nades cannot be assessed
NO No regional lymph nade metastasis
N1 Metastasis in a single ipsilateral lymph nade,~ 3 cm in
greatest dimension
N2 Metastasis as specified in N2a, N2b, or N2c below
N2a Metastasis in a sing le ipsi lateral lymph nade, > 3 cm
but ~ 6 cm in greatest dimension
N2b Metastasis in mu ltiple ipsi lateral lymph nades,
ali ~ 6 cm in greatest dimension
N2c Metastasis in bi lateral or contralateral lymph nades,
ali ~ 6 cm in greatest dimension
N3 Metastasis in a lymph nade > 6 cm in greatest dimension
Note: Midl ine nades are considered ipsilateral nades .

Glottis M - Distant metastasis

T1 Tumour limited to vocal cord(s) (may involve anterior or MO No distan! metastasis
posterior commissure), with normal vocal cord mobility M1 Distan! metastasis
T1a Tumour limited to one vocal cord
T1b Tumour involves both vocal cords Stage grouping
T2 Tumour extends to suprag lottis and/or subglottis, and/or Stage O Tis NO MO
with impaired vocal cord mobility Stage 1 T1 NO MO
T3 Tumour limited to larynx with vocal cord fixation and/or in- Stage 11 T2 NO MO
vades paraglottic space and/or inner cortex of the thyroid Stage 111 T1- 2 N1 MO
cartilage T3 N0-1 MO
T4a Tumour invades through the outer cortex of the thyroid Stage IVA T1-3 N2 MO
cartilage and/or invades tissues beyond the larynx; far T4a N0-2 MO
example, !rachea, soft tissues of neck including deep/ Stage IVB T4b Any N MO
extrinsic muscle of tangue (genioglossus, hyoglossus, AnyT N3 MO
palatog lossus, and stylog lossus), strap muscles, thyroid, Stage IVC AnyT Any N M1
oesophagus
T4b Tumour invades prevertebral space or mediastinal struc-
ªAdapted from Edge et al. 1625A} - used with permission of the American
tures , or encases carotid artery
Joint Committee on Cancer (AJCC), Chicago, lllinois; the original and prima-
ry source for this information is the AJCC Cancer Staging Manual, Seventh
Subglottis Edition (2010) published by Springer Science+Business Media - and Sobin
T1 Tumour limited to subglottis et al. {2228A}.
T2 Tumour extends to vocal cord(s), with normal or impaired bA help desk for specific questions about TNM classification is available at
http://www.uicc.org/resources/tnm/helpdesk.
mobi lity

TNM classification of carcinomas of the larynx 79

TNM classification of carcinomas of the hypopharynx

TNM classification•·b
M - Distant metastasis
T - Primary tumour MO No distan! metastasis
TX Primary tumour cannot be assessed M1 Distan! metastasis
TO No evidence of primary tumour
Tis Carcinoma in situ Stage grouping
T1 Tumour limited to one subsite of hypopharynx and/or Stage O Tis NO MO
s; 2 cm in greatest dimension Stage 1 T1 NO MO
T2 Tumour invades more than one subsite of hypopharynx or Stage 11 T2 NO MO
an adjacent site, or measures > 2 cm but s; 4 cm in Stage 111 T1 - 2 N1 MO
greatest dimension, without fixation of hemilarynx T3 N0- 1 MO
T3 Tumour > 4 cm in greatest dimension, or with fixation of Stage IVA T1 - 3 N2 MO
hemilarynx or extension to oesophagus T4a N0-2 MO
T4a Tumour invades any of the following: thyroid/cricoid Stage IVB T4b Any N MO
cartilage, hyoid bone, thyroid gland, oesophagus, central AnyT N3 MO
compartment soft tissue (which includes·prelaryngeal Stage IVC AnyT Any N M1
strap muscles and subcutaneous fat)
T4b Tumour invades prevertebral fascia, encases carotid
artery, or invades mediastinal structures

N - Regional lymph nodes (i.e. the cervical nodes)

NX Regional lymph nades cannot be assessed
NO No regional lymph nade metastasis
N1 Metastasis in a single ipsilateral lymph nade, s; 3 cm in
greatest dimension
N2 Metastasis as specified in N2a, N2b, or N2c below
N2a Metastasis in a single ipsilateral lymph nade, > 3 cm
but s; 6 cm in greatest dimension
N2b Metastasis in multiple ipsilateral lymph nades,
all s; 6 cm in greatest dimension
ªAdapted from Edge et al. {625A} - used with permission of the American
N2c Metastasis in bilateral or contralateral lymph nades,
Joint Committee on Cancer (AJCC), Chicago , lllinois; the original and prima-
all s; 6 cm in greatest dimension ry source for this information is the AJCC Cancer Staging Manual, Seventh
N3 Metastasis in a lymph nade > 6 cm in greatest dimension Edition (2010) published by Springer Science+Business Media - and Sobin
et al. {2228A} .
Note: Midline nades are considered ipsilateral nades. "A help desk for specific questions about TNM classification is available at
http://www.uicc.org/resources/tnm/helpdesk.

80 Tumours of the hypopharynx, larynx, trachea and parapharyngeal space

Tumours of the hypopharynx, larynx, Slootweg P.J.
Grandis J.R.
trachea and parapharyngeal space

lntroduction
Laryngeal and hypopharyngeal pathol -
ogy mainly encompasses lesions of the
covering mucous membrane, with un-
derlying soft tissues, salivary gland tis-
sue, and cartilage playing a minar role.
Therefare , this chapter emphasizes le-
sions that arise from the mucosa! lining .
The main difference from the previous
ed ition is in the discussion of mucosa!
premalignancies, about which the aim
was to achieve a universally accepted
consensus in arder to put an end to the
confus ion that can arise from the use of
severa! different classification systems.
Currently, a two -tiered classification
(consisting of low-grade and high -grade
dysplasia) is recommen ded, to which
guidelines have been ad ded on how to
recognize carcinoma in situ within the
high -grade dysplasia group in case a
three-tiered system is preferred . Far
neuroendocrine carcinomas, the widely
accepted distinction between low-, inter-
mediate-, and high-grade carcinoma has
been used, in line with the nomenclature
far histologically similar lesions at other
body siles . Discussion of soft tissue and
salivary gland lesions, as well as haema-
tol ymphoid tumours, has been limited to
the specific entities that are often found
in the laryngohypopharynx ar that have
an impartant differential diagnostic role
at this site.

Malignant surface epithelial tu mours

Convenüonalsquarnous
ce// carcinoma
Zidar N.
Brandwein -Gensler M.
Cardesa A .
Helliwell T.
Hille J.
Nada! A.

Definition
Conventional squamous cell carcinoma
(SCC) is a malignant epithelial tumour with
evidence of squamous differentiation .
ICD-0 code 8070/3
Synonym
Epidermoid carcinoma
Epidemiology
SCC of the larynx and hypopharynx is
the second most common respiratory
tract cancer, after lung cancer 1359). lt
accounts far 1.6- 2% of ali malignan! tu-
mours in men and 0.2-0.4% in women
1238). There is marked geographical
variation in the frequency of SCC, both
between countries and in different parts
of the same country.
lt occurs most frequently in the sixth and
seventh decades of life. Rare cases have
Fig. 3.01 Macroscopic appearance of conventional squamous cell carcinoma. A Supraglottic carcinoma of the larynx:
an ulcerated tumour with raised edges al !he base of !he epiglottis. B Subglottic carcinoma of the larynx: a partially
fiat and partially exophytic nodular tumour of !he subglottis, extending to the anterior commissure. C Hypopharyngeal
carcinoma of !he piriform sinus: a large, ulcerated tumour with raised edges in the piriform sinus, extending to the
aryepiglottic fold.
been described in children l137,1766l. Etiology
The tumours are more common in men Cigarette smoking and (to a lesser ex-
l359,1947l, although the male-to-female tent) alcohol consumption are the most
ratio is decreasing in sorne countries , importan! risk factors far laryngeal and
possibly due to increased incidence of hypopharyngeal SCC 1953). Elim inat-
smoking among women over the past ing smoking and alcohol consumption
two decades 1569). could prevent as many as 90% of laryn-
Tracheal carcinoma is rare , with ap - geal cancers l695l Other factors, such
proximately 1 tracheal carcinoma far as gastro -oesophageal reflux, diet, nu -
every 75 laryngeal cases; it accounts far tritional factors , and socioeconomic sta-
< 0.1% of cancer deaths. SCC accounts tus, have been linked to increased risk of
far 55- 73% of al i tracheal carcinomas laryngeal cancer, particularly in patients
l143 ,820l. who lack the majar risk factors 1480 ,665 ,
762,1333l.

Malignan! surface epithelial tumours 81

HPVs play a limited role in the pathogen-
esis of SCC of the larynx. In recent stud-
ies, transcriptionally active HPVs were
detected in 4-15% of cases {417,922,
1408,2095). Unlike in the oropharynx, the
morphology of laryngeal SCC does not
predict viral etiology 11408).
Localization
There are geographical differences in the
topographical distribution of laryngeal
SCC. The most common location for la-
ryngeal SCC is the supraglottis in sorne
countries (e.g. France, Spain , ltaly, Fin-
land, and the Netherlands) and the glot-
tis in others (e.g. the USA, Canada, the
United Kingdom, and Sweden) {143). The
rarest localization of laryngeal cancer is
the subglottis {2067).
Hypopharyngeal SCC occurs most fre-
quently in the piriform sinus (60-85% of
cases) and rarely in other localizations,
such as the posterior pharyngeal wall
(10-20%) and postcricoid area (5-15%)
1971,2449).
Tracheal SCC is usually located in the
lower third of the trachea (> 50% of cas-
es) and less frequently in the upper or
middle third 1820}.
Clinical features
The most common early symptoms of la-
ryngeal SCC are hoarseness (with glot-
tic and supraglottic SCC) and dyspnoea
and stridor (with subglottic SCC). Other
symptoms include dysphagia, change
in the quality of voice, sensation of a for-
eign body in the throat, haemoptysis, and
odynophagia {707,1949).
The most frequent symptoms of hy-
popharyngeal SCC are odynophagia,
dysphagia, and neck mass. Other symp-
toms include voice changes , otalgia, and
constitutional symptoms {2449).
Tracheal SCC usually presents with
dyspnoea, wheezing or stridor, acute res-
piratory failure, cough, haemoptysis, and
hoarseness 11970).
Laryngeal , hypopharyngeal, and tra-
cheal SCCs can spread directly to con-
tiguous structures or via lymphatic and
blood vessels, giving rise to lymph node
and distant metastases. These tumours
have a strong tendency to metastasize to
the regional lymph nodes. The localiza-
tion and frequency of lymph node metas-
tases depend on the site of the primary
tumour. Haematogenous metastases are
infrequent, but may occur in late stages
of the disease, most freq uently to the
82 Tumours of the hypopharynx, larynx, trachea and parapharyngeal space
lung, liver, and bones 12248); intracra-
nial metastases have also been reported
{544,2418).
The TNM staging system is widely used
for SCC. lt is presented in the text on
pages 79 and 80.
Macroscopy
Laryngeal and hypopharyngeal SCC
may present as an exophytic, flat, or
nodular tumour with raised edges; as a
polypoid lesion; or as a depressed, en-
dophytic lesion. Central ulceration is fre-
quently present.
Tracheal SCC usually presents as a
polypoid mass projecting into the lu-
men. Rarely, it grows as a circumferential
mass .
Cytology
Aspirates of metastases are cellular, with
sheets and small clusters of malignant
squamous cells with intracellular and
extracellular keratinization . Mixed inflam-
mation and necrosis can be present.
Histopathology
The main histological features of SCC
are squamous differentiation and inva-
sion. Squamous differentiation is charac-
terized by keratinization (with or without
keratin pearl formation) and/or intercel-
lular bridges. lnvasion manifests as in-
terruption of the basement membrane
of the surface epithelium and the down-
wards growth of tumour islands, cords,
or isolated tumour cells in the underly-
ing tissue. lnvasion is almost always ac-
companied by a desmoplastic stromal
reaction , which consists of proliferation
of myofibroblasts, excessive deposition
of an extracellular matrix, and neovascu-
larization {2728,2729). Tumour cells may
invade the lymphatic and blood vessels
or spread in the perineural plane or along
nerves.
SCCs are traditionally graded as well,
mod erately, or poorly differentiated, ac-
cording to the degree of differentiation,
cellular pleomorphism, and mitotic ac-
tivity. Well -differentiated SCC closely
resembles normal squamous epithe-
lium and contains large, differentiated,
keratinocyte-like squamous cells and
small basal-type cells, which are usually
located at the periphery of the tumour is-
lands. There are intercellular bridges and
typically full keratinization; mitoses are
scarce. Moderately differentiated SCC
exhibits more nuclear pleomorphism and
more mitoses, including abnormal mi-
toses; there is usually less keratinization.
In poorly differentiated SCC, basal-type
cells predominate, with frequent mitoses
(including abnormal mitoses), barely
discernible intercellular bridges, and
minimal or no keratinization. Although
keratinization is more likely to be present
in well- or moderately differentiated SCC,
it should not be considered an important
histological criterion in grading SCC. Of-
ten, in the presence of an intact surface
epithelium, intraepithelial dysplasia may
be seen in direct continuity with the SCC.
Tumour growth at the invasive front can
show an expansive or cohesive pattern
(characterized by large tumour islands
with well-defined pushing margins) and
an infiltrative pattern (characterized by
scattered small irregular cords or single
tumour cells , with poorly defined infiltrat-
ing margins).
lmmunophenotype
SCC expresses various epithelial mark-
ers (e.g. cytokeratins, p63, and EMA).
Well-differentiated SCC expresses me-
dium/high-molecular-weight cytokerat-
ins (e.g . CK5/6) but not low-molecular-
weight cytokeratins (e.g. CK8 and CK18),
similar to normal squamous epithelium.
Poorly differentiated SCC tends to lose
expression of medium/high-molecular-
weight cytokeratins, and expresses low-
molecular-weight cytokeratins 11518) and
vimentin {2474) .
Differentia/ diagnosis
Well-differentiated SCC must be distin-
guished from verrucous and papillary
carcinomas, as well as from benign con-
ditions such as pseudoepitheliomatous
hyperplasia. Verrucous carcinoma lacks
atypia, which is always present in SCC.
Papillae formation and the absence of
keratinization characterize papillary SCC,
distinguishing it from SCC. Pseudoepi-
theliomatous hyperplasia is a benign
condition that consists of deep, irregular
tangues of epithelium that lack the atypia
and abnormal mitoses seen in SCC.
Poorly differentiated SCC must be dif-
ferentiated from melanoma, lymphoma,
and neuroendocrine carcinoma. The cor-
rect diagnosis is best determined by the
use of appropriate immunohistochem-
istry and special stains for demonstra-
tion of mucin production. Melanoma is
distinguished from SCC by its expres-
sion of S100, HMB45 , melan A and other
 ~-
Fig. 3.02 Conventional squamous cell carcinoma. A Well-differentiated squamous cell carcinoma: islands of tumour cells with clearly visible squamous differentiation and mild
nuclear and cellular pleomorphism. B Moderately differentiated squamous cell carcinoma: islands and cords of tumour cells with evident squamous differentiation and moderate
nuclear and cellular pleomorphism. C Poorly differentiated squamous cell carcinoma: solid growth of tumour cells with marked nuclear and cellular pleomorphism, high mitotic rate,
and barely discernible squamous differentiation. D Lymphatic invasion by squamous cell carcinoma. A tumour island wilhin a thin-walled lymphatic vessel.

melanocytic markers.
Neuroendocrine carcinoma expresses
neuroendocrine markers (e.g. synapto-
physin and chromogranin) but typically
lacks p63 expression and does not show
significant squamous differentiation ,
whereas SCC does not express neu-
roendocrine markers. Lymphoma is dis-
tinguished from SCC by the presence of
CD45 (leukocyte common antigen) and
markers of B-cell or T-cell differentiation.
Genetic profile
Laryngeal and hypopharyngeal SCCs
develop as a result of multiple genetic
abnormalities and the development of
aneuploidy {478,846). LOH and com-
parative genomic hybridization studies
have shown gains of 3q , 5p, 8q, 11q13,
and 18p with losses at 3p, 5q, 8p, 9p,
11q23-24, 13q, and 18q {1117,2100,
2310}. Loss of multiple tumour suppres-
sors is common, with the most commonly
affected genes including COKN2A and
TP53. Amplified and mutated oncogenes
include EGFR, VEGFA (previously called
VEGF) , PTGS2, PIK3CA , and matrix
metalloproteinases {360,1515}. Specific
tumour suppressor microRNAs (the let-7
family, miR-7, and miR-206) are down-
regulated {2627}.
Prognosis and predictive factors
The overall 5-year survival rate is 80-
85% for glottic SCC, 65-75% for supra-
glottic SCC, about 40% for subglottic
SCC (143}, 62.5% for hypopharyngeal
SCC {2247}, and 25-47% for tracheal
scc {820,1970}.
Clinica/ prognostic factors
Stage remains the most significant pre-
dictor of survival , and is discussed in
detail elsewhere. Depth of invasion and
the presence of regional and distant me-
tastases are independent predictors of
survival.
Localization is an important prognos-
tic factor {143} . The best prognosis has
been reported for glottic SCC, and the
worst prognosis for subglottic and tra-
cheal SCC.
Other factors that may have a significant
impact on the outcome of SCC include
patient age at presentation {425,2184},
comorbidity (concurrent diseases) {395},
and performance status {425}.
Histopathological prognostic factors
Differentiation. The reports on the prog -
nostic significance of traditional grading
into well -, moderately, and poorly dif-
ferentiated SCC are conflicting. Sorne
investigators have suggested that the
grading system has a significant asso-
ciation with survival {1896,2134,2607},
whereas others have not confirmed this
observation {425 ,1113} The main criti-
cism of this widely used system of grad-
ing is related to its subjective nature and
lack of objective criteria.
lnvasive front. lt has been shown that
the histological features at the invasive
front are prognostically much more im-
portant than those in the central and su-
perficial parts of the tumour {284,285,
2677}. A simple grading system has

Malignant surface epithelial tumours 83

been proposed for evaluation of the in-
vasive front, which correlates closely with
prognosis. Four histological features are
evaluated: degree of keratinization, nu-
clear polymorphism, pattern of growth,
and inflammatory response. The score
for each parameter is summarized as a
total malignancy score , with a high score
indicating poor prognosis 1284,285}. Pat-
tern of invasion also features prominently
in a multiparameter risk model for see
1258}.
Vascular and perineural invasion. The
penetration of tumour cells in the lym-
phatic and/or blood vessels is associat-
ed with a high probability of lymph node
and/or distant metastases. Vascular inva-
sion tends to occur in aggressive see
and is associated with recurrence and
poor survival l2678f. Similarly, perineural
invasion is associated with an increased
risk of local recurrence, regional lymph
node metastases, and poorer survival
1258,684,2134,2241,2678}.
Extracapsular spread in lymph nade
metastases. Metastases in the lymph
nodes are the single most adverse prog-
nostic factor in head and neck see 1710,
1353}. The presence of extracapsular
spread in lymph nodes is also prognos-
tically important and is strongly associ-
ated with both regional recurrence and
the development of distant metastases,
resulting in poorer survival 1262,710,996,
2315}. However, sorne studies have failed
to confirm the independent prognostic
significance of extracapsular spread
11520,1896}.
Verrucous squamous
ce// carcinoma
Zidar N.
eardesa A.
Gillison M.
Helliwell T.
HilleJ.
Nadal A.
Definition
Verrucous squamous cell carcinoma
(Ve) is a variant of wel l-differentiated
squamous cell carcinoma (SeC) that
lacks the cytological features of malig- Fig. 3.03 Laryngeal verrucous carcinoma. A broad-
nancy, grows slowly, and is locally inva- based exophytic tumour with a warty surface.
sive but does not metastasize.
Etiology
ICD-0 code 8051 /3 ve has been etiologically linked to to-
bacco smoking (1255,1565,1783,2252}.
Synonym Recent studies using highly sensitive and
Ackerman tumour 1453} specific molecular methods suggest that
ve is not associated with HPV infection
Epidemiology (557,1760,1825}.
ve is a rare tumour; in the USA, the in -
cidence between 2000 and 2011 was Localization
0.024 cases per 100 000 population. The larynx is the second most common
Most cases present in older males, in site of occurrence of ve in the head and
their sixth or seventh decades of life 1610, neck, after the oral cavity (1255f. Most
1565}. cases arise from the true vocal cords, but
ve may also occur in the supraglottis and
subglottis (610,1255,1565}, hypopharynx
11255}, and trachea 12278}.

Resection margins. Resection margins

clear of tumour are associated with a
lower recurrence rate and better surviv-
al 11148,2211}. Margins are considered
clear if there is no invasive see, see
in situ , or dysplasia. An adequate mar-
gin of resection has not been precisely
defined , but a margin of 5 mm is gener-
ally believed to be adequate 1995}. Sorne
studies have shown that even margins
of 1-2 mm are adequate, particularly in
glottic cancer 11698}.

Molecular factors. A systematic review

failed to show any prognostic value of
p53 expression in laryngeal carcinomas
11679,23531.
Fig. 3.04 Verrucous carcinoma. Full-thickness view showing hyperkeratotic surface and projections and invaginations
of well-differentiated squamous epithelium, invading the stroma with well-defined pushing margins.

84 Tumours of the hypopharynx, larynx, trachea and parapharyngeal space

 ' '
Fig. 3.05 Laryngeal verrucous squamous cell carcinoma. A Projections and invaginations of well-differentiated squamous epithelium, invading the stroma with well-defined pushing
margins. B Marked surface keratinization (so-called church-spire keratosis). C Verrucous carcinoma in the upper part of the figure, with transition to well-differentiated conventional
squamous cell carcinoma in the lower part.
Clinical features
The symptoms and signs of ve are simi -
lar to those of conventional see, with
hoarseness as the most common pre-
senting symptom. Other symptoms in-
clude airway obstruction, weight loss,
dysphagia, and throat pain 11565,1783).
Macroscopy
ve presents as a large, tan to white,
broad-based exophytic tumour with a
warty surface. On cut surface, it is usu-
ally firm , with sharply defined margins.
Histopathology
ve consists of thickened , club-shaped
projections and invaginations of well-dif-
ferentiated squamous epithelium, com-
posed of one to severa! layers of basal
cells and an expanded layer of spinous
cells that lack cytological atypia. There is
marked surface keratinization (so-called
church-spire keratosis). Mitoses are rare
and confined to the basal cell layer, and
there are no abnormal mitoses. ve in-
vades the stroma with a well-defined
pushing border, and invasion below the
leve! of adjacent epithelium may be dif-
ficult to demonstrate in small biopsies
unless the edge of the carcinoma is in-
cluded. Lymphoplasmacytic inflamma-
tion is common. lntraepithelial microab-
scesses may be present in association
with Gandida species superinfection.
ves that contain foci of conventional
see are considered hybrid (mixed)
tumours 1158).
The diagnosis of ve requires careful clini-
cal and pathological correlation because
the histological features have a wide dif-
ferential diagnosis, including epithelial
hyperplasia, squamous cell papilloma,
well-differentiated conventional see,
papillary see, and hybrid carcinoma (in-
vasive see and VC) . lnvasion below the
basal cell layer of the neighbouring nor-
mal epithelium differentiates ve from ver-
rucous hyperplasia, but these diseases
may occur concurrently, with a confluent
interface. Squamous cell papilloma has
thin, well-formed papillary fronds and is
less keratinized. The lack of cytological
atypia in ve distinguishes it from con-
ventional see, papillary see, and hybrid
carcinoma 1330). An apparent discrep-
ancy between the cl inical impression of
malignancy and benign-looking mor-
phology should raise the suspicion of VC.
There is no specific immunohistochemi-
cal marker for ve 11759,1761}.
Genetic profile
Molecular studies on ve are limited, and
the genetic profile of laryngeal ve is
largely unknown. The pattern of expres-
sion of microRNAs in ve differs from that
in conventional see; the importance of
this finding in the pathogenesis and di-
agnosis of ve remains to be determined
11758,1759).
Malignant surface epithelial tumours
Prognosis and predictive factors
ve is locally invasive and can cause
extensive destruction if left untreated. lt
does not metastasize to regional lymph
nodes or distant organs. lt has a better
prognosis than does conventional see;
the reported 5-year survival rate for la-
ryngeal ve is 85-95% 1610,1255). The
most important prognostic factor is stage
at diagnosis; treatment is by surgery or
radiotherapy 11052}. Hybrid carcinoma
has the potential for metastasis and
should be treated as conventional see
11783}.
Basa/oíd squamous
ce// carcinoma
Lewis J.S.
Gillison M.
Westra W.H.
Zidar N.
Definition
Basaloid squamous cell carcinoma
(BSeC) is a clinically unfavourable vari-
ant of squamous cell carcinoma (See)
composed of a prominent basaloid com-
ponent and with evidence of squamous
cell differentiation.
ICD-0 code 8083/3
85
Fig. 3.06 Basaloid squamous cell carcinoma. A Tightly nested pattern with stromal hyalinization and moulding of nests in a so-called jigsaw-puzzle pattern.
B High-power view showing keratin pearl formation and tumour cells with round nuclei and sean! cytoplasm. C Occasionally, stromal hyalinization may be abundan! mimicking a
salivary gland neoplasm.
Epidemiology
Approximately 80% of patients with
BSCC are White men in their mid -60s.
Etiology
Laryngeal and hypopharyngeal BSCC is
strongly linked to tobacco use (reported
in 80-90% of patients) and alcohol con -
sumption {658) . Transcriptionally active
high -risk HPV, an established etiological
factor at other sites, is consistently ab-
sent in BSCC arising at these anatomical
subsites (171,415).
Localization
The larynx is a common site for BSCC,
with a predilection for the supraglottis.
The tumours also occur in the hypophar-
ynx (piriform sinus) {658,775) and rarely
in the trachea {1152).
Clinical features
The symptoms and signs vary according
to the site of origin, but usually include
dysphagia, hoarseness, weight loss,
sore throat, cough , haemoptysis, and
neck mass. BSCC usually presents atan
advanced stage at the time of initial diag-
nosis, with lymph node metastases and
occasionally distant metastases {658) .
Macroscopy
There is no characteristic gross appear-
ance. The tumour usually appears as a
flat or slightly elevated lesion with central
ulceration and poorly defined borders.
Rarely, it presents as a polypoid tumour
(658).
Cytology
Aspirates of metastatic BSCC are cellu-
lar, with variably sized basaloid clusters
of malignant cells exhibiting numerous
mitotic figures and apoptotic bodies.
Keratinization and definitive squamous
differentiation may be rare and difficult to
86 Tumours of the hypopharynx, larynx, trachea and parapharyngeal space
discern. Necrosis and mixed inflamma-
tion are often present.
Histopathology
BSCC consists of basaloid and conven -
tional squamous components (2521). The
tumours are submucosal, with rounded
nests with smooth borders and peripheral
palisading. They tend to be closely ap -
posed , with thin lines of hyalinized stroma
between them, as if they are moulding to-
gether in a jigsaw-puzzle pattern. There
is frequent comedonecrosis, and the tu -
mour cells are round to oval and hyper-
chromatic. Nucleoli are usually lacking
but occasionally prominent. Gland-like
foci with basophilic myxoid or mucoid ma-
terial are common and mimic true gland
formation . A variable degree of nuclear
pleomorphism is present, and high mitotic
activity, apoptosis , and necrosis are com-
mon. Stromal hyalinization is characteris-
tic; it can be linear between and around
nests and nodular within nests. The con-
ventional component may include abrupt
keratinization adjacent to basaloid cells,
dysplastic changes in the squamous epi-
thelium, and conventional SCC.
lmmunohistochemistry is strongly posi-
tive for high -molecular-weight cytokerat-
ins, p63, and p40 (in a diffuse pattern).
BSCC is negative for synaptophysin and
chromogranin {1649,2129) . The differ-
ential diagnosis includes adenoid cystic
carcinoma - which lacks squamous
differentiation and shows partial p63
reactivity {655) - and small cell
neuroendocrine carcinoma - which has
angulated nuclei with speckled chromatin,
is positive for neuroendocrine markers,
shows punctate perinuclear reactivity for
cytokeratin (CAM5.2), and usually lacks
reactivity for high -molecular-weight cy-
tokeratins (2129) The diagnosis of BSCC
can still be made for tumours with all of
the basaloid features even if they lack any
overt histological evidence of squamous
differentiation. However, there must be
definitive immunohistochemical evidence
of squamous differentiation, and adenoid
cystic carcinoma and neuroendocrine
carcinoma must be ruled out.
Prognosis and predictive factors
lt has been debated whether BSCC has
a worse prognosis than conventional
SCC. Most investigators have found la-
ryngeal/hypopharyngeal BSCC to be
more aggressive than conventional SCC
(776). Patients with laryngeal BSCC have
higher rates of nodal metastasis (~50 -
70%) {658), significantly higher rates of
distant metastasis, and poorer progno-
sis than do patients with conventional
SCC {133,776,1439,2618). Active smok-
ers and patients with nodal metastases
at presentation have worse prognosis.
Given the relative rarity of laryngeal and
hypopharyngeal BSCC, no predictive
markers of proven clinical significance
have been developed . Because HPV-
related oropharyngeal basaloid carcino-
mas can be otherwise indistinguishable
from laryngeal/hypopharyngeal BSCC,
any tumour that appears to arise in the
larynx/hypopharynx but involves the oro-
pharynx should be tested for p16 and/
or high -risk HPV. This allows for the dis-
tinction of aggressive BSCC from more
prognostically favourable HPV-related
oropharyngeal carcinomas that are histo-
logically similar.
Fig. 3.07 Papillary squamous cell carcinoma.
atypical epithelial proliferation.
Papillary squamous ce//
carcinoma
El-Mofty S.K.
Cardesa A.
Helliwell T.
Hille J.
Nadal A.
Definition
Papillary squamous cell carcinoma
(PSCC) is characterized by a papillary
growth pattern, with thin fibrovascular
cores covered by severely dysplastic
epithelial cells or immature basaloid cells
with minimal or no maturation .
ICD-Ocode
Epidemiology
PSCC is uncommon; its exact prevalence
in the head and neck is unknown . lt is
more common in male patients, with a
male-to-female ratio of 2-3:1 {623 ,1140,
2030,2298,2394} In one study, PSCC
constituted 0.5% of all laryngeal cancers
{623}. The average patient age is report-
ed as mid-60s, with a slightly older aver-
age age among patients with oral PSCC
{587,728,2030,2298 ).
Etiology
Etiological factors include tobacco use
and alcohol consumption {728,2030,
2394), and HPV has recently been
shown to be an etiological agent in a
subset of PSCCs, particularly in the oro-
pharynx and sinonasal tract {1140,1580,
2298).
Localization
PSCC has been reported in almost every
site in the upper aerodigestive tract {587, Prognosis and predictive factors
1140,1580,2030,2298,2394) PSCC has a better prognosis than con-
ventional squamous cell carcinoma,
Clinical features primarily due to low-stage presentation,
The lesions are described as exophytic with a low metastatic potential {587,623 ,
growths that may be painless or painful. 1580,2030,2394). HPV-related PSCCs
They can be pink, white, or both pink and of the oropharynx show a trend towards
white . Laryngeal tumours are associated better patient survival than is associated
with hoarseness and airway obstruction . with HPV-negative PSCC {1580} .
Nodal metastasis is uncommon, and dis-
tant metastasis is rare {587,623,2030,
2298,2394). Spindle ce// squamous
ce// carcinoma
Macroscopy
Grossly, the lesion is papillary, friable, Bishop J.A.
and soft, with a pinkish-grey colour. Cardesa A.
Tumour size ranges from 0.2 to 4.0 cm Helliwell T.
{2298,2394). Hille J.
8052/3 Nadal A.
Cytology
Aspirates of metastatic lesions show fea-
tures of keratinizing or non -keratinizing Definition
squamous cell carcinoma. Spindle cell squamous cell carcinoma (SC -
SCC) is a variant of squamous cell carci -
Histopathology noma (SCC) characterized by predominant
A significant component of PSCC is malignant spindle and/or pleomorphic cells.
composed of papillary projections with
central fibrovascular cores. lnvasion ICD-0 code 8074/3
may be difficult to estab lish morpho -
logically, but is implied by metastatic
potential. The papillae are covered with
malignant epithelial cells with little or
no keratinization. Two types of surface
epithelium are described : one resem -
bles high-grade keratinizing epithelial
dysplasia, and in the other, the epithelial
cells are immature and basaloid, with no
evidence of maturation or keratinization .
Laryngeal tumours are not frequently
HPV-associated, whereas oropharyn-
geal tumours are typ ically strongly posi-
tive for p16 and are HPV-re lated {1580, Fig. 3.08 Laryngeal spindle cell squamous cell carcinoma.
2298). A polypoid mass involving the larynx.
Malignant surface epithe li al tumou rs 87

Synonyms
Sarcomatoid carcinoma; carcinosarcoma
Epidemiology
sesee is rare, accounting far < 1% of
all laryngeal malignancies {608 ,2396l
lt generally affects elderly patients, and
has amale predilection {608 ,2396,2506l
Etiology
sesee is linked to cigarette smok-
ing and alcohol consumption. A subset
of sesees may be radiation-induced.
sesees of the larynx and hypopharynx
are almost always negative far HPV {201,
2396,2555l.
Localization
The larynx, especially the glottis, is the
most frequently involved site. The hy-
popharynx is infrequently affected {608 ,
1398,1749,2396l.
Clinical features
Patients present with airway obstruction
and/or hoarseness {1398,2396l.
88 Tumours of the hypopharynx, larynx, trachea and parapharyngeal space
Macroscopy
sesee is usually a polypoid mass pro-
truding into the airway, often with an ul-
cerated surface mucosa {1398 ,2396 ,
2506l.
Cytology
Aspirates of metastatic sesee often
show at least focal keratinizing see, but
a malignant spindle cell component may
be all that is observed in sorne cases.
Histopathology
sesee is derived from the squamous
epithelium and demonstrates divergent
differentiation by epithe lial-mesenchy-
mal transition {437,1259,1749,2727¡. lt
characteristically grows as an exophytic
mass with a predominantly ulcerated sur-
face, sometimes containing remnants of
dysplastic squamous epithelium and fre-
quently showing areas of transition to ma-
lignant spindled or pleomorphic tumour
cells. Most sesees demonstrate a hap-
hazard growth pattern of the spindled
cells, and 7-15% of cases exhibit hetera-
logous mesenchymal differentiation in
the form of malignant bone, cartilage,
or skeletal muscle {1398 ,2396,2702l
sesee is usually overtly malignant,
with hypercellularity, necrosis, atypi-
cal mitotic figures , and hyperchromatic
nuclei demonstrating marked nuclear
pleomorphism. However, a subset of
sesees are deceptively bland in areas,
with or without prominent areas of hya-
linization , mimicking reactive myofibro-
blastic proliferation or granulation tissue.
The diagnosis of sesee rests on dem-
onstrating epithelial differentiation , either
on routine morphology (i.e. squamous
dysplasia of residual surface epithelium
or foci of conventional see mixed with
sarcomatoid tumour) or by immunohisto-
chemistry far cytokeratins (e.g. AE1 /AE3),
EMA , p63, or p40 {1406,1749l Howev-
er, as many as one third of sesees are
purely spindled , and a significant subset
is negative far epithelial markers {1398 ,
1749,2396,2506l. True sarcomas of the
larynx/hypopharynx are rare, and a ma-
lignant spindle cell neoplasm arising at
these sites is best considered an sesee
until proven otherwise.
Genetic profile
sesee harbours complex genetic al-
terations, similar to poorly differentiated
Sees {436,437l.
Prognosis and predictive factors
Despite its poorly differentiated appear-
ance, sesee of the larynx/hypopharynx
(in particular the true vocal cord) tends
to present at a low stage and , stage-far-
stage, has a prognosis similar to that of
conventional see {187,608,1398,2396,
2506l. Exophytic sesees are more eas-
ily resected and have the best prognosis
{2396l.
Adenosquamous carcinoma
Prasad M.L.
Cardesa A.
Helliwell T.
Hille J.
Nada! A.
Definition
Adenosquamous carcinoma (ASC) is
a malignant tumour that arises from the
surface epithelium and shows both squa-
mous and glandular differentiation.
ICD-0 code 8560/3
Epidemiology
ASC is rare. lt has a male predisposition
and usually develops in the sixth or sev-
enth decade of life (patient age range:
34-81 years) {1209) .
Etiology
As with squamous cell carcinoma (SCC),
smoking and alcohol consumption are like-
ly predisposing factors (1209). No associa-
tion with HPV has been reported in ASC
from the larynx and hypopharynx (1553)
Localization
The larynx is a frequently affected site in
the head and neck (60,1194,1209). A few
cases in the hypopharynx have been re-
ported (1314,1548,1553,2093).
Clinical features
Patients may present with hoarseness ,
sore throat, dysphagia, haemoptysis, or
neck mass (1209).
Macroscopy
ASC may present as an exophytic or
polypoid mass (median size : 4 cm) or as
mucosa! induration or ulceration, similar
to SCC {825,1209}.
Cytology
Asp irates of metastases show features
of keratinizing SCC. Malignant glandular
components , including cells with intracy-
top lasmic mucin, can be seen.
Histopathology
ASC has a biphasic morphology, with
squamous and glandular differentiation.
Origin from surface epithelium is support-
ed by the presence of squamous dyspla-
sia. The squamous and adenocarc inoma-
tous components are distinct but located
Laryngeal adenosquamous carcinoma. A blending of !he squamous and glandular components.
in clase proximity, an important diagnostic
feature. The adenocarcinoma consists of
cribriform and tubuloglandu lar structures
and tends to occur in the deeper parts of
the tumour (1209). lntraluminal (or rarely,
intracytoplasmic) mucin may be demon-
strated by special stains, such as peri-
odic acid-Schiff (PAS), Alcian blue, and
mucicarmine. The tumour shows necrosis,
mitoses, and vascular an d perineural in -
vasion consisten! with its high-grade na-
ture. Metastatic ASC may display on ly one
component.
lmmunohistochemistry shows the expres-
sion of p63 in the squamous componen!;
carci noembryonic antigen, low-molecu-
lar-weight cytokeratin (CAM5.2), and CK7
in the adenocarcinomatous component;
and high -molecular-weight cytokeratin in
both components (1314,1548) . CK20 is
usually negative (1509}
The differential diagnosis includes mu-
coepidermoid carcinoma, adenoid SCC,
and conventional SCC invading the se-
romucinous glands. Distinction from mu-
coep idermoid carci noma is importan! be-
cause ASC has a worse prognosis (Table
Table 3.01 Differences between adenosquamous and mucoepidermoid carcinoma
Adenosquamous carcinoma
Evidence of origin from overlying squamous epithelium
(e.g. dysplasia)
Keratinization in squamous cells, keratin pearls
lnfiltrative glands al deeper parts
Squamous and adenocarcinoma adjacent to each other
Secondary invasion of submucosal glands
No intermediate cells
No MAML2 translocation
ªThe presence of MAML2translocation rules out adenosquamous carcinoma, but MAML2translocation is some-
times absent in mucoepidermoid carcinoma {1194).
Malignan! surface epithelial tumours
3.01). Demonstration of mucin and carci-
noembryonic antigen helps to distinguish
ASC from adenoid SCC. Conventional
SCC invading or entrapping seromuci-
nous glands is differentiated by its lobular
architecture and the ben ign cytomorphol-
ogy of its glandular cel ls (1209). Necrotiz-
ing sialometaplasia, which is rare in the
larynx, is characterized by the retention
of the lobular architecture of the seromu-
cous glands (despite being replaced by
squamous metaplasia), ischaemic necro-
sis of the acini, chronic inflammation, and
pseudoepitheliomatous hyperplasia of the
overlying squamous ep ithelium {1962)
Prognosis and predictive factors
ASC is more aggressive than convention-
al SCC, with a propensity for recurrence
and dissemination (60,703). Regional
lymph node metastases occur in about
75% of patients, and nearly 25% of pa-
tients develop distant metastases, most
common ly to lung {1209). Cl inical stage
at presentation seems to correlate with
prognosis. The 5-year survival rate is ap-
proximately 13-50% {1194,1209,2093).
Mucoepidermoid carcinoma
No evidence of origin from overlying squamous
epithelium
No keratinization or keratin pearls
Glands widespread with lobular arrangement
Epidermoid and glandular cells closely intermingled
within lobules of tumour
Arising from submucosal glands
lntermediate cells present
Usually associated with MAML2 translocationª
89
Lymphoepithelial carcinoma
Bishop J.A.
Gaulard P.
Gillison M.

Definition
Lymphoepithelial carcinoma (LEC) is a
squamous cell carcinoma morphological-
ly similar to non-keratinizing nasopharyn-
geal carcinoma, undifferentiated subtype.

ICD-0 code 8082/3

Synonym
Lymphoepithelioma-like carcinoma

Epidemiology Localization Histopathology

LEC of the larynx, hypopharynx, and tra-
chea is rare, with only about 40 reported
cases. lt affects older patients (mean pa-
tient age: 62 years), and there is a male
predominance. Unlike nasopharyngeal
carcinoma, which most frequently affects
Asian patients, LEC in the larynx usually
occurs in White patients (381 ,1507,2584,
2706).
Etiology
There is an association with smoking and
alcohol consumption (604,1507,2584).
There is also an association with EBV,
although notas strong an association as in
nasopharyngeal cases (1214,2584,27061.
LEC occurs more frequently in the lar-
ynx than in the hypopharynx. Rare cases
have arisen in the trachea (1363 ,1777,
2340).
Clinical features
Patients present with hoarseness, neck
mass, dysphonia, dysphagia, neck pain ,
and/or haemoptysis !604,1507,2584}
Cytology
Aspirates of metastases show findings
similar to those seen in aspirates of non-
keratinizing undifferentiated nasopharyn-
geal carcinoma .
LEC is defined by its resemblance to
non-keratinizing undifferentiated naso-
pharyngeal carcinoma (see Nasopharyn-
geal carcinoma, p. 65, Chapter 2). Unlike
in the nasopharynx, LEC uncommonly
harbours EBV in the larynx.
Prognosis and predictive factors
According to SEER data, laryngeal LEC
has a 5-year disease-specific survival
rate of approximately 60% (381) Re-
gional lymph node metastasis occurs in
approximately 75% of cases , with dis-
tant metastasis in approximately 25%
(1507).

90 Tumours of the hypopharynx, larynx, trachea and parapharyngeal space

Precursor lesions
Dysp/asia
Gale N.
HilleJ.
Jordan R.C .
Nada! A.
Williams M.O.
Definition
Dysplasia at this body site constitutes a
spectrum of architectural and cytological
epithelial changes of the upper aerodi-
gestive tract, caused by an accumulation
of genetic changes that can be associ-
ated with an increased likelihood of pro-
gression to squamous ce!! carcinoma.
ICD-0 codes
Dysplasia, low grade 8077/0
Dysplasia, high grade 8077/2
Synonyms
Squamous intraepithelial lesions; squa-
mous intraepithelial neoplasia
Epidemiology
Dysplasia is seen mostly in adults and af-
fects men more often than women, with a
male-to-female ratio as high as 4.6:1 (799) .
This disparity is especially evident after
the sixth decade of life. Epidemiological
studies of laryngeal dysplasia are scarce.
The annual incidence of laryngeal pre-
cancerous mucosa! changes in the USA
is 10.2 and 2.1 lesions per 100 000 males
and females, respectively {245).
Etiology
Cigarette smoking has been established
as the principal risk factor in laryngeal
carcinogenesis, especially in combina-
tion with alcohol abuse. The increased
risk is linked to age at the start of smok-
ing, duration of smoking, and quality of
tobacco (2039,2451 ). Gastro-oesoph-
ageal reflux disease is also considered
to be a possible risk factor {1395 ,2128).
High-risk HPV infection plays a minor role
in dysplasia development {621 ,803 ,1644,
1799). Only integrated and transcription-
ally active HPV can play a significant role
in carcinogenesis, and HPV 16 is the
most frequent genotype (922,1408) The
overa!! prevalence of HPV in dysplasia
Table 3.02 Morphological criteria for the classification of laryngeal precursor lesions {797)
Low-grade dysplasia (including previous category of mild dysplasia):
Low malignan! potenlial; a spectrum ol morphological changes ranging from squamous hyperplasia to an
augmentation ol basal and parabasal cells occupying as much as the lower hall ol the epithelium, while the upper
portian retains maturation
Stratification is preserved: transition ol basal cells or augmented basal/parabasal
cell layer with perpendicular orientation to the basement membrane to prickle cells
horizontally oriented in the upper part
Spinous layer: spectrum of changes ranging from increased spinous layer in the
Architectural criteria
whole thickness up to changes in which prickle cells are seen only in the upper
epithelial hall
Basal/parabasal layer: spectrum ol changes, from 2-3 unchanged layers to
augmentation ol basal and parabasal cells in the lower hall of the epithelium
Al most minimal cellular atypia
Parabasal cells: slightly increased cytoplasm compared to basal cells, enlarged
Cytological criteria nuclei, uniformly distributed chromatin, no intercellular bridges
Rare regular mitoses in ornear basal layer
Few dyskeratotic cells presenl
-High-grade dysplasia (including previous categories of moderate dysplasia, severe dysplasia, and -
carcinoma in situ):
A premalignant lesion; a spectrum ol changes including immature epithelial cells occupying at leas! the lower hall ol
the epithelium and as much as the whole epithelial thickness
Abnormal maturation
Variable degrees of disordered stralification and polarity in as much as the whole
epithelium
Altered epithelial cells usually occupying from hall to the entire epithelial thickness
Architectural criteriaª
Two subtypes: keratinizing (spinous-cell type) and non-keralinizing (basal-cell type)
Variable degree ol irregularly shaped rete (bulbous, downwardly extending), wilh an
intact basement membrane
No stromal alterations
Easily identified to conspicuous cellular and nuclear atypia, including marked
variation in size and shape, marked variation in slaining intensity with frequent
hyperchromasia, nucleoli increased in number and size
Cytological criteriaª lncreased N:C ratio
lncreased mitoses al or above the suprabasal level, with or without atypical forms
Dyskeratotic and apoptotic cells are frequenl throughout the enlire epithelium
-
ªcomplete loss ol stralification and polarity and/or severe cytological atypia and atypical mitoses qualifies as
carcinoma in situ il a three-liered system is used.
studies published since 2005 is 12% Voice change, hoarseness, sore throat,
(range: 0-38%) {621,803,1644,1799). and chronic cough are most common .
Localization Macroscopy
Dysplasia can occur anywhere in the lar- Dysplasias are clinically identified as leu-
ynx, but it occurs most frequently along koplakias (white patches), erythroplakias
one vocal cord and less frequently along (red patches), erythroleukoplakias (red
both vocal cords. The commissures as and white patches), or chronic laryngitis.
well as hypopharyngeal and tracheal They present as small or large patches
regions are rarely involved {801,1158, that are localized or diffuse, or as flat or
2349). exophytic and papillary lesions. Macro-
scopic appearance does not have any
Clinical features specific connotations for microscopy,
The symptoms and signs vary accord- which must always be determined histo-
ing to the location and size of the lesion . logically {247,801) .
Precursor lesions 91
Table 3.03 Terminology and grading systems used far dysplasia / squamous intraepithelial lesion {SIL) epithelial changes in order to determine
Level of the appropriate treatment {733 ,1574,
SIN Ljubljana 2076). A review of the currently used
abnormal WHO 2005 1 Amended Ljubljana WH02017
1
classification classification
maturation 1 {146} classification {797} histological grading systems and their
{850} {799}
(WHO 2005) approximate relationship is presented in
Squamous Squamous Squamous Table 3.03 {2592) .
hyperplasia hyperplasia hyperplasia Low-grade In an effort to harmonize the various
Low-grade SIL
Mild Basal/parabasal dysplasia concepts of the listed classifications,
Lower 1/3 SIN 1 with their various morphological crite-
dysplasia hyperplasia
Moderate
ria and different terminology, a unified,
1/3to1 /2 SIN 1orSIN2 two-g rade system is proposed, with
dysplasia
clear morphological criteria for defining
Moderate Atypical
Upper 1/2 to 3/4 High-grade SIL the prognostic groups: low-grade (mild
dysplasia hyperplasia High-grade
dysplasia) and high-grade (moderate
Severe dysplasia*
Full thickness SIN 2 and severe dysplasia / carcinoma in situ)
dysplasia
{797). lf a three-tiered system is preferred
Carcinoma Carcinoma for treatment purposes, the high-grade
Carcinoma in situ
in situ in situ 1
1 1 1 category can be further separated into
*lf a three-tiered system is used, carcinoma in situ is separated from high-grade dysplasia. high-grade dysplasia and carcinoma in
SIN, squamous intraepithelial neoplasia. situ {797). For a morphological descrip-
tion of each grade of dysplasia, see Ta-
ble 3.02.
Ancillary studies (e.g. p53 , p16 , Ki-67,
and EGFR) are currently not recommend -
ed for dysplasia classification.

Fig. 3.13 Leukoplakia ofthe left vocal cord. The anterior
par! of !he left vocal cord is irregularly thickened and
covered by whitish plaques.
Histopathology
Several classification systems have been
devised to represent the spectrum of his-
tological changes and their relation to bi-
ological behaviour, especially malignant
progression {732,797,1291 ,2582}.
Fig. 3.14 Low-grade dysplasia. Hyperplastic squamous
epithelium shows augmented parabasal cells extending
up to one third of !he epithelium thickness; !he upper hall
of !he epithelium is unchanged.
Although the grading of upper aerodi-
gestive tract dysplasia is to a certain
degree a subjective process , grade is
the most important prognostic factor for
the biological behaviour of disease, be-
cause clinicians need a descriptor of the
Genetic profile
Accumu lation of genetic alterations
produces aneuploidy in preneoplastic
cells {2072,2680). Laryngeal dysplas-
tic lesions show frequent chromosomal
changes/LOH at 9p21, 17p13, 3p26,
and 3p14, with alterations at 9p21 be-
ing the earliest and most frequent, sug-
gesting the implication of the CDKN2A
gene in the early phases of neoplastic
transformation. The most likely target of
17p13 LOH is TP53 {1679). Other mo-
lecular alterations consistently detected
in premalignant laryngeal lesions include
cyclin 01 overexpression {1814) and tel-
omerase activity reactivation {1451,1496,

~:li.J:~"Íl~-~¡.i: ~~~~~~~,.;¡~ ......·~

~ s - ~ 7 ' '!..t....,...,;. ...
Fig. 3.15 High-grade dysplasia. A The hyperplastic epithelium is entirely occupied with moderately pleomorphic epithelial cells of basaloid type; perpendicular orientation to !he
basement membrane is evident. B Two thirds of !he epithelial thickness is occupied by moderately polymorphic epithelial cells with spinous differentiation; mitoses are seen in !he
lower epithelial par!, and a !hin parakeratotic layer is present on !he surface.

92 Tumours of the hypopharynx, larynx, trachea and parapharyngeal space


Fig. 3.16 High-grade dysplasia I carcinoma in situ. Prominent architectural disorder; epithelial cells show severe
cellular and nuclear atypia, mitoses are present, !he basement membrane is intact, and a thick parakeratotic !ayer is
evident on !he surface (see Table 3.02, p. 91 ).
1497). None of these findings are cur-
rently of diagnostic or prognostic utility.
Prognosis and predictive factors
A retrospective follow-up study found a
highly significant difference in the risk
of malignant progression between low-
and high -grade lesions, at 1.6% and
12.5%, respectively j797,1184) Certain
high-grade dysplasias (i.e. carcinomas
in situ) are associated with higher risk of
progression to invasive growth (occurring
in 40% of cases) and may require more
extensive surgery or radiation therapy,
depending on the specific site (e.g . an-
terior commissure) and contributing risk
factors (e .g. alcohol consumption and to-
bacco use) 12710).
Squamous ce// papilloma and
squamous ce// papillomatosis
Richardson M.
Gale N.
Hille J.
Zidar N.
Definition
Squamous cell pap illoma and squamous
cell papillomatosis are benign exophytic
squamous epithelial tumours composed
of branching fibrovascular cores, usu-
ally associated with HPV infection (geno-
types 6 and 11)
ICD-0 codes
Squamous cell papilloma
Squamous cell papillomatosis
Synonyms
Recurrent respiratory papillomatosis; la-
ryngeal papillomatosis; juvenile papillo-
matosis; adult papillomatosis
Epidemiology
Squamous cell papilloma is the most
common benign epithelial tumour of the
larynx. Recurrent respiratory papilloma-
tosis (RRP) is characterized by multiple
contiguous, locally recurrent squamous
cell papillomas, although solitary lesions
present infrequently. RRP is a rare dis-
ease involving the respiratory tract that
occurs in both children and adults. The
true incidence and prevalence of RRP
are uncertain. The best projected esti-
mates of annual incidence are 4.3 cases
per 100 000 children and approximately
1.8 cases per 100 000 adults j331,570}.
The bimodal age distribution demon -
strates the first peak in children aged
< 5 years (juvenile cases) and the sec-
ond peak in patients aged 20-40 years
(adult cases) (331,1257) RRP is more
common in children and is the most ag-
gressive form of the disease, with 25% of
cases presenting during infancy (1969,
2604). There is no sex predominance
in children, but in adult patients there is
a male-to-female ratio of 3:2 (570,602,
1774). Although the disease is rare, mor-
bidity is notoriously high, compromising
functions such as vocalization , swallow-
~ ·..,
ing, and breathing (821,2605)
Etiology
HPV 6 and 11 are the most frequent
genotypes (seen in 90% of cases) asso-
ciated with RRP as well as solitary pap-
illomas (800,2605) A minority of cases
(4-5%) have coinfection with genotypes
HPV 6 and 11, and fewer cases (3-4%)
with other HPV genotypes (e.g . 16, 31,
33, 35, and 39) (2605) .
The modes of HPV transmission include
sexual contact, non-sexual contact,
and maternal contact (direct or indirect)
(1324). Most neonatal HPV infection oc-
curs by vertical transmission at birth
(2325). A triad of factors (first-born
child, vaginal delivery, and maternal age
< 20 years) has been noted to correlate
with RRP in children (1192). Caesarean
section provides a lower risk of trans-
mission but is not completely protective
8052/0 against infection. In contrast, active ma-
8060/0 ternal genital HPV infection at the time of
delivery increases exposure to a signifi-
cant viral load, with a high risk far trans-
mitting infection (1324,2325}. In adults,
the mode of viral transmission remains
unclear; transmission during sexual con-
tact and reactivation of a slow-progress-
ing laten! infection from childhood have
been suggested (1199,1775,2028). The
unpredictable clinical course of RRP
suggests possible host-specific genetic
and immunological factors. Differences
in HPV-specific immune response have
been demonstrated between patients
with RRP and controls (234,331,1742,
2003).
Precu rsor lesions 93
Localization
The papillomas usually involve the vo-
cal cords and ventricles, followed by
transmission to the false cords , epiglot-
tis, subglottic area, hypopharynx, and
nasopharynx. Rarely (in 1- 3% of cases),
the papillomas may extend to the lower
respiratory tract, which is associated with
high mortality {821,1742,2325). The distri-
bution of RRP follows a predictable pat-
tern, with the tumours occurring at sites
where ciliated and squamous epithelium
is juxtaposed.
Clinical features
The presentation includes progressive
hoarseness and stridor associated with
growths of exophytic \esions within the
larynx.
Macroscopy
The proliferative \uminal growths are exo-
phytic, sessile, or pedunculated masses
with bosselated surfaces. The papillo-
mas often grow as a friable cluster and
bleed easily with minor trauma.
Histopathology
Squamous ce\\ papillomas have a core
composed of an arborizing fibrovascular
network covered by squamous epithe-
lium. Parabasal cell hyperplasia is often
seen involving the lower half of the epi-
thelium. Pronounced to subtle koilocytic
Fig. 3.18 Laryngeal papillomatosis. Florid papillomas line the endolarynx in this case of recurren! respiratory
papillomatosis.
94 Tumours of the hypopharynx, larynx, trachea and parapharyngeal space
Fig. 3.17 Laryngeal papillomatosis. A Recurren! res-
piratory papillomatosis fills the endolaryngeal space.
B Endoscopic view of multicoated clusters of papillomas
within a larynx.
features are seen in the upper layers of
the epithelium. Mitotic features are seen
along the basal to medial aspect of the
epithelium. Premature keratinization of
individual epithelial cells contributes to
a disorganized appearance. Surface
keratinization is minimal. Premalignant
features are infrequent but should be re -
ported if present.
HPV genotype and variants can be de-
termined using sensitive conventional or
real-time PCR {1774). Although far \ess
sensitive, and unable to detect HPV vari-
ants, in situ hybridization has also been
used. Failure to detect HPV by in situ hy-
bridization is considered consistent with
a low copy number of HPV, be\ow the de-
tection sensitivity threshold of the in situ
hybridization technique. However, spe-
cific patterns of in situ hybridization sig-
nals indicate that the viral status is either
episomal (a diffuse signa\ pattern) or in-
tegrated (a punctate signal pattern). The
mechanism of squamous cell papilloma
recurrence in juveniles may be more at-
tributable to HPV integration {274).
Prognosis and predictive factors
The clinical course of RRP is unpredicta-
ble and ranges from complete remission,
to relatively stable lesions, to an aggres-
sive clinical course of rapid progressive
recurrences requiring surgical interven-
tion, and potentially life-threatening res-
piratory obstruction {570,1522,2325).
The clinical significance of variants of the
HPV 6 and 11 genotypes in patients with
RRP is unknown {1522).
Sorne studies have found the HPV 11
genotype to be the most important risk
factor for aggressive clinical course, but
this finding has not been consistently rep-
licated {1774, 2605). Other studies sug-
gest that patient age at onset is important
{286} Children diagnosed at < 3 years of
age are 3.6 times as likely to have more
than four surgeries per year as are chil-
dren diagnosed at an older age {1774,
1969). HPV 11 is more closely associated
with a younger age at diagnosis, and in
sorne studies it is associated with an ag-
gressive clinical course {2605). In adults,
both HPV 11 and an observation time
> 10 years have been found to be as-
sociated with aggressive clinical course
{1774). These data suggest that there are
factors other than HPV type and patient
age that determine disease course {286).
A retrospective sequence analysis of
HPV in RRP showed no evidence of
strain replacement in 95% of cases dur-
ing a median follow-up of 4 years, with
one case having 22 years of follow-up
{1257). These fin dings indicate that the
frequent recurrence of RRP is a conse-
quence of the long-term persistence of
the initial HPV genome variant. Whether
Neuroendocrine tumours
Well-differentiated
neuroendocrine carcinoma
Perez-Ordonez B.
Bishop J.A.
Gnepp D.R.
Hunt J.L.
Thompson L.D.R .
Definition
Well -differentiated neuroendocrine carci -
noma is a low-grade epithelial neoplasm
disease severity correlates with specific
HPV variants has yet to be determined,
but sorne initial reports suggest that there
may be significance {265,474,1086,1522}.
The quadrivalent vaccine (against HPV 6,
11, 16, and 18) protects against the most
common HPV genotypes associated with
composed of cells that demonstrate evi-
dence of neuroendocrine differentiation.
ICD-0 code 8240/3
Synonyms
Carcinoid; neuroendocrine carcinoma,
grade 1
Epidemiology
Well -differentiated neuroendocrine carci -
nomas are rare, accounting for approxi -
mately 5% of laryngeal neuroendocrine
RRP. The effect of this vaccine on trans-
mission has yet to be determined {331).
Malignant transformation of RRP into
squamous cell carcinoma is reported in
1- 4% of cases and occurs primarily in
the setting of irradiation, smoking, or an-
other promoter {570,1166,1199,1775) .
carcinomas {2230 ,2463). They are more
common in men and typically arise in
middle-aged patients (median patient
age: 62 years) {639,2230,2463).
Etiology
Most patients have a history of heavy to-
bacco use {2463).
Localization
More than 90% of cases develop in
the supraglottic larynx, with low-stage
disease {639,2463).
Neuroendocrine tumours 95

,. ......
Fig. 3.21 Well-differentiated neuroendocrine carcinoma (typical carcinoid tumour) demonstrating diffuse expression
of chromogranin.
Clinical features
Patients present with hoarseness, dys-
phagia, and airway obstruction (639,
2463) Rarely, a paraneoplastic syn-
drome (due to aberrant hormone pro-
duction by the tumour) may be identified
{218,709,2463,2586).
Macroscopy
The tumours present as submucosal
fleshy polypoid or sessile masses,
0.5-3 cm in size {2586).
Histopathology
The tumour cells grow in nests, cords,
sheets, and trabeculae of round to slight-
ly spindled cells with ample amphophilic
to eosinophilic granular (sometimes on-
cocytic) cytoplasm . Gland-like structures
or rosettes may be seen , exceptionally
containing mucin vacuoles. The tumour
nuclei exhibit stippled, evenly dispersed
chromatin in a salt-and -pepper pattern.
Minimal nuclear atypia is seen, mitotic
rates are low (< 2 mitoses per 2 mm 2 or
96 Tumours of the hypopharynx, larynx, trachea and parapharyngeal space
... . -
1O high-power fields) , and necrosis is ab-
sent. The tumour stroma is often fibrotic
and highly vascular.
The neoplastic cells are positive for cy-
tokeratins , EMA, and at least one neu-
roendocrine marker (e.g. synaptophysin ,
chromogranin, or C056). Peptides (e.g.
serotonin, calcitonin, and somatostatin)
may be positive, and TTF1 is variably
positive. Ki-67 immunohistochemistry is
not used in the grading of neuroendo-
crine tumours.
Prognosis and predictive factors
The prognosis is difficult to determine
dueto the rarity of this tumour, but seems
to be good after surgery or laser resec-
tion . Recurrence and metastasis rates as
high as 30% have been reported, with
a 5-year survival rate of approximately
80% {639 ,2463). Older studies reported
a more aggressive behaviour, due to the
inclusion of moderately differentiated
neuroendocrine carcinomas (2229 ,2230,
2463)
Moderately differentiated
neuroendocrine carcinoma
Perez-Ordonez B.
Bishop JA
Gnepp D.R.
Hunt JL
Thom pson L.D.R .
Definition
Moderately differentiated neuroendocrine
carcinoma is an epithelial neoplasm
demonstrating neuroendocrine differen-
tiation with a histological grade between
wel l-differentiated and poorly differenti-
ated neuroendocrine carcinoma.
ICD-0 code 8249/3
Synonyms
Atypical carcinoid ; neuroendocrine car-
cinoma , grade 11
Epidemiology
These are the most common neuroen-
docrine carcinomas of the larynx (2463,
2586,2631). They occur more frequently
in men, with a male-to-female ratio of
2.4:1 , and have a peak incidence in the
sixth and seventh decades of life (mean
patient age: 63 years) (2463 ,2586,2589).
Etiology
Most patients are heavy tobacco users
(2463 ,2589).
Localization
More than 90% of cases occur in the su-
praglottic region {2463 ,2589).

Fig. 3.23 Laryngeal moderately differentiated neuro-
endocrine carcinoma. Staining for calcitonin.
Clinical features
Patients present with hoarseness,
dysphagia, sore throat, and occasion-
ally haemoptysis !2586,2589}. Rarely, a
paraneoplastic syndrome (due to aber-
rant hormone production by the tumour)
may be identified j709,2463l.
Macroscopy
The tumours are tan-pink polypoid sub-
mucosal masses, 0.2-4 cm in size, and
often covered by an ulcerated surface
mucosa l2586,2589l.
Histopathology
The tumour cells grow in nests, cords ,
sheets, and trabeculae of round to
slightly spindled cells with ample ampho-
philic to eosinophilic granular cytoplasm.
Gland-like structures or rosettes may be
seen. The tumour nuclei may exhibit stip-
pled, evenly dispersed chromatin or may
show more nuclear atypia with prom i-
nent nucleoli. The defining features are
necrosis and/or 2-1 O mitos es per 2 mm 2
or 10 high -power fields. Sorne tumours
demonstrate oncocytic cytoplasm or
stromal amyloid deposition.
The neoplastic cells are positive for cy-
tokeratins and at least one neuroendo-
crine marker (e.g. synaptophysin, chro-
mogranin , or CD56). TTF1 is variabl y
expressed. These tumours are frequently
positive for calcitonin , which creates a
potential diagnostic pitfall, particularly in
a lymph node metastasis , where the tu-
mour can be mistaken for medullary thy-
roid carcinoma.
Prognosis and predictive factors
Approximately 30% of patients present
with advanced disease, with a recurrence
rate of about 60% and a 5-year survival
rate of 50% !2463,2589,2632). There are
no specific histological features that pre-
dict outcome.
Poorly differentiated
neuroendocrine carcinoma
Perez-Ordonez B.
Bishop J.A.
Gnepp D.R.
Hunt J.L.
Thompson L.D.R.
Definition
Poorly differentiated neuroendocrine car-
cinoma is a high-grade malignant epithe-
lial neoplasm with evidence of neuroen-
docrine differentiation. Two subtypes are
recognized : small cell neuroendocrine
carcinoma (SmCC) and large cell neu-
roendocrine carcinoma (LCNEC).
ICD-0 codes
Small cell neuroendocrine carcinoma
8041/3
Large cell neuroendocrine carcinoma
8013/3
Synonyms
Small cell carcinoma, neuroendocrine
type; oat cell carcinoma; neuroendo-
crine carcinoma, grade 111
Epidemiology
lt is the second most common neuroen-
docrine carcinoma of the larynx, tends to
arise in older men (median patient age:
60 years), and has a male-to-female ra-
tio of 2.3-4 .3:1 j848,855,1407,2463}.
Etiology
More than 90% of patients are cigarette
smokers !1407,2463). An association
with HPV has been identified , but may
not be as significant as the association
of HPV with oropharynx or sinonasal tract
tumours !2382).
....~·-.::-~·~--
Fig. 3.24 Small cell neuroendocrine carcinoma of the supraglottic larynx. Tumour composed of small cells with a high
N:C ratio, growing in sheets; the tumour cells exhibit dense hyperchromatic nuclei lacking visible nucleoli; numerous
mitoses and apoptotic cells are present.
Localization
Within the larynx, there is a predilection
for the supraglottic larynx, followed by
the subglottis !848,855,2463).
Clinical features
Patients present with non-specific symp-
toms , including hoarseness and/or dys-
phagia !848,855,1407,2463}. Many pa-
tients have regional or distant metastases
at presentation !1612}. Rarely, paraneo-
plastic syndromes are reported !709}.
Macroscopy
The tumour is a fleshy, ulcerated submu-
cosal mass !848,1404).
Histopathology
SmCC grows in nests, sheets , and tra-
beculae of cells, with occasional nuclear
palisading or rosette-like structures. lt is
highly infiltrative, with frequent perineural
and lymphovascu lar invasion. The tu -
mour is composed of small to medium-
sized cells with hyperchromatic nuclei,
finely granular chromatin, and indistinct
nucleoli with scant cytoplasm. Nuclear
moulding , prominent crush artefact, ne-
crosis, apoptosis, and DNA coating of
vessel walls (the Azzopardi phenome-
non) are classic features, accompanied
by a high mitotic rate (> 10 mitoses per
2 mm 2 or 10 high-power fields).
LCNEC shows organoid nesting , pali-
sading , rosettes, and/or trabeculae . lt is
composed of medium-sized to large cells
with abundant cytoplasm . The nuclei
have coarse chromatin (sometimes with
a speckled, salt-and-pepper quality) and
usually have a single prominent nucleo-
lus. The tumour exhibits comedonecrosis
and a high mitotic rate (> 10 mitoses per
2 mm 2 or 10 high-power fields) .
.... ....... __
·- ~'~-~~
!!.t'.:'!~~~
Neuroendocrine tumours 97
 _, ,
Fig. 3.25 Large cell neuroendocrine carcinoma of the supraglottic larynx. A The tumour exhibits a lobular architecture with central comedonecrosis; the tumour is composed of
large cells with vesicular nuclei and prominent nucleoli. B Numerous rosettes. The tumour cells show oval to elongated nuclei with readily visible nucleoli and numerous mitoses.
C Sheets of large cells showing slight moulding, with delicate salt-and-pepper nuclear chromatin; mitoses are easily identified throughout. D Expression of low-molecular-weight
cytokeratin; note the occasional perinuclear dot.

Rare examples of SmCC and LCNEC marker (e.g. synaptophysin , chromogra-

harbour a component of squamous cell
carcinoma, either within the invasive tu-
mour or withi n the overlying mucosa (i.e.
squamous cell carcinoma in situ). Com-
bined SmCC- LCNEC cases are rarely
seen {2631} .
Both SmCC and LCNEC are positive for
cytokeratins (in particular low-molecu-
lar-weight cytokeratins) by immunohis-
tochemistry, and SmCC may exhibit a
perinuclear or dot-like pattern. Neuroen-
- ... ~ _ .. --.. - docrine differentiation is confirmed by
Fig. 3.26 Small cell neuroendocrine carcinoma. Patchy
staining with at least one neuroendocrine
granular staining for chromogranin.
nin , or CD56). TTF1 immunoexpression is
variable . SmCC and LCNEC are negative
or only weakly positive for p63 and are
consistently negative for CK5/6.
Prognosis and predictive factors
These highly aggressive malignancies
have high rates of regional and distant
metastasis, with about 70% of patients
presenting with advanced disease, and
5-year survival rates of 5-20% {708,848 ,
1170,2463}.

98 Tumours of the hypopharynx, larynx, trachea and parapharyngeal space

Salivary gland tumours

Adenoid cystic carcinoma
Stenman G.
Gnepp D.R.
Wenig B.M.
Definition
Adenoid cystic carcinoma (ACC) is a
slow-growing and relentless salivary
gland malignancy composed of epithelial
and myoepithe lial neoplastic cell s that
form various patterns , including tubular,
cribriform, and solid forms.
See also the Adenoid cystic carcinoma
section (p. 164) in Chapter 7.
ICD-0 code 8200/3
Epidemiology
ACC is uncommon at these sites, but is
the most common salivary gland malig-
nancy in this location {318,426 ,609,704,
795 ,1058,1734,2371 ,2557} There is no
sex predilection and the tumours occur
over a wide patient age range , but are
most common in the sixth to eighth dec-
ades of life.
Localization
Most laryngeal tumours are subglottic,
with the supraglottis being the next most
common location (609,1665,1734 ,2371,
2699}.
Clinical features
Symptoms include airway obstruction,
dysphagia, dyspnoea, cough, hoarse-
ness, sore throat, haemoptysis , and pain
(1058,2557,2673}. Tracheal tumours may
present with specific and asthma-mim-
icking symptoms (1022}.
Macroscopy
The tumour is a submucosal mass with or
without surface ulceration.
Histopathology
The histology is simi lar to that seen in
ACCs found in the major and other minor
salivary gland sites; see the Adenoid cys-
tic carcinoma section (p.164).
Prognosis and predictive factors
Tracheal ACC often presents at an ad-
vanced stage (2300}. More than 50% of
patients have metastases, frequently to
the lungs (631 }. The 10-year survival rate
is influenced by margin status {2319}
In one study, most patients with larynge-
al ACC had T4 lesions at initial diagnosis,
although 87.9% had NO disease and only
6.1% had distant metastasis. The 5-year
disease specific survival rate was higher
among patients with laryngeal ACC who
underwent surgery versus those who did
not (609}.
Pleomorphic adenoma
Bell D.
Bullerdiek J.
Hunt J.L.
Definition
Pleomorphic adenoma (PA) is a benign
tumour with variable cytomorphological
and architectural manifestations. The
identification of epithelial and myoepithe-
lial/stromal components is essential for
the diagnosis of PA.
See also the P!eomorphic adenoma sec-
tion (p . 185) in Chapter 7 (Tumours of sali-
vary glands) .
ICD-0 code 8940/0
Synonym
Benign mixed tumour
Localization
Only a few examples of PA in the larynx and
hypopharynx have been reported in the
literature {612,2085}. They are typically lo-
cated in the epiglottis or aryepiglottic folds.
Clinical features
The common clinical presentation of PA
is that of a slow-growing, painless mass.
Histopathology
See the Pleomorphic adenoma section
(p. 185) in Chapter 7.
Prognosis and predictive factors
Complete resection is curative. Recurrent
lesions are associated with an unfavour-
able clinical course.
Oncocytic papillary
cystadenoma
Bloemena E.
Bell D.
Hunt J.L.
Definition
Oncocytic papillary cystadenoma is a
cystic lesion lined by oncocytic epithe-
lium, with occasional luminal papillary
projections.
ICD-0 code 8290/0
Synonyms
Oncocytic cyst; oncocytic papi llary cys-
tadenomatosis; oncocytic adenomatous
hyperplasia; oxyphilic adenoma; onco-
cytoma; adenoma in laryngocoele
Epidemiology
The tumour affects elderly patients , in the
sixth and seventh decades of life {253}.
Localization
The tumour occurs in the larynx, typically
in the supraglottis (1382 ,2274}.
Clinical features
The symptoms are hoarseness, dyspho-
nia, and rarely, airway obstruction (175 ,
2274}

Salivary gland tumours 99

Histopathology
The tumour consists of unilocular or mul-
tilocular cysts lined by oncocytic epitheli-
um, with occasional intraluminal papillary
projections. The lesion can be multifocal.
Hyperplastic cellular formation may re-
sult in more-salid nests of oncocytic cells
11382,2274)
Cell of origin
The cell of origin is the minar salivary
gland duct cell 11382,2274)
Prognosis and predictive factors
These lesions show benign behaviour
but may recur. An association with squa-
mous cell carcinoma has been described
in a case report 12274)
Soft tissue tumours
Granular ce// tumour
Allen C.M.
Gnepp D.R.
Wenig B.M.
Definition
Granular cell tumour is an uncommon
benign tumour of Schwann-cell differen-
tiation characterized by poorly demar-
cated accumulations of plump granular
cells 12458).
See also the Granular ce// tumour section
(p. 121) in Chapter 4.
ICD-0 code 9580/0
Synonyms
Granular cell myoblastoma; granular cell
schwannoma; granular cell neurofibro-
ma; Abrikossoff tumour
Epidemiology
Granular cell tumours most frequently
occur in the third to fifth decades of life
11057). No sex predilection has been
noted for laryngeal granular cell tumour,
but tracheal granular cell tumour has a
female predilection. Black populations
appear to be disproportionately affected
compared with other ethnic groups.
100 Tumours of the hypopharynx, larynx, trachea and parapharyngeal space
Fig. 3.27 Oncocytic papillary cystadenoma. Overview of a multilocular tumour with papillary projections into the lumen
of the cysts.
Localization
Laryngeal granular cell tumours most
commonly involve the posterior third of
the true vocal fold; tracheal granular cell
tumours usually affect the cervical por-
tian 12602).
Clinical features
Laryngeal granular cell tumours usu-
ally present with hoarseness. Tracheal
granular cell tumours may cause stridor,
cough, or haemoptysis 11153). Other
symptoms include sensation of a mass
and dysphagia. As many as 10% of cas-
es involve two or more tumours 12602).
Macroscopy
Granular cell tumours present as sessile
nodules measuring < 2 cm in diameter
192). On cut surface, the tumours are
pale tan to yellowish-white.
Histopathology
The tumour shows submucosal unen-
capsulated or poorly circumscribed cel-
lular proliferation with syncytial, trabecu-
lar, or nested growth, composed of cells
with round to oval nuclei and abundan!
coarsely granular eosinophilic cyto-
plasm. There is usually minimal nuclear
pleomorphism and mitotic activity. Pseu-
doepitheliomatous hyperplasia of the
overlying epithelium may also be seen in
l ' ••:
a substantial proportion of these lesions,
and care should be taken when evaluat-
ing a superficial biopsy sample to pre-
ven! an overdiagnosis of squamous cell
carcinoma, because occasional tumours
may be associated with mild to moderate
cytological atypia in the pseudoepithe-
liomatous hyperplasic componen!. The
granular cells are often intimately associ-
ated with nerves. The cytoplasmic gran-
ules give a diastase-resistant positive
periodic acid-Schiff (PAS) reaction. The
tumour cells express S100 protein, CD57,
and SOX10 172), as well as CD68.
Prognosis and predictive factors
Surgical excision is curative. The risk of
recurrence is low (< 10%).
Liposarcoma
Flucke U.
Franchi A.
Thompson L.D.R.
Definition
Liposarcoma is a malignan! neoplasm
recapitulating fat. Three biologically dis-
tinct categories are recognized: well-
differentiated/dedifferentiated (the most
common), myxoid, and pleomorphic.

ICD-0 code 8850/3
Synonym
Well-differentiated liposarcoma: atypical
lipomatous tumour
Epidemiology
These rare tumours predominantly affect
older males (mean patient age: 60 years)
{691 ,867).
Localization
The tumours occur in the pharynx,
mouth , larynx, and neck. The tangue is a
common intraoral location {55 ,691,867).
Clinical features
The tumour is a slow-growing, painless
mass causing dysphagia and airway ob-
struction {867,1708).
Macroscopy
The tumours present as submucosal , well-
circumscribed, fatty- fibrous nodules {1708)
Histopathology
The most common lipoma-like subtype
shows variation in adipocyte size, with
hyperchromatic, enlarged nuclei . The ir-
regular fibrous septa have atypical stro-
mal cells {1708). Dedifferentiated non-
lipogenic areas can exhibit a wide variety
of growth patterns and cytomorphology
(e.g . spindle-cell , pleomorphic, giant-
cell, round-cell, and meningothelial-like).
Heterologous elements (e.g. cartilage
and bone) are rare {1538). MDM2 and
CDK4 are positive in > 90% of the tu-
mours {192,1538}.
Genetic profile
Well-differentiated/dedifferentiated lipo-
sarcoma shows 12q13-15 amplification,
including MDM2 and CDK4 {192).
Prognosis and predictive factors
Multiple recurrences of lipoma-like/well-
differentiated lesions may occur after
surgical treatment, with late dedifferen-
tiation. Tumour site and grade seem to
influence prognosis, with laryngeal lipo-
sarcoma having a better outcome than
oral tumours, possibly due to earlier rec-
ognition {867).
lnflammatory
myofibroblastic tumour
Wenig B.M.
Flucke U.
Franchi A.
Definition
lnflammatory myofibroblastic tumour
is a distinctive neoplasm composed of
myofibroblastic and fibroblastic spindle
cells accompanied by an inflammatory
infiltrate of plasma cells, lymphocytes,
and/or eosinophils.
ICD-0 code 8825/1
Synonyms
lnflammatory pseudotumour; plasma cell
granuloma
Epidemiology
lnflammatory myofibroblastic tumours of
the head and neck tend to occur in men
and are most common in adults, although
they can occur in children {462,2004).
Localization
Laryngeal inflammatory myofibroblas-
tic tumours primarily arise in the glottic
region {194,2509,2585). Non-laryngeal
sites include the oral cavity, sinonasal
tract, pharynx , tonsils, parapharyngeal
space, salivary glands, and trachea
{404,405,573,961,1776}
Clinical features
Laryngeal inflammatory myofibroblastic
tumours present with hoarseness, stridor,
dysphonia, ora foreign body sensation in
the throat {194,2509,2585). In other sites,
symptoms include obstruction, epistaxis,
headaches, and dysphagia.
Macroscopy
The tumour is a polypoid, pedunculated
or nodular firm lesion with a smooth ap-
pearance and a fleshy to firm consist-
ency, measuring 0.4- 3 cm in greatest
dimension.
Histopathology
The tumour is a submucosal storiform
to fascicular loosely cellular proliferation
composed of spindle-shaped, stellate,
epithelioid, and/or axonal (spider-like)
cells with enlarged round to oval nuclei ,
Soft tissue tumours 101
inapparent to prominent nucleoli, and
abundant fibrillar-looking cytoplasm . ln-
tranuclear inclusions may be present in
epithelioid cells. Mitotic figures may be
numerous but atypical mitoses are not
seen . There is a variable admixture of
lymphocytes, plasma cells, and/or eo-
sinophils. lnflammatory myofibroblastic
tumours are immunoreactive for actins
(focally to diffusely). Staining for desmin
and cytokeratin is reported in 33% {464)
to 77% {1581) of cases. ALK expression
is seen in 36-60% of cases {366,376,
481 l Distinction from spindle cell squa-
mous cell carcinoma is critica!; areas of
squamous dysplasia or differentiation are
helpful in this differential diagnosis (see
Spindle ce// squamous ce// carcinoma,
p. 87).

Genetic profile
About 50-70% of cases (mainly in chil-
dren) have clonal rearrangements involv-
ing chromosome band 2p23 that fuse the
3' kinase region of the ALK gene {890).
Fusion partners include TPM3, TPM4,
CLTC, RANBP2, and AT/C{268,481,1351,
1416,1808)
Prognosis and predictiva factors
For laryngeal inflammatory myofibro-
blastic tumour, surgical resection is usu -
ally curative {573,901,2004,2585), but
recurrence can rarely occur {901,2004,
2585). Rare examples of extrapulmonary
.: ... f~\
~'
Fig. 3.30 lnflammatory myofibroblaslic tumour. A The myofibroblasts may also appear epithelioid or histiocytoid,
characterized by round to oval nuclei, enlarged nucleoli, and ample basophilic to eosinophilic granular cytoplasm;
an inflammatory cell infiltrate is present. B The myofibroblasts include spindle-shaped to stellate cells with enlarged
round to oblong nuclei and abundan! basophilic-appearing fibrillar cytoplasm; cells with long cytoplasmic extensions are
seen. C lmmunohistochemical expression of ALK, including cytoplasmic staining as well as staining of !he intranuclear
inclusions.
(non-head and neck) inflammatory myo- a favourable prognostic indicator {462) .
fibroblastic tumour metastasize and ALK-negative cases may carry higher
may be associated with the presence risk of metastasis and death from dis-
of RANBP2 and round cell morphol - ease {462) .
ogy {402,1539). ALK reactivity may be

Cartilage tumours

Chondroma and Chondrosarcoma, grade 1 9222/1

chondrosarcoma Chondrosarcoma, grade 2/3 9220/3

Gale N. Epidemiology
Hunt J.L. Cartilaginous tumours account for
Lewis J.S. < 0.2% of ali laryngeal tumours, but
Thompson L.D.R. are the most common non -epithelial
tumours, with chondrosarcomas being
much more common than chondromas
Definition {347,460,711,1397). Chondromas oc-
Chondroma is a benign mesenchymal cur across a wide patient age range,
tumour of larynx hyaline cartilage. Chon - of 24-79 years (mean: 56 years), with a
drosarcoma is a malignant mesenchymal male-to-female ratio of 2:1 {1397).
tumour of larynx hyaline cartilage . Chondrosarcomas tend to occur in
slightly older patients, with a patient age Fig. 3.31 Laryngeal chondrosarcoma. Cut section of a
ICD-0 codes range of 25- 91 years (mean : 63 years), chondrosarcoma arising from !he cricoid cartilage and
Chondroma 9220/0 and have a male-to-female ratio of 3.2:1 showing a solid, focally lobular and glistening greyish-
Chondrosarcoma 9220/3 {611 ,1397,2387). Chondrosarcomas are blue surface.

102 Tumours of the hypopharynx, larynx, trachea and parapharyngeal space

significantly more common in Whites
than in Blacks, ata ratio of 7:1 {112).
Etiology
The etiology remains unclear, although
several hypotheses have been proposed.
Disordered ossification, which is found
only in hyaline cartilage (cricoid and rare-
ly thyroid cartilage) in older patients and
wh ich occurs in areas of muscle inser-
tion, may serve as a nidus for tumour de-
velopment {112). lschaemic changes in
chondroma may be a predisposing fac-
tor {2387) Other possible predisposing
factors are radiotherapy, polytetrafluoro-
ethylene (Teflon) injection, and repeated
laryngeal trauma {1773).
Localization
The most common site for laryngeal
chondromas is the cricoid cartilage (ac-
counting for -70% of cases), followed by
the thyroid, arytenoid, and tracheal carti-
lages, in decreasing order of frequency
{112,1361 ,1 397} Chondrosarcomas de-
velop in the same locations , specifically
along the anterior surface of the posterior
lamina of the cricoid cartilage {112,1773,
2387) Rare tumours arise in the epiglot-
tis {2387).
Clinical features
Both tumours grow slowly, commonly as
endolaryngeal masses . The symptoms
of chondroma and chondrosarcoma are
similar and depend on tumour size and
location. Slowly progressive hoarseness,
dyspnoea, dysphagia, and stridor are
usually present. lf the tumour is located
in the thyroid cartilage, the patient may
present with a palpable neck mass {112,
1773,2387} MRI may help in delineating
Fig. 3.33 Chondrosarcoma. A Neoplastic proliferation with increased cellularity, chondrocytes showing mild nuclear and cellular pleomorphism and hyperchromasia, and invasion
of the ossified region of the cricoid cartilage. B Moderately differentiated chondrosarcoma, grade 2. Remarkable cellularity, frequent binucleation in the !acunar spaces, and more
pronounced nuclear and cellular pleomorphism.
Fig. 3.32 Chondroma. Well-circumscribed tumour
composed of hyaline cartilage, with low cellularity, lack
of nuclear atypia of chondrocytes, and a single nucleus
with in a !acuna.
tumour extent {112) . CT reveals a hy-
podense, well-defined tumour with inter-
na! calcifications, cartilage destruction,
and structural distortion {166,2541,2619}.
FDG-PET may help with tumour grading,
metastasis detection, and local recur-
rence assessment {1773).
Macroscopy
Both tumours presentas smooth , lobulat-
ed, submucosal masses covered by nor-
mal mucosa. On cut surface, the lesions
are glassy, firm, white, or grey. Chon-
dromas are usually < 2 cm in diameter,
whereas chondrosarcomas can be as
large as 12 cm (mean diameter: 3.5 cm.
Dedifferentiated chondrosarcomas have
foci with a fleshy appearance {347,809,
1397,2387).
Histopathology
Chondromas are composed of mature
hyaline cartilage histologically resembling
normal cartilage. Hypocel lular areas con-
tain evenly distributed, bland-looking
chondrocytes in an abundan! basophilic
matrix. Chondrocytes have small, uniform ,
""' . .
single nuclei surrounded by eosinophilic
cytoplasm and there is usually only one
cell per lacuna. Cellular pleomorphism,
mitoses, and binucleated chondrocytes
are absent. Scattered foci of calcification
and ossification may be seen.
Chondrosarcomas show variably in-
creased cellularity, pleomorphism, multi-
nucleation, and mitoses, features useful
in tumour grading. Most laryngeal chon-
drosarcomas are low-grade (grade 1),
showing a pattern of lobular disarray
and destructive invasion of native carti-
lage and bone. Chondrosarcomas have
higher cellularity than chondromas, bi-
nucleation in the lacunar spaces, slight
nuclear pleomorphism, and nuclear hy-
perchromasia. Moderately differentiated
(grade 2) tumours show a higher degree
of cellularity and nuclear pleomorphism
than do grade 1 tumours, and may have
scattered mitoses. High-grade (grade 3)
tumours have high cellularity; significan!
multinucleation, nuclear pleomorphism,
and hyperchromasia; necrosis; and in-
creased mitoses. Ossification and calci-
fication can be seen in all grades {112,
1397,2387).
Rare cases of laryngeal clear cell chon-
drosarcoma have also been described,
characterized by a sharp transition of
conventional chondrosarcoma to a pop-
ulation of large clear cells with distinct
cellular membranes but lacking typical,
dense chondroid matrix {45) High-grade
chondrosarcomas are rare, accounting
for only about 5% of all laryngeal chon-
drosarcomas {2387). Dedifferentiated
laryngeal chondrosarcomas are exceed-
ingly rare; they show a biphasic appear-
ance with well-differentiated chondro-
sarcoma juxtaposed with a high-grade
• TUJ"'""- __,,~~~- _ _..... . . . .....,.
Cartilage tumours 103

Fig. 3.34 Laryngeal plasmacytoma with amyloid deposition. Amyloid deposits are present among the monotonous
plasma cell infiltrates.
Fig. 3.35 MALT lymphoma arising in the larynx. There is a dense, diffuse infiltrate of marginal zone cells; neoplastic
cells invade a submucosal gland to form a lymphoepithelial lesion.
non-cartilaginous sarcoma {809 ,2387).
lmmunohistochemistry is rarely neces-
sary, but the chondroid cells are immu-
noreactive with S100 protein and 02-40.
Prognosis and predictive factors
The 1-year, 5-year, and 10-year disease-
specific survival rates for chondrosar-
coma are 96.5%, 88.6% , and 84.8%, re-
spectively, although the local recurrence
rate is relatively high (18-50%) , usually
dueto incomplete resection {611,2387).
Tumour grade and tumour subtype do not
seem to influence outcome (other than
possibly for dedifferentiated tumours)
{1992} , which encourages conservative ,
function-preserving surgery (including
laser therapy) as primary treatment {347,
2387). Distant metastases are exceed-
ingly rare {460) .
104 Tumours of the hypopharynx, larynx, trachea and parapharyngeal space
Haematolymphoid tumours
Ferry JA
Chuang S.-S .
Definition
Haematolymphoid tumours are primary
malignant neoplasms of lymphoid, plas-
ma cell, or myeloid origin.
Epidemiology
Lymphomas arising in the larynx and
trachea are rare, accounting for < 1%
of neoplasms at these sites (717,1028,
1541} Approximately 4% of head and
neck lymphomas arise in the larynx;
tracheal lymphomas are even less com-
mon {934). Lymphomas affect women
more often than men . Laryngeal plas
Wmacytomas constitute 5-6% of extra-
osseous plasmacytomas of the head
and neck (116 ,2078); nearly all patients
are adults. Extramedullary myeloid sar-
coma and mast cell neoplasms are very
rare {1028). Among patients with wide-
spread lymphoma or leukaemia, subtle
laryngeal involvement is common {1028}.
Localization
Lymphoma and plasmacytoma involve
the larynx more often than the trachea .
Lymphoma involves the supraglottic lar-
ynx more often than the subglottic larynx.
Primary parapharyngeal or hypopharyn -
geal origin of haematolymphoid neo-
plasms is very rare. Lymphomas (545,
1028,1300,1444) and plasmacytomas
{1483,2143,2304} are usually localized;
sorne MALT lymphomas involve multi-
ple mucosa-associated lymphoid tissue
sites {997)
Clinical features
Patients present with cough , dyspnoea,
and hoarseness {1300 ,1444,2304,2718).
Macroscopy
Lymphomas and extraosseous plasma-
cytomas are usually smooth-surfaced,
raised or polypoid lesions {1028 ,1300,
2718}. Lymphomas may be multinodular
and/or circumferential {586 ,2701 }.
Histopathology
The most common primary lymphoma at
this body site is MALT lymphoma {586,
1300,1444,2343 ,2718}, but rare cases
of diffuse large B-cell lymphoma {1028} ,
extranodal NK/T-cell lymphoma {1637),
anaplastic large cell lymphoma {1220),
and other lymphomas have also been
reported. Laryngeal extraosseous plas-
macytoma is sometimes associated with
laryngeal amyloidosis {1483}.
Prognosis and predictive factors
The prognoses of lymphomas at this
body site are similar to those of their
counterparts in other sites . Extraosseous
plasmacytoma has a favourable progno-
sis {1028}, although patients may devel-
op recurrences and a minority of cases
progress to plasma cell myeloma (116 ,
2078).
•

CHAPTER 4

Tumours of the oral cavity and

mobile tongue
Malignant surface epithelial tumours
Oral potentially malignant disorders and
oral epithelial dysplasia
Papillomas
Tumours of uncertain histogenesis
Soft tissue and neural tumours
Oral mucosa! melanoma
Salivary type tumours
Haematolymphoid tumours
WHO classification of tumours of the oral cavity and
mobile tongue

Epithelial tumours and lesions Neurofibroma 9540/0

Squamous cell carcinoma 8070/3 Kaposi sarcoma 9140/3
Oral epithelial dysplasia Myofibroblastic sarcoma 8825/3
Low grade 8077/0
High grade 8077/2 Oral mucosal melanoma 8720/3
Proliferative verrucous leukoplakia
Salivary type tumours
Papillomas Mucoepidermoid carcinoma 8430/3
Squamous cell papilloma 8052/0 Pleomorph ic adenoma 8940/0
Condyloma acu minatum
Verruca vulgari s Haematolymphoid tumours
Multifocal epithelial hyperpl asia CD30-positive T-cell lymphoproliferative
disorder 9718/3
Tumours of uncertain histogenesis Plasmablastic lymphoma 9735/3
Congenital granular cell epu lis Langerhans cell histiocytosis 9751/3
Ectomesenchymal chondromyxoid tumour 8982/0 Extramedullary myeloid sarcoma 9930/3

Soft tissue and neural tumours

Granu lar cell tumour 9580/0 The morphology cedes are from the lnternational Classification of Diseases for
Oncology (ICD-0) {776A). Behaviour is ceded /0 for benign tumours;
Rhabdomyoma 8900/0 / 1 for unspecified, borderl ine, or uncertain behaviou r; /2 for carcinoma in
Lymphangioma 9170/0 situ and g rade 111 intraepithelial neoplasia; and /3 for malignant tumours. The
Haemangioma 9120/0 classification is modified from the previous WHO classification, taking into
account changes in our un derstand ing of these lesions.
Schwannoma 9560/0

106 Tumours of the oral cavity and mobile tangue

TN M classification of carcinomas of the lip and oral cavity

TNM classification of carcinomas of the lip and oral cavity•·b N2b Metastasis in multiple ipsilateral lymph nades,
al l !> 6 cm in greatest dimension
T - Primary tumour N2c Metastasis in bilateral or contralateral lymph nades,
TX Primary tumour cannot be assessed ali !> 6 cm in greatest dimension
TO No evidence of primary tumour N3 Metastasis in a lymph node > 6 cm in greatest dimension
Tis Carcinoma in situ
T1 Tumour !> 2 cm in greatest dimension Note: Midline nades are considered ipsilateral nades.
T2 Tumour > 2 cm but $ 4 cm in greatest dimension
T3 Tumour > 4 cm in greatest dimension M - Distant metastasis
T4a (lip) MO No distan! metastasis
Tumour invades through cortical bone, inferior alveolar M1 Distan! metastasis
nerve, floor of mouth, or skin (of chin or nose)
T4a (oral cavity) Stage grouping
Tumour invades through cortical bone, into deep/extrinsic Stage O Tis NO MO
muscle of tangue (genioglossus , hyoglossus, palatoglos- Stage 1 T1 NO MO
sus, and styloglossus}, maxillary sinus, or skin of lace Stage 11 T2 NO MO
T4b (lip and oral cavity) Stage 11 1 T1-2 N1 MO
Tumour invades masticator space, pterygoid plates, or T3 N0-1 MO
skull base; or encases interna! carotid artery Stage IVA T1-3 N2 MO
T4a N0- 2 MO
Note: Superficial erosion alone of bone / tooth socket by Stage IVB AnyT N3 MO
gingival primary is not sufficient to classify a tumour as T4. T4b Any N MO
Stage IVC Any T Any N M1
N - Regional lymph nades (i.e. the cervical nades)
NX Regional lymph nades cannot be assessed
' Adapted from Edge et al. (625A} - used with permission of the American
NO No regional lymph node metastasis
Joint Committee on Cancer (AJCC), Chicago, lllinois; the original and prima-
N1 Metastasis in a single ipsilateral lymph node, !> 3 cm in ry source for this information is the AJCC Cancer Staging Manual , Seventh
greatest dimension Edition (2010) published by Springer Science+Business Media - and Sobin
N2 Metastasis as specified in N2a, N2b , or N2c below et al. [2228A}.
N2a Metastasis in a single ipsilateral lymph node, > 3 cm bA help desk for specific questions about TNM classification is available at
http://www.uicc.org/resources/tnm/helpdesk.
but !> 6 cm in greatest dimension

TNM classification of carcinomas of the lip and oral cavity 107

Tumours of the oral cavity and
mobile tongue
lntroduction
In the previous edition , tumours of the oral
cavity and oropharynx were discussed
together in one chapter. Now, diseases
of these two anatomical regions are the
subjects of two separate chapters; this
chapter being devoted to the oral cavity
and Chapter 5 (p 133) to the oropharynx.
Furthermore, as in other chapters, in an
effort to minimize overlap, only selected
non-epithelial and soft tissue tumours,
salivary neoplasms and haematolym-
phoid tumours are highlighted. The out-
come of this approach is that the content
of this chapter is much reduced in com-
parison with the previous edition.
Lesions that deserve prime attention in
this chapter are the mucosa! diseases.
The most pivota! malignancy of the oral
108 Tumours of the oral cavity and mobile tongue
cavity and mobile tongue is squamous
cell carcinoma (SCC) arising from the
mucosa! epithelium. More than 90% of
oral cancers are SCC. Most cases of oral
SCC are moderately to well differenti-
ated. For more detailed information on
subtypes of SCC, see the correspond -
ing sections in Chapter 3 (Tumours of the
hypopharynx, larynx, trachea and para-
pharyngea! space, p. 77).
Oral potentially malignan! disorders,
clinical presentations carrying a risk of
cancer development, and oral epithelial
dysplasia, a spectrum of histological and
cytological changes with an increased
risk of progression to SCC, are also im-
portan! lesions for secondary prevention
of oral SCCs. There are different kinds of
grading systems for epithelial dysplasia.
In this chapter, a traditional three-tiered
Takata T.
Slootweg P.J.
grading system and a binary system are
described. For other grading systems and
related terminology used for dysplasia/
squamous intraepithelial lesion , refer to
the corresponding sections in Chapter 3
(Tumours of the hypopharynx, !arynx, tra-
chea and parapharyngeal space, p. 77).
Although the cause of oral SCC is mul-
tifactorial, accumulated information on
etiological and genetic factors in oral
SCC and related precursor lesions sup-
ports targeted diagnosis and therapy
of oral SCC. The content of this chapter
reflects the increase in knowledge on
oral diseases and its practica! applica-
tion in diagnosis and treatment. Hitherto
unrecognized new entities deserving to
be listed as such in this chapter have not
been identified.
Malignant surface epithelial tumours
Squamous ce// carcinoma
Definition
Oral squamous cell carcinoma (OSCC) is
a carcinoma with squamous differentia-
tion arising from the mucosal epithelium.
The proportion of cases that arise in clini-
cally evident oral potentially malignant
disorders is unknown. lt is most frequent
in the fifth and sixth decades of life and
is typically associated with risk factors
such as smoking , alcohol consumption ,
and betel-quid chewing.
ICD-0 code 8070/3
Epidemiology
More than 90% of cancers in the oral
cavity are OSCCs. With respect to the
epidemiology of oral cancer, spec ific ge-
ographical regions must be considered
separately, because there is marked vari-
ation in incidence. Overal l, oral cancer
(when oropharyngeal sites are included)
is the sixth most common cancer in the
world {2548} The GLOBOCAN project
estimated 300 373 new cases in 2012 ,
with a global age-standardized incidence
rate of 4.0 cases per 100 000 population
per year and a global mortality rate of
1.9 deaths per 100 000 population per
year {702}. High incidence of oral can-
cer is found in southern Asia (e.g. India;
Pakistan ; Sri Lanka ; and Tai wan , Ch ina),
with age-standardized incidence rates of
> 10 cases per 100 000 population per
year in parts of India and Pakistan {702}.
lncidence is also high in eastern and
western Europe (e.g. Hungary, Slovakia,
Slovenia, and France), Latin America
and the Caribbean (e.g. Brazil, Uruguay,
and Puerto Rico), and Melanesia (e.g.
Papua New Guinea) {702}. Worldwide ,
oral cancer incidence is higher among
males (5 5 cases per 100 000 popula-
tion per year) than females (2.5 cases
per 100 000). However, the ratio is the
reverse in India and Thailand , where the
reported male-to-female ratios are 1:2
and 1:1.56, respectively (1280}. Most
oral cancers occur in patients aged 50-
70 years. As smoking rates decline, the
Sloan P.
Gale N.
Nylander K
Reibel J.
Hunter K. Salo T.
Lingen M. Zain R.B .
8cth HXH
. 5.1-
- 38·51
'5-38
Cl 1 9-2.5
o < 19
A
Csnoin of th • !ip ltld 0t1I cavi!y
- 2 .2•
- 1.6-2 2
- 1.1.1 .e
oe1-1.1
D <0 01
No05l:a
B
Fig. 4.01 Worldwide age-standardized rate (ASR) of (A) incidence and (B) mortality per 100 000 population per year,
both sexes, of lip and oral cavity cancer. Reprinted from GLOBOCAN 2012, Ferlay J et al. {702}.
incidence of intraoral cancer is decreas- tobacco) or dipping (snuff). Smokeless
ing in sorne countries , whereas slight tobacco in chewing ar dipping forms
increases among younger patients have causes oral cancer; however, sorne
been reported in other countries (1456, studies (in particular studies of Swedish
2159} snuff) show negligible risk {229 ,1072}.
Areca nut and/or tobacco can be mixed
Etiology with other substances (e.g . slaked lime,
Smoking is by far the most importan! betel inflorescence, condiments , sweet-
cause of oral cancer. There is a dose- ening agents , and spices) to create be-
dependent increase in risk, and risk de- tel quid. Betel-quid chewing increases
creases after smoking cessation {1071 , the risk of oral cancer whether or not to-
2550}. Alcohol consumption interacts bacco is added {900}. HPV, in particular
synergistically with smoking, resulting in type 16, is a recognized etiological factor
a more than additive risk (121,865,1073}. in oropharyngeal cancer but is only seen
Smokeless tobacco is used orally in most in a small minority (3%) of osees {515,
parts of the world, by chewing (chewing 840 ,1438,2135}. Exposure to sunlight is
Malignan! surface epithelial tumours 109
an establ ished risk factor for ip cancer.
1 Table 4.01 Subtypes of squamous cell carcinoma (SCC) of !he oral cavity and mobile tangue
In Western Australia, lip cancer accounts
foras many cases as all intraoral sites to-
gether (7). Poor oral health is associated
with oral cancer (591,899} but has not
been proven an independent risk factor
(2547). A diet rich in fruits and vegetables
seems to have sorne protective effect
against oral cancer {264,1503) .
Localization
Oral cancer can affect any area of the
oral mucosa. The most common sites for
intraoral cancer in many populations are
the tongue, floor of the mouth, and gin-
giva, accounting for more than half of ali
oral cancers (1337,1544,2423). However,
site distribution varíes depending on
the prevailing risk factors. Among many
Asían populations, osee most common -
ly affects the buccal mucosa, due to to-
bacco chewing and betel-quid chewing .
Clinical features
Oral cancers can be detected by visual
inspection and palpation followed by bi-
opsy and histopathological examination.
Evaluation of the neck is also important.
Small cancers may be asymptomatic,
whereas advanced tumours give rise to
various symptoms and signs such as
discomfort, pain, reduced mobility of the
tongue, and irritation from wearing den-
tu res. The clinical presentation is that
of variab ly white, erythematous , mixed,
nodular, and ulcerated changes; when
present, ulcerated changes often have
raised margins (120}. Non-healing ulcer-
ation is a feature suggestive of malignan-
cy; however, in a recent study, ulceration
in osee (including its variants) was seen
in slightly less than half of the cases {56).
eancer of the lower lip typically presents
as a crusting lesion, often preceded by
actinic cheilitis. An essential part of the
diagnostic procedure for oral cancer is
palpation of the lesion , typically reveal ing
induration. Unfortunately, small cancers
are often unapparent to both patients
and health professionals, resulting in di-
agnostic delay (872). One reason is that
small cancers can mimic other lesions
commonly seen in the oral cavity.
Macroscopy
Squamous cell carcinomas are firm in-
filtrative tumours , with a tan or wh ite cut
surface.
110 Tumours of the oral cavity and mobile tangue
Oral SCC subtype Features References
High-grade carcinoma, more-frequent metastasis but overall
Basaloid SCC 1 {774,2653)
prognosis comparable to that of conventional SCC
Worse prognosis than conventional SCC in oral cavity and mobile
Spindle cell SCC tangue; typically occurs as postradiation recurrence or second {187,824)
primary 1
Adenosquamous Highly infiltrative and aggressive, frequent metastasis, worse
{1194,1553,2113)
carcinoma prognosis than conventional SCC
Well differentiated, usually on mucoperiosteum, locally destructive
-
Carcinoma
deep burrowing pattern, metastasis rare, recurs locally but rarely if {2312)
cuniculatum
ever metastasizes
Well-differentiated non-metastatic varían! with pushing superficial
Verrucous SCC invasion, exophytic, lacks atypia, good prognosis; may progress to 1 {1517,1759,2060)
invasive conventional SCC
Lymphoepithelial Rare, present al high stage, 70% associated with regional lymph
{2034)
carcinoma node metastasis; not all are EBV-positive 1
j Keratinizing and non-keratinizing types, often arises on gingivae;
Papillary SCC 1 {1517,2060}
better prognosis than conventional SCC
High-risk cutaneous variant that may occur on the lip; acantholysis
Acantholytic SCC can result in an adenoid appearance in poorly differentiated intraoral {605,807,2730}
scc
Cytology differentiated; poorly differentiated squa-
lntraoral tumours are usually evaluated mous cell carcinoma is less frequent.
by surgical biopsy. Meta-analysis shows Well-differentiated osee is characterized
that adjunctive tests cannot replace scal- by nests, cords , and islands of large cells
pel biopsy and histological assessment with pink cytoplasm, prominent intercellu-
for oral cancer diagnosis (1985). Fine- lar bridges, and round nuclei, which may
needle aspiration is useful for the detec- not be obviously hyperchromatic. Dys-
tion of lymph node metastasis. Aspirates keratotic cells and squamous pearls are
are cellular, with sheets and small clus- prominent. eellular and nuclear pleomor-
ters of malignan! squamous cells with phism , nuclear hyperchromasia, and mi-
intracellular and extracellular keratiniza- totic figures (including atypical forms) in-
tion . Mixed inflammation and necrosis crease with tumour grade. Grading alone
can be present. does not correlate well with prognosis. In
poorly differentiated osee, features of
Histopathology squamous differentiation are minimal or
Most cancers of the oral cavity and absent, requiring immunohistochemical
mobiie tangue are moderately or well confirmation; AE1/AE3, eK5/6, p63, and
Fig. 4.02 Conventional, moderately differentiated oral squamous cell carcinoma showing keratin pearl formation.

Fig. 4.03 Oral squamous cell carcinoma of mobile tongue showing an adverse pattern of infiltration.
p40 are useful markers. Well-differentiat-
ed tumours tend to invade in large islands,
whereas less-differentiated tumours tend
to have jagged or finger-like projections
or small islands and dispersed individual
cells at the invasive front. Significant des-
moplastic stroma with inflammatory host
response can be found around nests
of invading tumour cells . Adjacent mu-
cosa frequently shows various grades
of epithelial dysplasia. Perineural and
lymphovascular invasion are seen , more
frequently in poorly differentiated tumours
{258 ,297,1424,2494)
Genetic profile
Most osees are genetically unstable
{183,1885,2070}, with chromosomal loss
at 3p, 8p, 9p, 17p and gains at 3q and
11q {396,2375). These changes may ex-
tend for sorne distance from the clinical
lesion, underpinning the clinical phe-
nomenon of field cancerization {249).
Genes reported to have a role in osee
(e.g . TP53, CDKN2A, PTEN, HRAS, and
PIK3CA) are mutated with sufficient fre-
quency to support their potential role
as drivers in cancer development {818 ,
1492,1712,1885,2288,2375).
Malignant surface epithelial tumours
Genetic susceptibility
The evidence of inherited genetic sus-
ceptibility for the development of osee
is limited. osee may arise as part of a
more general cancer syndrome , such as
in patients with Li-Fraumeni syndrome
{1924) or Fanconi anaemia {223}.
Prognosis and predictiva factors
eonventional osee is aggressive, with
a propensity for local invasion and early
lymph node metastasis. The most signifi-
cant prognostic factors are tumour size ,
nodal status, and distant metastasis.
eonventional histological grading corre-
lates poorly with clinical outcomes {259).
Histological risk factors associated with a
worse prognosis include a non-cohesive
pattern of invasion {1424}, perineural and
lymphovascular invasion {2636 ,2640},
bone invasion {625}, and thickness
> 4 mm {57) . Margins from the resec-
tion specimen predict local control better
than margins from the tumour bed {1562).
High-grade dysplasia at a mucosal mar-
gin correlates with local recurrence and
second primary tumours {1424 ,2561 j. Ex-
tracapsular spread from metastasis in the
neck, two or more positive nades, and
involvement of levels IV and V correlate
with adverse outcome.
111
Oral potentially malignant disorders
and oral epithelial dysplasia
Oral potentially malignant
disorders
Definition
Oral potentially malig nant disorders
(O PMOs) are c linical presentations that
carry a risk of cancer development in the
oral cavity, whether in a c li nically defin-
ab le precursor lesion or in clin ically nor-
mal oral mu cosa .
Epidemiology
In western countri es, the repo rted preva-
lence of leukoplakia generally ranges
from 1% to 4%. Hig her p revalence rates
are reported in parts of south-eastern
Asia {1704}. The global p revalence of leu-
koplakia is 2- 3% {1871} In contrast, oral
erythroplakia is a rare lesion, with preva-
lence betwee n 0.02% and 0.83% {1972).
Men are affected muc h more common ly
than women. Other OPMOs can be com-
mon, but have muc h lower transformation
rates.
Etiology
O PM Os have different causes. Tobacco
use (smoki ng and/or chewing) and al-
cohol consumption are associated with
sorne leukoplakias {1704}. The use of
areca nut, with or without tobacco, caus-
es oral sub mucous fi brosis {2404). For
many cases of OPMOs, no etio log ical
factors are known. Hi gh-risk HPV infec-
tion is only very rarel y p resent in OPMDs
Table 4.02 Oral potentially malignan! disorders
Erythroplakia
Erythroleukoplakia
Leukoplakia
Oral submucous fibrosis
Dyskeratosis congenita
Smokeless tobacco keratosis
Palatal lesions associated with reverse smoking
Chronic candidiasis
Lichen planus
Discoid lupus erythematosus
Syphilitic glossitis
Actinic keratosis (lip only)
112 Tumours of the oral cavity and mobile tongue
{1567,2629}, and whether it plays a ro le in
transformati on has yet to be determined .
Localization
O PM Ds can involve any intraoral site.
Their d istri b ution varies by specific dis-
ord er, with etiolog ical factors, and to a
certain extent patient age and sex {1704}
Erythroplakia is most frequently see n on
th e soft palate, fl oor of the mouth, and
b uc c al mucosa {1 972}.
Clinical features
Most high -risk OPMDs form red , white,
or speckled oral lesions. "Leukoplakia"
is a c lin ical term used to describe white
p laq ues of questionable risk , once other
specific conditions and other O PMDs
have been ruled out {2551} , which nor-
mally re qui res biopsy. Leukoplakias can
be hom oge neo usly wh ite or pred omi-
nantly w hite with nod ular, verrucous, or
red areas . Predominantly white examples
with re d areas are called erythroleuko-
p lakias (speckled leukoplakias). Oral
eryth rop lakia is defined equ ivalentl y,
b ut as a red patch. Specifically defined
OPM Ds have c haracteristic presenta-
tions, and ep ithelial dysplasia may or
may not be present. Other O PMDs have
been reviewed elsewhere {2475}.
Genetic susceptibility
OPMDs are seen in the rare disord ers
Fanconi anaemia {889} and dyskeratosis
congen ita {932}, but no genetic pred is-
positi on is present in most cases.
Prognosis and predictive factors
The transformation risk in many O PMOs
is low, and many regress {1307}. For leu -
kop lakia, a mean global transformation
rate of 1-2% has been estimated {1871 }.
A meta-analys is of cases with oral epithe-
li al dysp lasia fo und a transformation rate
of 12% {1579). Presence of oral epithelial
dysplasia is the most importan! prog nos-
tic factor for malignant transformati on ,
but clinical c haracteristics such as ap-
pearance (homogeneous vs. non-homo-
geneous) , size , and site also have impli -
cations for clinical management {1704}.
Reibel J.
Gale N.
Ti lakaratne W.M .
Westra W. H.
H illeJ.
Hunt J. L.
Williams M.O.
Vigneswaran N.
Lingen M. Fatani HA
Muller S. Odell E.W.
Sloan P. Zain R.B .
Oral epithelial dysplasia
Definiti on
Oral epithelial dysplasia (O ED) is a spec-
trum of arch itectural and cytological epi -
thelial changes caused by accumu lation
of genetic changes, associated with an
increased risk of progression to squa-
mous ce ll carcinoma.
ICD-0 codes
Low grade 8077/0
High grade 8077/2
Synonyms
Epithelial precursor lesions; intraepithe-
lial neoplasia; squamous intraep ithelial
lesions
Histopathology
OED includes abnormal proliferation, matu-
ration, and differentiation of ep ithel ial cell s.
The epithelium may be atrophic, acanthot-
ic, keratinized , or non -keratinized . Dyspla-
sia is present in a minority of leukoplakias
but is a consisten! find ing in erythroplakia
and erythroleukoplakia.
Table 4.03 lists the architectural and cyto -
logical disturbances that are used to diag -
nose OED. The number and combination
of features vary between lesions. There is
no good evidence to ind icate how the pres-
ence of ind ividual features could be trans -
lated into a grade of dysplasia. No specific
combination of features reliably distinguish -
es hyperplasia from mild dysplasia. OED
may be diagnosed on the basis of architec-
tural or cytological features alone .
Traditionally, OED is divided into three
grades of severity. Judging the number
of third s of the epithelium affected is one
factor in defining a grade. Mild dysplasia
can be defined by cytological atypia lim -
ited to the basal third, moderate dysp lasia
by extension into the middle third, and se-
vere dysplasia by extension into the upper
third. However, architectural and cytolog i-
cal atypia and the architecture of the con -
nective tissue interface should increase the
grade. Marked atypia in the basal third of
the epithelium may be sufficient for a di-
agnosis of severe dysplasia. Carcinoma in
Table 4.03 Diagnostic criteria tor epithelial dysplasia; adapted from Barnes Letal. {146) {316,2017) in combination with two addi-
Architectural changes Cytological changes tional markers at 4q and 17p (2712}.
Irregular epithelial stratification Abnormal variation in nuclear size
Prognosis and predictive factors
Loss of polarity of basal cells Abnormal variation in nuclear shape Although the presence of dysplasia
Drop-shaped rete ridges Abnormal variation in cell size correlates with the development of
lncreased number of mitotic figures Abnormal variation in cell shape squamous cell carcinoma, most OEDs
never progress to carcinoma. A meta-
Abnormally superficial mitotic figures lncreased N:C ratio
analysis of lesions with OED showed a
Premature keratinization in single cells Atypical mitotic figures transformation rate of 12% {1579). Gen -
Keratin pearls within rete ridges lncreased number and size of nucleoli erally, the more advanced the degree
Loss of epithelial cell cohesion Hyperchromasia of dysplasia, the higher the likelihood of
developing squamous cell carcinoma
Table 4.04 Grading systems tor epithelial dysplasia {1366,1579,2176,2552). The 15-year
malignant transformation rates of mild,
WHO dysplasia grade Binary system
moderate, and severe dysplasia (as
Mild dysplasia defined by the traditional three-grade
Low-grade dysplasia
system) are approximately 6% , 18%,
Moderate dysplasia
and 39% , respectively, and the pres-
High-grade dysplasia
Severe dysplasia ence of dysplasia in dicates long-term
- risk {2250). The general problem of low
The cut-off point between low-grade and high-grade dysplasia, as suggested by Kujan O et al. {1291), is tour
architectural and five cytological changes (see Table 4.03), irrespective of the level within the epithelium. reproduc ibility of current diagnostic cri -
According to Nankivell P et al. {1702), a cut-off point of tour architectural and four cytological changes may improve teria underlies the poor correlation with
prognostication. transformation found in sorne studies
(276,601,1016}.
situ in the oral cavity is considered synony- HPV has been described, histologically
mous with severe dysplasia. characterized by epithelial hyperplasia
Dysplasia grading is poorly reproducible and marked karyorrhexis and apoptosis Proliferative verrucous
between observers. Sorne studies show throughout the epithelium {2629). Accord- leukoplakia
good prognostic value {2250}, but others ing to conventional criteria, these qualify
find a poor association with outcome {721 , as severe dysplasia, but the risk of trans- Definition
1505). Consensus grading after review by formation has yet to be determined. lmmu- Proliferative verrucous leukoplakia (PVL)
more than one pathologist may enhance nostaining for p16 alone cannot be used is a distinct and aggressive form of oral
diagnostic reliability {733,2249,2250). To as a surrogate marker for HPV infection in potentially malignan! disorder {2551). lt is
improve reproducibility, sorne authors ad- OED. multifocal, has a progressive course, and
vocate a binary system {1291,1702,2553}, is associated with high recurrence and ma-
in line with proposals for laryngeal lesions Genetic profile lignan! transformation rates {2,839,936}.
(798}, but binary scoring requires validation Prognostic genetic and molecular mark-
before it can be routinely applied in the oral ers far malignan! transformation have Epidemiology
cavity. been reported {1902 ,1971}, most notably PVL is rare in comparison with conven-
An unusual subset of OEDs positive for LOH at chromosomal arms 3p and 9p tional oral leukoplakia. lt occurs in older
Table 4.05 Selected recen! reports on malignan! transtormation of oral leukoplakia; in part adapted from Warnakulasuriya S and Ariyawardana A {2549)
Frequency
Observation period of malignant
Authors/year Country Cases Notes
(years) transforma·
tion
Saito T et al. 2001 {2046) Ja pan 142 a,b 4 (0.6-1 6) 1
6.3%
1 1
Holmstrup P et al. 2006 {1016) Denmark 254 a, b 6 (1.1-20.2) 1
6.7%

Warnakulasuriya Set al. 2011 {2552); 1

United Kingdom 335 a, b 9 6.9%
Sperandio Metal. 2013 {2250} 1

Ho MW et al. 2012 {1007} United Kingdom 83 a, c 5 24.1%

Liu W et al. 2012 {1450) China 320 a, c 5.1 (1 -20) 1
17.8%
1
Brouns E et al. 2014 {276) Netherlands 144 a, b 4.7 (1-14.9) 1
11.0%
Dos! F et al. 2013 {600) Australia 368 a, c,d Not available 1
7.1°/o•
Mehanna HM et al. 2009 {1579) Meta-analysis 992 c, d Not applicable ¡ 12.1%
"rreated and untreated cases. bWith and without dysplasia. coysplasias only. dlncludes clinical diagnoses other than leukoplakia. •Annual transformation rate: 1%.

Oral potentially malignant disorders and oral epithelial dysplasia 113

 exophytic growth resulting in a warty (ver-
rucoid) surface with focal erythematous
areas, and (4) development of verrucous
or squamous cell carcinoma 1839). How-
ever, not every PVL goes through these
clinical stages, and development of car-
cinoma has been noted in PVL clinically
presenting as multifocal flat patches.

Histopathology
Fig. 4.04 Proliferative verrucous leukoplakia. A61-year-old woman presented with an advanced proliferative verrucous Histopathology corresponds to the varied
leukoplakia involving the dorsal (A) and ventral surfaces of the tangue and palate (B). The palien! had undergone clinical features of PVL: localized flat or
multiple biopsies and surgeries during the previous 4 years, which had resulted in diagnoses of invasive and in situ verrucous hyperorthokeratosis with mini -
squamous cell carcinomas. mal or no dysplasia, resulting in the un-
derestimation of risk of malignan! trans-
patients (aged > 60 years), with a female- Localization formation of these lesions during their
to-male ratio of 4 1 12,311} PVL frequently involves gingiva, alveolar early stages. Dysplasia develops only
mucosa, and palate 1839). The lateral during the late stages of PVL, befare pro-
Etiology and ventral surfaces of the tangue and gressing into either verrucous or squa-
The etiology is unknown. In Europe and floor of the mouth are rarely involved dur- mous cell carcinoma 1839). Definitive
North America, PVL is not associated ing the early stages of PVL. diagnosis of PVL requires clinical and his-
with known risk factors of oral cancers topathological correlation. PVL frequently
(i .e. tobacco use and alcohol consump- Clinical features shows interface mucositis characterized
tion). Neither HPV nor any other virus is PVL exhibits varied clinical features in four by a band -like, lymphohistiocytic infiltrate
associated with the development of PVL clinical stages: (1) focal flat white kerato- subjacent to the basal cells; therefore, it
1811). sis, (2) diffuse and multifocal white patch - may be misdiagnosed as lichen planus
es, (3) slowly progressive horizontal and in early stages 1311,839). However, the

Fig. 4.05 Oral epithelial dysplasia. A Hyperkeratosis with normal architecture and cytology. B Mild dysplasia: lack of polarization of basal cells, abnormal variation in nuclear size,
shape, and stainability (hyperchromasia), and increased number of mitotic figures . Changes are confined to the basal third of the epithelium. C Moderate dysplasia: drop-shaped
rete ridges, mild abnormal variation in nuclear size and stainability (hyperchromatism), increased nuclear/cytoplasmic ratio, and atypical mitotic figures in the basal/parabasal area.
Changes extend to the mid-third of the epithelium.

Fig. 4.06 Severe dysplasia. A Loss of cohesion of epithelial cells, loss of polarity of basal cells, marked abnormal variation in nuclear size and shape, and abnormal variation in cell
shape. Changes extend to the upper third of the epithelium. B Loss of basal cell polarity, epithelial differentiation and cellular cohesion. lncreased mitotic figures and abnormal variation
in nuclear and cellular features of the full epithelial thickness characterize severe dysplasia I carcinoma in situ .

114 Tumours of the oral cavity and mobile tangue

presence of any dysplasia precludes the
diagnosis of lichen planus. Diagnosis
also requires the distinction of PVL from
other white oral lesions by correlating the
clinical and microscopic presentations
both retrospectively and prospectively
through clase surveillance.
Genetic profile
lnactivation (by homozygous deletion)
of CDKN2A (also called P16/NK4a and
P14ARF) , which codes for the tumour
Papillomas
Squamous ce// papilloma
Muller S.
Gale N.
Odell EW
Richardson M.
Syrjanen S.
Definition
Squamous cell papilloma is a benign hy-
perplastic exophytic localized prolifera-
tion with a verrucous or cauliflower-like
morphology (2284}
ICD-0 code 8052/0
Epidemiology
Squamous cell papillomas are common
and can occur in patients of any age,
although they occur more frequently
in the third to fifth decades of life
(1914,1925,2284} There is an equal sex
distribution .
suppressor proteins p16 (p161NK4a) and
p14ARF, is more frequent in PVL (1279}
than in other oral potentially malignant
disorders. Like other oral potentially ma-
lignant disorders, PVLs also develop
chromosomal instability, and DNA an-
euploidy can predict their risk of devel-
oping into carcinoma (1234}.
Prognosis and predictive factors
As many as 70% of PVLs develop into
invasive cancer, resulting in a mortality
Etiology
HPV infection has been reported, with
the most common types being 6 and 11
(886,1168,1668,2324}. Reported preva-
lence rates of HPV DNA in oral squa-
mous cell papillomas range from 0% to
100% (average: 34%) (1168,1668}. This
considerable variation may be due to dif-
ferences in the HPV detection techniques
used.
Localization
Any oral site can be involved, but the
most common sites are the soft palate,
tangue, lips , and gingiva (1914,1925,
2284).
Cl inical features
Squamous cell papillomas may be pe-
dunculated or sessile. The pedunculated
lesions are composed of a cluster of fin-
ger-like fronds and may be white or mu-
cosa! in colour, depending on the degree
of keratinization. The sessile lesions are
rate of 30-40% (2,311}. Carcinomas aris-
ing from PVL have better prognosis and
long-term survival than do conventional
oral cancers. The development of multi-
ple primaries at different locations is not
uncommon in patients with PVL ¡36}.
dome-shaped and have a more nodular,
papillary, or verrucous surface (1925,
2284}. Most squamous cell papillomas
are solitary and grow rapidly to about
0.5 cm. Clinically distinguishing oral
squamous cell papilloma from verruca
vulgaris, condyloma acuminatum, and
multifocal epithelial hyperplasia is diffi-
cult (2325}. Multiple papillomas can be
seen in the setting of salid organ trans-
plant and HIV infection .
Histopathology
The lesions are exophytic, composed
of papillary proliferations of hyperplas-
tic stratified epithelium that are either
covered by a layer of parakeratin or or-
thokeratin of variable thickness or are
non-keratinized (2284). The finger-l ike
epithelial projections extend from a nar-
row base, supported by fibrovascular
cores containing dilated capillaries. The
stroma may be oedematous or hya-
linized. Koilocytes are infrequent and
Papillomas 115
Fig. 4.08 Squamous cell papilloma. A Typical low-power appearance of squamous cell papilloma composed of numerous finger-like projections of keratinized epithelium.
B The papillary projections are supported by fibrovascular cores. No cytological atypia or koilocytes are noted, and this lesion was negative for HPV by immunohistochemistry.
mitotic activity unusual, except in the set-
ting of trauma or inflammation {2284).
Prognosis and predictive factors
Treatment is simp le excision , and recur-
rence is unusual {1914). There have been
no reports of malignant transformation or
dissemination .
Condyloma acuminatum
Vigneswaran N.
Lippman S.
Muller S.
Williams M.O.
Definition
Oral condyloma acuminatum (CA) is the
oral equivalent to anogenital CA.
Synonym
Venereal condyloma
Epidemiology
Oral CAs are frequently transmitted
sexually, with a peak incidence in young
adu lts and a male predominance {1258,
2284). Autoinoculation in patients with
genital CA has been reported. Occur-
rence in children may be associated with
sexual abuse {2284). Multiple CAs may
indicate immunodeficiency.
116 Tumours of the oral cavity and mobile tongue
Etiology
HPV type 6 or 11 is identified in most
cases. Neither histolog ical appearance
nor HPV type is an accurate indicator of
genital orig in , and non-sexual transmis-
sion is possible {2325) .
Localization
CAs most often occur on the lab ial mu-
cosa, soft palate, and frenulum {2284) .
Clinical features
Clinically, CA presents as a single or
cluster of asymptomatic, painless ses-
sile masses with an exophytic growth
pattern. Th e surface is finely nodular,
pink to slightly red , and flatter than that
of verruca vulgaris. The lesions are larger
than squamous cell papillomas; reaching
15 mm in diameter {976,2284).
Fig. 4.09 Condyloma acuminatum. Clinically, a sessile,
finely nodular, pink mass is identified on the frenulum of
the tongue.
Histopathology
Histopathology shows a hyperplastic
squamous proliferation associated with
fibrovascular cores, exophytic growth,
and a broad base. Basilar nuclear en -
largement may be present, but keratino-
cyte maturation is maintained , typically
without the keratinization seen in verruca
vulgaris. Compared with squamous ce ll
papillomas, CAs have broader papil lae,
wh ich are often blunted. The rete pro-
cesses are bulbous, short, and straighter
than those seen in papillomas, and
koilocytes are more readily identified
{77). In situ DNA hybridization or PCR
amplification studies may be required
for detection and typin g of HPV to distin-
guish these lesions from other exophytic
growths, including verrucous squamous
cell carcinoma .
Prognosis and predictive factors
Recurrence after excision is common and
more frequent than in squamous ce ll pap-
illomas. Malignant transformation has not
been reported in oral CA. HPV vaccines
that protect against types 6 and 11 cou ld
also help to prevent associated CA {993).
Verruca vulgaris
Muller S.
Lippman S.
Williams MO.
Definition
Verruca vulgaris (VV) is a benign virus-
induced hyperplastic localized prolifera-
tion with a verrucous or cauliflower-like
morphology (2284).
Epidemiology
VV is the most common HPV-related le-
sion of the skin, but can also occur in the
oral mucosa, perhaps as a result of au -
toinoculation {886,1925) Oral VV is most
common in the third to fourth decade of
life, with a slight male predilection.
Etiology
Commonly reported HPV types include
2, 4, 40, and 57 (541 ,1455,2284).
Localization
The most commonly reported oral sites
are the lips, hard palate, anterior tongue,
and gingiva.
Clinical features
VV is asymptomatic lt may be peduncu-
lated or sessile with a rough pebbly or
papillary white surface (1455 ,1925,2284).
VVs grow rapidly (to a maximum size
of < 5 mm), and multiple or clustered
lesions can occur.
Histopathology
VVs are exophytic, composed of papil-
lary proliferations of hyperplastic strati-
fied epithelium that are covered by a
thick layer of orthokeratin (1925,2284)
The elongated rete ridges converge to-
wards the centre. A prominent granular
cell layer with keratohyalin granules often
shows koilocytic changes.
Prognosis and predictive factors
Spontaneous regression is seen, par-
ticularly in children. Treatment is simple
excision , and recurrence can occur (886,
1455,1925).
AAulüfocalepftheHalhyperplasia
Vigneswaran N.
Carlos R.
Lippman S.
Mosqueda-Taylor A.
Muller S.
Williams MO.
Definition
Multifocal benign squamous epithe-
lial proliferation exclusively affecting oral
mucosa, caused by human papilloma
virus (HPV) {1965,2042)
Synonyms
Heck disease; focal epithelial hyperplasia
Fig. 4.11 Multiple papules in !he lower lip mucosa of a
15-year-old boy.
Epidemiology
Multifocal epithelial hyperplasia (MFEH)
is more prevalent in children and ado-
lescents with a female predominance as
high as 5:1 (1965,2042). First reported in
Native Americans and Eskimo peoples,
it is panracial, documented in almost
every ethnic group and geographical
region {2042} .
Etiology
HPV types 13 and 32 are implicated.
However, other genotypes such as 1, 6,
11, 16, 18 and 55 have also been detect-
ed (974 ,2042). MFEH in older patients is
mainly caused by HPV 32 (2042). Low
socioeconomic status, malnutrition and
crowded living conditions are thought
to be contributing factors. These prob -
ably explain the striking epidemiologi -
cal differences between developed and
developing countries . HIV patients have
increased risk for MFEH {2042,1233}
Localization
The most common locations for MFEH
are the lips, buccal mucosa, and bor-
ders of the tongue. Hard palate and gin -
giva are rarely affected {2042} . The low-
er lip is characteristically more affected
than the upper lip, and most lesions in
the buccal mucosa are located along the
occlusal plane.
Clinical features
MFEH presents as multiple papules sim -
ilar in colour to the adjacent mucosa,
measuring up to 5- 10 mm . They may
coalesce, forming plaques that may be-
come secondarily keratinized . The most
common appearance is a papulonodular
form with a smooth surface that occurs in
the non-keratinized mucosa.
Papillomas 117

Fig. 4.12 Focal epithelial hyperplasia, viral change and mitosoid body (inset).
Histopathology
MFEH shows mild hyperkeratosis and
prominent acanthosis, with preserva-
tion of normal cell maturation {2042).
Occasional koilocytes and "mitosoid"
figures composed of cells with karyor-
rhectic nuclei that may mimic mitoses,
118 Tumours of the oral cavity and mobile tangue
functional inactivation of the RB gene
and hence p16 immunohistochemistry
has no diagnostic role .
Genetic susceptibility
Famil ia! transmission of MFEH is linked to
the presence of HLA-DRB1 *0404 {810).
Prognosis and predictive factors
Most lesions in children spontaneously
disappear at puberty or with improved
living conditions.
representing a cytopathic nuclear viral
damage, are noted with in all epithelial
layers {2042). The mitosoid figures are
the most important feature of this entity;
they are not present orare extremely rare
in other HPV-related lesions. HPV sub-
types implicated in MFEH do not cause
Tumours of uncertain histogenesis

Congenital granular ce// epu/is overlying surface epithelium is usually at-

tenuated, and pseudoepitheliomatous
Allen C.M. hyperplasia is not a feature. The tumour
Bullerdiek J. nuclei are typically small, uniform, and
RoJY pale-staining , with no evidence of mitotic
activity (428) . In most cases, numerous
small, thin -walled blood vessels are uni -
Definition formly distributed throughout the lesion.
Congenital granular cell epulis is a rare Unlike the lesiona! cells of granular cell
benign tumour that affects the alveo- tumour of the tangue , those of congenital
lar processes of newborns and is com- Fig. 4.14 Congenital granular cell epulis of !he maxilla. granular cell epulis show no reactivity for
posed of sheets and nests of cells with SIOO protein.
abundant granular cytoplasm (479}.
Prognosis and predictive factors
Synonyms Conservative excision is the treatment
Congenital epulis ; congenital epulis of of choice , particularly if the lesion in-
the newborn; congenital gingival granu - terferes with eating or breathing (1304).
lar cell tumour; Neumann tumour Excisional biopsy may also be indicated
if the clinical diagnosis is uncertain . For
Epidemiology smaller lesions, observation may be ap-
Congenital granular cell epulis affects propriate, because spontaneous regres-
newborns. Most series identify a striking sion has been noted occasionally. Recur-
female predilection {2698} . Fig. 4.15 Congenital granular cel l epulis. Lesiona! rence is not seen.
cells with small, uniform nuclei and abundan! granular
Localization cytoplasm.
Most cases develop on the maxillary Ectomesenchymal
anterior alveolar process, although the from < 1 cm to several centimetres in di- chondromyxoid tumour
mandibular anterior alveolar process can ameter {1293}.
also be affected {428) . Bishop JA
Histopathology Gnepp D.R.
Clinical features Congenital granular cell epulis is char- RoJY
Congenital granular cell epulis typically acterized by sheets and nests of large
presents as a pedunculated soft tissue polygonal cells with demarcated cell
mass of normal mucosal colour, ranging membranes and granular cytoplasm. The Definition
Ectomesenchymal chondromyxoid tu-

>. -
... mour (EMCMT) is a benign mesenchy-

..... , p-
'
.. ...1 _ ..~ _ /;:ll'r- --, -
~::'., . • ,.... .,,. :.,.....,Ita;.: ·s
.. . ,.:"'~.... -~ mal neoplasm composed of cells pheno-
._-_...,.,
..-
_--=--·~.
- • •-

~ ...,.:- ...-::i:~ ~.., .. .

~ - ,.¿
-~..-: · -;'-'Al. -.. . ;~·... ...... ,...
_
-- --e•
:-
...
,. .... .
" - ~ .,,.;,.,1 ,. --.5 ""• typically resembling myoepithelial cells.
. ,., ,-¡t ~ . . .._ ~ ...,, ,, ........~- ·i!·\ ~- ti'!' ~.. .............. • ........ ,_ -
_,,_ _ - • ~. "' • J.·· --·~, ' ,. ~ • • . - ... ~~,-·
~.: · :: -i, ·º ~.;-::,..· ..,. -'-""'"' -- -:.... ..;.~-:.. ~·. . . . . " 'tt.,.• l ..... ~-... ?"" •~ ., _.. ~ .J . 6 ".,
• - ·~ ~ ... -,;. -.·· - ·.::. - ~"'- - '" --~,,. --~- -· • ... ir4 !--.·
_.¡. • ICD-0 code 8982/0
·- • • , .. " ::r_::.. \ .--:;. •.#:i.T
• ...... ~": ' ........ -- ...-~... - !...~
;~ ..
' .-,- '~ ' '•r , . .! /11 .,.. .,; ,'";.,, ' """:C: • '_, ...: ~ ?- -·~·1 t .• .·:~ 'J"*:,
~, 1 ,·'! -• /. •••,.,.., ~ " , ~ /'" . ., ...! .:_. !:.."'--;. • ,,.~ .~ ~· - ."• •• ,. .t-•c._.,. ~z.. Synonym
't:

•-''· ~ *.....
• ,- .,,,.
_. , ~.... ~ """..

'- ~~ "" •~ ~ ....., ~ ~ "'•1..· I~- - ~~~':.

• lf ~- ,.~,,, ... --~ •
.....
...
_, • ,.
tt •
· - ""' 1
11 ..
.. r' ...... ..-·. ~. .--. ......••, ..
_, "

._ · .
... A e
. . ~·.•~
,. , •·· . ~ '·· • ..,
Myoepithelioma {1736,2630)
, l1.~•=-
.. . ..,. •
. . . . . . , ..
' 4 " . '
4

-¡
Jo t

..~ ........~
'l· ~
, ,.- , .. J _., • ..
I• " •
.
.....

•
~·
l _
f .,

t•, . . .. ..
• ~
. > .,, ~ # :.~
~' .. . . . , ~ ra 'I "lf~
Epidemiology
--· . ..~
'
(¿, •- . -'!,;
~
,,,.
. ....
~...\;.
.. of.,
_,
,, ~ ,. ....
....
1 1''' , • ~", '\,, •-..'*~ ..,.'!~.., .f..
!: ' 1 #"' '·
.. ~ - .. , ... • •
....
• _. _ , c1, .~·
~
-
•
~ · "':-: ••
-::. . . . ~r
# •
'
'
.-
~
•
• .fl!'
About 60 cases of EMCMT have been
••,, • 4 · ,. 1••A r
.,,4 " • " · •' .a ..:' • /.- ~- .. , fl'° ':J
,.. • -: reported , affecting a wide patient age
••-: " ,-.. ~'/! •, Au, .... 11j · rL
~
~ aft, /f~'"•
1
_: ',·,-. range (7-78 years), with a mean patient
f..... •)· ... , .. .. ~ ~ ' ~ '. , .. -r ,. • ..
. ...i • .. ~ • !1': ,,.•; • • .f ' . .. • •t"P • • ~·,, !' •" ,. , ,,. • 11
age of 37 years. No sex predilection is
~ ~· '_,.,..~ ~
~ Y ';:_ " . - .
- ~
.....

- ~ '!lt.'.i. .
4,

- -
;.~i • ~~ ~ - •_,,~~"i
4' ·

- - --· ¿" .. • ,, . 1
1
1, - ., . . 4 -
~·
,,
~ .
•• '
._~ ~ 1
•
\
"
~ apparent (44 ,2218)
Fig. 4.13 Congenital granular cell epulis. Bland , attenuated surface oral epithelium and underlying sheets of uniformly
distributed lesiona! cells with scattered delicate blood vessels.

Tumours of uncertain histogenesis 119

 ; •
P'. , '
~.·~[~~~·.,¡,,. ' l •

L . .- - - ~ i.:-"f)- -.
::;.<,
..
~ Alit:
' <~
- -
Fig. 4.16 Ectomesenchymal chondromyxoid tumour. A The tumour grows in !he submucosa as circumscribed bu! unencapsulated nodules separated by fibrous bands.
B Tumour cells are round, oval, or fusiform, set in a myxoid stroma; tumour nuclei are hyperchromatic with irregular borders and indistinct nucleoli. C Sorne cases exhibit overtly
chondroid differentiation. D Tumours are consistently positive for GFAP by immunohistochemistry.

Localization Histopathology EMCMT is consistently immunoreactive

In the oral cavity, EMCMT arises almost ex-
clusively in the dorsum of the anterior tongue.
Rare cases have been reported in the poste-
rior tongue and hard palate {44,1735).
Clinical features
EMCMT presents as a longstandi ng
(present for months or even years), pain-
less, submucosal tongue mass without
ulceration.
Macroscopy
EMCMTs are generally small (< 2 cm),
circumscribed, tan-grey nodules with a
gelatinous gross appearance.
Cytology
Cytology shows cellular smears with
myxoid to thick fibrillary tissue fragments,
with clusters of oval , polygonal , or spin-
dled cells with uniform nuclei {440) .
EMCMT is an unencapsulated but
generally well -circumscribed neoplasm
within the tangue submucosa. Entrap-
ment of skeletal muscle libres may be
seen. At low power, EMCMT grows as
lobules of cells separated by fibrous
bands, with frequent slit-like clefts within
the tumour. The tumour cells are round ,
fusiform, or spindled cells arranged in
cords, sheets, or a reticulated pattern
within a myxoid or chondromyxoid
stroma. Tumour cells have moderate
amounts of eosinophilic to amphophilic
cytoplasm, indistinct cell borders, and
nuclei with irregular membranes (e.g.
with indentations or pseudoinclusions).
Hyperchromatic nuclei and nuclear
enlargement or multinucleation may be
encountered. Mitotic figures are rare.
Plasmacytoid cells and ductal structures
are not encountered.
far GFAP and usually immunoreactive far
8100 protein and CD57. lmmunostaining
far cytokeratins, EMA, actin, and p63 is
variable {44 ,2218).
Cell of origin
The cell of origin is unknown. EMCMT
may arise from undifferentiated ectomes-
enchymal cells from the embryonic neu-
ral crest mesenchyme of the first branchi-
al arch {2218). Minor salivary gland origin
is less likely, given the inconsistent cy-
tokeratin immunostaining and absence of
minar salivary glands in the dorsal ante-
rior tangue {880).
Prognosis and predictive factors
The prognosis is excellent, with a low risk
of recurrence.

120 Tumours of the oral cavity and mobile tangue

Soft tissue and neural tumours

Granular ce// tumour

Allen C.M.
Gnepp D.R.
Ro J.Y.

Definition
Granular cell tumour is an uncommon
benign tumour of Schwann-cell differen-
tiation characterized by poorly demar-
cated accumulations of plump granular
cells (2458).

ICD-0 code 9580/0

Synonyms
Granular cell myoblastoma; granular cell
schwannoma; granular cell neurofibro-
ma; Abrikossoff tumour (ali obsolete)

Epidemiology
Most granular cell tumours are diagnosed
during the third to fifth decades of life,
although they may occur in patients
of any age. Most reports describe a
female-to-male ratio of 2:1, and a higher
incidence in Black populations has been
noted.
Localization
Although granular cell tumour can affect
any subcutaneous or submucosal site ,
approximately 30-40% of cases occur
on the tongue. The bucea! mucosa is the
second most common intraoral site.
Fig. 4.17 Granular cell tumour. Sessile nodule of the
dorsal tangue showing intact surface mucosa that is
stretched by the underlying tumour.
Clinical features
Granular cell tumour presents as a non-
tender, rubbery-firm, slow-growing, ses-
sile, submucosal mass. On palpation, the
tumour often feels demarcated, but not
encapsulated. lf the tumour is near the
surface, a yellowish to creamy-white col-
our is often apparent. Most granular cell
tumours are solitary, but multiple tumours
have infrequently been reported (2074).
Macroscopy
On cut surface, the tumo ur is a pale tan
to yellowish-white submucosal nodule.
Histopathology
This unencapsulated submucosal tumour
intermingles with the adjacent normal tis-
sue. The lesiona! cells usually appear po-
lygonal and exhibit abundant eosinophil-
ic granular cytoplasm. The tumour nuclei
may be centrally or eccentrically located
and are typically uniformly small, round ,
and pale-staining. The granular cells are
often intimately associated with adja-
cent muscle fascicles or nerves. Sorne
granular cell tumours have a significant
degree of background fibrosis, with rela-
tively few lesiona! cells. The cytoplasmic
granules give a diastase-resistant posi-
tive periodic acid-Schiff (PAS) reaction.
lmmunohistochemistry is positive for
8100 protein, CD57, and SOX10 (72).
CD68 antibodies also label the cytoplas-
mic granules. Pseudoepitheliomatous
hyperplasia overlies a substantial propor-
tion (30-50%) of these lesions; therefore,
care should be taken when evaluating a
superficial biopsy sample to prevent an
erroneous diagnosis of squamous cell
carcinoma. Rare cases of granular cell
tumour with concurrent squamous cell
carcinoma have been reported, so care-
ful and thorough evaluation of sections is
necessary (168}. Rare examples of ma-
lignant granular cell tumour (character-
ized by pleomorphism, mitotic activity,
spindle-shaped lesiona! cells, and ne-
crosis) have also been described (2458).

Soft tissue and neural tumours 121

Cell of origin
lmmunohistochemical studies suggest
differentiation consistent with an origin
from Schwann cells {1976) .
Prognosis and predictive factors
Although recurrence is possible, the like-
lihood seems to be low, even when le-
siona! tissue appears to have been tran-
sected at the margins {2458).
Rhabdomyoma
Bullerdiek J.
Ro J.Y.
Thompson L.D.R.
Definition
Rhabdomyoma is a benign tumour with
skeletal muscle differentiation .
ICD-0 code
Epidemiology
Rhabdomyoma is divided into fetal , ju-
venile, and adult subtypes on the basis
of histology rather than patient age. For
adult rhabdomyoma, patient age var-
ies broadly (with a median age in the
sixth decade of lite {457)). Fetal rhabdo -
myoma usually occurs in newborns and
during early childhood. There is a male
predominance.
Localization
Rhabdomyomas occur predominantly
in the head and neck. About 15% of pa-
tients with adult rhabdomyoma present
with multifocal disease {1427) . Common
localizations are the parapharyngeal
Fig. 4.19 Adult rhabdomyoma. A A compact arrangement of large polygonal hypereosinophilic cells showing characteristic vacuolated (so-called spider) cytoplasm; the nuclei are
small and round . B Delicate cross-striations are noted within the abundan! granular, eosinophilic cytoplasm; the nuclei are round and bland.
122 Tumours of the oral cavity and mobile tongue
space (affected in 36% of cases) , larynx
(15%), submandibular (14%) , paratrache-
al region adjacent to the thyroid gland
(12%) , tongue (11%), and floor of the
mouth (9%) {540).
Clinical features
The tumours present as soft, painless
and non-tender masses.
Macroscopy
Rhabdomyoma presents as a well-de-
lineated, rounded or coarsely lobulated,
sessile or pedunculated smooth submu-
cosal mass that is greyish-yellow to red-
dish-brown on cut surface. The tumours
can be 0.5-10 cm , with most examples
measuring 1-3 cm. There is no haemor-
rhage or necrosis.
Histopathology
The adult type is composed of variably
sized , deeply eosinophilic polygonal
8900/0 cells and cells with vacuolated cytoplasm
(spider cells) . Rod-shaped cytoplasmic
crystals (so-called jackstraws) or cross
striations may be seen . Necrosis and mi-
toses are absent. The fetal type is com-
posed of an intimate, haphazard-looking
mixture of round or spindled mesen-
chymal cells and differentiated cells
with myofibrils within an occasionally
myxoid mucopolysaccharide-rich matrix.
There is a gradient of cellularity or matu-
ration towards the periphery. Strap cells
with eosinophil ic cytoplasm , occasionally
with cross striations, may be seen. There
is immunopositivity for SMA, desmin, my-
oglobin, and MY001; fetal myosin may
be seen in the fetal type . Si 00 protein
and GFAP may be focally expressed .
~ ~
Genetic profile
Aberrations of the PTCH1 locus have
been reported in fetal rhabdomyomas
{982), which may be associated with
naevoid basal cell carcinoma syndrome.
Prognosis and predictive factors
Recurrences are uncommon after surgi-
cal excision. Malignant transformation
does not occur.
Lymphangioma
Bullerdiek J.
Flucke U.
Definition
Lymphangioma is a congenital malfor-
mation of lymphatic vessels .
ICD-0 code 9170/0
Synonyms
Lymphangioepithelioma (obsolete);
lymphangiomatous polyp
Epidemiology
Lymphangiomas are relatively uncom-
mon. They are usually diagnosed in in-
fancy or early childhood.
Localization
The skin and subcutaneous tissue of the
head and neck region is the most com-
mon localization for lymphangiomas, but
they are only occasionally reported in
the oral cavity. lntraoral lymphangiomas
arise most commonly on the dorsum of
the tongue, followed by the palate, buc-
cal mucosa, gingiva, and lips {2450).
-...:

Fig. 4.20 Lymphangioma of the tongue. Irregular, thin-walled, fluid-filled spaces lined by lymphatic endothelium
surrounded by a fibrous stroma with lymphocytic aggregates.
Clinical features
Clinical behaviour varies, with erratic
growth, progression, or even spontaneous
regression during the first two decades
of life. Symptoms are related to size and
perturbation of structure (280,2450). The
lesions can be pedunculated or sessile.
Histopathology
The malformations consist of variably
sized, irregular, thin-walled fluid -filled
spaces lined by lymphatic endothe-
lium surrounded by a stroma of fibrous,
smooth-muscle, and adipose tissue,
along with lymphocytes (280). The vas-
cular endothelial cells are immunoposi-
tive for CD31 or CD34 (1186}, podoplanin
(as recognized by 02-40), PROX1, and
VEGFR3. Lymphatic endothelial cells
stain for LYVE1 (280,1163,1536). The
walls of the lymphatic vessels stain posi-
tively for SMA (1186,1977).
Genetic susceptibility
Like other vascular anomalies, malfor-
mations of lymphatic vessels are com-
mon in Proteus syndrome (465}, which is
caused by a somatic activating mutation
in AKT1 (1437). Other genetic disorders
associated with lymphangioma include
Turner syndrome (45,X syndrome) and
trisomy 21 (280)
Prognosis and predictive factors
Recurrences may occur after surgical
resection (280).
Haemangioma
Bullerdiek J.
Flucke U.
Definition
Oral haemangiomas are benign vascular
hamartomas affecting the mucosa. They
are distinct from vascular ectasias, vas-
cular malformations, and s (also called
lobular capillary haemangiomas).
ICD-0 code
Epidemiology
Haemangiomas are frequent childhood
tumours with a female predominance.
They occur commonly in the head and
neck region in both children and adults,
but only rarely in the oral cavity (including
the tangue) (11,235,1290). However,
haemangioma (infantile haemangioma)
is the most common benign tumour of
the oral cavity and mobile tangue in the
paediatric population (1502 ,2080}
Localization
In the oral cavity, haemangioma can
arise in the tangue, lips, bucea! mucosa,
gingiva, and palate {1502,1669,2682}.
Clinical features
The tumours present as smooth reddish-
purple polypoid or pedunculated mass-
es, often with increasing size and occa-
sional bleeding.
Histopathology
Capillary haemangiomas consist of
multilobular arrangements of proliferat-
ing endothelial cells and capillaries of
various shapes and sizes surrounded by
pericytes. The lumina may be subtle or
dilated, especially in infantile haemangi-
omas {280,1141}. Cavernous haemangio-
mas show larger dilated vascular spaces
lined by endothelial cells. The endothe-
lial cells are positive for CD34, CD31 ,
and ERG (280,1611}. GLUT1 is positive
in infantile haemangioma but negative
in pyogenic granuloma, vascular ecta-
sias, and congenital haemangioma (280,
1141 ,1746). Haemangiomas must be dis-
tinguished from pyogenic granulomas,
which are ulcerated reactive Jesions fre-
quently arising on the gingiva and char-
acterized by lobular accumulations of
maturing vascular granulation tissue.
Genetic susceptibility
Haemangiomas have been described
in carriers of various chromosomal ab-
normalities {39,2425,2484) and are fre-
quently associated with full or partial
polysomy 13 (108,1443,2007).
Prognosis and predictive factors
lnfantile haemangiomas initially grow rap-
idly, but most subsequently involute and
require no intervention . Successful treat-
ment options are beta blockers, steroid
injection, endovascular sclerotherapy,
9120/0 and surgery (15,1669,2577).
Schwannoma and neurofibroma
Flucke U.
Wenig B.M.
Definition
Schwannoma and neurofibroma are be-
nign peripheral nerve sheath tumours.
Schwannoma consists of Schwann cells ,
and neurofibroma consists of an admix-
ture of Schwann cells, fibroblasts, peri-
neurial-like cells, and axons.
ICD-0 codes
Schwannoma 9560/0
Neurofibroma 9540/0
Synonyms
Schwannoma: neurilemmoma;
neurinoma
Epidemiology
Schwannomas usually occur in adults.
Neurofibromas are the most common
benign peripheral nerve sheath tumour
affecting infants, children, adolescents,
Soft tissue and neural tumours 123
and adults {357,933,2005) .
Etiology
Most lesions occur sporadically {933,
2005).
Localization
lntraorally, the tongue is the most com -
mon site, fo llowed by the palate, buccal
mucosa, floor of the mouth, lips, gingiva,
and jaws {656,933,1311,1440,1499}.
Clinical features
Patients present with a slow-growing,
sometimes painful, submucosal mass.
Multiple neurofibromas are associated
with neurofibromatosis type 1 {357,933,
952).
Macroscopy
Both lesions are nodular with a tan-
white, glistening cut surface. An associ-
ated nerve can occasionally be identified
{357,2005).
Histopathology
In mucosal sites, schwannomas are typi -
cally submucosal and circumscribed but
unencapsulated. They are composed of
a spindle-cell proliferation arranged in al -
ternating cellular Antoni A and hypocellu -
lar Antoni B areas. The spindle cells have
oval, tapered, or buckled nuclei with poorly
defined eosinophilic cytoplasm. Nuclear
palisading is a frequent feature, occasion -
ally with Verocay body formation. Degen -
erative nuclear atypia and mitotic figures
should not be interpreted as ominous
signs . Assoc iated hyalinized blood vessels
and foamy histiocytes are common. Haem-
orrhage and lymphocytes may be present
{952,2005).
Neurofibromas are characterized by
124 Tumours of the oral cavity and mobile tongue
random rearrangement of spindle cells in a
collagenous to myxoid stroma. The nuclei
are wavy and the cytoplasm inconspicu-
ous . Mitotic figures are usually absent. The
collagen bundles typically have a so-called
shredded -carrots appearance {2005).
Schwannomas show strong and diffuse
nuclear and cytoplasmic S100 protein
expression, as well as nuclear SOX10
reactivity Scattered CD34-positive cells
may be seen. In contras!, neurofibromas
show heterogeneous expression of these
markers {357,952,1183,1797,2005).
Genetic profile
Schwannomas are characterized by loss
of chromosome 22 and inactivating mu-
tations in NF2 {2267). Neurofibromas
are characterized by inactivation of NF1
{357) .
Genetic susceptibility
Neurofibroma is associated with neurofi-
bromatosis type 1 {357,2005).
Prognosis and predictive factors
Both tumours fo llow a benign clinical
course . Neurofibromas have the potential
for malignant transformation, especially
in patients with neurofibromatosis type 1
{357,933,952,2005,2069}.
Kaposi sarcoma
Thompson L.D.R.
RoJY
Wenig B.M.
Definition
Kaposi sarcoma is a locally aggressive
vascular neoplasm of intermediate type,
uniformly associated with HHV8.
ICD-0 code 9140/3
Synonym
Kaposi disease
Epidemiology
Kaposi sarcoma is separated into four
distinct epidemiological categories (Ta-
ble 4 06); of these, only the AIDS-related
(HIV-1-related) type is associated with
oral manifestations {697,1812,1897). As
many as 20% of individuals with HIV-1
infection develop oral Kaposi sarcoma,
usually in the fourth to fifth decades of
lite. In industrialized countries, it is most
common in horno- and bisexual HIV-1-
infected men, whereas there is no sex
difference in developing countries {1811,
2538}.
Etiology
Kaposi sarcoma is always associated
with the gamma-2 herpesvirus HHV8
(also called Kaposi sarcoma-associ -
ated herpesvirus; KSHV). The neoplasm
develops in a complex dynamic with
HIV-induced immunosuppression and
environmental and genetic factors after
exposure to HHV8 in saliva or blood {122,
1347).
Table 4.06 Clinical and epidemiological forms of Kaposi sarcoma. Adapted from Barnes Letal. {146) and Fletcher CDM et al. {735) Myofibroblastic sarcoma
Type Risk group Sites of involvement Clinical course
> 70% elderly men;
Flucke U.
Classic Skin of lower extremities lndolent Franchi A.
Slavic, Jewish, ltalian
1 Skin of extremities; visceral
Endemic involvement common; lym- lndolent in adults;
Children and middle-aged men Definition
(African) phadenopathic type common aggressive in children
1 in children Myofibroblastic sarcoma is a low-grade
Salid organ transplant recipients malignant infiltrative tumour of the deep
latrogenic/ Variable; may resolve soft tissue, with a predilection for the
(0.5% of renal transplant patients); Skin of extremities; may have
transplant- upan cessation of im-
patients receiving immunosuppres- visceral involvement head and neck. lt has a variety of ap-
associated munosuppressants
sive therapy pearances, from fasciitis-like or fibroma-
HIV-infected patients; more com- Skin of head and neck, tosis-like to fibrosarcoma-like.
mon in horno- and bisexual men extremities, genitals, mucosa
AIDS-related Aggressive
at younger age than classic Kaposi of upper aerodigestive trae!; ICD-0 code 8825/3
sarcoma lymph nades
Synonym
Localization mitoses {299,697,1811 l. Papillary tufting Myofibrosarcoma
The hard palate, followed by the gingiva within large dilated anastomosing ves-
and tongue, is the most common oral site. seis is seen in lymphangiomatous Kaposi Epidemiology
Up to 70% of patients with cutaneous Ka- sarcoma {1931l . The neoplastic cells are The tumours can occur in patients of any
posi sarcoma also have oral lesions. positive for HHV8, podoplanin (as recog- age, with a mean patient age of 40 years
nized by 02-40), LYVE1 , VEGFR3 , PROX1, {724,1591)
Clinical features CD34, CD31, FLl1, and ERG , with HHV8
Patients present with multiple red to viola- positivity being most specific {1813l. Localization
ceous macules or papules that progress The oral cavity, including the tongue, is
to plaques or nodules. Bleeding, ulcera- Cell of origin a preferred site. Rarely, these tumours
tion, and pain may be seen in advanced Phenotypically, the cells of origin are arise in the nasal cavity and paranasal
disease. Lymphoedema is uncommon lymphatic endothelial cells {322). sinuses. Origin in bone, notably gnathic
{697,1812,1837l. bone, can also occur. Low-grade myofi-
Prognosis and predictive factors broblastic sarcoma can arise subcutane-
Histopathology Oral Kaposi sarcoma has a higher fatal- ously or in a submucosal localization but
The histopathological appearance devel - ity rate than does AIDS-related Kaposi is in most cases deep-seated {312,724,
ops with disease progression. The patch sarcoma of the skin, due to associated 1268,1591}.
stage shows irregularly shaped, slit-like poor prognostic factors such as immune
vascular spaces dissecting collagen bun- status (e .g. CD4 count < 300 cells/ml), Clinical features
dles, often parallel to the epithelium , with ulceration, and nodular type {458 ,1545). Myofibroblastic sarcoma presents as a
extravasated erythrocytes and lympho- Kaposi sarcoma is often multifocal but painless swelling or enlarging mass {1591}.
cytes; the plaque stage shows further spin- rarely metastasizes.
dle-cell proliferation associated with intra- Macroscopy
and extracellular hyaline globules; and The lesions are firm, with fibrous cut sur-
the nodular stage shows widely infiltrat- faces and typically poorly defined mar-
ing atypical spindled cells with increased gins {1591).

Soft tissue and neural tumours 125


Fig. 4.23 Myofibroblastic sarcoma. Note the slight cellular atypia and the typical infiltration of the skeletal muscle.
Histopathology
The pattern is that of a rather cellular,
fibromatosis-like or fibrosarcoma-like
lesion composed of fascicles or broad
sheets of cells , with or without focal
herringbone or storiform arrangement.
Checkerboard-like infiltration of the adja-
cent voluntary muscle is a key diagnos-
tic feature . The tapered myofibroblastic
Oral mucosal melanoma
Definition
Oral mucosal melanoma is a malignant
neoplasm of melanocytes.
ICD-0 code 8720/3
Epidemiology
Oral mucosal melanoma is a rare en-
tity, accounting for only about 0 .5% of
melanomas. There is a slight male pre-
dominance, and the median patient age
at diagnosis is 55-66 years (385 ,1584,
2238}.
Fig. 4.24 Oral mucosa! melanoma. Clinical presentation
shows an irregular, variably pigmented lesion on the hard
palate.
126 Tumours of the oral cavity and mobile tangue
nuclei are atypical and show hyperchro-
masia. Mitotic figures are variably present.
There are scant or moderate amounts of
cytoplasm . The background can be col-
lagenous or myxoid. Transformation into
high-grade sarcoma has been reported
(312,724,1591}. lmmunohistochemistry
shows a myofibroblastic immunopheno-
type , with variable expression of SMA ,
Etiology
Mucosal melanomas, w hich are biologi-
cally distinct from lesions of cutaneous
origin , are caused by unknown factors.
Localization
Most cases arise on the palate or gingiva
{546,1958 ,2243 ,2338}.
Clinical features
The neoplasm, which is often asymptomat-
ic, presents as a 1.5-4 cm , blackish-
grey, irregular, flat or nod ular lesion , with
Fig. 4.25 Oral mucosa! melanoma. A Large epithelioid cells with ample eosinophilic cytoplasm are scattered within
the epithelial junction and submucosa. Pigmentation may not be identified. B S100 immunohistochemical staining
highlights the melanocytic cells, showing both an in situ and an invasive pattern of growth.
desmin, calponin , and CD34. In rare
cases, h-caldesmon is detected, with only
focal expression (724,1591}. Expression of
beta-catenin does not rule out this tumour
type ¡335}.
At the ultrastructural level , the neoplastic
cells are spindle-shaped , with oval , often
indented nuclei. The cytoplasm contains
numerous rough endoplasmic reticulum
c isternae (which often contain flocculent
material) and subplasmalemmal bundles
of actin filaments , with or without focal
densities, sometimes associated with
subplasmalemmal attachment plaques.
Pinocytotic vesicles and fibronexus junc-
tions are present in sorne cases {681 ,725}.
Genetic profile
Complex genetic aberrations have been
identified (734}.
Prognosis and predictive factors
Local recurrences are common, but
metastatic sp read (to lung, soft tissue, or
bone) occurs rarel y {1591}.
Williams M.O.
Speight P.
Wenig B.M.
ulceration present in one third of cases.
Lymph node metastases at presentation
are common, present in about 30% of
cases {984).
Cytology
Aspirates of metastatic oral melanoma are
identical to those of cutaneous melanoma.
Preparations show malignant epithelioid,
spindled, or undifferentiated cells .
Histopathology
Atypical pigmented melanocytes are
present at the junction (in situ) and/or
Salivary type tumours
Mucoepidermoid carcinoma
lnagaki H.
Bell D.
Brandwein-Gensler M.
Definition
Mucoepidermoid carcinoma is a dis-
tinctive salivary gland malignancy com-
posed of mucinous, intermediate (clear-
cell), and squamoid tumour cells forming
cystic and salid patterns.
See also the Mucoepidermoid carcinoma
section (p . 163) in Chapter 7 (Tumours of
salivary glands) .
ICD-0 code 8430/3
Synonym
Mucoepidermoid tumour
(not recommended)
Epidemiology
lt is a rare tumour {213} that most com-
monly manifests as intraoral salivary gland
carcinoma (in 37-53% of cases), with a
slight female predilection . A wide patient
age has been reported, with the mean age
in the sixth decade of life {292,2402} .
Localization
The palate is the most common intraoral
site, accounting for > 50% of intraoral
cases {292,2402) .
Clinical features
The tumours are often asymptomatic, but
may cause symptoms, depending on the
site and histological grade.
invasive nests, and single cells infiltrate
the submucosa. The cells are usually
epithelioid, with prominent nucleoli, but
spindled cells may be seen.
Genetic profile
Associated mutations include alterations
in KIT (occurring in 10- 30% of cases),
RAS genes (in 10- 20%), and BRAF (in
< 10%) {343,1475,1996}.
Genetic susceptibility
lncidence varies among different ethnici-
ties {1475,2243,2338}.
Macroscopy
Many appear as bluish, domed swellings.
Histopathology and genetic profile
See the Mucoepidermoid carcinoma
section (p . 163) in Chapter 7 (Tumours of
salivary glands) .
Prognosis and predictive factors
This tumour has a favourable outcome. Most
patients present with low-grade tumour and
low-stage tumour {1700,1769).
Pleomorphic adenoma
Bell D.
Brandwein -Gensler M.
Chiosea S.
Definition
Pleomorphic adenoma (PA) is a benign
tumour with variable cytomorphological
and architectural manifestations. The
identification of epithelial and myoepithe-
lial/stromal components is essential for
the diagnosis of PA .
See also the P!eomorphic adenoma sec-
tion (p. 185) in Chapter 7 (Tumours of sa/i-
vary glands) .
ICD-0 code 8940/0
Synonym
Benign mixed tumour
Localization
PAs of the oral cavity most commonly
arise in the palate, upper lip, and cheek
Prognosis and predictive factors
Cutaneous melanoma prognostic factors
(e .g . Clark leve! of invasion and Breslow
tumour thickness) do not apply. The over-
all prognosis is poor, with a median sur-
vival of 2 years {1131,1480,1918,2238}.
{678,1834,1900,2082). PA within the mo-
bile tangue is uncommon {2355,2504) .
Clinical features
The tumour presents as a slow-growing,
painless, submucosal, fixed (hard pal -
ate), or mobile (bucea! mucosa) mass.
Palatal PAs are located laterally and rare -
ly cross the midline. The tumour is typi -
cally detected early and rarely attains a
size > 1- 2 cm.
Macroscopy
lntraoral PAs often lack encapsulation .
Palatal examples frequently involve the
periosteum or bone .
Histopathology
PAs at these siles display plasmacytoid
myoepithelial cytological features and
are often unencapsulated . Cutaneous
adnexal differentiation can be seen in
palatal and lip PAs (i.e. tricholemmal, se-
baceous, and infundibular cystic features
with trichohyalin granules) {2098) . Ec-
tomesenchymal chondromyxoid tumour
is the main differential diagnostic consid-
eration, especially in the tongue {52).
Genetic profile
See the P!eomorphic adenoma section
(p. 185) in Chapter 7 (Tumours of sa!ivary
g!ands).
Prognosis and predictive factors
Prognosis of PA is generally good. PA
does not recur after adequate surgical
excision. See also the P!eomorphic ade-
noma section (p . 185) in Chapter 7 (Tu-
mours of salivary glands) .
Salivary type tumours 127
Haematolymphoid tumours
Overview
Definition
Oral haematolymphoid tumours are neo-
plasms of lymphoid, plasma cell , histio-
cytic/dendritic, and myeloid origin arising
in the oral cavity.
Epidemiology
Lymphoma accounts for 3.5% of oral cav-
ity malignancies !897). Approximately 2%
of extranodal lymphomas arise in the oral
cavity {761,2339). Among immunocom-
petent patients, lymphomas mainly af-
fect older adults, and only rarely children.
There is a slight male preponderance
{897,909,1211,2464). Almost all HIV-pos-
itive patients are young to middle-aged
adult men {909). The oral cavity is the
most common head and neck site for
involvement by myeloid sarcoma {2724).
Oral plasmacytoma is rare, accounting
for 0-6% of head and neck extraosseous
plasmacytomas {116,2078). Histiocytic/
dendritic cell neoplasms are rare {1810).
Etiology
Most lymphomas arise sporadically. A
minority of patients are HIV-positive {878,
909,1211) or iatrogenically immunocom-
promised {1387,1652) .
Localization
Lymphomas most often involve the pal-
ate or gingiva (and may involve subja-
cent bone), and less often involve the
tongue, buccal mucosa, floor of the
mouth, or lips. One third to half of all
lymphomas arise from bone; the rest
arise from the mucosa {1211,1952,
2464). Most patients have localized
(stage 1/11) disease {897).
Clinical features
Non-tender swelling is most common
{897,1211,1952 ,2464), followed by ulce-
ration {1211), pain, paraesthesia, and
numbness {1211,2464). Systemic symp-
toms are uncommon {2464).
128 Tumours of the oral cavity and mobile tongue
.. ..,........._ a!m;, .,• •~..~
Fig. 4.26 EBV-positive Burkitt lymphoma involving !he gingiva of an HIV-positive male. Neoplastic cells are medium-
sized, with coarse chromatin, small nucleoli, and admixed tingible-body macrophages. lnset: Tumour cells are positive
for EBV-encoded small RNA (ESER) by in situ hybridization.
Macroscopy
Oral haematolymphoid tumours present
as poorly defined or discrete masses,
with or without ulceration.
Histopathology
Lymphomas occurring in immunocom-
petent patients are heterogeneous. Dif-
fuse large B-cell lymphoma is most com-
mon !909,1211), with germinal-centre
and non-germinal-centre B-cell pheno-
types reported {1790). Others include
follicular lymphoma !909,1211}; MALT
lymphoma {909,1211); Burkitt lympho-
ma {1952) ; mantle cell lymphoma {898 ,
2464); rare B-lymphoblastic lymphoma
{2464); and high-grade B-cell lymphoma,
NOS {1790). Burkitt lymphoma is among
the most frequent of the rare paediatric
lymphomas {1952). T-cell and NK-cell
lymphomas are rare in western popula-
tions {1211) but are not infrequent among
Asians {1952). HIV-positive patients fre-
quently develop diffuse high-grade B-
cell lymphomas, including diffuse large
B-cell lymphoma {909), plasmablastic
Ferry J.A.
Li X.-Q .
lymphoma (see Plasmab/astic /ympho-
ma, p. 129), and Burkitt lymphoma {878,
909}. Most immunodeficiency-associated
lymphomas are EBV-positive {560 ,909).
Lymphomas must be distinguished from
indolent and self-limited disorders, such
as primary mucosal CD30-positive T-cell
lymphoproliferative disorder (see below)
{1000,2057) and EBV-positive mucocu-
taneous ulcer {595) . The latter presents
as a circumscribed ulcerative lesion in
the tangue or buccal mucosa of immu-
nocompromised or elderly patients and
is characterized by a polymorphous in-
filtrate with atypical large B cells often
resembling Reed-Sternberg cells. EBV-
positive mucocutaneous ulcer regresses
spontaneously or has a relapsing -remit-
ting course.
Prognosis and predictive factors
Outcome depends on the type of lym-
phoma, disease stage, and patient char-
acteristics, including HIV status {878,897,
909,2464).
CD30-positive T-cell
/ymphoproliferative disorder
Feldman A.L.
Boy S.
Ferry J.A.
Ko Y.-H.
Li X-0.
Pileri S.A.

Definition
CD30-positive T-cell lymphoproliferative
disorder (TLPD) is a neoplastic prolifera-
tion of large, CD30 -positive T cells aris-
ing in the oral cavity or occasionally other
Fig. 4.27 Primary CD30-positive T-cell lymphoproliferative disorder of the tongue. There is ulceration and infiltration
mucosa! sites in the head and neck. This of the skeletal muscle.
entity constitutes a clinicopathological
spectrum of lymphoproliferative lesions,
analogous to the spectrum observed in
primary cutaneous CD30-positive TLPD.
This disorder must be distinguished from
reactive inflammatory conditions of the
oral cavity and from secondary involve-
ment by systemic anaplastic large cell
lymphoma.

ICD-0 code 9718/3

Epidemiology
There is a male predominance, with a
male-to-female ratio of 2:1. The disorder
primarily affects adults, with a mean pa-
tient age in the sixth decade of lite 12108,
2542}.
Localization
The proliferation typically presents in the
oral cavity or tongue, but similar lesions
have been described in the nasophar-
ynx, conjunctiva, and orbit {2013,2108,
2339,2542).
Clinical features
CD30-positive TLPD typically presents
with a mass lesion, often with ulcera-
tion. Spontaneous regression may occur
{716) . Clinical history and staging are im -
portant for excluding secondary involve-
ment by a systemic lymphoma.
Histopathology
Primary mucosal CD30-positive TLPD
demonstrates a morphological spectrum
similar to that observed in primary cutane-
ous cases. The neoplastic cells are large
atypical lymphoid cells with pleomorphic
nuclei and abundant cytoplasm. Cells re-
sembling the hallmark cells of anaplastic
large cell lymphoma often are seen . Most
cases show a diffuse or sheet-like growth
pattern. A mixed inflammatory back-
ground may be present, including areas
with prominent eosinophils or neutrophils
{58,2108,2542) . Sorne cases of traumatic
ulcerative granuloma with stromal eosin -
ophilia may represent the indolent end
of the spectrum of CD30-positive TLPD
{1000).
By definition, CD30 is positive, and stain-
ing is strong and uniform. The large lym -
phoid cells typically show a T-cell phe-
notype, but often demonstrate loss of
one or more pan-T-cell antigens. CD4 is
expressed more frequently than CD8 .
Cytotoxic markers (i.e. TIA1 , granzyme B,
and perforin) are often expressed, and
EMA may be positive. CD56, ALK, and
EBV are negative {2542). The EBV-pos-
itive cases that have been reported in
children most likely represent chronic ac-
tive EBV infection instead {1019)
Genetic profile
Clonal T-cell receptor gene rearrange -
ments have been detected in most cases
12108,2542). Occasional cases carry re -
arrangements of the DUSP22-IRF4 locus
on 6p25.3, similar to the rearrangements
A Most areas show sheets of large
observed in sorne primary cutaneous
cases of CD30-positive TLPD and ALK-
negative anaplastic large cell lympho-
mas 12108).
Prognosis and predictive factors
Most cases show complete resolution
with local therapy (excision with or with-
out radiotherapy), with or without the
addition of systemic chemotherapy 123,
2108,2542). Occasional cases show
spontaneous regression.
Plasmablastic lymphoma
Boy S.
Ferry J.A.
Definition
Plasmablastic lymphoma (PBL) is a high -
grade B-cell non-Hodgkin lymphoma with
plasma cell immunophenotype and a pre-
dilection for extranodal siles. Diagnosis is
challenging dueto the overlap with plasma
cell neoplasms and B-cell lymphomas with
plasmablastic differentiation. ALK-positive
large B-cell lymphoma is excluded.

Haematolymphoid tumours 129

Fig. 4.29 Plasmablastic Jymphoma. Typical appearance
in a 39-year-old HIV-positive man; the palate and buccal
vestibu/e are most commonly affected in oral mucosal
plasmablastic lymphoma.
ICD-0 code
Epidemiology
PBL is strongly associated with HIV-
related immunosuppression, in the set-
ting of which it is AIDS-defining. lt also
occurs in HIV-negative older adults and
iatrogenically immunocompromised pa-
tients . HIV-associated PBL affects males,
usually with advanced-stage disease, at
an average age of about 40 years. HIV-
negative PBL more commonly affects
females (aged > 60 years) with localized
disease. Post-transplant PBL, which is
rare, usually affects older patients with
advanced -stage disease.
Etiology
PBL is associated with EBV infection,
which is known to cause a surge in
plasmablasts {720}, and MYC deregula-
tion , which enhances cellular prolifera-
tion {350 ,1235}, but the exact molecular
pathogenesis is unknown.
Localization
Head and neck sites, especially the oral
cavity {560}, oropharynx , nasopharynx,
and sinonasal tract, are affected. Lymph
nades are occasionally involved, typi-
cally in HIV-negative patients.
Clinical features
A mass in the mouth, nose, or sinuses is
the most common clinical presentation,
with skin or nodal involvement usually
seen in post-transplant PBL {350,1445,
1467,1652).
Histopathology
PBL exhibits a mixture of immunoblast-like
cells and plasmablasts (medium-sized to
large cells with round nuclei, clumped
chromatin, large nucleoli , and ampho-
philic cytoplasm) with varying numbers
130 Tumours of the oral cavity and mobi le tangue
9735/3 of reactive T cells , mature plasma cells, Langerhans ce// histiocytosis
and pleomorphic giant cells. The neo-
plastic cells are negative for CD19, CD20, Pileri S.A.
PAX5, ALK, and HHV8, although there is Feldman A.L.
controversy regarding the allowance of Cheuk W.
sorne positivity for B-cell markers {246). Slater L.
Variable expression of CD45 , CD10,
CD79a, CD56 , EMA, CD38, VS38c ,
CD138, CD30, and cytoplasmic immu- Definition
noglobulins has been described. MUM1/ Langerhans cell histiocytosis is a neo-
IRF4, PRDM1 /BLIMP1 , and XBP1 typi- plastic proliferation of Langerhans cells
cally show strong, diffuse positivity, and {1888}
the Ki-67 index is usually > 80%. EBV is
positive in > 70% of HIV-associated and ICD-0 code 9751/3
post-transplant cases and in 50% of HIV-
negative cases. Synonyms
Histiocytosis X; eosinophilic granuloma;
Genetic profile Hand-Schüller- Christian disease; Letter-
MYC aberrations (translocations or gains) er-Siwe disease
occur in about half of all cases {248,1652,
2455). Epidemiology
This is a rare tumour, with an annual in-
Prognosis and predictive factors cidence of 5 cases per 1 million pop-
PBL is highly aggressive, with poor sur- ulation. The peak incidence is among
vival (6-12 months) {349 ,350,1467,1652} patients aged 3-5 years and there is a
Favourable prognostic factors include slight male predominance, with a male-
EBV and CD45 positivity {1445 ,1652}, to-female ratio of 1.5-2:1 {914,977,1729,
low stage, HIV negativity, younger pa- 2058}.
tient age, and absence of MYC-IGH gene
fusion {350 ,351 }. Localization
Head and neck involvement occurs in
,..
Fig. 4.31 Langerhans cell histiocytosis. A Neoplastic ce/Is show a large rim of acidophilic cytoplasm and grooved
nuclei; in this case, mild atypia can be seen, as well as sorne eosinophils. B Neoplastic ce/Is express CD207 (langerin),
as shown by immunoperoxidase.
 • ~
Fig. 4.32 Extramedullary myeloid sarcoma. A Note the characteristic fine chromatin pattern, delicate nuclear membrane, and granular cytoplasm of the myeloblasts. B Tumour cells
are immunopositive for myeloperoxidase.
60- 80% of cases {287,1410 ,1730}, of which
25% are part of multisystemic disease
{1730). The most commonly involved
sites are bone (skull vault, temporal bone,
orbit, and jawbone), scalp and periauric-
ular skin, cervical lymph nades, parana-
sal sinuses, and oral mucosa {977,1093).
Clinical features
Depending on the site of involvement,
the clinical presentation may include pain
and swelling, orbital mass, skin rash, cer-
vical lymphadenopathy, aural discharge,
earache, vertigo, facial nerve palsy, and
oral uleer or mass.
Histopathology
The neoplastic cells have grooved nuclei
with minimal atypia {1888) . They are ad-
mixed with a variable number of inflam-
matory cells and express 8100, CD1a,
and CD207 (langerin) . Ultrastructurally,
they contain Birbeck granules {1344,
1888}.
Genetic profile
Clonal rearrangement of IGH and/or
T-cell receptor genes occurs in 30% of
cases {403}, sometimes signifying trans-
differentiation of a lymphoid malignancy
{699,2596}. BRAFV600E mutations (or
less commonly, MAP2K1 or ARAF muta-
tions) occur in about half of ali cases {118 ,
1719,1720).
Prognosis and predictive factors
Patients without high -risk organ involve-
ment (e .g. of liver, spleen, bone marrow,
or lung) have a favourable prognosis,
with a mortality rate of < 10% {791,977) .
However, permanent organ damage
(e.g. permanent hearing loss, loss of
dentition) and disease reactivation are
_1Eilliííl: - •
not uncommon in head and neck tumours
{287,1943).
Extramedullary myeloid
sarcoma
Li X.-0.
Gaulard P.
Definition
Extramedullary myeloid sarcoma is a tu-
mour mass consisting of myeloid blasts
with or without maturation, involving an
extramedullary anatomical site. lt occurs
de novo or can precede, coincide with, or
follow the presentation of acule myeloid
leukaemia, or can constitute blastic trans-
formation of a myelodysplastic syndrome
or myeloproliferative neoplasm {1887).
ICD-0 code
Synonyms
Granulocytic sarcoma; chloroma
Epidemiology
Extramedullary myeloid sarcoma has
been reported to occur in 3- 8% of pa-
tients with acule myeloid leukaemia {319).
The median age of patients with head
and neck involvement is 61 years (range:
1-85 years), with a male-to-female ratio
of 1.2-2.4:1 {2505,2724) .
Localization
Any head and neck site can be involved,
with the oral cavity being most frequently
affected {2724) Rarely, the nasopharynx
is involved {61,1957,2505}.
Clinical features
The clinical presentation is often non -
specific.
Histopathology
The tumour mass consists of diffuse
sheets of myeloblasts characterized by
round to folded nuclei, fine chromatin,
small nucleoli , and sean! to moderate
amounts of eosinophilic cytoplasm, in-
termingled with a variable number of
eosinophilic myelocytes. lmmunohisto-
chemically, the tumour cells express vari-
ous myeloid or myelomonocytic mark-
ers, such as myeloperoxidase, CD68 (as
recognized by KP1), lysozyme, CD33,
CD34, KIT/CD117, and CD163. CD43 is
commonly positive.
Genetic profile
A variety of chromosomal aberrations,
such as monosomy 7, trisomy 8, and
9930/3 inv(16), have been reported {1887) . The
t(8;21)(q22;q22) translocation is more
commonly observed in paediatric series
{1887,2107) . About 16% of cases har-
bour NPM1 mutations {688) .
Prognosis and predictive factors
The prognosis varies, but is often unfa-
vourable. Patients without bone marrow
involvement and !hose who undergo al -
logeneic or autologous stem cell trans-
plantation seem to have a better out-
come {1887,2505,2724).
Haematolymphoid tumours 131
 CHAPTER 5

Tumours of the oropharynx

(base of tongue, tonsils, adenoids)
Squamous cell carcinoma
Salivary gland tumours
Haematolymphoid tumours
WHO classification of tumours of the oropharynx
(base of tongue, tonsils, adenoids)
Squamous cell carcinoma Lymphocyte-rich cl assical Hodgkin lymphoma 9651 /3
Squamous cell carcinoma, HPV-positive 8085/3* Lymphocyte-depleted classical Hodgkin
Squamous cel l carcinoma, HPV-negative 8086/3* lymphoma 9653/3
Burkitt lymphoma 9687/3
Salivary gland tumours Follicular lymphoma 9690/3
Pleomorph ic adenoma 8940/0 Mantle cell lymphoma 9673/3
Adenoid cystic carcinoma 8200/3 T-lymphoblastic leukaemia/lymphoma 9837/3
Polymorphous adenocarcinoma 8525/3 Follicu lar dendritic cell sarcoma 9758/3

Haematolymphoid tumours
The morphology codes are from the lnternational Classification of Diseases
Hodgkin lymphoma, nodular lymphocyte for Oncology (ICD-0) (776A}. Behaviour is coded /O for benign tumours;
predominant 9659/3 / 1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in
Classical Hodgkin lymphoma situ and grade 111 intraepithelial neoplasia; and /3 for malignan! tumours .
The classification is modified from the previous WHO classification , taking
Nodular sc lerosis classical Hodgkin lymphoma9663/3 into account changes in our understanding of these lesions.
Mixed cel lularity classical Hodgkin lymphoma 9652/3 *These new codes were approved by the IARC/WHO Committee for ICD-0.

TNM classification of carcinomas of the lip and oral cavity

TNM classification of carcinomas of the lip node, > 3 cm but :,;; 6 cm in greatest dimension
and oral cavity8·b N2b Metastasis in multiple ipsilateral lymph
nodes, all :,;; 6 cm in greatest dimension
T - Primary tumour N2c Metastasis in bilateral or contralateral lymph
TX Primary tumour cannot be assessed nodes, all :,;; 6 cm in greatest dimension
TO No evidence of primary tumour N3 Metastasis in a lymph node > 6 cm in greatest
Tis Carcinoma in situ dimension
T1 Tumour :,;; 2 cm in greatest dimension
T2 Tumour > 2 cm but :,;; 4 cm in greatest dimension Note: Midline nodes are considered ipsilateral nodes.
T3 Tumour > 4 cm in greatest dimension
T4a (lip) M - Distant metastasis
Tumour invades through cortical bone, inferior MO No distant metastasis
alveolar nerve, floor of mouth, or skin (of chin or M1 Distant metastasis
nose)
T4a (oral cavity) Stage grouping
Tumour invades through cortical bone , into deep/ Stage O Tis NO MO
extrinsic muscle of tongue (genioglossus , Stage 1 T1 NO MO
hyoglossus, palatoglossus , and styloglossus), Stage 11 T2 NO MO
maxillary sinus , or skin of face Stage 111 T1 - 2 N1 MO
T4b (lip and oral cavity) T3 N0-1 MO
Tumour invades masticator space , pterygoid Stage IVA T1 - 3 N2 MO
plates , or sku ll base; or encases interna! T4a N0- 2 MO
carotid artery Stage IVB AnyT N3 MO
Note: Superficial erosion alone of bone / tooth socket by T4b Any N MO
gingival primary is not sufficient to classify a tumour as T4. Stage IVC AnyT Any N M1

N - Regional lymph nodes (i.e. the cervical nodes)

NX Regional lymph nodes cannot be assessed
NO No regional lymph node metastasis
N1 Metastasis in a single ipsilateral lymph node,
:,;; 3 cm in greatest dimension
N2 Metastasis as specified in N2a, N2b, or N2c below
N2a Metastasis in a single ipsilateral lymph
ªAdapted from Edge et al. (625A} - used with permission of the American
Joi nt Committee on Cancer (AJCC) , Chicago, lllinois; the original and prima-
ry source for thi s information is the AJCC Cancer Staging Manual, Seventh
Edition (2010) published by Springer Science+ Business Media - and Sobin
et al. (2228A}.
"A help desk for specific questions about TNM classification is available at
http://www. uicc.org/resources/tnm/helpdesk.

134 Tumours of the oropharynx (base of tongue, tonsils, adenoids)

TNM classification of carcinomas of the oropharynx

TNM classification of carcinomas of the oropharynx•.b N2b Metastasis in multiple ipsilateral lymph
nades, ali ::; 6 cm in greatest dimension
T - Primary tumour N2c Metastasis in bilateral or contralateral
TX Primary tumour cannot be assessed lymph nades, ali::; 6 cm in greatest
TO No evidence of primary tumour dimension
Tis Carcinoma in situ N3 Metastasis in a lymph nade > 6 cm in greatest
T1 Tumour::; 2 cm in greatest dimension dimension
T2 Tumour > 2 cm but::; 4 cm in greatest dimension
T3 Tumour > 4 cm in greatest dimension, or Note: Midline nades are considered ipsilateral nades.
extension to lingual surface of epig lottis
T4a Tumour invades any of the following: larynx, M - Distant metastasis
deep/extrinsic muscle of tangue (genioglossus, MO No distant metastasis
hyoglossus, palatoglossus, and stylog lossus), M1 Distant metastasis
medial pterygoid, hard palate, mandible; note
that mucosa! extension to lingual surface of Stage grouping
epiglottis from primary tumours of the base of the Stage O Tis NO MO
tangue and vallecula does not constitute invasion Stage 1 T1 NO MO
of the larynx Stage 11 T2 NO MO
T4b Tumour invades any of the following: lateral Stage 111 T1-2 N1 MO
pterygoid muscle, pterygoid plates, lateral T3 N0-1 MO
nasopharynx, skull base; or encases the carotid Stage IVA T1-3 N2 MO
artery T4a N0-2 MO
Stage IVB T4b Any N MO
N - Regional lymph nades (i.e. the cervical nades) AnyT N3 MO
NX Regional lymph nades cannot be assessed Stage IVC AnyT Any N M1
NO No regional lymph node metastasis
N1 Metastasis in a single ipsilateral lymph nade,
ªAdapted from Edge et al. {625A} - used with permission of the American
::; 3 cm in greatest dimension
Joint Committee on Cancer (AJCC), Chicago, lllinois; the original and prima-
N2 Metastasis as specified in N2a, N2b, or N2c below ry source for this information is the AJCC Cancer Staging Manual , Seventh
N2a Metastasis in a single ipsilateral lymph Edition (2010) published by Springer Science+Business Media - and Sobin
nade, > 3 cm but ::; 6 cm in greatest et al. {2228A}.
dimension •A help desk for specific questions about TNM classification is available at
http://www.uicc.org/resources/tnm/helpdesk.

TNM classification of carcinomas of the oropharynx 135

Tumours of the oropharynx
(base of tongue, tonsils, adenoids)
lntroduction
Like the nasopharynx, the orophar-
ynx is characterized by lymphoid-
based mucosa and is the target of
viral-associated carc inoma. The high
incidence of HPV-associated oro-
pharyngeal carcinoma has been firmly
val idated and this carcinoma is now
considered a distinct entity. Accordingly,
a separate chapter on tumours of
the oropharynx has been estab-
lished . Because of the geographical
Squamous cell carcinoma
Squamous ce// carcinoma,
HPV-positive
Westra W.H .
Boy S.
El-Mofty S.K .
Gillison M.
Schwartz M.R.
Syrjanen S.
Yarbrough W.G.
Definition
Oropharyngeal squamous cell carcino-
ma (OPSCC) associated with high-risk
HPV (OPSCC- HPV) is an epidemiologi-
cally, pathologically, and clinically dis-
tinct form of head and neck squamous
cell carcinoma.
ICD-0 code 8085/3
Synonym
Non -keratinizing squamous cell
carcinoma
Epidemiology
The incidence of OPSCC - HPV has ris-
en over the past three decades {391,
392,1980}. Patients with OPSCC - HPV
are typically male, White, and of higher
socioeconomic status {392,841}. The
median patient age is 50-56 years {79,
841}, with a male-to-female ratio of 4:1.
136 Tumours of the oropharynx (base of tongue, tonsils , adenoids)
El-Naggar A.K .
Takata T.
and ethnic differences in the prevalence to the parent Chapter 7 (Tumours of sa/i-
of HPV-associated squamous cell car- vary g!ands, p. 159). Similarly, only hae-
cinoma, a separate entry for HPV-nega- matolymphoid disorders commonly en -
tive oropharyngeal squamous cell carci- countered at this location are presented
noma has been included. and discussed.
To minimize redundancy and to maintain
consistency, only selected salivary neo-
plasms commonly reported in the oro-
pharynx are briefly discussed in this
chapter. For more detailed information on
these tumours, the readers are referred
Table 5.01 Comparison of HPV-positive and HPV-negative oropharyngeal squamous cell carcinoma (SCC)
Characteristics 1
HPV-positive HPV-negative
Median age 50-56 years 60-70 years
Risk factors Sexual behaviour Smoking and alcohol use
Lymph node metastasis Frequently cystic Uncommonly cystic
Reticulated epithelium of
Postulated origin Surface epithelium
invaginated crypts
Dysplasia Rare Often present
Morphology Commonly non-keratinizing SCC Conventional SCC
Grading Not applicable Applicable
p16 immunostaining Positive Negative
Overall survival rate (3 years) 82% 57%
Etiology Clinical features
OPSCC- HPV is caused by high -risk Unlike HPV-negative OPSCC, OPSCC-
HPV, with type 16 responsible for > 90% HPV typically presents at an advanced
of ali cases {507,841,2105) Oral sex is clinical stage, often as a small primary
an established risk factor for oral HPV in - tumour with nodal involvement. Cervi -
fection . lndividuals with OPSCC-HPV are cal lymphadenopathy, which may be
less likely than patients with HPV-nega- cystic, is the most common clinical
tive OPSCC to be smokers; yet tobacco presentation .
smoking is associated with significantly
higher oral HPV prevalence and thus Macroscopy
may play sorne role in the progression Although primary tumours may be large,
from oral HPV infection to OPSCC-HPV most are small and not apparent on
{685) . gross inspection. Nodal metastases are
often large and cystic {862).
Localization
OPSCC-HPV has a strong predilection Cytology
for the base of tongue and the palatine Aspirates of metastatic lesions are cel -
tonsils {169). lular, with tumour cells forming cohesive
 '~
Fig. 5.01 HPV-associated oropharyngeal squamous cell carcinoma. A Carcinoma tends to originate from the tonsillar crypts. B Strong expression of p16 serves as a surrogate
marker for high-risk HPV. C Nests of basaloid cells permeated by tumour-infiltrating lymphocytes. D Lymphoepithelioma-like carcinoma is one of the many morphological variants.
sheets and clusters and having hyper-
chromatic, pleomorphic, and overlap-
ping nuclei {1115} . The presence of
squamous differentiation and keratiniza-
tion is uncommon. Demonstration of p16
or HPV in tumour cells strongly suggests
an oropharyngeal primary.
Histopathology
OPSCC-HPV generally exhibits distinc-
tive non-keratinizing morphology; grad-
ing is not currently advocated. Unlike in
HPV-negative cases, dysplasia of the
surface epithelium is rarely identified.
OPSCC-HPV arises from crypt epithe-
lium and grows beneath the surface
epithelial lining as nests and lobules, of-
ten with central necrosis {2599). Tumour
nests are often embedded in lymphoid
stroma, and may be penetrated by lym-
phoid cells . Tumour cells display a high
N:C ratio and a high mitotic and/or apop-
totic rate , which often imparts a basaloid
appearance.
Histological grading is not currently ad-
vocated. Keratinization is absent or in-
conspicuous in most cases {414,842},
although a small subset of cases show
keratin formation .
The morphological spectrum of OPSCC-
HPV includes variants with papillary {635,
1580}, adenosquamous {1553}, lympho-
epithelioma-like {2187}, sarcomatoid
{201}, and small-cell features {204). Tu-
mours resembling basaloid squamous
cell carcinoma have also been described
{171}, as have tumours with populations of
ciliated cells 1206} The clinical behaviour
of the morphological variants (other than
the small -cell variant) is similar to that of
OPSCC-HPV with typical morphology.
HPV-related small cell neuroendocrine
carcinoma has an aggressive clinical
behaviour and is morphologically char-
acterized by small anaplastic cells with
hyperchromatic moulded nuclei , numer-
ous mitoses, and necrosis. Recognition
of the small-cell variant is facilitated by
an immunohistochemical profile that in-
cludes weak expression of squamous
markers (e.g. p63, p40, and CK5/6) and
acquisition of neuroendocrine markers
(e.g. synaptophysin , chromogranin, and
CD56)
HPV detection
HPV can be detected by molecular
assays (e.g. in situ hybridization and
PCR-based assays) performed individu-
ally or in combination {2598) . Diffuse im-
munoreactivity for p16 is a reliable surro-
gate marker for the presence of high-risk
HPV in oropharyngeal carcinomas, and
may be sufficient as a standalone test
for HPV status in tumours with appropri-
ate morphology arising at this site {1401 l.
The possibility of loss of p16 expression
should also be considered (especially
in patients with traditional risk factors),
and additional testing for high-risk virus
should be performed. Positive HPV test-
ing may also point to the oropharynx as
the most likely primary site for cervical
lymph node metastasis of undetermined
primary {170l .
When p16 or HPV testing is not available,
OPSCC can be diagnosed as "squa-
mous cell carcinoma, HPV status un-
known " or, if the tumour shows the char-
acteristic non-keratinizing morphology,
as "sq uamous cell carcinoma, HPV not
tested, morphology highly suggestive of
HPV association".
Genetic profile
HPV oncoproteins E6 and E7 inacti-
vate p53 and RB by targeting them for
Squamous cell carcinoma 137
protein degradation. Somatic mutations
in TRA F3, an immune regulator, are
unique to OPSCC-HPV.
Oncogenic PIK3CA mutation or gene
amplification is significantly more com-
mon in OPSCC-HPV than in HPV-nega-
tive cases (1817,2375).
Prognosis and predictive factors
OPSCC-HPV is associated with signifi-
cantly better survival outcomes than is
HPV-negative OPSCC {79,686 ,1911). but
this favourable prognosis may be tem-
pered by the adverse effects of cigarette
smoking (79 ,843).
The risk of tumour recurrence and of the
development of second primary malig-
nancies is lower with HPV-positive OP-
SCCs than with HPV-negative cases, but
longer follow-up data are needed (79) .
Squamous ce// carcinoma,
HPV-negative
Syrjanen S.
Assaad A.
El-Mofty S.K.
Katabi N.
Schwartz M.R .
Definition
HPV-negative oropharyngeal squamous
cell carcinoma (OPSCC) is a subset of
OPSCC that lacks association with high-
risk HPV.
ICD-0 code 8086/3
Synonym
Keratinizing squamous cell carcinoma
Epidemiology
Patients with HPV-negative OPSCC are
older on average than patients with HPV-
related OPSCC (O PSCC-HPV; see Table
5.01 , p. 136) (2471 ).
Etiology
See the Squamous ce// carcinoma sec-
tion (p . 109) in Chapter 4.
Localization
Whereas most examples of OPSCC-
HPV target the base of tangue and the
palataine tonsils , HPV-negative OP-
SCC more commonly involves the soft
palatine.
138 Tumours of the oropharynx (base of tongue, tonsils , adenoids)
;.'!~
p HPV
lnlection
fft¡f
©JHU
.--.;:::::::::::::::::::::==:::::::::::;;:;:;::
' P16 immunohistochemistry
2012
Fig. 5.02 Pathogenetic pathway of HPV in oropharyngeal squamous cell carcinoma. Viral DNA is integrated into host
DNA. Transcription of HPV E6 and E7 mRNA leads to inaclivation of p53 and RB proteins, and indirectly to accumulation
of p16. Curren! methods can detect HPV al !he level of DNA (in situ hybridization or PCR), mRNA (in situ hybridization
or RT-PCR), and protein (p16 immunohislochemistry as a surrogate marker). Reprinted from Bishop JA et al. {200).
Clinical features cell carcinoma al other head and neck
Patients typically present with sore throat siles.
and difficulty in swallowing or a neck mass
{487). Genetic profile
See the Squamous ce// carcinoma sec-
Macroscopy tion (p. 109) in Chapter 4. The TP53 gene
See the Squamous ce// carcinoma sec- is commonly mutated , in contras! to the
tion (p. 109) in Chapter 4. wildtype TP53 found in OPSCC-HPV.
Cytology Prognosis and predictive factors
Aspirates of metastatic lesions usually See Table 5.01 (p. 136).
show features of keratinizing squamous
cell carcinoma, with sheets and small
clusters of malignan! squamous cells
with intracellular and extracellular kerati-
nization. Occasional cases have cyto-
logical features identical to !hose of HPV-
positive tumours (i .e. non -keratinizing
squamous cell carcinoma) (241 ,637).
Histopathology
Unlike OPSCC-HPV, HPV-negative OPSCC
typically exhibits differentiated squamous
features (i.e. keratinization, desmoplastic
stromal reaction , and surface dysplasia)
identical to !hose of squamous cell carcino-
mas at other head and neck mucosal siles
{1405). HPV status is negative (by p16
immunohistochemistry and/or molecular
detection of HPV). The histological grad-
ing is similar to that used for squamous
Salivary gland tumours

Pleomorphic adenoma Localization Adenoid cystic carcinoma

Pleomorphic adenoma of the base of
Bell D. tongue, tonsils , and adenoids is rare {179,
Bullerdiek J. 1710,2687}.
Katabi N.
Clinical features
Presenting symptoms include a slow-
Definition growing mass and mild dysphagia {1710} .
Pleomorphic adenoma is a benign tu-
mour with variable cytomorphological Histopathology
and architectural manifestations. The Pleomorphic adenomas of the minor
identification of epithelial and myoepi- salivary glands, compared with those
thelial and stromal components is es- occurring in major glands, are typically
sential for the diagnosis. See also the more cellular, with a less predominant
Pleomorphic adenoma section (p. 185) stromal component {930 ,2123}. Both epi-
in Chapter 7. thelial and myoepithelial components are
found , in varying compositions {2082}.
ICD-0 code 8940/0
Prognosis and predictive factors
Synonym Complete excision is generally curative. Re-
Benign mixed tumour currence is not uncommon, due to micro-
scopic satellite extension. The myxoid varían!
may have a higher recurrence rate {2082}.
Stenman G.
Bell D.
Gnepp D.R.
Definition
Adenoid cystic carcinoma is a slow-
growing and relentless salivary gland
malignancy composed of epithelial and
myoepithelial neoplastic cells that form
various patterns , including tubular, cribri-
form, and solid forms.
See also the Adenoid cystic carcinoma
section (p . 164) in Chapter 7.
ICD-0 code 8200/3
Epidemiology and clinical features
See the Adenoid cystic carcinoma sec-
tion (p. 164) in Chapter 7.
Histopathology
The histology is identical to adenoid
cystic carcinomas of major and other
minor salivary gland siles; see the Ade-
noid cystic carcinoma section (p. 164) in
Chapter 7 (Tumours of salivary glands).

Genetic profile
See the Adenoid cystic carcinoma sec-
tion (p . 164) in Chapter 7.

Prognosis and predictive factors

The prognosis is similar to that of ad-
enoid cystic carcinomas from the major
and other minor salivary gland siles {22 ,
1104); see the Adenoid cystic carcinoma
section (p. 164) in Chapter 7.

Fig. 5.03 A Unencapsulated submucosal pleomorphic adenoma of soft palate. B Pleomorphic adenoma. Myoepithelial
cell nests in fibromyxoid and hyalinized stroma.

Sal ivary gland tumours 139

 ~, K
n e
•
. ,.
10 11 12

. JI
13 14 1S
I

16
.
t

"
,..

17 18

•:
21 22

B Karyotype of !he same case shown in Fig. A, with a !(6;14)

Polymorphous adenocarcinoma Localization Cytology

Polymorphous adenocarcinoma occurs The cytological features are not specific
Fonseca l. predominantly at the junction of the hard for the diagnosis .
Bell D. and soft palate !239,461 ,1915,2198}.
Gnepp D.R. Histopathology
Seethala R. Clinical features See the Polymorphous adenocarcinoma
Weinreb l. The tumours present as painless masses section (p . 167) in Chapter 7.
!352}.
Genetic profile
Definition Macroscopy The genetic profile !2569,2574) is dis-
Polymorphous adenocarcinoma is a Polymorphous adenocarcinoma pre- cussed in the Polymorphous adenocarci-
malignant neoplasm characterized by sents as a firm , circumscribed, unencap- noma section (p. 167) in Chapter 7.
cytological uniformity, morphological di- sulated, yellowish-tan tumour !1832).
versity, and an infiltrative growth pattern . Prognosis and predictive factors
See also the Polymorphous adenocarci- The overall survival rate is excellent ¡352,
noma section (p . 167) in Chapter 7. 671 ,1231 ,1832), but aggressive behav-
iour can occur. See the Polymorphous
ICD-0 code 8525/3 adenocarcinoma section (p. 167) in
Chapter 7.
Synonyms
Polymorphous low-grade adenocarci-
noma; terminal duct carcinoma; cribriform
adenocarcinoma

Epidemiology
The female-to-male ratio is 2:1 , and Fig. 5.05 Polymorphous adenocarcinoma. The cribriform
> 70% of patients are aged 50-70 years variant is frequently characterized by !he presence of
!239,1832,1915,2198). optically clear nuclei.

140 Tumours of the oropharynx (base of tangue, tonsils, adenoids)

Haematolymphoid tumours
lntroduction
Ferry J.A.
Ko Y.-H.
Definition
Oropharyngeal haematolymphoid tu-
mours are neoplasms of lymphoid, plas-
ma-cell , histiocytic/dendritic, or myeloid
origin arising in the oropharynx.
Epidemiology
The Waldeyer ring (pharyngeal lymphoid
ring) is the most common extranodal head
and neck site for development of lympho-
ma (100), affected in 36% (666,934} to
67% (37,682) of cases. Patients can be
affected in childhood (905) through ad-
vanced age (1338 ,1372,1429,1790), with
mean and median patient ages in the
sixth (37,682,1372) and seventh (1790}
decades of life. The male-to-female ratio
is about 1- 2:1 (905,1338,1372,1790), al-
though MALT lymphomas show a slight
female preponderance (1260}.
Oropharyngeal plasmacytoma accounts
for 13-19% of all head and neck extra-
osseous plasmacytomas (116,494,2078).
Myeloid sarcoma (2724) and histiocytic/
dendritic cell neoplasms (1810} are rare.
Etiology
A few patients are immunocompromised;
their lymphomas may be EBV-positive (1790).
)
,r,
Localization
Within the Waldeyer ring, lymphoma
most commonly involves tonsil , followed
by nasopharynx, with the base of tangue
least often affected (37,682,1338,1372).
Most lymphomas are localized (stage 1/11)
(37,905,1338,1372).
Clinical features
Dysphagia, odynophagia, and cervical
lymphadenopathy are common (934,
1260,1338,2183}
Macroscopy
Tonsillar or base-of-tongue swelling , with
or without ulceration, is apparent macro-
scopically (905,934).
Histopathology
Diffuse large B-cel l lymphoma is most
common by far (37,682,1372), with ger-
minal-centre and non-germinal -centre
B-cell phenotypes reported (1790,1968).
Others include MALT lymphoma (333,
1260, 1372, 2239); extranodal N K/T-cell
lymphoma (1372); mantle cell lymphoma
(1260,1372,1790); follicular lymphoma
(1260,1372); peripheral T-cell lymphoma,
NOS (1372); and rare classical Hodgkin
lymphoma (1939) . Burkitt lymphoma is
rare in adults (1372} but common among
chi ldren (905).
lnfectious mononucleosis can mimic dif-
fuse large B-cell lymphoma and classical
Hodgkin lymphoma (1479), and should be
excluded befare diagnosing lymphoma.
EBV-positive mucocutaneous ulcer is also
an importan! differential diagnosis for cir-
cumscribed ulcers (595). MALT lymphoma
should be distinguished from atypical mar-
ginal zone hyperplasia of mucosa-associ-
ated lymphoid tissue - a rare monotypic,
polyclonal lymphoproliferative disorder in-
volving the tonsils of children (101).
Prognosis and predictive factors
The prognosis is relatively favourable.
Outcome is worse with older patient age
(682,1372), T-cell phenotype (1372), non-
tonsil primary, and high levels of lactate
dehydrogenase (682).
Hodgkin Jymphoma
Jaffe E.S.
Ott G.
Definition
Hodgkin lymphoma is a B-cell-derived
neoplasm in which relatively few neo-
plastic cells are seen, in a background
rich in inflammatory cells . The two major
forms are classical Hodgkin lymphoma
and nodular lymphocyte-predominant
Hodgkin lymphoma. The characteristics
of the neoplastic cells and the nature of
the inflammatory background differ in
these two major subtypes (1524).
Haematolymphoid tumours 141

•
Fig. 5.07 Classical Hodgkin lymphoma of !he tonsil.
High-power view shows classic Reed-Sternberg cells
and variants in a background of small lymphocytes.
ICD-0 codes
Hodgkin lymphoma, nodular lymphocyte
predominant 9659/3
Classical Hodgkin lymphoma
Nodular sclerosis classical Hodgkin
lymphoma 9663/3
Mixed cellularity classical Hodgkin
lymphoma 9652/3
Lymphocyte-rich classical Hodgkin
lymphoma 9651/3
Lymphocyte-depleted classical
Hodgkin lymphoma 9653/3
Synonym
Hodgkin disease
Localization
Both forms of Hodgkin lymphoma pre-
sent most often in lymph nodes. Primary
presentations in oropharyngeal lymphoid
tissue are rare {1103,1175).
Histopathology
In classical Hodgkin lymphoma, the neo-
plastic cells (i.e. Reed- Sternberg cells
and variants) frequently show downregu-
lation of the B-cell programme. They are
positive for PAX5 but most often negative
for C020 and C079a. There is positivity
for C030 in virtually ali cases and for COI 5
in most. The inflammatory background is
composed mainly of T cells, with variable
numbers of plasma cells, histiocytes,
and eosinophils. EBV sequences are
found in 15- 25% of cases overall , but the
incidence of EBV positivity in classical
Hodgkin lymphoma involving the Wal-
deyer ring (pharyngeal lymphoid ring) is
higher: approximately 65% in one study
{1175). In nodular lymphocyte-predomi-
nant Hodgkin lymphoma, the neoplastic
142 Tumours of the oropharynx (base of tongue, tonsils, adenoids)
cells have lobulated nuclear contours,
basophilic nucleoli, anda thin rim of pale
cytoplasm. The neoplastic cells (i.e.
lymphocyte-predominant [LP] cells) re-
tain expression of most B-cell antigens,
including C020, C079a, PAX5 , and
OCT2, and are positive for BCL6. A nod-
ular growth pattern is usually evident,
with the B cells often distributed within
the remnants of primary follicles. Nor-
mal small B cells are frequent, particu-
larly early in the course of the disease.
The LP cells are rosetted by T cells
with the phenotype of T follicular helper
(TFH) cells, expressing C04 and POI
(C0279), and T cells usuall y become
more numerous over time. Overlap with
T-cell lymphoma or histiocyte-rich large
B-cell lymphoma may be seen {949) .
Primary nodular lymphocyte-predomi-
nant Hodgkin lymphoma in the Waldeyer
ring is rare .
Burkitt lymphoma
Pileri S.A.
Nakamura S.
Definition
Burkitt lymphoma (BL) is a peripheral B-
cell lymphoma that has an extremely high
proliferation rate and often presents in
extranodal sites. lt is composed of mono-
morphic medium-sized cells . Transloca-
tion involving MYC is highly characteristic
but not specific. The diagnosis requires
the combination of morphology, pheno-
type , and genetics.
ICD-0 code 9687/3
Epidemiology
BL accounts for < 1% of ali peripheral B-
cell lymphoma cases {2377). Three vari-
ants are recognized : endemic (occurring
in malaria-endemic regions of the world),
sporadic (occurring where malaria is not
endemic), and immunodeficiency-as-
sociated (occurring in immunocompro-
mised, typically HI V-positive, patients)
{1639 ). Oespite their common morphol-
ogy and phenotype, these variants differ
in terms of patient age and pathobiology.
Endemic BL occurs in children and ado-
lescents, whereas sporadic and immu-
nodeficiency-associated Bls typically
occur in adults {1639}.
Etiology
In endemic BL, the neoplastic cells invari-
ably contain EBV {1639). However, recent
data suggest that the pathogenesis of this
variant may be polymicrobial {3 ,2460}.
EBV infection is detected in about 30% of
sporadic cases and 25-40% of immuno-
deficiency-associated cases {1639}.
Localization
lnvolvement of the head and neck (espe-
cially the jawbones) is frequent in endem-
ic BL but rare in the other variants {1639).
Clinical features
Patients often present with bu lky disease
and a high tumour burden , sometimes
with leukaemic spread {2244). A pure
leukaemic presentation, which is exceed-
ingly rare , is usually associated with CNS
involvement {2244) .
Histopathology
The neoplastic cells tend to be cohesive
and undergo apoptosis {1639,2434).

Fig. 5.09 Burkitt lymphoma. MYC gene rearrangement, as shown by a dual-colour break-apart probe (in situ
hybridization, DAPI nuclear staining).
They are intermingled with phagocytizing
macrophages, which contribute to the
characteristic starry-sky pattern {1639,
2434). The number of mitotic figures is ex-
ceedingly high. Features of plasma-cell
differentiation can be seen , especially in
the immunodeficiency-associated vari-
ant {2434) . On immunophenotyping, the
neoplastic cells are positive for CD20 ,
CD10 , and BCL6; negative for BCL2; and
positive for MYC and Ki-67 (with a Ki-67
proliferation index of 100%) {2434) . In
situ hybridization for EBV-encoded small
RNA (EBER) reveals a variable preva-
lence of EBV infection, depending on the
BL variant {1639,2434).
Genetic profile
The tumours cells carry clonal rearrange -
ments of the IG gene family, with somatic
hypermutation. FISH shows MYC translo-
cation at band 8q24 to the IGH region at
14q32 or less frequently to IGL at 22q11
or IGK at 2p12 {178,1844). In about 10%
of cases, FISH fails to demonstrate MYC
translocation, but mostly due to techni-
cal limitations {1639). The few BL cases
that actually lack MYC translocation are
characterized by deregulation of genes
on 11q {2050). Gene expression profil-
ing studies have shown that the endemic
and immunodeficiency-associated BL
variants have almost identical signatures,
whereas the endemic and sporadic vari-
ants have been found to diverge in their
expression of 124 genes dependent on
RBL2 activity {531,1884). Next-genera-
tion sequencing has highlighted differ-
ences between endemic BL and sporadic
BL {3} . The endemic variant shows cyto-
megalovirus and HHV8 (also called Ka-
posi sarcoma-associated herpesvirus)
infection within the non-neoplastic tissue
in > 50% of cases; expression of EBV lyt-
ic genes, inversely associated with TCF3
activity; recurrent alterations in genes
rarely mutated in the sporadic variant
(ARID1A, CCNF, and RHOA); and fewer
mutations in genes commonly altered in
sporadic cases (MYC, 103, TCF3, and
TP53) {3,2099).
Prognosis and predictive factors
Both endemic BL and sporadic BL are
highly aggressive but potentially curable .
Staging is performed according to the
system developed by Murphy and Hustu
{1677) and modified by Magrath {1511} .
lntensive chemotherapy regimens are
associated with cure rates of 90% and
60-80% for patients with low- and high-
stage disease, respectively {1639), with
particularly excellent results in childhood
{1639}.
Fig. 5.10 Follicular lymphoma of the tonsil. Ti1e tonsillar parenchyma shows infiltration by crowded atypical follicles
that efface the normal architecture.
Follicu/ar lymphoma
Ott G.
Nakamura S.
Definition
Follicular lymphoma is a malignant lym -
phoma composed of centroblasts and
centrocytes, with at least a partially fol -
licular pattern .
ICD-0 code 9690/3
Epidemiology
Cases involving the Waldeyer ring (pha-
ryngeal lymphoid ring) typically con-
stitute secondary tonsillar extension in
individuals with widespread nodal dis-
ease {95) . lsolated manifestation in the
oropharynx, which is rare, is more often
seen in children and young adults.
Histopathology
The cytomorphology of follicular lympho-
ma in the tonsil is the same as that of its
counterpart in the lymph node. Crowded
atypical follicles that consist of centro-
blasts and centrocytes efface the normal
architecture. The follicles are uniform in
size and poorly demarcated; the starry-
sky pattern is usually absent. Large
B-cell lymphoma with or without a follicu -
lar component in Waldeyer ring arising in
children or young adults more often fea-
tures large, expansile follicles composed
of centroblasts or intermediate-sized
blastoid cells exclusively, as well as at-
tenuated mantle zones {1446,1477,1785,
1942).
Classic follicular lymphoma expresses
CD20 and germinal centre markers (e.g.
Haematolymphoid tumours 143
C010, BCL6, and HGAL), and is BCL2-
positive in 85-90% of cases. In contrast,
large B-cell lymphoma wi th IRF4 re-
arrangement of the tonsil , which has a fol-
licular growth pattern in many cases and
arises in children and young adults, con-
sistently and strongly expresses MUM1/
IRF4 in addition to germinal centre mark-
ers. lt variably expresses BCL2, and has a
high proliferation index {1446,1942,2051}.
Genetic profile
Typical follicular lymphoma involving the
tonsil in the setting of widespread disease
usually harbours the t{14;18)(q32;q21)
translocation . In contrast, MUM1/IRF4-
positive large cell lymphomas occurring
in children and young adults lack the
t{14;18) translocation, and a MUM1/IRF4
translocation can be demonstrated in
about 50% of cases {1446 ,2051}. In the
4th edition update of the WHO classifi-
cation of tumours of haematopoietic and
lymphoid tissues , MUM1/IRF4+ lympho-
ma in children and young adults is classi-
fied as "large B-cell lymphoma with IRF4
rearrangement" instead of a form of follic-
ular lymphoma.
Prognosis and predictive factors
MUM1/IRF4 expression and/or MUM1/
IRF4 translocation in follicular lymphoma
of the tonsil is associated with favourable
outcome.
Mantle cel/ lymphoma
Ko Y.-H.
Ferry J.A.
Definition
Mantle cell lymphoma (mantle cell neopla-
sia) is a mature B-cell neoplasm of small
to medium-sized lymphoid cells, usually
characterized by CCND1 translocation
leading to cycli n 01 overexpression.
ICD-0 code 9673/3
Epidemiology
The overall incidence of MCL is ap-
proximately 0.5 cases per 100 000 per-
son-years. The male-to-female ratio is
2.3-2.5:1 . The median patient age at di-
agnosis is 70 years {1393,2216,2725).
Localization
The head and neck region is the second
144 Tumours of the oropharynx (base of tongue, tonsils , adenoids)
most common extranodal site, involved
in 6.2% of MCLs {68}. MCL accounts for
2.6% of all Waldeyer ring (pharyngeal
lymphoid ring) non-Hodgkin lymphoma
cases, occurring most often in the tonsil
{1372,2217).
Clinical features
Patients typically have a mass causing
odynophagia and dysphagia. MCL of the
head and neck presents with advanced
disease at diagnosis less commonly (in
41% of cases) than does lymphoma of
the lymph nodes (in 87%) {68)
Histopathology
MCL shows a diffuse, vaguely nodular
or mantle-zone pattern, with proliferation
of small to medium-sized lymphoid cells
with slight nuclear irregularity. Epithe-
lioid histiocytes may be evenly scattered
throughout the tumour.
Sorne cases have blastoid or pleomor-
phic morphology {27,2674). In rare cas-
es, cyclin 01 -positive lymphocytes are
localized within mantles of hyperplastic
lymphoid follicles (with in situ mantle cell
neoplasia) {1264). The neoplastic cells
are positive for slgM, lgO, C020, and
C05 and negative for C010 , C023, and
BCL6. Cyclin 01 is expressed in virtually
all cases. SOX11 is useful for identifying
rare cyclin 01-negative MCL (310,1693).
Aberrant immunophenotypes (e.g. with
C05 negativity, C010 positivity, or C023
positivity) may occur {34 ,2258,2479,
2723).
Genetic profile
Most cases have CCND1-IGH transloca-
tion. Cyclin 01-negative MCL may have
CCND2 translocation {1597,2052,2164,
2623) Mutations involving ATMand TP53
are common , occurring in 41% and 28%
of cases , respectively {165 ,1 116).
Prognosis and predictive factors
MCL is an aggressive non-Hodgkin lym-
phoma, with a median overall survival of
< 4 years {1393,2064). The Mantle Cell
Lymphoma lnternational Prognostic ln-
dex correlates well with prognosis {2513).
Adverse prognostic factors include blas-
toid or pleomorphic morphology, diffuse
pattern, high proliferation index, high
expression of p53 protein, and MYC ab-
errations with overexpression {182,434,
2403}. Patients with primary extranodal
disease (including in the head and neck)
have better survival than do those with
nodal disease {68}.
T-lymphoblastic
/eukaemia/lymphoma
Ferry J.A.
Gaulard P.
Definition
T-lymphoblastic leukaemia/lymphoma
(T-LBL/L) is a neoplasm of lymphoblasts
com mitted to T-cell lineage.
ICD-0 code 9837/3
Epidemiology
lnvolvement of head and neck by
T-LBL/L is rare. Among 109 reported
cases of nasopharyngeal lymphoma,
only one (0.9%) was T-LBL/L {1054). In
a large series of childhood non-Hodgkin
lymphomas, 1% of all lymphomas and

~--
Fig. ..5.12 - -
A,B lndolent T-lymphoblastic proliferation. A The interfollicular compartment
a proliferation of TdT-positive T cells. B High-power view shows a population of relatively small, uniform cells,
sorne with minimally enlarged nuclei and fine chromatin. C T-lymphoblastic lymphoma involving the tonsils.
In contras! with indolent T-lymphoblastic proliferation, there is a monotonous infiltrate containing medium-sized blast
cells with convoluted nuclei and fine chromatin.
5% of ali T-LBL/L cases were T-LBL/L of
the head and neck (2642). Patient age
ranges from childhood to advanced age
(771,2642).
Localization
T-LBL/L cases have been reported in-
volving the oropharynx {2642l, nasophar-
ynx (1054,2642}, salivary gland {2642l,
tongue {771l, and larynx {1541). Staging
may revea! widespread disease involving
lymph nodes, mediastinum, and/or bone
marrow (771,1541).
Clinical features
The symptoms are related to the pres-
ence of a mass.
Histopathology
Evaluation reveals a diffuse infiltrate of
small to medium-sized cells with oval or
slightly to prominently irregular nuclei,
dispersed to finely stippled chromatin,
variably conspicuous nucleoli, and scant
cytoplasm. Mitoses are frequent. T-LBL/L
is typically positive for CD3, TdT, CD?,
and CD1a; variably positive for CD10;
and either double-positive or double-
negative for CD4 and CDS.
The differential diagnosis includes indo-
lent T-lymphoblastic proliferation; a rare
- ----
..... is filled and expanded by
disorder characterized by a prolifera-
tion of immature T cells in lymphoid tis-
sue. Patients present with sore throat,
hoarseness, or airway obstruction. Ex-
amination reveals prominent hypertrophy
of oropharyngeal and nasopharyngeal
lymphoid tissue, sometimes with cervi-
cal lymphadenopathy (2290,2489). Mi-
croscopic examination reveals sheets or
clusters of small to medium-sized cells
with fine chromatin, inconspicuous nu-
cleoli, and a high mitotic rate, but with no
significant cytological atyp ia and sparing
follicles. The cells are positive for CD3
and TdT, and have a high proliferation
index. T-cell receptor genes are not clon-
ally rearranged. The appearance resem-
bles that of the normal thymic cortex,
although without thymic epithelium. After
therapy (surgical excision or chemo-
therapy) indolent T-lymphoblastic proli-
feration may repeatedly recur, although
without progression to bone marrow or
peripheral blood involvement {1764,1765,
2290,2489).
Genetic profile
Limited information is available about
head and neck cases, but T-LBL/L in
general has clonally rearranged T-cell
receptor genes, and a minority of cases
have clona! IGH. Cytogenetic and mo-
lecular genetic changes are heteroge-
neous. Many cases have an abnormal
karyotype; translocations involving T-cell
receptor genes are common (884,1889,
2329). Activation of Notch signalling and
loss of CDKN2A (also called P16/NK4a
and P14ARF), which codes for the tumour
suppressor proteins p16 (p161NK4a) and
p14ARF, are also common {2476).
Prognosis and predictive factors
The outcome appears to be similar to that
of T-LBL/L in other sites.
Follicular dendritic
ce// sarcoma
Cheuk W
PileriSA
Definition
Follicular dendritic cell (FDC) sarcoma is
a tumour of nodal and extranodal sites
that exhibits phenotypic features of FDCs.
ICD-0 code 9758/3
Epidemiology
FDC sarcoma accounts for < 1% of ali
head and neck tumours, although the
head and neck region is the most com-
mon anatomical site of occurrence of this
tumour. lt typically affects patients in mid-
adulthood (mean patient age: 42 years).
Although the patient age range is wide
(9-80 years), only 6% of ali cases occur
in children (1187} There is no sex predi-
lection (1488,1810}.
Etiology
A minority (15%) of FDC sarcomas arise
in the setting of hyaline-vascular Castle-
man disease, and a hyperplasia-dyspla-
sia-neoplasia model of FDC proliferation
has been proposed {373,379,412}. Sorne
.:.."'1¡.:;.z
.....,,,......_ ___
. ,-
. --:·
~·--
..
;ó'
.. t...
~"'-._·
.-r.~
'
·. . :
Fig. 5.13 Follicular dendritic cell sarcoma of the tonsil.
The surface epithelium is intact; this tumour shows partial
involvement of the tonsil (left field) and exhibits pushing borders.
Haematolymphoid tumours 145
 v. ..
-
. ..Jl
Fig. 5.14 Follicular dendritic cell sarcoma of the oral cavity and oropharynx. A This palatal tumour invades in pushing fronts; the main tumour is seen al the right; smooth-
contoured nodules (upper field) invade !he adjacent normal structures. B Uncommon nodular growth pattern, recapitulating the ability of follicular dendritic cells to form follicles.
C Typical storiform pattern, accompanied by an admixture of lymphocytes.

~~~~~~~~~ uass~~ . . ., ___.. . . ., ._.:. . ;. . .,.

...,.,_-"-"r..-.~-....~· -- . ~ ........:
Fig. 5.15 Follicular dendritic cell sarcoma ofthe oral cavity and oropharynx. A This tumour consists of spindle cells with elongated nuclei, fine chromatin, and small distinct nucleoli;
sorne cells have poorly defined cell borders, whereas others exhibit well-defined borders. B The tumour cell nuclei often appear haphazardly distributed, with sorne focal clustering;
a few multinucleated tumour cells are also evident; the cytoplasm exhibits a fibrillary quality. CThis example, composed of plump ovoid cells, shows a moderate degree of nuclear
atypia and pleomorphism; nucleoli are prominent.

studies have found clonal abnormalities in
FDCs in hyaline-vascular Castleman dis-
ease, which may precede FDC sarcoma
overgrowth (469,1840). Overexpression
of EGFR has been demonstrated in FDC
sarcomas and dysplastic FDCs in hyaline-
vascu lar Castleman disease, providing
a further link between the two conditions
(2311 ). Ligand-dependent EGFR activation,
which may be important for the survival and
proliferation of neoplastic FDCs, could be a
potential therapeutic target (2496).
Localization
In the head and neck region, the most
frequently affected sites are the cervi-
cal lymph nodes (involved in 40-50%
of cases), followed by the Waldeyer ring
(pharyngeal lymphoid ring; in 24-40%)
and the soft tissue of the neck (in 10%)
(1187,1810). Other head and neck mu-
cosa! sites can also be affected.
Clinical features
Cases with lymph node involvement
present with a neck mass. Tumours
arising in the Waldeyer ring present with
intraoral swelling or dysphagia. Sys-
temic symptoms are rare. Most patients
(80- 90%) have localized disease at
presentation .
Macroscopy
The mean size of FDC sarcomas in the head
and neck is 4.5 cm (1810). The tumours
are solitary, round to ovoid circumscribed
masses with a fleshy cut surface. Areas of
haemorrhage and necrosis may be present.
Histopathology
The morphological features are similar
to those of FDC sarcoma in other parts
of the body. The tumours, which tend to
have pushing invasive fronts, are com -
posed of spindle to ovoid cells arranged
in fasc icu lar, whorled, or storiform pat-
terns, accompanied by an admixture
of small lymphocytes or lymphoid ag -
gregates around blood vessels. The
tumour cells have a moderate amount
of pale eosinophilic cytoplasm and in -
distinct cell borders, imparting a syn-
cytial appearance. The nuclei are oval
or elongated, with vesicular or granular
finely dispersed chromatin, small dis-
tinct nucleoli, and a smooth nuclear
membrane. Nuclear pseudoinclusions,
binucleated tumour cells, and multinu -
cleated tumour cells are often seen. The
mitotic rate is usually 0-1 O mitoses per
10 high-power fields . High-grade nucle-
ar pleomorphism, atypical mitoses, and
coagulative necrosis are uncommon.
The tumour cells are positive for FDC
markers such as CD21, CD23, CD35,
clusterin , CXCL13, and podoplanin (as
recognized by 02-40). Cytokeratin is
negative and EMA is often positive. Ex-
ceptionally, the cells can be positive for
cytokeratin and TTF1 {1105,2452).
Prognosis and predictive factors
FDC sarcoma is a low- to intermediate-
grade malignant tumour with a recurrence
rate of ::?: 40% and a distant metastasis
rate of::?: 25% {377,1810) . The overal l and
disease-specific survival rates, respec-
tively, are 91% and 64% at 2 years and
81% and 34% at 5 years . Surgery is po-
tentially curative for early-stage disease,
but late recurrence and metastasis can
occur many years after initial presentation
(438). The most common metastatic sites
are lung , liver, and lymph nodes. Large
tumour size (> 4-6 cm) has consistently
been shown to correlate with poor prog -
nosis (1810,2088). Other proposed poor
prognostic factors include disseminated
disease, extensive necrosis, high mi-
totic rate (> 5 mitoses per 10 high -power
fields) , and significant nuclear atypia (377,
521 ,1 856)

146 Tumours of the oropharynx (base of tangue, tonsils, adenoids)

 CHAPTER 6

Tumours and tumour-like lesions of

the neck and lymph nodes
Tumours of unknown origin
Haematolymphoid tumours
Cysts and cyst-like lesions
WHO classification of tumours and tumour-like lesions of the
neck and lymph nodes

Tumours of unknown origin

Carcinoma of unknown primary The morphology codes are from the lnternational Classification of Diseases
for Oncology (ICD-0) (776A} . Behaviour is coded /0 for benign tumours;
Merkel ce// carcinoma 8247/3 /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in
Heterotopia-associated carcinoma 8010/3 situ and grade 111 intraepithelial neoplasia; and /3 for malignant tumours.
The classification is modified from the previous WHO classification , taking
into account changes in our understanding of these lesions.
Haematolymphoid tumours

Cysts and cyst-like lesions

Branchial cleft cyst
Thyroglossal duct cyst
Ranula
Dermoi d an d te ratoid cysts

lntroduction Schwartz M.R .

Vielh P

The neck contains lymph nodes, soft
tissue , fascia, skeletal muscle, nerves,
blood vessels , lymphatic vessels, carti-
lage, bone , and paraganglia. Tumours
and tumour-like lesions can arise in any
of these components. An understanding
of anatomy is critica! in the evaluation of
lesions in the neck. Table Fig. 6.01 sum-
marizes the levels used to classify the lo-
cation of lymph nodes in the neck.
The general diagnostic approach to le-
sions of the neck includes identification
of where in the neck the lesion is, as well
as clinical features such as patient age,
sex, and clinical presentation. Correlation
with radiographical findings, including
determination of location , adjacent struc-
tures , size , solid versus cystic nature,
and whether the lesion is circumscribed
or infiltrative, is helpful .
Given the close proximity of vital struc-
tures in the neck, core needle biop-
sies are generally performed only by
experienced clinicians . Fine-needle
aspiration and excision are more fre -
quently employed . Table 6.01 presents
a systematic approach to the evalua-
tion of fine-needle aspirations from the
neck. Given the complexity and the
small size of samples obtained, adjunc-
tive tests are useful in the evaluation of
cytological and tissue specimens . These
tests include immunohistochemistry,
flow cytometry (for haematopoietic and
la - Submental triangle
lb - Submandibular triangle
' lla -Anterior·inferior to spinal accessory
llb - Posterior-superior to spinal accessory
' - - -- 111- Middle 113 of intemal jugular vein
IV- Lower 1/3 of intemal jugular vein
V - Posterior triangle
VI -Anterior central compartment
cdJ
Fig. 6.01 Schematic anatomy of relevan! siles far the
recording of tumours in neck lymph nades.
lymphoid lesions) , gene rearrangements ,
in situ hybridization , cytogenetics, and
PCR.
Lymph nades
The lymph nodes are the most frequent
site of tumours in the neck. Lymph nodes
can be involved by metastatic tumours ,
haematolymphoid tumours , and benign
Table 6.01 Systematic approach to the evaluation of
fine-needle aspirations from the neck
Is the aspirate satisfactory far evaluation?
What is the cellularity?
Is the lesion viable?
Is the lesion salid ar cystic?
What type of general process is it - neoplastic, infec-
tious, ar other?
Is ita haematopoietic, epithelial, mesenchymal, ar
neurogenic process?
Is ita polymorphous or monomorphous population?
Are the cells cohesive (favours epithelial lesion) or
dyshesive (favours haematopoietic, neuroendocrine)?
What sized cell groups are present?
What is in the background (e.g. necrosis, mucin,
clean background, lymphoglandular bodies)?
Is the lesion benign, malignan!, ar indeterminate?

148 Tumours and tumour-like lesions of the neck and lymph nodes
Table 6.02 Lymph nodes most commonly involved by head and neck carcinoma the most common malignancy in neck
Site Most commonly involved nodes (in descending order of frequency) nades . Table 6.02 summarizes the most
Oral tongue J Subdigastric, submandibular, midjugular
common sites of metastases from key
primary sites in the head and neck {47,
Retromolar trigone ' Angle of mandible, midjugular 1436,1998}.
Floor of mouth 1 Jugulodigastric, submandibular The evaluation of cervical nodal metas-
Tonsils ; Angle of mandible, midjugular, lower jugular, ipsilateral and contralateral posterior tases of unknown primary has changed
cervical, parapharyngeal dramatically over the past decade {1934 ,
Base of tongue Midjugular, lower jugular; bilateral involvement common 2189,2292). This is due largely to the
marked increase in incidence of HPV-re-
Pharyngeal wall Subdigastric, midjugular, posterior cervical, parapharyngeal, retropharyngeal
lated oropharyngeal squamous cell car-
Supraglottic larynx Subdigastric, midjugular cinomas. Many carcinomas previously
Glottis Typically no nodal metastases diagnosed as cervical nodal metastases
Hypopharynx 1 Upper, mid-, and lower jugular of unknown primary are now identified as
be ing from occu lt oropharyngeal prima-
Jugular, posterior cervical, supraclavicular; bilateral involvement common; wide
Nasopharynx ries {2491 ,2672). These cases often pre-
distribution common
sent with small primaries and large bul ky
Paranasal sinuses 1 Subdigastric, submandibular cervical nodal metastases {80 ,392,862).
Ala nasi and nasal vestibule Submandibular Evaluation of nodal metastases for p16
Skin; upper/midface, temporal 1 Preauricular, intraparotid, periparotid expression (a surrogate marker for high-
risk HPV infection) and/or for high-risk
Skin; posterior scalp, neck ' Postauricular, occipital, posterior triangle
HPV by molecular tests helps in the iden -
tification of likely HPV-related primaries.
processes. common ly from primaries outside the Although rare , ectopic thymic tissue and
The most common malignancies in neck head and neck) and metastatic mela- thymic tumours may be encountered and
nades are metastatic carcinoma from noma. Metastatic squamous cell carci- should be considered in the differential
primaries in the head and neck (and less noma from a head and neck primary is diagnosis {200,637,1277,2022).

lntroduction 149
Tumours of unknown origin

Carcinoma of unknown primary cervical nodal CUPs, constitute only

1-2% of head and neck malignancies
Lewis J.S. 1911,2293). The literature contains only
Richardson M. limited data addressing squamous cell
Syrjanen S. carcinoma (SCC) versus undifferentiated
Westra WH. carcinomas as cervical CUPs; most se-
ries group the two tumour types. SCCs
constitute 75- 80% of cases and undif-
Definition ferentiated carcinomas 2- 20% 1883,911,
Metastatic carcinoma of unknown prima- 1129,2293,2412}, depending on geo-
ry (CUP) is usually squamous or undif- graphical location. For example, in areas Fig. 6.03 Lymph node with metastatic non-keratinizing
ferentiated and metastatic to neck lymph of endemic EBV infection such as south- squamous cell carcinoma of unknown primary mimicking
nades with no known primary tumour eastern Asia, the proportion of CUPs that branchial cleft cyst. A primary oropharyngeal carcinoma
identified at initial presentation or after a are undifferentiated carcinomas may be was subsequently identified .
thorough clinical work-up. higher 12412}.

ICD-0 codes Localization

Coding should be according to the
morphology type.
Synonym
Cancer of unknown primary
Epidemiology
Although the reported figures have var-
ied over time and by study type, in gen-
eral, cervical metastatic carcinomas with
no primary tumour immediately apparent
at initial presentation (i.e. CUP) constitute
about 5% of all head and neck malig -
nancies 1911,1842). However, extensive
clinical and radiographical work-up will
identify primary tumour in most patients,
and the remaining cases, so-called true
CUPs occur most commonly in level 11
nades, followed by level 111 nades, and
< 10% of patients have bilateral neck
involvement 1883,2293) Approximately
50% of cases involve a single lymph
nade. Most are of N stage N2a, b, or c
12412). In patients with CUP, the distribu -
..
~- ~ -~ .,~_ .,
tion of lymph nade involvement may pro- .¡-. . :'.'~~ :·•. .::-~­
vide clues as to the site of tumour origin Fig. 6.04 Metastatic non-keratinizing squamous cell
11670} EBV-related undifferentiated car- carcinoma of unknown primary. lmmunostaining for p16
cinomas of the nasopharynx initially me- shows strong, diffuse nuclear and cytoplasmic positivity.
tastasize to retropharyngeal lymph nades
and level 11 and V nades. HPV-related lymph nades. Supraclavicular metasta-
oropharyngeal carcinomas typically me- ses are more suggestive of a primary ori-
tastasize to levels 11 and 111 1448,1670). gin outside the head and neck.
Carcinomas of the facial skin and scalp
frequently metastasize to intraparotid

A - -~ - ~ • -
Fig. 6.02 Metastatic non-keratinizing squamous cell carcinoma of unknown primary with cystic change. A Low-power view displaying multiple cystic spaces with eosinophi lic,
proteinaceous contents and lined by a thin !ayer of tumour cells. B Tumour cells lining the cystic spaces show prominent mitotic activity and no obvious squamous maturation; these
are typical features of (although not completely specific for) HPV-related carcinomas.

150 Tumours and tumour-like lesions of the neck and lymph nades
Clinical features cells or be lymphoepithelial. In lympho- Merkel ce// carcinoma
CUP most commonly occurs in patients epithelial cases, the tumour cells have
in their fifth or sixth decade of life, and a syncytial appearance, with poorly de- Perez-Ordonez B.
frequently occurs in current or former fined cell borders, modest eosinoph ili c Gnepp D.R.
smokers. The male-to-female ratio is cytoplasm, and large round vesicular Thompson L.D.R.
;?: 4:1 {1100 ,2540} The tumours present nuclei with prominent nucleoli. Most tu- Williams MO.
with symptoms of a neck mass and less mours, despite being histologically undif-
often with pain, weight loss, and/or dys- ferentiated, show immunohistochemical
phagia {883} evidence of squamous differentiation, Definition
being positive for p63, p40, and CK5/6 Merkel cell carcinoma (MCC) is a prima-
Cytology {1202,2186}. ry neuroendocrine carcinoma of lymph
The cytology of aspirates of metastatic Neuroendocrine carcinomas and ad - nodes with microscopic, immunohisto-
lesions may be helpful in determining enocarcinomas arising in head and neck chemical, and genetic features similar to
possible primary sites. For SCC, see Ta- sites occasionally present with nodal those of cutaneous MCC.
ble 5.01 (p. 136), Chapter 5. Many CUPs disease, but the primary site is usually
are associated with HPV or EBV. Detec- evident on microscopic examination and ICD-0 code 8247/3
tion of HPV DNA or p16 immunopositivity clinical evaluation.
suggests the oropharynx as a likely pri - Synonyms
mary site, whereas identification of EBV Prognosis and predictive factors Extracutaneous Merkel cell carcinoma;
suggests a nasopharyngeal origin. The survival rates vary with clinical stage Merkel cell carcinoma of lymph node;
and tumour type , and are better for CUP nodal Merkel cell carcinoma; unknown
Histopathology related to high -risk HPV {1128,2189,2421 , primary Merkel cell carcinoma; Merkel
The morphology of CUPs mirrors that 2576}. cell carcinoma of unknown primary
of tumours of known primary site. A
large proportion of the tumours are non -
keratinizing , consisting of large, rounded
nests or ribbons of cells with a high N:C
ratio, hyperchromatic ovoid nuclei with
inconspicuous nucleoli, brisk mitotic ac-
tivity, frequent apoptosis, and numerous
foci of necrosis {1405}. Cystic change is
particularly common in non -keratinizing
SCC metastases {862}; these features
are strongly associated with HPV-related
oropharyngeal carcinoma. More rarely,
cystic tumours have gland formation and
even ciliated lining cells; these cases
shou ld not be misinterpreted as carcino-
ma arising in a branchial cleft cyst {206,
1946}. Other tumours are conventional
keratinizing SCC.
Undifferentiated carcinomas can either con-
sist of nondescript sheets of pleomorphic

Tumours of unknown origin 151

Fig. 6.07 Merkel cell carcinoma of lymph node. A Tumour composed of small cells with inconspicuous cytoplasm and largely round to oval nuclei with dense chromatin; note the
absence of nucleoli. B Perinuclear CK20 staining.
Epidemiology
Nodal MCCs are extremely rare, ac-
counting for only 0.05% of al l MCCs
{237). They may represent metastasis
from a regressed dermal primary.
Etiology
Origin via malignant transformation of
pre-existing intranodal epithelial rests or
pluripotent stem cells has been postu-
lated {670). Merkel cell polyomavirus has
been detected in 31% of nodal MCCs
{543,1807). An association with other
malignancies, particularly small lympho-
cytic lymphoma and chronic lymphocytic
leukaemia, has been noted in as many as
36% of cases {1807,2358).
Localization
The head and neck lymph nades are
one of the most common sites of nodal
MCC (affected in 21% of cases), second
only to the inguinal nades (affected in
56%) {1807,2358). lt is unclear whether
a subset of parotid gland small cell neu-
roendocrine carcinomas may be nodal
MCCs.
Clinical features
Nodal MCC presents as an enlarged
lymph node. lt is most common in Cau -
casian males (male-to-female ratio:
4.5:1). The reported patient age range
is 48-92 years (mean: 65 years) {1807,
2358). Clinical history, physical examina-
tion, imaging, and follow-up are negative
for cutaneous MCC.
Macroscopy
Nodal MCCs replace most of the in -
volved lymph nades, display central
necrosis , and range in size from 1.5 to
27 cm (mean: 6 cm) {1807,2358).
152 Tumours and tumour-like lesions of the neck and lymph nades
Cytology
Aspirates of metastatic lesions show
cytolog ical findings identical to those of
small cell neuroendocrine carcinomas
from other sites {491).
Histopathology
The pathological and immunohistochem-
ical features are similar to those of cuta-
neous MCCs. Tumours grow in sheets,
with geographical necrosis, salid and
organoid nests, trabeculae, and cords,
often separated by fibrovascular septa.
Tumour cells are medium -sized and
have scant cytoplasm , a high N:C ratio,
and round to ovoid nuclei with fine ly dis-
persed salt-and -pepper chromatin with
incon sp icuous or small nucleoli. Rare
cases have moderate amounts of cyto-
plasm with dense chromatin and visible
nucleoli {670 ,1807).
MCCs show diffuse expression of
pancytokeratins, low-molecular-weight
cytokeratins, and CK20, usually in peri-
nuclear dots. Synaptophysin, chromogra-
nin A, and CD56 are also positive. TdT
and PAX5 are expressed in two thirds of
cases . TTF1 and CK7 are usually nega-
tive {1807). Merkel cell polyomavirus large
T antigen and DNA are detected by im-
munohistochemistry and PCR in 31% of
cases {543 ,1807}. Ultrastructurally, tu-
mour cells contain perinuclear globular
aggregates of intermediate filaments and
neurosecretory granules {670).
Prognosis and predictive factors
Nodal MCCs are classified as stage lllB
or IV disease and have a lower
recurrence rate and better survival (me-
dian: 104 months) than do known cu -
taneous MCCs of similar stage {567,
2358) Stage ll lB nodal MCCs have
a 2-year disease-specific survival of
76.9% and can metastasize to brain ,
liver, bone, and non-regional lymph
nades {1807,2358) The only prognostic
factor is high-stage disease.
Heterotopia-associated
carcinoma
Ro J.Y.
Brandwein-Gensler M.
Schwartz M.R.
Definition
Heterotopia-associated carcinoma is a
carcinoma arising from heterotopic tissue
elements (i.e. histologically normal tissue
of a particu lar type that is present at an
abnormal anatomical site). In the neck,
most heterotopias consist of salivary or
thyroid tissue, but heterotopic gastric and
colonic tissues have also been (rarely)
reported. Most carcinomas arising from
heterotopic tissue are of salivary gland or
thyroid origin .
ICD-0 code 8010/3
Synonyms
Choristoma; ectopia; accessory tissue-
associated carcinoma
Epidemiology
Carcinomas arising from ectopic thyroid
tissue or ectopic salivary tissue are rare,
and < 1% of carcinomas arise in hetero-
topic thyroid or salivary tissue. Of the few
reported heterotopia-associated carcino-
ma cases, most thyroid and salivary can-
cers presented during the th ird and sixth
decades of life, respectively {523 ,1555)
They occur more commonly in women.

Localization
Heterotopia-associated salivary carcino-
ma is usually seen in periparotid lymph
nodes or along low anterior sternocleido-
mastoid muscle, with a right-side pre-
dilection {920). Heterotopia-associated
thyroid carcinoma has been reported in
lingual thyroid, thyroglossal duct cysts,
ectop ic intratracheal thyroid , midline
ectopic thyroid , lateral neck, and branchi -
al cleft cysts {706,1251).

Clinical features
Heterotopia-associated carcinoma usu-
ally presents as a mass , but may be de-
B Primary mucoepidermoid carcinoma in periparotid lymph node with mucinous carcinoma componen!.
- "-!:
_ .-_:
Fig. 6.08 Heterotopia-associated carcinoma. A Primary mucoepidermoid carcinoma in periparotid lymph node.

tected incidentally.

Macroscopy
Th e lesions are usually 1.5-3.0 cm, but
may reach > 4 cm.

Cytology
Aspirates show cytological features
identical to those of aspirates of the same
lesions arising in their typical primary
sites.

Histopathology
Papillary thyroid carcinoma is by far the
most common thyroid malignancy in het-
erotopic siles , followed by follicular carci -
noma, squamous cell carcinoma, Hurthle
cell carcinoma, anaplastic carcinoma,
and medullary carcinoma (1251).
Tumours arising in heterotopic salivary
gland tissue are rare, and about 80%
are benign . Mucoepidermoid carcino-
ma is the most common carcinoma in
this setting , followed by acinic cell car-
cinoma; adenocarcinoma, NOS; and
cystadenocarcinoma. Other types of
carcinoma have also been reported,
but unlike among eutopic salivary gland
carcinomas, adenoid cystic carcinoma is
particularly rare (1725)
Fig. 6.09 Papillary thyroid carcinoma arising in association with thyroglossal duct cyst. Papillary structures and
occasional psammoma bodies are seen; at the right, a respiratory epithelium- lined cyst and skeletal muscle fibres are
seen; also seen are scattered benign thyroid follicles.
The majar differential diagnosis is metas- Prognosis and predictive factors
tasis to lymph node. Most cases of carci- The most importan! prognostic factors
noma in lateral neck ectopic thyroid are are tumour size , stage, and grade. With
thought to constitute nodal metastasis reported follow-up ranging from 1 month
from an undetected primary in the thyroid to 17 years , most patients are alive and
gland . Most alleged carc inomas aris- disease-free (523,1251).
ing in branchial cleft cysts are thought
to be metastatic squamous cell carci-
noma from an undetected oropharyngeal
carcinoma.

Tumours of unknown orig in 153

Haematolymphoid tumours
Definition
Lymphomas are neoplastic clonal prolif-
erations of lymphoid cells. This category
is subdivided into Hodgkin lymphoma
(HL) and non-Hodgkin lymphoma (NHL).
Epidemiology
Both HL and NHL are more common in
developed countries. There is a slight
male predominance. Caucasians have
the highest incidence of NHL, whereas
the indigenous peoples of North Amer-
ica are least affected. After the age of
10 years, the incidence of NHL increases
with each passing decade. The incidence
of HL spikes in the second to fourth dec-
ades of life. NHLs are subdivided into
B-cell , T-cell, and NK-cell types, with
80-85% of being B-cell neoplasms. Fol-
licular lymphoma and diffuse large B-cell
lymphoma are the most common NHLs
encountered in neck nodes. HL has two
major subtypes: classical and nodular
lymphocyte-predominant, with the classi -
cal variant constituting 95% of ali cases.
Localization
Lymphomas typically arise from lymph
nodes in the anterior or posterior cer-
vical , postauricular, occipital, or su-
praclavicular regions . HL may arise in
a single node or a chain of nodes, but
only rarely in extranodal siles. Although
typically nodal, NHL may develop in
;:.m_ ....... _ _
Fig. 6.10 A Mantle cell lymphoma. An isomorphic population of small lymphocytes displays irregular nuclear contours, evenly dispersed chromatin, absent nucleoli, and minimal
cytoplasm (Romanowsky stain). B Hodgkin lymphoma. A classic Reed-Sternberg cell dwarfs surrounding lymphocytes and neutrophils; huge nuclei mirroring one another contain
enlarged misshapen nucleoli (Papanicolaou stain).
154 Tumours and tumour-like lesions of the neck and lymph nodes
various extranodal sites in the head and
neck {2373).
Clinical features
Lymphomas commonly present as a
painless nodal swelling in the neck. In
sorne lymphomas, a concomitan! anterior
mediastinal mass is present. Non-specif-
ic constitutional symptoms include weak-
ness and fatigue. Lymphomas may be
associated with so-called B symptoms:
fever, weight loss, and night sweats.
Macroscopy
Enlarged neck nodes may be single or
matted together as a group. The cut sur-
face shows a homogeneous pale-tan to
off-white, soft or firm, bulging mass. Yel-
lowish necrotic foci may exist in sorne
high-grade lymphomas. Sorne HL sub-
types display a nodular cut surface
showing a variable amount of fibrosis that
manifests as strands of connective tissue
arborizing throughout the node.
Cytology
The use of cytopathology in the diagno-
sis of haematolymphoid neoplasms has
evolved over the past three decades. Al-
though the diagnostic standard for newly
diagnosed patients remains histopathol-
ogy in many centres, fine-needle asp i-
ration cytopathology has proven useful
in centres that use ancillary techniques
•
'
• '
•
• •
B •
Wakely PE.
Li X.-0 .
Schwartz M.R.
{2522). Accurate distinction of lymphoma
from other non -lymphoid neoplasms and
from reactive conditions is possible when
cytology is coupled with appropriate an-
cillary tests such as flow cytometry, im-
munohistochemistry, in situ hybridization,
FISH, cytogenetics, and/or assessment
of gene rearrangements. A variety of
NHLs can be subclassified in this man-
ner. Fine-needle aspiration is particularly
applicable in cases where recurrent lym-
phoma is suspected.
Histopathology
The characteristic low-power appearance
of ali nodal -based NHLs is partial or com -
plete alteration of the normal architecture
of the lymph node by a proliferation of ab-
normal lymphoid cells. This proliferation
may show a foll icular, sinusoidal, mantle-
zone, or diffuse confl uent pattern of ef-
facement. Higher-grade lymphomas are
associated with increased mitotic figu res,
tingible body macrophages, and necro-
sis (manifesting as individual cell apop -
tosis or geographical zones of necrosis).
The cells of large cell lymphoma have a
diameter 2-4 times that of small resting
lymphocytes, round to ovoid nuclei with a
vesicular appearance, coarsely granular
chromatin, and discrete nucleoli. The cyto-
plasm is modest in amount and basophilic.
More anaplastic forms of large cell lym-
phoma display multinucleation , irregular
,. •
~"'"'
:t
• ••
• .. • •4
•
.;
• •
•t
•
nuclear contours , and large acidoph ilic
nucleoli. Small cell subtypes of NHL have
a monotonous population of lymphocytes
that are slightly larger than mature resting
lymphocytes. Depending on the subtype,
nuclei are rounded or angulated with finely
granular or clumped chromatin. Nucleoli, if
visible , are small.
Reed-Sternberg cells and variants are a
minor component of the polymorphous
population of lymphocytes, eosinophils,
plasma cells, and neutrophils in classical
HL. The common nodular sclerosis variant
of classical HL typically contains so-called
Cysts and cyst-like lesions
Branchial cleft cyst
RoJY
Bell D.
Gnepp D.R.
Wenig 8.M .
Definition
A branchial cleft cyst is a lateral neck cyst,
derived most often (approximately 90%
of all cases) from remnants of the sec-
ond branch ial apparatus. First, third, and
fourth branchial cleft anomalies are rare.
Synonyms
Lateral neck cyst; cervical lymphoepithe-
lial cyst
Epidemiology
Branchial cleft cyst accounts for about
20% of cervical cysts and 90% of lateral
cervical cysts (879). lt has bimodal pa-
tient age peaks at < 5 years (accounting
Fig. 6.11 Branchial cleft cyst. A Scattered mature squamous epithelial cells are seen admixed with neutrophils, lymphocytes, histiocytes, and necrotic debris (Diff-Quik stain).
B A unilocular cyst, lined by stratified squamous epithelium. Under the epithelial lining, lymphoid tissue with germinal centres is present. C The cyst is lined by respiratory epithelium,
with scattered goblet cells; beneath the cyst, only a few lymphocytes and eosinophils are present.
lacunar-type Reed-Sternberg cells, which
have polylobated nuclei and a retracted
cytoplasm in formalin-fixed tissue . Positive
CD30 , CDl5, and PAX5 staining is helpful
for recognizing these cells.
Genetic profile
Most NHLs show clonal rearrangements
of either IG genes (in 8-cell lympho -
mas) or T-cell receptor genes (in T-cell
lymphomas). Several 8-cell lympho-
mas have characteristic genetic abnor-
malities that can be used in differential
diagnosis.
for 20% of cases) and 20- 40 years (ac-
counting for 75%). Males and females are
equally affected (599,906).
Etiology
Branchial cleft cysts were previously de -
scribed as congenital malformations re-
sulting from imperfect obliteration of the
branchial clefts, arches, and pouches.
Other theories of their etiology include
cervical lymph node cystic transforma-
tion and incomplete obliteration of cervi-
cal sinus or thymopharyngeal ducts {251,
594,866,2173}
Localization
The typical localization is the lateral neck
near the mandibular angle, along the an-
terior border of sternocleidomastoid mus-
cle, but these cysts can occur anywhere
from the hyoid bone to the suprasternal
notch . They are equally distributed on the
left and right sides of the neck, with rare
bilateral occurrence {599,906).
B
Prognosis and predictive factors
The prognosis of NHL is highly vari-
able, depending on histological type
and the lnternational Prognostic lndex,
which consists of clinical stage, serum
lactate dehydrogenase, patient age,
performance status, and involvement
of extranodal siles {2732). HL is curable
by radiation and chemotherapy in about
85% of cases. Clinical stage is the prin-
cipal prognostic factor in determining
survival.
Clinical features
Patients present with painless cervical
swelling. Bilateral lesions suggest syn-
dromic or familia! association. Dyspha-
gia, dysphonia, dyspnoea, and stridor
may occur. Spontaneous rupture of an
infected cyst may occur, resulting in a
purulent draining sinus to the skin or
pharynx.
Macroscopy
The cysts are unilocular and contain
clear to grumous material. They have a
wide size range, and can reach IO cm.
Cytology
Preparations show neutrophils, lympho-
cytes, and debris admixed with mature
squamous cells, including degenerate
forms {906,2378).
Histopathology
Branchial cleft cysts are usually unilocu -
lar. They are lined by stratified squamous
Cysts and cyst-like lesions 155
epithelium in 90% of cases and less com-
monly by respiratory epithelium, with oc-
casional goblet cells and transitional areas
in both epithelial types. The lumen is filled
with keratin debris. Lymphoid tissue with
germinal centres is present in the wal l. Car-
cinoma either does not occur in branchial
cleft cysts or is vanishingly rare (251}.
Presumed branchial cleft cysts with cyto-
logical atypia in patients aged > 40 years
should raise the possibility of metastatic
carcinoma from the oropharynx. In this set-
ting, the value of p16 immunostaining for
differential diagnosis is limited , because
p16 is overexpressed in almost 50% of
branchial cleft cysts (326 ,2663}.
Prognosis and predictive factors
Branchial cleft cysts are benign. After
complete surgical excision, there is on ly
a low risk of recurrence (< 3%) without
infection befare surgery, but the risk in-
creases to nearly 20% if the cyst is in-
fected or previously incised , drained, or
incompletely removed.
Thyroglossal duct cyst
Prasad M.L.
Bell D.
Gnepp D.R.
Richardson M.
Definition
A thyroglossal duct (TGD) cyst is a cystic
dilatation of a persistent TGD .
Synonyms
Thyroglossal duct remnant; thyroglossal
cyst (1640)
156 Tumours and tumour-like lesions of the neck and lymph nodes
Epidemiology
TGD cyst is the most common congen ital
mass in the neck, presenting in patients
of any age, with no sex predilection {277,
547,1334,1434). Thyroglossal tract rem-
nants are found in 7% of autopsies (651 ,
1310}.
Etiology
The TGD arises from the endoderm at
the base of tangue and descends in the
midline of neck to form the thyroid gland.
Persistence of TGD with accumulation of
secretions from its epithelium may lead to
cyst formation (51).
Localization
The typical localization is the midline of
the neck or with in 2 cm of it, at the level of
the hyoid, infrahyoid , or suprahyoid (sub-
mental). Uncommon locations include
intralingual, intrahyoid , and intrathyroidal
(1334,2240).
Clinical features
TGD cysts may present as an asymp-
tomatic mass, draining sinus , fistula, or
recurrent swelling that moves with swal-
lowing. Ultrasonography confirms the
presence of thyroid gland and detects
any associated malignancy (439).
Macroscopy
The cysts are generally < 2 cm in size
(range: 0.5-10 cm) (51,790). The cyst
contents are thin and mucoid , unless
infected. Solid areas shou ld raise suspi-
cion for malignancy (439).
Cytology
Aspirates show inflammatory cells and
debris admixed with mature squamous
cells or ciliated columnar cells. Thyroid
follicular epithelium is sometimes seen.
Histopathology
TGD cyst is lined by benign epithelium,
usually respiratory or squamous in type,
and may show thyroid follicles and mu-
cous glands in the wall. Severe inflam-
mation, abscess, and granulomatous
reaction with cholesterol granulomas
may obliterate the cyst lining. Malignancy
(most often papillary thyroid carcinoma)
can infrequently supervene.
Genetic susceptibility
TGD cyst may rarel y be inherited in an
autosomal dominant manner (2089}.
Prognosis and predictive factors
Recurrences may occur after inadequate
excision {547). The prognosis of papillary
thyroid carcinoma complicating a TGD
cyst is excellent (439,948,1827).
Ranula
Katabi N.
Gnepp D.R
Wenig B.M.
Definition
Extravasation of mucus within an intraoral
cystic cavity, usually associated with the
sublingual gland (647).
Synonyms
Mucocoele; retention cyst; mucus
extravasation
 by epithelium, which can be squamous,
cuboidal, or columnar. A plunging ranula
is a pool of mucin surrounded by fibrous
tissue and inflammatory cells (frequently
histiocytes), without an epithelial lining.
Mucicarmine staining or periodic acid-
Schiff (PAS) with diastase may be helpful
in identifying extravasated mucin.

Prognosis and predictive factors

Complete excision, including removal of Fig. 6.14 Dermoid cyst. Cut surface of a midline neck
the traumatized salivary duct, is the treat- dermoid cyst; the cyst is unilocular and filled with keratin.
ment of choice {2720} . lnadequate exci-
sion can result in recurrence .

Dermoid and teratoid cysts

Epidemiology
These are rare lesions. There is no sex
predilection, and they can affect patients
of any age (2592}.
Etiology
Trauma to an excretory duct is the most
common etiology.
Localization
Simple ranulas occur in the (lateral) floor
of the mouth in association with the ex-
cretory duct of the sublingual gland
{2592) In plunging ranula , extravasated
mucin dissects through the muscle of the
floor of the mouth into the neck {2720}
Clinical features
There are two types of ranulas: simple
and plunging (deep) {2592,2720). Simple
ranulas presentas a painless mass in the
oral cavity floor. Plunging ranulas present
as a painless neck mass. Ranulas are
usually unilateral and unifocal, but may
be bilateral or multiple {2592).
Macroscopy
Ranulas usually present as blue, fluctu-
ant, painless masses, and can reach sev-
era! centimetres in size {142).
Histopathology
A simple ranula is a pseudocyst that
contains mucin and may be focally lined
Chiosea S.
Gnepp D.R.
Wenig B.M.
Definition
A dermoid cyst is a cyst containing ec-
toderm- and mesoderm-derived tissues.
The additional presence of endodermal
derivatives defines a teratoid cyst.
Synonyms
Nasal dermoid sinus cyst; cystic der-
moid; cystic teratoma
Epidemiology
Dermoid cysts of the head and neck ac-
count for as many as 7% of all dermoid
cysts {1929). There is no clear sex pre-
dilection {1815) . About two thirds of der-
moid cysts are recognized in patients
aged < 5 years.
Localization
The cysts are predominantly subcuta-
neous. The most common sites are the
midline neck or nose, nasolabial fold , and
lateral third of the eyebrow (i.e. embryo-
logical fusion lines) {1780} Lateral der-
moid cysts are rare {2372).
Clinical features
Dermoid cysts presentas a non-pulsatile
painless mass, pit (with protruding hair),
/'
Fig. 6.15 Teratoid cyst. Squamous epithelium-lined cyst
with difieren! lineage-derived normal tissue structures
typical of this entity.
or fistula. Midline nasal dermoid cysts
must be assessed (by imaging studies)
for intracranial or deeper soft tissue and/
or bony extension.
Macroscopy
The cysts can reach 12 cm in size
and have keratinous (yellowish-white)
contents .
Histopathology
Dermoid cysts are lined by squamous
epithelium with mature cutaneous ad-
nexal structures (e.g. sebaceous glands
and hair fo lli cles). The absence of cuta-
neous adnexal structures is indicative of
epidermoid cyst. ldentification of endo-
dermal derivatives (e.g. gastrointestinal
or respiratory mucosa or smooth muscle)
is diagnostic of a teratoid cyst.
Prognosis and predictive factors
Complete surgical excision is the primary
treatment {1780). Recurrence is rare.

Cysts and cyst-like lesions 157

 CHAPTER 7

Tumours of salivary glands

Malignant tumours
Benign tumours
Non-neoplastic epithelial lesions
Benign soft tissue lesions
Haematolymphoid tumours
WHO classification of tumours of salivary glands

Malignant tumours Lymphadenoma 8563/0*

Mucoepidermoid carcinoma 8430/3 Cystadenoma 8440/0
Adenoid cystic carcinoma 8200/3 Sialadenoma papilliferum 8406/0
Acini c cell carcinoma 8550/3 Ductal papillomas 8503/0
Polymorphous adenocarcinoma 8525/3 Sebaceous adenoma 8410/0
Clear ce ll carcinoma 8310/3 Canalicular adenoma and other
Basal cell adenocarcinoma 8147/ 3 ductal adenomas 8149/0
lntraductal carcinoma 8500/2
Adenocarcinoma , NOS 8140/3 Non-neoplastic epithelial lesions
Salivary duct carcinoma 8500/3 Sc lerosing polycystic adenosis
Myoepithelial carcinoma 8982/3 Nodular oncocytic hyperplasia
Epithelial- myoepithelial carcinoma 8562/3 Lymphoepithelial sialadenitis
Carcinoma ex pleomorphic adenoma 89 41/3 lntercalated duct hyperpl asia
Secretory carcinoma 8502/3*
Sebaceous adenocarcinoma 8410/3 Benign soft tissue lesions
Carcinosarcoma 8980/3 Haemangioma 9120/0
Poorly differentiated carcinoma Lipoma/sialol ipoma 8850/0
Undifferentiated carcinoma 8020/3 Nodular fasciitis 8828/0
Large cell neuroendocrine carcinoma 8013/3
Small cell neuroendocrine carcinoma 8041/3 Haematolymphoid tumours
Lymphoepithelial carcinoma 8082/3 Extranodal marginal zone lymphoma of
Squamous cell carcinoma 8070/3 mucosa-associated lymphoid tissue
Oncocytic carcinoma 8290/3 (MALT lymphoma) 9699/3
Uncertain malignant potential
Sialoblastoma 8974/1

Benign tumours
8940/0 The morphology codes are from the lnternational Classification of Diseases
Pleomorphic adenoma
for Oncology {ICD-0) {776A). Behaviour is coded /0 for benign tumours;
Myoepithelioma 8982/0 /1 for unspecified , borderline, or uncertain behaviour; /2 for carcinoma in
Basal cell adenoma 8 147/ 0 situ and grade 11 1 intraepithel ial neoplasia; and /3 for malignant tumours.
Warth in tumour 856 1/0 The classification is modified from the previous WHO classification , taking
into account changes in our understanding of these lesions.
Oncocytoma 8290/0 ·rhese new codes were approved by the IARC/WHO Committee for ICD-0.

160 Tumours of salivary glands

TNM classification of carcinomas of the
major salivary glands

TNM classification•.b.c M - Distant metastasis

MO No distan! metastasis
T - Primary tumour M1 Distan! metastasis
TX Primary tumour cannot be assessed
TO No evidence of primary tumour Stage grouping
T1 Tumour:::; 2 cm in greatest dimension, without Stage 1 T1 NO MO
extraparenchymal extension Stage 11 T2 NO MO
T2 Tumour > 2 cm but:::; 4 cm in greatest dimension, Stage 11 1 T3 NO MO
without extraparenchymal extension T1 -3 N1 MO
T3 Tumour > 4 cm and/or with extraparenchymal extension Stage IVA T1 -3 N2 MO
T4a Tumour invades skin, mandible, ear canal, or facial nerve T4a N0-2 MO
T4b Tumour invades base of skull or pterygoid plates, or Stage IVB T4b Any N MO
encases carotid artery Any T N3 MO
Stage IVC Any T Any N M1
Note: Extraparenchymal extension is clinical or macroscopic evi-
dence of invasion of soft tissues or nerve, except !hose tissues/
nerves listed under T4a and 4b. Microscopic evidence alone
ªThis classification applies to carcinomas of the majar sal ivary glands: pa-
does not constitute extraparenchymal extension far classification
rotid , submandibular (submaxillary), and sublingual; carcinomas arising in
purposes. minar salivary glands (i.e. the mucus-secreting glands in the lining mem-
brane of the upper aerodigestive tract) are not included in this classification ,
N - Regional lymph nodes (i.e. the cervical nodes) but instead at their anatomical site of origin (e.g. the lip).
NX Regional lymph nades cannot be assessed bAdapted from Edge et al. {625A} - used with permission of the American
Joint Committee on Cancer (AJCC), Chicago , lllinois; the original and prima-
NO No regional lymph nade metastasis
ry source for this information is the AJCC Cancer Staging Manual, Seventh
N1 Metastasis in a single ipsilateral lymph nade, :::; 3 cm in Edition (2010) published by Springer Science+Business Media - and Sobi n
greatest dimension et al. {2228A}.
N2 Metastasis as specified in N2a, N2b, or N2c below cA help desk for specific questions about TNM classification is available at
http://www .uicc.org/resources/tnm/helpdesk.
N2a Metastasis in a single ipsilateral lymph nade, > 3 cm but
:::; 6 cm in greatest dimension
N2b Metastasis in multiple ipsilateral lymph nades, ali :::; 6 cm
in greatest dimension
N2c Metastasis in bilateral or contralateral lymph nades, ali
:::; 6 cm in greatest dimension
N3 Metastasis in a lymph nade> 6 cm in greatest dimension

Note: Mid line nades are considered ipsi lateral nades.

TNM classification of carc inomas of the major salivary glands 161

lntroduction
In this volume, Chapter 7 is the main
reference on all salivary gland tumours
occurring throughout the head and neck.
In recognition of cytology as an initial
tool in assessing salivary gland masses,
it has been included, when appropriate,
in most malignant and selected benign
entities .
To allow flexibility in grading and the
enrolment of patients in clinical trials
the term "low-grade" has been omitted
across entities.
Another notable modification in this edi -
tion is the grouping of rare epithelial
carcinoma subtypes that share similar
pathological and clinical characteristics
under "adenocarcinoma, NOS", includ-
ing cystadenocarcinoma, mucinous ade-
nocarcinoma, and intestinal adenocarcino-
ma. Similarly, ductal papilloma subtypes
(intraductal and inverted) are discussed
together in a single section. Given the
i62 Tumours of salivary glands
multitude of existing entities and the re -
markable overlap of cellular and pheno-
typic features within and between sali-
vary gland carcinomas, only thoroughly
documented new phenotypes were con -
sidered. This approach led to the inclu-
sion of secretory carcinoma as the only
new entity in this edition. Reported enti-
ties and subentities lacking consensus
support and/or validation by independent
investigators have not been included in
this edition.
In this chapter, efforts were made to limit
the histomorphological, lineage, and bio -
logical features discussed to those con -
sidered to be validated and relevan! to
current diagnostic and clinical practice.
Similarly, only molecular and cytogenetic
findings that have been identified by in-
dependent authors and in large series
are discussed. Although the future inte-
gration of molecular genetic findings into
El-Naggar A.K.
the biological and therapeutic stratifica-
tion of certain salivary carcinomas is in-
evitable, none of the reported markers
are yet clinically applicable.
As in other chapters of this 4th edition
volume, poorly differentiated carcino-
mas (small cell and large cell) have
been renamed poorly differentiated neu-
roendocrine and non-neuroendocrine
carcinomas for consistency. Lastly, sialo-
blastoma and paraganglioma have been
reclassified from indeterminate to mal ig-
nant and coded accordingly.
Malignant tumours

Mucoepidermoid carcinoma
Brandwein-Gensler M.
Bell D.
lnagaki H.
Katabi N.
Leivo l.
Seethala R.
Triantafyllou A.
Definition
Mucoepidermoid carcinoma (MEC) is
a distinctive salivary gland malignancy
composed of mucinous, intermediate
(clear-cell), and squamoid tumour cells
forming cystic and solid patterns.
ICD-0 code
Synonym
Mucoepidermoid tumour
Epidemiology
MEC occurs overa wide age distribution,
and is the most common salivary gland
malignancy in children and young adults ,
with a peak incidence in the second dec-
ade of life {1995).
Etiology
MEC may develop secondary to radiation
or chemotherapy during childhood , with a
median latency period of 8 years {2495)
Localization
The parotid is the most common site for
MEC, followed by the palate, submandi-
bular gland, and other intraoral minor sal-
ivary gland siles {309 ,1899). Primary in-
traosseous (central) MECs are rare {275,
1425)
Clinical features
The clinical presentation varies depend-
ing on tumour site, size, and grade. Cyst-
ic intraoral MEC can mimic a mucocoele.
Mucinous MEC may fluctuate in size due
to cyst rupture and may presentas a mu-
cin-draining cutaneous fistula.
Macroscopy
MECs typically present as a soft or firm
circumscribed or infiltrative mass, com-
monly with a cystic componen!.
8430/3 Cytology
Aspirates of low-grade, mostly cystic le-
sions show predominately mucus and
macrophages. Occasional bland epi-
thelial cells may be seen. Aspirates of
higher-grade lesions are more cellular,
showing an admixture of epithelial cell
types typical of the lesions. Cytological
pleomorphism, mitotic activity, and ne-
crosis may be seen {1248).
Histopathology
MEC is characterized by variable com-
ponents of squamoid, mucin-producing,
and intermediate-type cells, with a cystic
and solid growth pattern. Overt keratini-
zation is rare. Oncocytic, clear-cell , and
sclerosing variants have been described.
Mucicarmine staining and periodic
acid-Schiff (PAS) stain with diastase
demonstrate intracytoplasmic staining in
mucinous cells.
The rare oncocytic variant is composed
mainly of polygonal/columnar oncocytic
cells with scattered mucocytes, and few
if any squamoid cells {782). The scleros-
ing variant is characterized by dense
hyalinizing fibrosis {1585,2360). Solid
MECs tend to demonstrate predominan!
squamoid and intermediate cells, with
a subtle transition between these two
components.
Low-grade MEC is cystic, mucous cell-
rich, and well circumscribed . lntermedi-
ate-grade MECs are generally more solid
and less circumscribed and show a di-
versity of appearances , including mucin
extravasation. High-grade MEC displays
one or more of the following features: nu-
clear anaplasia; necrosis; increased mi-
totic rate; and perineural, lymphovascular,
or bony invasion {105,124,255,876). The
diagnosis of high-grade MEC requires at
least focal intracellular mucin positivity;
the tumours typically contain foci of low or
intermediate MEC. The diagnosis should
be reconsidered in the presence of kera-
tin pearls, extreme nuclear pleomorphism,
or a history of skin cancer. Necrotizing
sialometaplasia, pleomorphic adenoma
with squamous metaplasia, and scleros-
ing polycystic adenosis can be misclas-
sified as MEC. Cystic oncocytic MEC with
lymphoid componen! can mimic Warthin
tumour (MEC may develop in Warthin tu-
mour). The sclerosing variant can be mis-
taken for sclerosing sialadenitis.

Fig. 7.01 Mucoepidermoid carcinoma. A Circumscribed tumour with dominan! clear-cell composition. B Oncocytic variant. The finding of larger intermediate cells with clear
cytoplasm guides this diagnosis to mucoepidermoid carcinoma; intracytoplasmic mucin is also present. C lntracytoplasmic mucin is a requisite finding.

Malignant tumours 163

Fig. 7.02 A Low-grade mucoepidermoid carcinoma. Cystic ductal spaces lined by mucinous epithelial cells. B lntermediate-grade mucoepidermoid carcinoma. Nests of tumour cells
with mucinous, clear and squamoid features with minimal cystic formation . C High-grade mucoepidermoid carcinoma. Poorly differentiated tumour with focal mucin-producing cells.
Genetic profile
Most MECs are characterized by a
t(11 ;19)(q21 ;p13) translocation and
CRTC1-MAML2 gene fusion {1122 ,2116),
whereas a small subset show a t(11 ;15)
(q21 ;q26) translocation and CRTC3-
MAML2 gene fusion {1700). Tumours with
translocation and gene fusion tend to be
of low to intermediate grade {1122 ,2116}
and reported in younger patients {1700),
but high-grade MEC can also be fusion-
positive. Rare cases with t(6;22)(p21 ;q12)
translocation and EWSR1-POU5F1 gene
fusion have been reported {1638) . Al -
though these fusion findings have been
validated, their diagnostic and clinical
implications in the pathological evalua-
tion of these tumours remain uncertain.
Prognosis and predictive factors
Low- and intermediate-grade MECs are
less aggressive and are generally cured
by complete surgical excision {1195,
1569) The 10-year overall survival rates
for low-, intermediate-, and high-grade
MECs are approximately 90% , 70%, and
25%, respectively {1899)
Adenoid cystic carcinoma
Stenman G.
Licitra L.
Said-Al-Naief N.
van Zante A.
Yarbrough W.G.
Definition
Adenoid cystic carcinoma (ACC) is a
slow-growing and relentless salivary
gland malignancy composed of epithelial
and myoepithelial neoplastic cells that
form various patterns, including tubular,
cribriform , and solid forms.
ICD-0 code
164 Tumours of sa\ivary glands
Epidemiology
The annual incidence of ACC is about
2 cases per 100 000 population in the
USA {646), and the median patient age
at diagnosis is 57 years. There is no eth-
nic predilection, and the female-to -male
ratio is about 1.5:1 {244,646). ACC ac-
counts for < 1% of ali head and neck
cancers and < 10% of ali salivary gland
neoplasms.
Localization
ACC occurs most frequently in the major
salivary glands, but more than one third
of cases occur in minor glands in the oral
cavity, sinonasal tract, or (rarely) other
sites {244 ,646)
Clinical features
Patients usually present with swelling
or masses , and may have numbness,
paraesthesia, or pain. lnvolvement of
motor nerves can cause facial or tongue
weakness {517,2253).
Macroscopy
ACC typically presents as a firm, grey-
ish-white, unencapsulated and infiltrative
mass of variable size {2251). The rare
Fig. 7.03 Adenoid cystic carcinoma. Spectral karyotype of a MYB-NFIB fusion-positive tumour with a t(6;9)(q22-
8200/3 23;p23-24) chromosomal translocation as the sole cytogenetic anomaly.
finding of necrosis and/or haemorrhage
may indicate the presence of high-grade
tumour {2117).
Cytology
Aspirates are composed of groups of
compact uniform basaloid cells, usually
associated with metachromatic spheres
or cylinders of acellular hyaline stroma
{1247,1671,1690). Neither the cytological
features of a high-grade malignancy nor
keratin ization is seen.
Histopathology
ACCs can manifest a variety of tubular
and cribriform structures with variably
solid components. The most recogniz-
able architectural form is the cribriform
pattern , characterized by nests of tumour
cells interrupted by sharply punched-out
spaces filled with basophilic matrix. The
tubular pattern is composed of bilayered
tubules with true lumina. The tumour
cells show scant cytoplasm and typically
have small angulated and hyperchro-
matic nuclei. The solid growth pattern is
characterized by sheets of tumour cells
without lumen formation and may consist
of epithelial or myoepithelial elements.
Perineural invasion is virtually ubiquitous.
Rarely, ACC can undergo high-grade
transformation or dedifferentiation; this
diagnosis should not be made in the ab-
sence of conventional ACC (1681,2117).
lmmunohistochemical staining for KIT
(CD117) is typically restricted to inner
epithelial cells and p63 and SMA to pe-
ripheral myoepithelial cells ¡78). MYB and
MYB-NFIB antibodies are currently being
evaluated {270 ,2597).
The major entities to be distinguished
from ACC are pleomorphic adenoma ,
polymorphous adenocarcinoma , epithe-
lial-myoepithelial carcinoma, and basal
cell adenocarcinoma.
Genetic profile
The key genomic alterations are a t(6 ;9)
chromosomal translocation or more
rarely a t(8;9) translocation, resulting
in fusions involving the MYB or MYBL 1
oncogenes and the transcription fac-
tor gene NFIB {266,1629,1745,1861)
MYB/MYBL 1 activations due to gene fu-
sion or other mechanisms are found in
> 80% of ACCs and may be useful po-
tential therapeutic targets {270 ,1630,
2271 }. Losses of 1p and 6q are associ-
ated with solid form tumours with poor
prognosis, whereas losses of 14q are
exclusively seen in main ly tubular and
cribriform pattern tumours (1862,1955).
Whole-exome sequencing of ACCs has
revealed a wide mutational diversity and
a low exonic somatic mutation rate, with
mutations in genes involving a wide va-
riety of pathways, including fibroblast
growth factor, insulin-like growth factor,
Pl3K and NOTCH signalling (P!K3CA,
FOX03, INSRR, NOTCH1, and NOTCH2)
{1002,2277). KIT and EGFR, which are
frequently overexpressed in ACC, are
only rarely mutated or amplified {516,
1002,1625,2277)
Genetic susceptibility
Germline BRCA mutations and genetic
variants in DNA double-strand break re-
pair genes have been associated with an
increased risk of salivary gland cancers,
including ACC (2157,2658)
Prognosis and predictive factors
The 10-year survival rate is 50-70% (459,
1535,1981), and the local recurrence rate
is highly variable. Lymph node involve-
ment is uncommon, but is more frequent
in solid variants (2477). Distant metasta-
sis is reported in > 50% of cases, most
commonly to the lungs, followed by
bone, liver, and brain (2185). Factors
that influence survival include tumour
stage, node status, patient age, tumour
site, large nerve perineural invasion, and
surgical margins (71,449,1981). Gener-
ally, tumours with tubular and cribriform
growth patterns have a less aggressive
clinical course than do tumours with a
solid component constituting more than
one third of the tumour {509 ,2328).
Radical surgical excision, with or without
postoperative radiation, is the treatment
of choice; overall survival is poorer with
a single-modality approach (1981 }. lnten-
sity-modulated radiotherapy plus carbon
ion boost has recently been shown to im-
prove locoregional control and progres-
sion-free and overall survival {1126,1127,
1348).
C Cellular nodules formed of
Malignan! tumours 165
Acinic ce// carcinoma
Simpson R.H.W.
Chiosea S.
Katabi N.
Leivo l.
Vielh P.
Williams M.O.
Definition
Acinic cell carcinoma is a malignant sali-
vary gland neoplasm composed of can-
cer cells with acinar features. A subset of
this entity has been reclassified as secre-
tory carcinoma !208).
ICD-0 code
Synonyms
Acinic cell adenocarcinoma; acinar cell
carcinoma
Epidemiology
The mean patient age at presentation is
approximately 50 years, with a female-to-
male ratio of 1.5:1 !430,1826). About 35%
of patients are aged > 60 years , and 4%
are aged < 20 years. Acinic cell carcino-
ma is the second most common salivary
gland malignancy in children.
Localization
More than 90-95% of acinic cell carcino-
mas occur in the parotid glands.
Clinical features
Th e tumours typically present as slow-
growing , solitary, unfixed masses, but
sorne are multinodular and/or fixed to
skin. One third of patients experience
pain and 5-10% develop facial paralysis.
Fig. 7.06 Acinic cell carcinoma with high-grade
transformation. Note the lack of differentiation of the high-
grade componen! (right).
166 Tumours of salivary glands
8550/3
Fig. 7.07 Acinic cell carcinoma. A Serous acinar cell type. B Microcystic type: vacuolated/microcyst formation along
with serous acinar cell type. C Clear plus serous acinar cell type. D Follicular growth pattern.
Macroscopy
Most tumours are circumscribed (occa-
sionally cystic) solitary nodules of varying
size, but sorne are poorly defined.
Cytology
Aspirates are usually cellular, and com-
posed of sheets, microcystic structures,
or follicles of serous acinar cells. The
cells typically display granular cyto-
plasm encasing hyperchromatic, round,
relatively monomorphic nuclei. Admixed
capillaries are often seen !48,1245).
Histopathology
Acinar and ductal cells with variable
vacuolated, clear, oncocytic, and hobnail
features forming salid , microcystic, and
follicular patterns are present. The pap-
illary cystic component, if present, has
macrocystic spaces with papillary prolif-
erations. A prominent lymphoid infiltrate
can be seen !103,1604). The acinar cells
are large and polygonal, with basophilic
granular cytoplasm and round, eccentric
nuclei. The granules give a diastase-re-
sistant positive periodic acid-Schiff (PAS)
reaction, which may be focal, but the test
is not necessary for diagnosis. Acinic cell
carcinomas rarely show mitoses, necro-
sis, or significant pleomorphism, and can
be considered low-/intermediate-grade
malignancies. The presence of neural in -
vasion and stromal hyalinization is associ-
ated with aggressive behaviour !152,641 ,
649,2255).
1
Fig. 7.08 Acinic cell carcinoma. DOG1 stains most acinic
cell carcinomas.
A subset of tumours may display an un -
differentiated component, predominantly
salid or cribriform with glandular patterns
and areas of necrosis (poorly differenti -
ated transformation or dedifferentiation)
!430,2199,2384).
Although non-specific, DOG1 and
SOX1 O are immunopositive in acinar and
intercalated duct cells {408,1767) . Acinic
cell carcinoma is usually immunonega-
tive for mammaglobin , which is useful in
its distinction from secretory carcinoma.
Genetic profile
Pl3K pathway alterations have been
reported {581), but the biological and
therapeutic significance of these findings
remains unknown {669) .
Prognosis and predictive factors
Although acinic cell carcinoma is general-
ly not aggressive, a proportion can metas-
tasize to cervical lymph nades and lung.
A recurrence rate as high as 35% has
been reported (649,928,973,1013,1400,
1703,2405). The 20-year survival rate is
approximately 90%, with a slightly better
rate for females {1826).
Poor prognostic factors include large tu-
mour size, involvement of the deep lobe
of the parotid gland, and incomplete re -
section. Multiple recurrences and cervi-
cal lymph node and distant metastases
predict poor prognosis. Compared with
conventional acinic cell carcinomas, cas-
es with high-grade transformation have
been reported to be associated with a
shorter mean overall survival (40 months
versus 125 months) {430} .
Polymorphous adenocarcinoma
Fonseca l.
Assaad A.
Katabi N.
Seethala R.
Weinreb l.
Wenig B.M .
Definition
Polymorphous adenocarcinoma (PAC) is
a malignant epithelial tumour character-
ized by cytological uniformity, morpho-
logical diversity, andan infiltrative growth
pattern.
ICD-0 code 8525/3
Synonyms
Polymorphous low-grade adenocarci-
noma; terminal duct carcinoma; lobular
carcinoma; cribriform adenocarcinoma
of tongue/minor salivary glands
A:' s.:. >.t · ~
Fig. 7.09 Polymorphous adenocarcinoma. A Tumour of minar salivary gland presenting as submucosal, well-circumscribed nodule. B A storiform pattern may be present in the
periphery; neurotropism is common .
Fig. 7.10 Polymorphous adenocarcinoma. Note !he
multinodular surface and !he haemorrhage.
Epidemiology
PAC is the second most common
intraoral malignant salivary gland tumour,
accounting for 26% of all carcinomas at
this site {2524) . The female-to-male ratio
is about 2:1. The patient age ranges from
16 to 94 years, with a mean of 59 years
{1832). More than 70% of patients are
aged 50-70 years {1832}. Few examples
of PAC have been reported in children
{1231,1832,2430}.
Localization
Approximately 60% of PAC cases involve
the palate. Other intraoral locations are
the buccal mucosa, retromolar region,
upper lip, and base of tangue (1231,
1832}. Uncommon locations include the
majar salivary and lacrimal glands, naso-
pharynx, and nasal cavity {1231,1832,
2587}.
Clinical features
PACs typically present as a painless
mass of variable duration (from a few
weeks to 40 years) {352} Bleeding, telan -
giectasia, and ulceration of the overlying
mucosa may occasionally be found.
Macroscopy
PACs typically present as firm, circum-
scribed, unencapsulated, yellowish-tan
lobulated nodules of variable size (aver-
age: 2.1 cm) {1832).
Cytology
Oue to their locations, PACs are rarely
sampled by aspiration. lf accessible,
smears show sheets and clusters of
epithelial cells , with papillary formations.
The cytological features of high-grade
malignancy and squamous differentia-
tion are not seen unless dedifferentiation
is present {1250}.
Histopathology
PAC is typically submucosal in location
and unencapsulated. The tumour histo-
pathology is characterized by cytologi-
cal uniformity, histological diversity, and
an infiltrative growth pattern . Due to the
aggressive clinical behaviour of sorne of
these tumours, the term "low-grade" is
omitted but can be used on a case-by-
case basis. Neoplastic cells are small to
medium-sized and uniform in shape, with
bland, minimally hyperchromatic, oval nu -
clei and only occasional nucleoli . Mitoses
are uncommon and necrosis is seen in
high-grade transformation. A salient and
prominent feature is the wide variation
of morphological configurations within
and between tumours. The main micro-
scopic architectural patterns are lobular,
trabecular, microcystic or cribriform (as
in adenoid cystic carcinoma), salid, and
papillary-cystic. An eddy-like pattern can
be observed at the peripheral boundaries
of tumour. Foci of oncocytic, clear, squa-
mous, or mucous cells can be observed.
Tumour stroma can be mucinous or hya-
li nized. Perineural involvement is common .
,. __
Malignant tumours 167
 ~~""--·"..::'.~-:11" . " .,"..;J.•:'11.i), _ _. ..,_· ~}:~,.¿y¡ .. ~. "
Fig. 7.11 Polymorphous adenocarcinoma of minar salivary glands. A Cribriform variant of adenocarcinoma. B Cribriform pattern in polymorphous adenocarcinoma. Pale, optically
clear and vesicular nuclei, similar to !hose of papillary thyroid carcinoma.
lnvasion into adjacent bone may be seen
in tumours of the palate or mandible. A cri-
briform variant {1604A}, initially reported
at the base of tangue and later in other
minar salivary gland sites, is considered
by sorne authors to constitute a separate
entity {1604A,2198}; however, this phe-
notype is considered a feature within the
PAC morphological spectrum by others.
Accordingly, this variant is considered an
emerging entity pending further evidence
to justify a separate classification (2655A}.
The tumour cells are immunoreactive for
cytokeratins (e.g. CK7, in 100% of cases)
{1577}, S100 protein (in 97%), CEA (54%),
GFAP (15%), MSA (13%), and EMA (12%)
{1855 ,1916,2587} Expression of galec-
tin 3 has been reported to be significant
in PACs {1850). BCL2 is overexpressed in
most cases {1855}, and mammaglobin is
positive in 67-100% of tumours (207,1927}.
Staining for p63 is reported in 100% of
cases, whereas p40 is consistently nega-
tive; this pattern is helpful (although not in-
fallible) in the differential diagnosis (2011}.
KIT (CD117) positivity has been described
in about 60% of tumours (1850).
Genetic profile
A variety of molecular and genetic find-
ings have been reported in PAC , among
these are HRAS mutations (2569}, in-
cluding alterations of the PRKD gene
family {2574): rearrangements of PRK01 ,
PRKD2, and PRK03 {2574) and activat-
ing mutation of PRKD1 (p.Glu710Asp,
exon 15). This activating mutation has
also been rarely detected in other sali-
vary gland tumou rs {2569}. PRK01 and
PRKD3 rearrangements have also been
found in clinically aggressive tumours.
The diagnostic and biological signifi-
cance of these findings is unknown.
168 Tumours of salivary glands
. _ _,
Prognosis and predictive factors
The overall survival of patients with PAC
is generally good (352,671 ,1231 ,1832,
2118). A review of large series with long -
term follow-up found local recurrence
rates of 10- 33% (average: 19%) (1231 ,
1832}. Of these, 50% occurred 5 years
after initial diagnosis (1231,1832} The
range of reported regional metastasis
rates is 9-15% (352 ,1231 ,1832). Distant
metastases have seldom been reported
(352,1231,1832,2118}. Deaths have oc-
curred after prolonged periods (352, 1231 ,
1832). High-grade transformation of PAC
has been reported and is associated with
an unfavourable prognosis (1681,2180).
Clear ce// carcinoma
Wenig B.M.
Bell D.
Chiosea S.
lnagaki H.
Seethala R.
Definition
Clear cell carcinoma (CCC) is a low-grade
salivary gland carcinoma composed of
malignant cells with clear cytoplasm, with
or without hyalinization. lt has a squamoid
phenotype and lacks features of other
clear cell- rich salivary gland carcinomas.
ICD-0 code 8310/3
Synonym
Hyalinizing clear cell carcinoma
Epidemiology
CCC is more common in women (1614,
1755,2 137,2231} and typically presents
•.
in the fifth to eighth decades of life. CCC
is rare in children.
Localization
CCCs most frequently occur in intraoral
salivary gland sites (palate and base of
tongue) {1614 ,2137,2182,2530} but may
also occur in other sites (361,659, 783 ,
784,951 ,988,1694,1755,1993,2053,2231,
2308 ,2719}.
Clinical features
CCC most commonly presents as swell -
ing and may be ulcerated or associated
with pain, bone invasion, and soft tissue
fixation .
Macroscopy
Tumours present as a poorly circum-
scribed, solid , greyish-white mass.
Prominent hyalinization may be grossly
apparent.
Cytology
Aspirates comprise groups (often sheets)
of cohesive small and large epithelial
cells with prominent cell borders and uni-
form , round to ovoid nuclei with granular-
looking chromatin , small nucleoli, and
abundant clear cytoplasm.
Histopathology
CCCs are unencapsulated and infiltrative
with solid sheets, nests, cords, trabecu-
lae, and single-cell growth patterns. Peri -
neural and bone invasion are common.
Ducts and gland-like spaces can be
seen . Most cases are characterized by
sclerotic or hyalinized stroma surround -
ing tumour nests juxtaposed to variable
fibrocellular myxoid stroma (1614}. The
tumour cells are polygonal, with distinct
cell borders and lightly eosinophilic to
clear cytoplasm (1614). CCC may also
show overt squamous and even muci-
nous differentiation.
lntracytoplasmic glycogen that gives
a diastase-sensitive positive periodic
acid-Schiff (PAS) reaction is present in
CCC. The tumour may also show punc-
tate or even overt intracytoplasmic muci -
carmine staining . CCCs are positive far
cytokeratins and p63, and negative far
other myoepithelial markers (361,1326,
1614,2137,2182,2530).
Genetic profile
CCC shows consistent EWSR1 -ATF1
gene fusion (84,2137,2354,2566).
Prognosis and predictive factors
CCCs are low-grade malignancies as-
sociated with a good prognosis after
complete surgical excision. Local recur-
rence and nodal metastases may occur
{2231). Distant metastasis and death due
to disease occur rarely {1754). lnstances
of high-grade transformation of CCC with
EWSR1 rearrangement have been re-
ported {1135).
Basal ce// adenocarcinoma Localization
Most BACs occur in the parotid gland
Fonseca l. {502,650,745,1816).
Gnepp D.R.
Seethala R. Clinical features
Simpson R.HW. BAC usually presents as a slow-growing
Vielh P. nodule. A subset of basal cell adenocar-
Williams M.O. cinomas may be associated with multiple
skin adnexal tumours {650,1069,2111,
2691).
Definition
Basal cell adenocarcinoma (BAC) is a Macroscopy
salivary gland malignancy with variable BAC presents as an unencapsulated,
basal and myoepithelial neoplastic cells firm, light-tan mass.
farming nests and glandular structures.
Cytology
ICD-0 code 8147/3 Aspirate smears are cellular and show
basaloid clusters of monomorphic small
Synonyms cells, with scant cytoplasm and frequent
Basal cell adenocarcinoma ex monomor- naked nuclei {1241,2432). Stroma is scant
phic adenoma; malignant dermal ana- to absent; in the membranous type, it con-
logue tumour sists mainly of hyaline matrix that ranges
from interdigitating strands to small cylin-
Epidemiology droma-like droplets. Squamoid and seba-
BAC is rare {502,745,1816,2709). Most ceous features may be noted (2262).
patients are in their sixth or seventh dec-
ade of life (502,745,1816,2709) There is Histopathology
no sex predilection {650 ,2709) Tumours may exhibit salid , tubular, tra-
becular, and membranous patterns with
infiltrative borders. Tumour cells typically
Malignant tumours 169

Fig. 7.14 Basal cell adenocarcinoma. A lnvasive growth into surrounding tissues. B Salid growth pattern. C Squamous metaplasia. D Areas of high-grade transformation can be
seen in about 10% of cases.
display peripheral palisading of basal
cells with occasional inner lighter epithe-
lial cells with variable deposition of base-
ment membrane-like material. Perineural
and vascular invasion is found in about
one quarter of cases.
Compared with adenoid cystic carci-
noma, BAC shows more vesicular nu-
clei, peripheral palisading, and squa-
mous and sebaceous elements. BACs
are distinguished from adenomas by
their infiltrative features and perineu-
ral and angiolymphatic invasion, and
may show increased mitotic activity and
necrosis. They consist of small nests,
cords, and ducts with peripheral basal
and inner cuboidal epithelial cells .
Staining for cytokeratins and myoepithe-
lial markers highlights the dual-cell com-
position of BAC.
170 Tumours of salivary glands
• l! .-:1'. .~ -
Genetic profile lntraductal carcinoma
A subset of these tumours, mainly of
the membranous type, contain CYLO Loening T
alterations {435). Leivo l.
Simpson R.H.W.
Genetic susceptibility Weinreb l.
Rare examples of BACs occur in the set-
ting of familial/multiple cylindromatosis
syndromes, such as Brooke-Spiegler Definition
syndrome (multiple familia! trichoepithe- lntraductal carcinoma is characterized
lioma), presumably in association with by intracystic/intraductal proliferations of
germline CYLD mutations {435). neoplastic epithelial cells {225).
Prognosis and predictive factors ICD-0 code 8500/2
Local recurrence occurs in approximate-
ly one third of BACs {1674}, but complete Synonyms
surgical excision with clear margins is Cribriform cystadenocarcinoma, low-
curative in most cases. Regional lymph grade; intraductal carcinoma, low-grade;
node metastasis, distant metastasis, and salivary duct carcinoma
disease-related death are rare.
Epidemiology
These are rare tumours , with insufficient
epidemiological data {561,1077,1303,
1322).
Localization
The parotid gland is the most common
site (256,561,1303}.
 · .· (with or without necrosis) and numerous
mitotic figures characterize intermedi-
ate- and high-grade forms of intraductal
.:~ . ' . ~
carcinoma (256,561,2361,2573}. These
·~· ( . .....·
.. ot:- -- ~' •. •• lesions must be distinguished from vari -
ants of adenocarcinoma, NOS , including
cystadenocarcinoma.

Prognosis and predictive factors

The prognosis is excellent after complete
excision . Nodal and distant metastases
have not been reported to date. The signif-
icance of focal invasion by these lesions is
uncertain (256,561,1303,1313,1697,2178).

Adenocarcinoma, NOS
Leivo l.
Brandwein-Gensler M.
Fonseca l.
Katabi N.
Loening T.
Simpson R.H.W.

Definition
Salivary gland adenocarcinoma, NOS,
represents a spectrum of epithelial car-
cinomas forming duela! and/or glandular
structures (with or without cystic forma-
tion) exclusive of known epithelial salivary
gland carcinomas.

ICD-0 code 8140/3

Synonyms
Unclassified adenocarcinoma; ductal
carcinoma/adenocarcinoma; cystadeno-
carcinoma; mucinous cystadenocarci-
noma; papillary cystadenocarcinoma; in-
testinal-type adenocarcinoma (53,1621,
2256 ,2524,2603}
-·- ~
Fig. 7.15 lntraductal carcinoma. A Low-power view of lobular and cystic areas. This cyst is lined by epithelium
with partly rigid (cribriform) structures; the arrow indicates a neighbouring invasive carcinoma. B Mixture of cysts Epidemiology
and smaller ducts, as well as of florid and atypical ductal hyperplasia (equivalen! to low-grade intraductal carcinoma). Adenocarcinoma, NOS, accounts for
C lntraductal carcinoma (intermediate to high grade). Large ducts lined by neoplastic cells with micropapillary features. approximately 10-15% all salivary gland
carcinomas (213,2256,2524). The aver-
Clinical features intermediate-grade, or high-grade intraduct- age patient age is about 58 years, but a
Patients may present with a swelling, which al carcinoma on the basis of the degree of wide age range has been reported (213 ,
is commonly asymptomatic (1303,2573). the cytological abnormalities. 2520). These tumours are extremely rare
Low-grade tumours are mostly cystic with in children (1521).
Macroscopy cribriform and papillary patterns, simi-
The reported tumours have been de- lar to breast lesions, ranging from florid Localization
scribed as typically small, unencapsulat- ductal hyperplasia to ductal carcinoma More than 50% of these tumours arise in
ed, and cystic (256 ,561 }. in situ (256,561} . The tumour cells are the parotid gland (213,750,2256) ; 40%
monotonous and may display cuboidal, arise in minor glands, most often in the
Histopathology mucinous, and apocrine features, with hard palate, bucea! mucosa, and lips
These lesions display a range of cytological occasional intracytoplasmic iron pig- (750,2524,2536) .
features and can be graded as low-grade, ment. Moderate to marked cellular atypia

Malignan! tumours 171


Fig. 7.16 Adenocarcinoma, NOS. A This tumour has an organoid growth pattern and cells have partly clear cytoplasm.
B Periodic acid-Schiff (PAS) staining shows abundan! glandular differentiation. C Proliferation of glandular and
cribriform nests of malignan! ducts. D Tubular and papillary formation of malignan! ductal epithelium.
Fig. 7.17 lntestinal-type adenocarcinoma. Ductal neoplastic structures lined by tall columnar neoplastic cells.
Clinical features
Most tumours of major glands present
as asymptomatic solitary firm or cystic
masses. Occasionally, they may be pain-
ful. Tumours in the palate are often ulcer-
ated and may erode bony structures. The
duration of these tumours varies consid-
erably, from 1 to 10 years {2256) .
Macroscopy
The tumours may be partly circum-
scribed, but may have an irregular and
infiltrative appearance. The cut surface is
commonly tan or yellow, with or without
172 Tumours of salivary glands
areas of necrosis and haemorrhage.
Cytology
The cytological features are non-specific
and depend on the neoplasm's grade
and other histological features {2256}.
Histopathology
Tumours display ductal or glandular prolif-
erations with or without cystic formation . The
tumour cells can be cuboidal , columnar,
polygonal, clear, mucinous, oncocytoid,
and/or plasmacytoid in morphology and
arranged in a variety of growth patterns,
including small confluent nests or cords,
large islands with intervening connective
tissue, and solid densely cellular stroma.
Tumours can be graded (on the basis of
the degree of cellular atypia) as low-, in-
termediate-, or high-grade. Ductal and
glandular structures are common in low-
and intermediate-grade tumours but less
frequent in high-grade tumours .
For the diagnosis of adenocarcinoma,
NOS, to be rendered, the most common
primary subtypes must first be exclud-
ed, including salivary duct carcinoma,
high-grade mucoepidermoid carcinoma,
polymorphous adenocarcinoma and
metastatic adenocarcinoma {1737}. lm-
munohistochemistry can be helpful in
distinguishing adenocarcinoma, NOS,
from acinic cell carcinoma (CK18, DOG1)
{1081}, and from tumours with myoepi-
thelial/basal-cell composition (calponin ,
SMA, CK5/6, p63).
The uncommon subtypes of these tu-
mours include mucinous adenocarcino-
ma with variable cystic formation (former-
ly called cystadenocarcinoma) {53,750 ,
1621,2603,2659A}, and intestinal-type
adenocarcinoma {173 ,838,2215}. lntesti-
nal-type adenocarcinomas can be posi-
tive for CK20 and CDX2. These tumours
have an aggressive clinical course.
Whether they constitute a separate entity
is unclear.
Prognosis and predictive factors
Prognosis is influenced by tumour loca-
tion, tumour grade, and clinical stage
{214,2256,2520,2524}. High-grade ad-
enocarcinoma, NOS, is an aggressive
malignancy {2520) . A study of adeno-
carcinoma, NOS (excluding the cystad-
enocarcinoma and intestinal subtypes)
reported 15-year survival rates for low-,
intermediate-, and high-grade tumours of
54%, 31% , and 3%, respectively {2256}.
Generally, survival of adenocarcinoma
with significant cystic formation is excel-
lent after adequate su rgical resection ,
with few reported recurrences {750). The
reports of intestinal-type adenocarci-
noma suggest an aggressive behaviour
(173,838}, but further validation of these
findings is needed.
Sa/ivary duct carcinoma
Nagao T.
Licitra L.
Loening T.
Vielh P.
Williams MO.

Definition
Salivary duct carcinoma (SDC) is an ag-
gressive epithelial malignancy resem-
bling high-grade mammary ductal car-
cinoma. lt can occur de novo or as the
outcome of a malignant component of
carcinoma ex pleomorphic adenoma.
ICD-0 code 8500/3
Synonym
High-grade ductal carcinoma
Epidemiology
SDC accounts foras many as 10% of all
salivary gland malignancies {850). lt has
a distinct male predilection and generally
affects elderly individuals, with peak inci-
dence in the sixth and seventh decades
of life {143 ,1106,1119).
Localization
Most tumours arise from the parotid
gland {1106 ,1119,2470).
Clinical features
SDC presents as a rapidly growing tu -
mour, commonly associated with facial
nerve palsy, pain, and cervical lymphad-
enopathy. In cases arising as carcinoma
ex pleomorphic adenoma, a rapid in-
crease in size of a longstanding pre-ex-
isting mass is commonly reported.
Macroscopy
The tumours vary in size and are infil-
trative. On cut surface, they are grey to
white, with occasional small cysts and
foci of necrosis.
Cytology
Aspirates are cellu\ar and typically con-
tain 30 c\usters , sometimes with papillary
configurations and flat sheets of epithelial
tumour cells with necrotic backgrounds
{1205 ,1249). The tumour cells are large
and po\ygonal, with abundant cytoplasm.
The nuclei are pleomorphic and have
prominent nucleoli.
Histopathology
The tumour has a striking resemblance
to high-grade ductal carcinoma of the
breast, including large ducts with come-
donecrosis and cribriform and Roman-
bridge-like features. Both lymphovascular
and perineural invasion is common. A hya-
linized nodule suggestive of a pre-existing
pleomorphic adenoma may be identified.
SDC cells are typica\\y apocrine, onco-
cytoid, and characterized by abundant

Fig. 7.18 Salivary duct carcinoma. A The intraductal componen! consists of cribriform structures with so-called Roman-bridge architecture; note that the central portian of
the ductal cell nests undergoes comedonecrosis. B The invasive componen! consists of irregular glands and cords of cells that elicit a prominent desmoplastic reaction .
C Carcinoma cells exhibit large pleomorphic nuclei with coarse chromatin and prominent nucleoli; the cytoplasm is abundan! and granularly eosinophilic.

Ma\ignant tumours 173


Fig. 7.21 Salivary duct carcinoma. FISH analysis is positive far ERBB2 (also called HER2) gene amplification,
showing numerous red signals (ERBB2) versus a normal number of green signals (centromere 17).
cytoplasm and large pleomorphic nuclei
with coarse chromatin and prominent nu-
cleoli. Mitotic figures are easily identifia-
ble. Rhabdoid features {1315}, squamous
features, and osteoclast-like giant cells
are rare {2433}. Severa! histological mani-
festations of SDC have been described
{2610}, including sarcomatoid {975 ,1682},
mucin-rich {2181}, invasive micropapillary
{1683}, and oncocytic carcinomas {2178) .
Approximately 70% of SDCs in both men
and women show diffuse nuclear stain-
ing for androgen receptor {578,1171,1558,
2610). Estrogen receptor and progester-
one receptor are negative {578,1171 ,1396,
2606). High ERBB2 (also called HER2)
expression is found in approximately 25-
30% of cases {578,1465,1558,2611}.
Genetic profile
AR copy-number gain and splice vari-
ants (as seen in prostate) have been
identified in both sexes {1464). ERBB2
(also called HER2) gene amplification is
seen in as many as 25% of cases {431,
1558,1705,2611). PLAG1 and/or HMGA2
rearrangements are identified in most
cases of SDC ex pleomorphic adenoma
(123,1196}.
Fig. 7.22 Myoepithelial carcinoma. A Clear cells dominate, with myxoid matrix. B Myxoid, with a cord-like myoepithelial tumour pattern.
myoepithelial cellular nests with dense fibrous stroma.
174 Tumours of salivary glands
Prognosis and predictive factors
SDC is one of the most aggressive ma-
lignant salivary gland tumours , with fre-
quent local recurrence and regional
lymph node and distant metastasis {143,
1106,1119}. Of the reported patients with
SDC, 55-65% have died of disease, usu-
ally within 5 years {1106 ,1119,1146).
Myoepithelial carcinoma
Bell D.
Di Palma S.
Katabi N.
Schwartz M.R.
Seethala R.
Skálová A.
Definition
Myoepithelial carcinoma is a malignancy
entirely composed of neoplastic myoepi-
thelial cells with an infiltrative growth.
ICD-0 code
Synonym
Malignant myoepithelioma
Epidemiology
Myoepithelial carcinomas are uncommon
and can present in patients of any age,
with no sex predilection.
Localization
Most cases occur in the parotid gland.
The palate and submandibular gland are
the next most common sites.
Clinical features
Patients present with a painless mass,
occasionally with a recent rapid increase
in size. Facial weakness/paresis may oc-
cur if there is facial nerve involvement.
Macroscopy
Myoepithelial carcinomas typically pre-
sent as unencapsulated soft to firm
masses. The cut surface is grey to tan-
white and occasionally haemorrhagic,
with cystic degeneration and necrosis.
Cytology
Aspirate smears show a mixture of spin-
dled , epithelioid , and/or plasmacytoid
cells in small groups or large fragments.
Nuclei can be round or oval, with variable
cytoplasmic features {421 }.
Histopathology
Myoepithelial carcinomas are composed
of disorganized nodules of malignant
myoepithelial cells , with pushing to in-
filtrati ve borders. The tumour cells can
form solid , trabecular, and reticular pat-
terns. The stroma can be myxoid and/or
hyalinized. The tumour may display cen-
tral necrosis and pseudocyst formation .
Tumour cells display a mixture of spin -
dle, plasmacytoid, epithelioid, and clear-
cell morphological features . Vacuolated/
signet ring-like morphologies have also
8982/3 been described {148 ,852).
The tumours typically express myo-
epithelial markers such as SMA and
p63 , as well as S100 and cytokeratins.
Genetic profile
An EWSR1 gene rearrangement has
been described in a subset of myoepi-
thelial carcinomas that have aggressive
features and are composed predomi-
nantly of clear cells , with frequent necro-
sis {2204).

Prognosis and predictive factors

Myoepithelial carcinomas are associated
with diverse clinical outcomes and have
a propensity for distant (usually lung) me-
tastasis rather than regional lymph node
metastasis {577,1271,2083,2297). About
one third of patients are cured with resec-
tion and one third experience metastatic
and progressive disease {1271).

Epithelial-rnyoepithelial ~ ~ .•::
-·'J(: .~
carcinoma _.,.};·~· .~
Fig. 7.24 Epithelial-myoepithelial carcinoma. A Microscopically, epithelial- myoepithelial carcinoma recapitulates the
Seethala R. gross appearance, with a multinodular septated growth pattern and frequent sclerosis. B High-grade transformation.
Bell D. A relatively monomorphic tumour componen! (bottom) shows high-grade transformation of both luminal and abluminal
cells (top). C This example shows a typical clear myoepithelial abluminal cell layer but is ductal-predominant, with
Fonseca l.
tubular to cribriform growth. D Epithelial-myoepithelial carcinoma classically shows a tubular growth, with clear,
Katabi N. polygonal, abluminal myoepithelial cells and small eosinophilic luminal ducts.

Localization ductal cells with dense eosinophilic cy-

Definition
Epithelial-myoepithelial carcinoma (EMC)
is a malignant salivary gland tumour
composed of a biphasic arrangement of
inner luminal ductal cells and outer myo-
epithelial cells.
ICD-0 code
Synonym
Adenomyoepithelioma
Epidemiology
EMC is an uncommon salivary gland
neoplasm, accounting for < 5% of ali
salivary gland malignancies {2486}. lt
predominates in the sixth and seventh
decades of life and has a slight female
predilection.
Most cases arise in the parotid gland and
submandibular gland {2115,2486} Less
common sites include the sinonasal cav-
ity and palate {2115).
Clinical features
EMC typically presents as a slow-grow-
8562/3 ing painless mass. Facial nerve symp-
toms and lymphadenopathy are rare.
Macroscopy
EMC is characteristically a multinodu-
lar, firm to rubbery mass with a pushing
border. Partial encapsulation and cystic
change are noted in 30% of cases {2115).
EMCs of the minor salivary and sinonasal
seromucinous glands are submucosal
and less delineated, and 40% of cases
show overlying mucosa! ulceration.
Cytology
The tumour cells present as 30 clus-
ters with a dual-cell population of larger
pale myoepithelial cells and smaller eo-
sinophilic ductal cells. Naked nuclei are
common and stroma is scant, with sorne
hyaline globules {1616).
toplasm and outer abluminal polygonal
myoepithelial cells with classically clear
cytoplasm {744,2114,2115) Solid over-
growth and necrosis may be present.
Perineural invasion is common and
vascular invasion less so {744,2115). A
spectrum of phenotypes (i.e. oncocytic,
spindled, clear, sebaceous) may be seen
in both cell components in a small sub-
set of tumours. Myoepithelial anaplasia
and high-grade transformation have also
been described {2114,2115,2119).
Low-molecular-weight cytokeratins are
strongly positive in the ductal componen!
and are less intense in the myoepithelial
component. Myoepithelial markers (e.g.
SMA, HHF35, p63, and calponin) high-
light the abluminal compartment {21 15).
8100 stains both the myoepithelial and the
ductal components to variable degrees.
Genetic profile
No characteristic genetic landmarks
have been identified.

Fig. 7.23 Epithelial-myoepithelial carcinoma. This Histopathology

parotid tumour shows a multinodular pattern of invasion, EMC displays a multinodular pattern and
abutting dermis; tumour nodules are firm and white, with is characterized by a biphasic or bilay-
central haemorrhage and cystic degeneration. ered arrangement of small inner luminal

Malignan! tumours 175

Prognosis and predictive factors
EMC is usually indolent, but local recur-
rence is not uncommon {2115}. Lymph
node and distant metastasis is rare. In the
SEER database, the disease-specific sur-
vival rate is 80% at 180 months {2486}. Sig-
nifican! prognostic factors include tumour
size, margin status, high-grade transforma-
tion, myoepithelial anaplasia, necrosis, and
angiolymphatic invasion {744,2021,2115}.
Carcinoma ex pleomorphic
adenoma
Williams M.O.
lhrler S.
Seethala R.
Definition
Carcinoma ex pleomorphic adenoma
(PA) is an epithelial and/or myoepithelial
malignancy developing from primary or
recurrent PA. The carcinoma componen!
can be either purely epithelial or myoepi-
thelial in presentation, with infiltration into
the surrounding glandular and extraglan-
dular tissue.
ICD-0 code 8941/3
Epidemiology
Carcinoma ex PA accounts for 3.6%
of all salivary gland tumours (range:
0.9-14%) and 12% of all salivary gland
malignancies (range: 2.8-42.4%). On
average, 12% of cases (range: 7-27%)
develop in the setting of recurren! PA
{63,104,1399,1453}. This malignancy oc-
curs slightly more often in women than
in men , with peak incidence in the sixth
and seventh decades of life (one dec-
ade later than the peak incidence of PA)
{892,1196,2564} .
Localization
Most cases of carcinoma ex PA arise in
the parotid gland {1197,1228,2415 ,2564}.
Clinical features
Carcinoma ex PA often presents as a rap-
idly growing mass (which may be painful)
within a pre-existing, longstanding mass
(PA).
Macroscopy
The gross appearance of carcinoma ex
PA varíes , and as many as 64% of cas-
es are infiltrative {1399,1453}. A residual
176 Tumou rs of salivary glands
A - - _______
.. ....
Fig. 7.25 Carcinoma ex pleomorphic adenoma of !he parotid gland. A Well-circumscribed heterogeneous mass
with peripheral hyalinized pleomorphic adenoma. B Minimally invasive carcinoma ex pleomorphic adenoma shows
a hyalinized pre-existing pleomorphic adenoma with a 3 mm focus of carcinoma extending beyond the pleomorphic
adenoma capsule (arrows).
PA component is grossly visible in most (often low-grade), which accounts for
cases, usually as a sclerotic, calcified 35% of cases {1197,1399,2203 ,2204}.
nodule. lntracapsular carcinomas constitute car-
cinomas confined within the PA. They
Cytology are typically ductal and high-grade {63,
Smears typically show features of PA or 576 ,892,1399} Minimally invasive carci-
high -grade adenocarcinoma. Rarely, both noma ex PA may constitute early disease
components are identified {1240 ,1242}. {2415 ,2564}. Assessing this feature is not
always feasible in tumours with positive
Histopathology margins or in those originating in minor
Carcinoma ex PA should not be consid- salivary gland siles or within multinodu -
ered a standalone diagnosis, because the lar/recurrent PA {892}.
type and extent of the carcinoma compo-
nen! impact the management of patients. Genetic profile
The histological type of the malignan! Carcinoma ex PA shares fusion genes
componen! must be recorded. Most tu- identified in PA (i.e. the transcription fac-
mours are high-grade adenocarcinoma, tor genes PLAG1 and HMGA2) {1860,
typically of salivary duct carcinoma phe- 2009,251 O}. The alterations frequently
notype {1197,1399}. Other common carci- reported in the salivary duct carcinoma
nomas include myoepithelial carcinoma subtype are mutations in TP53 (present
Pleomorphic lntracapsular Minimally invasive Widely invasive
carcinoma Breach of the PA capsule Extending into the gland
adenoma(PA)
Precursor lesion: Mixed Abnormal proliferation by carcinoma cells, and often soft t issue. The
measured in mm PA component may be
luminal cells( q within/between existing
forming ducts ( ( ) ) ducts in a PA hyalinized
and abluminal ( Abnormal Luminal (~ lproliferation
supporting cells • Nuclear enlargement
• Prominent nucleoli
• Crowdlng
i •
r Luminal (ductal)
Express CK7, CK18
Abluminal
(myoepithelial)
Express CK14, p63, SMA
• Interna! proliferation of
abluminal cells may be difficult
to call carcinoma ex-PA until
invasive (next inset)
Fig. 7.26 Schematic illustration of !he development of carcinoma ex pleomorphic adenoma as a multistep progression
from pleomorphic adenoma.
in 50-75% of cases), amplification in
MDM2 and HMGA2 (12q13-15; in 50%),
and amplification in ERBB2 (also called
HER2; in 31-38%) (431,1860 ,1988,2009)
Recent genomic studies have shown that
most tumours have a high degree of ge-
netic instability and many copy-number
alterations !954,2510,2661).
Prognosis and predictive factors
Carcinoma ex PA is an aggressive malig-
nancy, with local or distant metastasis oc-
curring in as many as 70% of cases and
a 5-year overall survival rate of 25-65%.
More-favourable outcomes are seen with
intracapsular and minimally invasive tu-
mours, together accounting for 21-58%
of cases (892,1197,1399,2564). lntraca-
psular carcinoma ex PA has a very low
reported rate of recurrence or regional
metastasis (576 ,580 ,1082,1453). More-
recent studies have found minimally in-
vasive tumours (defined as < 4-6 mm
extension beyond the pleomorphic ad-
enoma border) to be prognostically fa-
vourable !892,1197,1399,2564}, with this
criterion showing superior prognostic
significance over pT classification alone
!2415,2564) The risks of local recur-
rence , metastasis, and fatal outcome are
greatly increased with invasive tumours .
Further validation of this preliminary
threshold for defining extent of invasion
is required.
Epidemiology
A 2008 study of mammary acinic cell
carcinomas found secretory carcinoma
to be distinct from acinic cell carci-
noma !1975). Secretory carcinoma was
first documented in salivary glands in a
2010 study !2202}, and 232 cases have
been reported since. Secretory carci-
noma usually presents in adults, with a
mean patient age of 46.5 years (range:
10-86 years) and an equal sex distribu-
tion !196,208,429,1514,2132,2138,2191 ,
2202).
Localization
The most common site of occurrence is
the parotid gland , followed by the oral
cavity and submandibular gland {196 ,
208,429,2132, 2138,2191 ,2202).
Clinical features
Secretory carcinoma most commonly
presents as a painless, slow-growing
mass.
Macroscopy
Grossly, tumours are poorly defined and
rubbery, with a light-tan cut surface. Oc-
casionally, cyst formation with yellowish-
white fluid is encountered.
Cytology
Aspirate material consists of cohesive
epithelial cells and/or papillary fragments
or dispersed cells, sometimes with cystic
debris. The neoplastic cells are pheno-
typically epithelial, with abundan! and
variable, granular to vacuolated , eosino-
philic to clear cytoplasm and single nu-
cleoli {210 ,891,1156,1 935,2062}.
Histopathology
Secretory carcinoma can be circum-
scribed or (often) infiltrative, with occa-

Secretory carcinoma
Skálová A.
Bell D.
Bishop JA
lnagaki H.
Seethala R.
Vielh P

Definition

Secretory carcinoma is a generally low-

grade salivary gland carcinoma charac-
terized by morphological resemblance
to mammary secretory carcinoma and
ETV6-NTRK3 gene fusion.

ICD-0 code 8502/3

Fig. 7.27 Secretory carcinoma. A The tumour displays a lobulated growth pattern with fibrous sepia and is
composed of microcystic/solid and tubular structures. B Macrocystic pattern with abundan! homogeneous secretion.
Synonym
C The tumour cells have bland vesicular round to oval nuclei, with finely granular chromatin and distinctive centrally
Mammary analogue secretory carcinoma located nucleolus. D Abundan! eosinophilic homogeneous secretions in microcystic and tubular spaces. E Glandular
secretion gives a positive periodic acid-Schiff (PAS) reaction before and afterenzyme digestion. F Trabecularneoplastic
cellular structures embedded in a sclerotic stroma.

Malignan! tumours 177

sional perineural invasion. The tumours
exhibit a lobulated growth pattern with fi-
brous septa and are composed of micro-
cystic/solid, tubular, follicular, and pap-
illary-cystic structures with distinctive
luminal secretion . The tumour cells have
eosinophilic granular or vacuolated cyto-
plasm with small, uniform nuclei. Unlike
acinic cell carcinomas, secretory carci -
nomas show no secretory zymogen cyto-
plasmic granules that give a true positive
periodic acid-Schiff (PAS) reaction . Se-
cretory carcinoma with high -grade trans-
formation has been reported {2201).
Secretory carcinomas are characteristi -
cally positive for S100 protein and mam -
maglobin. Most cases are DOG1 -nega-
tive /408}.
Genetic profile
Secretory carcinoma harbours a recur-
rent translocation t(12;15)(p13;q25),
which results in fusion of the ETV6 gene
on chromosome 12 and the NTRK3 gene
on chromosome 15. The presence of
ETV6-NTRK3 fusion has not yet been
demonstrated in any other salivary gland
tumours. Rarely, ETV6 can be fused with
non-NTRK3 partners {1102A}. However,
the fusion has been considered to be a
multilineage alteration in several non-sal-
ivary gland tumours {76 ,1275,1325,1374).
Prognosis and predictive factors
Secretory carcinoma is usually an indo-
lent salivary gland malignancy. Lymph
node metastases are reported in as
many as 25% of cases, but distant me-
tastases are rare {430,1514,2130,2132,
2138,2201,2447). High clinical stage and
high-grade transformation are the main
adverse prognostic factors.
Fig. 7.28 Salivary gland sebaceous adenocarcinoma. A Nests of high-grade adenocarcinoma with sebaceous cell features . B Severa! solid tumour nests with moderate pleomorphism
and scattered cells with vacuolated cytoplasm; note the large vacuolated sebaceous cell al centre.
178 Tumours of salivary glands
Sebaceous adenocarcinoma
Gnepp D.R.
Assaad A.
RoJY
Definition
Sebaceous adenocarcinoma is a malig-
nant tumour composed mainly of neo-
plastic sebaceous cells of variable ma-
turity arranged in sheets and/or nests,
that display variable degrees of pleomor-
phism, nuclear atypia, and invasiveness.
ICD-0 code
Epidemiology
Sebaceous adenocarcinomas are rare
tumours with a biphasic age distribution.
The peak incidences are in the third and
seventh to eighth decades of life, with a
wide patient age range (6-93 years) {64 ,
851}. The male-to-female ratio is approxi -
mately 1:1 {64,2337)
Localization
To date, about 50 cases of salivary gland
sebaceous adenocarcinoma in head and
neck sites have been reported {64,851,
1530,2337,2537) In the parotid gland,
35 cases arose de novo and 2 tumours
occurred as the carcinoma component
of carcinoma ex pleomorphic adenoma
{466). Only 3 tumours have been report-
ed in the submandibular gland, and the
rest occurred in various minor glands.
Clinical features
Patients typically present with a painful
mass and varying degrees of facial
nerve paralysis, and occasionally with
fixation to the skin. In rare cases, patients
develop a non -tender mass.
Macroscopy
Tumours range from 0.6 to 9.5 cm in
greatest dimension and are frequently
well circumscribed or partially encapsu -
lated, with pushing or locally infiltrating
margins. Their cut surfaces can be yel -
low, tan-white, greyish-white, white, or
pale pink {851}.
Cytology
Smears are cellular, showing neoplastic
cells arranged in groups and scattered
8410/3 single pleomorphic tumour cells with
vacuolated cytoplasm .
Histopathology
The adenocarcinomas are arranged
in multiple, variably sized nests and/or
sheets composed of tumour cells with hy-
perchromatic nuclei , abundant clear vac-
uolated to eosinophilic cytoplasm, and
mild to marked cellular pleomorphism .
Cellular pleomorphism and cytological
atypia are much more prevalent than in
sebaceous adenomas. Tumour necrosis
is frequent. Perineural invasion is noted
in approximately 20% of cases, whereas
vascular invasion is rare. Rare oncocytes
and foreign -body giant cells with histio-
cytes may be observed . Sebaceous ade-
nocarcinoma is typically positive for EMA,
CA15-3, and androgen receptor; nega-
tive with BerEP4; and positive with anti-
adipophilin {83} .
 _ ,
Fig. 7.30 Carcinosarcoma. A Sarcomatoid salivary adenocarcinoma (right and upper right}. Ductal adenocarcinoma (lower right) and high-grade sarcomatous (upper left)
transformation. B Heterologous carcinosarcoma. Ductal epithelial carcinoma (lower left) and a malignan! cartilaginous componen!.
Prognosis and predictive factors
The tumours may recur and can rarely
metastasize. The 5-year overall survival
rate is 62%, which is slightly lower than in
sebaceous adenocarcinoma in the skin
or orbit (84.5%) {851}. Oral tumours may
have a better prognosis: none of 6 tu-
mours included in a recent review had re-
curred or metastasized ; however, follow-
up was < 5 years for 4 of the cases {42).
Carcinosarcoma
Williams M.O.
Di Palma S.
Gillison M.
Nagao T.
Simpson R.H.W.
Definition
Carcinosarcoma is a biphasic salivary gland
malignancy composed of distinct carcinoma
and heterologous sarcomatous components.
. .. ~~ff+~
ICD-0 code 8980/3
Epidemiology
Carcinosarcoma is a rare entity, with
< 100 reported cases. The mean patient
age at diagnosis is in the sixth to seventh
decade of life, with a wide age range po-
tentially affected {849 ,2275,2480}. There
is a male predom inance.
Etiology
Carcinosarcomas have been described
arising both de novo and from longstand -
ing or recurrent pleomorphic adenomas
(carcinosarcoma ex pleomorphic adeno-
ma) {938,1317,2346).
Localization
Most carcinosarcomas arise in the major
salivary glands, with two thirds of cases
arising within the parotid {2275).
Clinical features
Patients often present with a rap idly grow-
ing mass .
!r.&t:s.
Macroscopy
Carcinosarcoma usually presents as
a large mass of variegated fleshy tu-
mour with necrotic and haemorrhagic
features.
Cytology
Aspiration preparations typically show
highly pleomorphic malignant cells with
epithelial and mesenchymal characteris-
tics {1099,1343).
Histopathology
Carcinosarcoma is composed of a malig-
nant epithelial component - typically poor-
ly differentiated (adeno)carcinoma, NOS -
and a high-grade sarcoma component,
which can be chondrosarcoma, osteosar-
coma, or pleomorphic rhabdomyosarco-
ma. Staining for cytokeratins predominant-
ly highlights the carcinoma component,
and there is gain of mesenchymal markers
in the sarcoma component.
Carcinosarcoma should not be confused
with sarcomatoid carcinoma or with de-
Malignant tumours 179
differentiation within distinct salivary
gland carcinomas, including salivary
duct carcinoma, for management pur-
poses {1096 ,1482,1533).
Prognosis and predictive factors
This is an aggressive malignancy,
with morbidity due to both local recur-
rence and metastatic spread (to lung ,
bone, and CNS). Surgery combined with
radiation therapy may aid local control.
Mean survival is< 2.5 years (2275,2480}.
Poorly differentiated
carcinoma
Chiosea S.
Gnepp D.R.
Perez-Ordonez B.
Weinreb l.
Definition
Poorly differentiated carcinomas of sali-
vary glands are primary carcinomas
showing large and small cell types with
or without neuroendocrine differentiation .
These diagnoses can only be made after
excluding metastasis and other primary
salivary gland tumours.
ICD-0 codes
Undifferentiated carcinoma 8020/3
Large cell neuroendocrine carcinoma
8013/3
Small cell neuroendocrine carcinoma
8041 /3
Synonyms
Large cell carcinoma; neuroendocrine
carcinoma ; anaplastic/undifferentiated
carcinoma; small cell carcinoma (SmCC)
Epidemiology
Among the reported cases of these tu-
mours (2131}, the median patient age
at presentation is 64 years (range:
5-91 years) , and the male-to-female ratio
is about 2.4:1 (413,859,1206,2660}.
Localization
Most large cell neuroendocrine carci-
nomas (LCNECs), small cell neuroen -
docrine carcinomas (SmCCs), and non-
neuroendocrine carcinomas of salivary
glands occur in the parotid gland (2660}.
Clinical features
Most patients with high-grade neuro-
180 Tumours of salivary glands
Fig. 7.31 Small cell neuroendocrine carcinoma. A Small cell carcinoma invading adjacent salivary tissue. B Coagulative
necrosis, tumour cells with nuclear moulding and sean! cytoplasm. C Positive synaptophysin immunohistochemistry.
endocrine carcinoma and non-
neuroendocrine carcinoma present with
a painless mass. Sorne present with
facial nerve paralysis. More than 50% of
patients with SmCC present with regional
lymph node metastases {346 ,1170,1689,
2131).
Macroscopy
High-grade neuroendocrine carcinoma
usually presents as a poorly defined firm
white mass measuring 2-5 cm.
Cytology
The cytological features seen in aspi-
rates are identical to those seen in aspi-
rates of SmCCs or LCNECs from other
sites (1243).
Histopathology
Both SmCCs and LCNECs are high-
grade carcinomas characterized by
organoid cellular growth with minimal
differentiation , high mitotic rates , and
the frequent presence of coagulative
necrosis. SmCCs are distinguished from
LCNEC by their scant cytoplasm , smaller
cell size (< 2- 3 times the diameter of a
normal lymphocyte), angulated moulded
nuclei with inconspicuous nucleoli , and
smudgy basophilic material surrounding
intratumoural blood vessels. LCNEC
cells have relatively abundant cytoplasm
and prominent nucleoli (2044,2655) A
case of SmCC arising in pleomorphic
adenoma has been reported (452). The
tumour cells may express synaptophysin
and/or chromogranin by immunohisto-
chemistry {413). SmCC can show perinu-
clear dot-like positivity for pancytokerat-
ins and CK20, similar to the expression
pattern seen in cutaneous Merkel cell
carcinoma (413 ,2525). Whether these tu-
mours constitute primary Merkel cell car-
cinoma is still uncertain. One case each
of parotid and submandibular gland Mer-
kel cell carcinoma- like carcinoma with
polyomavirus has been reported (543,
1469) The small-cell variant should be
distinguished from small round blue cell
tumours (e.g . desmoplastic small round
cell tumour and other Ewing family tu-
mours), salid adenoid cystic carcinoma
(197,1411,1809), metastatic neuroblas-
toma, lymphomas, and melanoma.
Genetic profile
Sufficient data are not yet available. RB1
inactivation in virus-negative Merkel cell
carcinoma has been reported in 4 cases
of salivary gland neuroendocrine carci-
noma, but the significance of this finding
is unknown. Mutations and copy-num-
ber variation have also been reported
in TP53, NOTCH1, PTEN, and COKN2A
(also called P16) {881,1689).

Prognosis and predictive factors

The 2-year overall survival rate for pa-
tients with SmCC is 56% {2131}. In one
study, 3 of 7 patients with well-charac-
terized cases of LCNEC died of disease
despite receiving chemoradiotherapy
{2660}.

Lymphoepithelial carcinoma
Lewis J.S.
El-Mofty S.K .
Nicolai P.

Definition
Lymphoepithelial carcinoma (LEC) is an
undifferentiated carcinoma character-
ized by a syncytial growth pattern and a
dense, non-neoplastic lymphoid infiltrate.

ICD-0 code 8082/3

Synonyms
Malignant lymphoepithelial lesion; undiffer-
entiated carcinoma with lymphoid stroma;
lymphoepithelioma-like carcinoma.

Epidemiology
LEC is an uncommon salivary gland ma-
lignancy, with an incidence of < 1%. LEC
is rare in western countries but is more
common in certain populations, includ-
ing North American Eskimo peoples (the
lnuit in particular), the indigenous peo-
ples of Greenland {43}, South-Eastern
Asians {2154,2426}, Japanese {1684},
and Northern Africans !926,1391}. The
average palien! age is in the sixth dec-
ade of life, and there is no clear sex
predilection .
Etiology
Overall , most LECs are associated with
EBV infection (1301}, but in western pop-
ulations, only a minority of cases are re-
lated to EBV (69}
Localization
Most LECs arise in the parotid gland .
Clinical features
Patients typically present with a painless
mass {1301). Very few have pain or facial
Fig. 7.33 Lymphoepithelial carcinoma of the parotid gland. High-power view showing haphazardly arranged
tumour cells with poorly defined borders (syncytial appearance), vesicular chromatin with prominent nucleoli, dense
lymphoplasmacytic inflammatory infiltrate, and apoptotic bodies.
nerve paralysis {2154 ,2533).
Macroscopy
Grossly, the tumours are well circum -
scribed and lobulated, with a firm , tan-
white cut surface {2584).
Cytology
Aspirate smears show single to clus-
tered, medium-sized to large, polygonal
and spindled cells with prominent nu-
cleoli. Most LECs have an admixed, het-
erogeneous population of lymphoid cells
{910,2041). The cytolog ical findings are
identical to !hose seen in aspirates of
metastatic undifferentiated non-keratiniz-
ing nasopharyngeal carcinomas .
Histopathology
The tumours consist of sheets, nests , generally round nuclei with promi -
and cords of cells with modest eosino- nent nucleoli and indistinct cell bor-
philic cytoplasm and large, vesicular, ders. There is typically abundant

Malignant tumours 181

lymphoplasmacytic cell infiltrate in and
around the tumour nodules {2084,2154,
2533).
Squamous differentiation, spindle-cell
features, and basaloid features are oc-
casionally present. Mitotic activity is
brisk, and areas of necrosis may be
present {769,2584). The tumours
are positive for cytokeratins and are
typically diffusely positive for EBV-
encoded small RNA (EB ER) by in
situ hybridization {2584) . The differ-
ential diagnosis for primary LEC in-
cludes primary undifferentiated carci-
noma and metastatic undifferentiated
nasopharyngeal carcinoma {2533).
Prognosis and predictive factors
Nodal metastases occur in as many
as 40% of patients {1413,2533) . Dis-
tant metastases occur in 10-20% of
patients. Overall and progression -free
survival rates at 3 years of more than
90% have been reported {1413}, and
the 5 -year overall survival rate averag -
es 70- 80% across studies {1038,1413 ,
2154,2533}.
Squamous ce// carcinoma
Chiosea S.
Hunt J.L.
Nagao T.
Westra W.H.
Definition
Primary salivary gland squamous cell
carcinoma (SCC) is rare and the diagno-
sis can only be made after the exclusion
of prior cutaneous SCC.
ICD-0 code 8070/3
Epidemiology
Primary salivary gland SCC is very rare
{407,746,2254}. The majority of published
cases most likely constitute squamous
differentiation of other salivary gland car-
cinomas or metastatic SCC from dermal
primary {401,741,817,1543).
Localization
The reported cases have been limited to
the parotid.
Etiology
Primary salivary gland SCC may arise
in patients with longstanding ductal ob-
182 Tumours of salivary glands
Fig. 7.35 Moderately differentiated squamous cell carcinoma arising in a salivary duct.
struction and lithiasis as a result of ductal Oncocytic carcinoma
squamous metaplasia and dysplasia.
Nagao T.
Clinical features Fonseca l.
Patients usually present at advanced Seethala R.
disease stage, with a painful mass and
facial nerve palsy.
Definition
Macroscopy Oncocytic carcinoma is a malignant epi -
Most tumours are firm and infiltrative. thelial neoplasm composed exclusively
of neoplastic oxyphilic cells and does not
Histopathology display any histopathological features of
The tumours are typically moderately to other specific salivary gland tumour types.
well-differentiated SCCs with infiltrative
growth, desmoplasia, and infiltration of ICD-0 code 8290/3
periglandular soft tissue arising from or
near a major salivary duct. The findings of Synonyms
squamous dysplasia and transition from Malignan! oncocytoma; oncocytic
dilated salivary duct support a primary adenocarcinoma
salivary gland origin . Oral mucosal dys-
plasia extending into the submandibular Epidemiology
salivary duct should be ruled out {519). Oncocytic carcinoma is an extremely
Most parotid SCCs derive from primary rare salivary gland malignancy.
cutaneous SCC, most commonly through
metastasis. The differential diagnosis Localization
includes cystic metastatic SCC {1686, Most reported cases have been located
2543). in the parotid gland. The submandibu lar
Squamous differentiation may be seen gland is the second most common site.
in salivary gland carcinomas undergoing
high-grade transformation {2117}. The ab- Clinical features
sence of mucous and intermediate cells Patients usually present with painless,
and keratinization excludes high-grade slow-growing swellings.
mucoepidermoid carcinoma {407}.
Macroscopy
Prognosis and predictive factors The tumour is generally described as a
The prognosis and predictive factors are greyish -yellow, irregular but well -defined
unknown dueto the entity's rarity. mass.
Histopathology
Oncocytic carcinoma is characterized
by large polyhedral cells (with abun-
dant granular eosinophilic cytoplasm
 ~~

Fig. 7.36 Oncocytic carcinoma. A lnvasion into the surrounding adipose and connective tissue with multinodular architecture., -~·-
B Carcinoma cells, which exhibit abundan! granular
eosinophilic cytoplasm and vesicular nuclei with prominent nucleoli, are arranged in alveolar nests accompanied by luminal structures containing eosinophilic substance; there is mild
nuclear pleomorphism.

and round to oval vesicular nuclei) form- Sialoblastoma Epidemiology

ing organoid nests and trabeculae with
infiltrative features. Tubular structures ,
nuclear pleomorphism and vascular in-
vasion may be seen 11570,2302).
The differential diagnosis includes the
oncocytic variant of mucoepidermoid
carcinoma as we ll as salivary duct car-
cinoma. Oncocytic mucoepidermoid
carcinoma displays the features typi-
cal of mucous cells 1808,2571). Salivary
duct carcinoma can mimic oncocytic
carcinoma but exhibits other patterns ,
especially comedonecrosis_
Cases previously diagnosed as high-
grade oncocytic carcinoma may in fact
constitute a subtype of salivary duct car-
cinoma 1713)
Prognosis and predictive factors
The rarity of this entity precludes a reli-
able assessment of its biological behav-
iour. Complete excision is generally cu-
rative 11570)
Most tumours are identified al birth or
Brandwein-Gensler M. shortly afterwards, with no sex predilection_
Li J_ Occasional sialoblastomas may present in
RoJY the second decade of life 11835,2073).
Simpson RHW
Skálová A. Localization
Most sialoblastomas arise in the parotid
l495' 1662, 2497}
Definition
Sialoblastoma is a rare primitive basa- Clinical features
loid salivary gland tumour of infancy with Most affected infants present with facial
marked resemblance to salivary gland swelling and occasional skin ulceration.
anlage structures and uncertain malig - There have been case reports of concur-
nan! potentiaL ren! sialoblastoma and hepatoblastoma
12286}, sebaceous naevi {887,2236}, and
ICD-0 code 8974/1 congenital naevus 12112).
Synonyms Macroscopy
Congenital basal cell adenoma; congeni- The gross appearance is that of an ex-
tal hybrid basal cell adenoma-adenoid pansile lobulated mass that either is cir-
cystic carcinoma; embryoma cumscribed or extends into surrounding
tissues.

. . "'
Fig. 7.37 Sialoblastoma. A Low-power view of extraparotid soft tissue invasion ; note the recapitulation of salivary anlage: large ducts surrounded by organoid nests of epithelioid
cells. B Note the jigsaw-like pattern formed by the solid islands, reminiscent of a salivary basal cell tumour.

Malignan! tumours 183

 -
Fig. 7.38 Sialoblastoma. A Adenoid cystic-like pattern.
Histopathology
Two distinct patterns are observed; one
consists of differentiated budding ducts
and the other is solid, organoid, and
lobular. The budd ing ducts have columnar
cells or primitive basaloid-appearing
reserve cells. The solid form is composed
of cuboidal epithelial cells with round to
oval nuclei, single or few nucleoli, fine
chromatin, and pink cytoplasm. Subtle
peripheral palisading and cribriform
pseudoglands may be seen.
184 Tumours of salivary glands
Sorne tumours display malignant cyto- recurrence (single or multiple) or disease
logical features (e.g. brisk mitotic rate, persistence is reported in approximately
necrosis, pleomorphism , and perineural one quarter of patients {1041,2366,2483,
invasion), especially with disease pro- 2612). lsolated metastasis (to cervical
gression {1781) . lymph node or lung) is uncommon (re-
ported in 3 of 38 cases).
Prognosis and predictive factors
Primary resection is curative for two
thirds of patients {320,524,2019,2483).
lncreased mitotic rate, high Ki-67 prolif-
erative index, and tumour necrosis are
associated with poor prognosis. Local
Benign tumours
Pleomorphic adenoma
Bel! D.
Bullerdiek J.
Gnepp O.R.
Schwartz M.R.
Stenman G.
Triantafyllou A.
Definition
Pleomorphic adenoma (PA) is a benign
tumour with variable cytomorphological
and architectural manifestations. The
identification of epithelial and myoepithe-
lial/stromal components is essential for
the diagnosis of PA.
ICD-0 code 8940/0
Synonym
Benign mixed tumour
Epidemiology
PA is the most common salivary gland
tumour in both children and adults , ac-
counting for the majority of ali salivary
gland neoplasms. The annual inci-
dence is approximately 2-3 .5 cases per
100 000 population !1895). PA occurs in
individuals of ali ages, but is most com-
mon in the third to sixth decades of life;
the average patient age at presentation is
approximately 45 years !1895,2251). The
female-to-male ratio is 2:1.
Etiology
The incidence of PA has been reported to in-
crease 15-20 years after exposure to radiation.
A B
Fig. 7.39 Pleomorphic adenoma. A Grossly, pleomorphic adenoma is typically a single, firm, mobile, well-circumscribed
mass. B Recurren! tumours characteristically presentas multiple nodules of variable size.
Localization
Most examples occur in the parotid, with
the remainder occurring in other sites
(typically the palate and submandibular
gland) !677,2251} PA is usually solitary,
but metachronous and synchronous tu-
mours do occur !482,857,1048,1615,
2079).
Clinical features
PA is a slow-growing , painless mass,
which may be present for many years .
The symptoms and signs depend on the
location !2251 }. Facial nerve weakness
and rapid enlargement are more likely to
be associated with tumours of large size
and with malignan! transformation {217).
PA in the deep lobe of the parotid may
present as an oral retrotonsillar mass ora
parapharyngeal space tumour.
Macroscopy
PAs typically present as a single, firm ,
mobile, well-circumscribed mass. On cut
surface, they vary from light tan to grey,
with or without cartilaginous features
!1863). Degenerative and cystic changes
can be seen. Haemorrhage and infarc-
tion may occur secondary to prior fine-
needle aspiration. Recurrent tumours
characteristically present as multiple
nodules of variable size.
Cytology
Aspiration preparations contain variable
combinations of bland ductal epithe-
lial cells , myoepithelial cells , and chon-
dromyxoid stroma. ldentification of the
typical fibrillary stroma is essential, and
it characteristically appears magenta
on air-dried Romanowsky preparations
{1244,2503).
Histopathology
The tumours are composed of variable
epithelial and myoepithelial/stromal com-
ponents in a mixture of patterns. Spin-
dled myoepithelial cells stream from the
ductal elements into the chondromyxoid
stroma. Cells may show a spectrum of
phenotypes, including oval , spindled ,
epithelioid , clear, and plasmacytoid (hya-
line). Verocay-like arrangements can be
seen. Squamous metaplasia and keratin
pearls are not unusual. Mucous cells, se-
bocytes, and oncocytic phenotypes are
less common {2420).
The stromal elements can be myxoid,
lipomatous, chondromatous, and/or os-
seous. Tyrosine-rich crystalloids, colla-
genous stellate fibrillar structures, and
microliths can be present !2420). Ouctal
atypia, diffuse fibrosis, and necrosis
should prompt more extensive sampling
to exclude malignancy. lntravascular tu-
mour cells may be an artefactual finding
caused by either fine -needle aspiration
or intraoperative trauma {2192}.
Genetic profile
Approximately 70% of PAs show trans-
locations (with breakpoints in 8q12
and 12q14-15) or intrachromosomal re-
arrangements with sporadic non-clona!
changes !2269,2270). The transloca-
tions and rearrangements result in gene
fusions involving the transcription fac-
tor genes PLAG1 on 8q12 !1190) and
j~ \
Fig. 7.40 Pleomorphic adenoma, well delineated from
the salivary gland by a fibrous capsule.
Benign tumours 185
 i!
Fig. 7.41 Pleomorphic adenoma. A Variable features, including tubular and ductal, cystic, and squamous features. B Plasmacytoid phenotype. Nests of plasmacytoid myoepithelial
cells in dense fibrous stroma.
HMGA2 on 12q14-15 {828,829,2269,
2270). PLAG1 encodes a cell cycle
progression- related zinc finger protein
that is activated due to promoter swap-
ping with various fusion partner genes
(i.e. CTNNB1, FGFR 1, LIFR, CHCHD7, or
TCEA 1). Overexpression leads to deregu-
lation of PLAG1 target genes, most impor-
tantly /GF2{2270,2515). HMGA2encodes
a high-mobility group protein that func-
tions as an architectural transcription fac-
tor. The gene is activated by gene fus ions
in which the 3' end of HMGA2 is replaced
by the 3' ends of the fusion partner genes
NFIB, WIF1 , or FHIT In a subset of tu-
mours, the HMGA2- WIF1 fusions are co-
amplified with the MDM2 gene on 12q15
{1860) . HMGA2 fusions activate expres-
sion of the cell cycle regulators cyclin A1
and cycl in B2 (2270) . PLAG1 and HMGA2
fusions have not been encountered in any
subtype of salivary gland tumour except
carcinoma ex PA, and may therefore be
used as biomarkers to distinguish PA from
its morphological mim ics (1196,2269,
2270). Downregulation of WIF1 (WNT in-
hibitory factor 1) was recently described
in a subset of PAs, associated with an in-
creased risk of malignant transformation
(1951). Mutation and overexpression of
HRAS has also been found in a subset of
186 Tumours of salivary glands
.
·l ' '
~ - 1. -
PAs (1613,2272) A recent study demon - followed by head and neck and lung
strated that myoepithelial cel ls in PA ex- {1532) The prognosis of most histologi-
press the stem cell marker CD44 {1070). cally benign lesions is generally good .
Prognosis and predictive factors
Recurrence rates are low. Complete re- Myoepithelioma
section ensures the lowest rates (470).
Tumour disruption and spillage have also Fonseca l.
been reported as variables with an inde- Bell D.
pendent effect on recurrence; 26.9% of Bishop J.A.
punctured tumours and 80% of cases Gnepp D.R .
with sp ill age recurred (1982) . Female
sex, young age al initial treatment, and
enucleation rather than parotidectomy Definition
may be risk factors for recurrence {2622). Myoepithelioma is a benign salivary gland
Malignant transformation occurs in ap- tumour composed almost exclusively of
proximately 6.2% of PAs (849). Multiple cells with myoepithelial differentiation.
recurrences, deep parotid lobe location,
male sex, and older patient age are as-
sociated with increased malignancy.
Metastasizing pleomorphic adenoma
Metastasizing PA is histologically indis-
tinguishable from PA, but produces sec-
ondary tumours in distan! sites. To date,
81 cases have been described (1252).
Metastasizing PA often occurs after mul -
tiple local recurrences, with a reported
interval between diagnosis of primary PA Fig. 7.43 Myoepithelioma. Gross view showing a we\1-
and distant metastases of 3-52 years . circumscribed tumour with a tan-fieshy, partially cystic
The most common distant site is bone, cut surface.
Fig. 7.44 Myoepithelioma. A Epithelioid cell type. B Plasmacytoid cell type. C Organoid arrangement of epithelioid myoepithelial cells.

ICD-0 code 8982/0 Histopathology Basal ce// adenoma

Synonyms
Myoepithelial cell tumour; myoepithelial
adenoma; monomorphic adenoma
Epidemiology
Myoepitheliomas account for 1.5% of
all tumours in the major and minor sali-
vary glands and constitute 2.2% and
5.7%, respectively, of all benign major
and minor salivary gland tumours . Males
and females are affected with equal
frequency {59,144,526 ,2110,2179,2437).
Most tumours occur in adults, but rare
examples in children have been reported
{1328,2662}. The patient age range is
9-85 years (mean: 44 years), with an in-
cidence peak in the third decade of life.
Localization
Myoepitheliomas develop most com-
monly in the parotid gland, followed by
the hard and soft palate (accounting for
40% of cases) {647).
Clinical features
Myoepitheliomas are well-circumscribed
solid tumours. They typically present as
painless slow-growing masses {59,2179,
2437).
Macroscopy
Myoepitheliomas have a solid, tan to
yellow appearance, with glistening cut
surface.
Myoepithelioma can display spindle, plas-
macytoid, hyaline, epithelioid , and clear-
cell features. The tumours typically show
nests or cords of round to polygonal cells ,
with centrally located nuclei and a variable
amount of eosinophilic cytoplasm. Occa-
sional ducts and intercellular microcystic
spaces may be present. The reticular vari-
ant of myoepithelioma is characterized by
net-like arrangements of interconnected
cell cords {526l. lntracellular mucin and
signet ring -shaped cells have also been
recently described {852,853).
Myoepitheliomas are positive for cyto-
keratins (CK7 and CK14). The tumour
cells variably display immunoreacti vi ty
to anti-alpha-SMA , MSA, calponin , 8100,
and GFAP. Occasional myoepitheliomas
(especially cases of the plasmacytoid
variant) may not stain with any of the myo-
epithelial markers.
Prognosis and predictive factors
Myoepitheliomas are benign neoplasms.
Recurrences are infrequent and are more
commonly associated with incomplete ex-
cision {1378 ,2110). Myoepitheliomas may
rarely undergo malignant transformation
to malignant myoepithelial carcinoma,
especially in longstanding tumours and
in cases with multiple recurrences {59).
Li J.
Fonseca l.
Definition
Basal cell adenoma (BCA) is a benign
salivary gland neoplasm composed of
small basaloid cells, with occasional in-
ner ductal epithelial cells forming nests
and cords.
ICD-0 code 8147/0
Synonyms
Monomorphic adenoma; basaloid sali-
vary gland adenoma; membranous
adenoma
Epidemiology
BCAs account for 1-3.7% of all salivary
gland tumours {668,2402}. They are most
frequent in elderly adults; the average
patient age at presentation ranges from
57 years to > 70 years , with a slight fe-
male predilection.
Localization
Most BCAs arise in the major salivary
glands. The parotid gland is the most
common site (accounting for > 80% of

Cytology
Smears show single cells and cell clus-
ters with a variable stroma component.
The neoplastic cells are typically bland
and can appear spindled, epithelioid, or
plasmacytoid . Cytoplasmic features vary
•W.~IE·~~v~~ ~1.~:i.a;....::~:l<J
between tumours. Fig. 7.45 Basal cell adenoma. A Salid pattern: various shapes and sizes of islands of basaloid cells, wilh peripheral
palisading. B Tubular pattern: numerous small lumina lined by ductal cells. One to several layers of basaloid cells
surround ductal cells.

Benign tumours 187


Fig. 7.46 Basal cell adenoma. A Focally, cystic degeneration is common. B Trabecular pattem of basal cell adenoma.
C CK7 immunopositivity is conftned to the ductal cells. D SMA immunoexpression is typically localized in peripheral
tumour cells, indicating myoepithelial differentiation.
cases), followed by the submand ibular
gland. BCA is extremely rare in the minor
glands {2402 ,2615}.
Clinical features
The tumours are typically well-defined
and movable solitary masses. The mem-
branous type may present as multiple
nodules and may coexist with dermal
cylindromas or trichoepitheliomas {1069,
2111 ,2691 }.
Macroscopy
BCAs present as well-circumscribed ,
usually encapsulated nodules measur-
ing 0.2-5.5 cm {2615), except for the
membranous type, which may be mul-
tinodular. On cut section, they are solid
and homogeneous or partially cystic ,
with a greyish-white to pinkish-red colour
{2401 }. Histologically this entity can only
be distinguished from its malignant coun-
terpart by the lack of invasiveness into
surrounding tissues.
Cytology
Aspirate smears typically show numer-
ous uniform basaloid cells with round
or oval nuclei and scant cytoplasm. The
cells form irregular nests and trabeculae,
and occasionally tubular or peripheral
palisading structures. Background stro-
ma both separate from and intermixed
with the epithelial cells may be seen
{1159,1241 ,2499}.
188 Tumours of salivary glands
Histopathology
The tumours show a mixture of solid, tra-
becular, tubular, and membranous pat-
terns. They are composed of basaloid
cells with scant cytoplasm , indistinct cell
borders, and round to oval nuclei , and
may show peripheral palisading. Large
cells with paler-staining nuclei may be
present in the centre of the basaloid
nests. The membranous pattern features
prominent hyaline material , with intercel-
lular coalescing droplets with in tumour
nests {1208 ,1412,1485,2401 ,2615}.
Pancytokeratin staining is positive in ali
tumour cells but most intense in ductal
cells . The palisading cells stain for myo-
epithelial markers, indicating basal/
myoepithelial differentiation {1642,1685).
Genetic profile
A few studies have reported frequent al-
terations at chromosomes 8p22, 19q13.4,
and 16q12-13 {435 ,642), and a case re-
port of t(7;13) and inv(13) has been pub-
lished {2190}.
Genetic susceptibility
Sorne BCAs occur in the setting of
Brooke-Spiegler syndrome (multiple fa-
milia! trichoepithelioma), a rare autoso-
mal dominant hereditary disorder caused
by mutations of the CYLD gene on chro-
mosome 16 {1208,2111}.
Prognosis and predictive factors
The prognosis is generally very good,
with a very low recurrence rate; except
for the membranous type , which has a re-
currence rate of approximately 25% . Ba-
sal cell carcinoma transformation of BCA
occurs rarely, with a higher frequency in
the membranous type {153).
Warthin tumour
Nagao T.
Gnepp D.R.
Simpson R.H.W.
Vielh P.
Definition
Warthin tumour is a benign salivary gland
tumour composed of oncocytic epithelial
cells lining ductal, papillary, and cystic
structures in a lymphoid stroma.
ICD-0 code 8561/0
Synonyms
Adenolymphoma; papillary cystadenoma
lymphomatosum; cystadenolymphoma
Epidemiology
Warthin tumour is the second most com-
mon salivary gland tumour, accounting
for approximately 5-15% of ali salivary
gland tumours. These tumours com-
monly affect individuals in their sixth
to seventh decade of life. A slight male
predominance has been reported {679) .
Warthin tumours have been linked to cig-
arette smoking {1895A,2038A).
Etiology
Radiation exposure has been suggest-
ed to be associated with tumorigenesis
{2048). A relationship between Warthin
tumours and autoimmune diseases {804,
1778) and EBV infection has also been
Fig. 7.47 Warthin tumour presenting as a well-circum-
scribed, mottled light-tan mass.
 _ ¿
Fig. 7.48 Warthin tumour. A Low-power view shows a !hin fibrous capsule delineating the tumour from the adjacent parotid gland parenchyma. B Metaplastic variant. Marked
squamous metaplasia, accompanied by severe stromal fibrosis. Granulation tissue formation is evident; cystic spaces are filled with necrotic debris (this may have resulted from a
fine-needle aspiration). Note the residual oncocytic epithelial componen! of a typical Warthin tumour at the upper right.
reported {2071), but has not been sub-
stantiated {2469}.
Localization
The tumours are almost exclusively re-
stricted to the parotid gland but some-
times occur in the periparotid lymph
nades 1645,2465) Most tumours are
located in the inferior pole of the parotid
gland. The tumours occasionally oc-
cur multifocally, either synchronously or
metachronously, in the same or bilateral
glands 11329,1513} They may be asso-
ciated with other types of salivary gland
tumours {857).
Clinical features
Patients present with painless, slow-
growing, and fluctuant swellings. Pain or
facial nerve palsy is uncommon 1679) but
may occur in the metaplastic (or infarct-
ed) variant 1680). On technetium-99m
pertechnetate imaging, Warthin tumours
present as hot lesions.
Macroscopy
Most Warthin tumours are well-circum-
scribed spherical to oval masses. Solid
areas and multiple cysts with papillary
projections are apparent on the cut sur-
face. The cystic spaces often contain
mucoid , creamy white, or brown fluid.
Cytology
Smears typically show bland, oncocytic
epithelial cells with polymorphous lym-
phocytes and cellular debris {128,736,
1246). Squamous cells and mucinous dif-
ferentiation with mixed inflammation and
cytological atypia can be uncommonly
seen 1736,2487,2502).
~
Histopathology with eosinophilic granular cytoplasm
The tumours are composed of varying resulting from an accumulation of
proportions of papillary-cystic struc- mitochondria.
tures lined by oncocytic epithelial cells
and a lymphoid stroma with germinal ICD-0 code 8290/0
centres {2121) . The epithe lial component
is formed of inner columnar and outer Synonyms
cuboidal cells. Limited foci of squamous, Oncocytic adenoma; oxyphilic adenoma
mucous, ciliated, and sebaceous cells
can be present. Epidemiology
A granulomatous reaction with Langhans- Oncocytoma is uncommon, account-
type giant cells may be seen 12033). ln- ing for about 2% of al i salivary gland
farcted or metaplastic tumours may have neoplasms. lt occurs most commonly in
marked mucinous or squamous meta- the sixth to eighth decades of life, with a
plasia and stromal reaction, which may mean patient age of 64 years and no sex
present diagnostic challenges 1579,680, predilection overall. However, a marked
1095,2116,2121,2203}.
Prognosis and predictive factors
Complete surgical excision with an ad-
equate margin is usually curative 1664).
The local recurrence rate is low; when
recurrence does occur, it is probably
due to multifocal tumours or inadequate
excision 1667). Malignant transformation
in Warthin tumour is extremely rare; how-
ever, there are a few reported examples
in both the epithelial 1748,749,1225,1688, Fig. 7.49 Oncocytoma of the parotid gland with central
2195,2614) and the lymphoid component fibrosis .
1131,298,1583,1868).
Oncocytoma
Katabi N.
Assaad A.
Definition
Oncocytoma is a benign salivary gland
tumour composed predominantly of on- Fig. 7.50 Conventional oncocytoma. Sheets of mono-
cocytes, which are large epithelial cells tonous cells with oncocytic cytoplasm.
Benign tumours 189
female predilection has been reported
among patients with clear cell oncocy-
toma {143) .
Etiology
There is a link between radiation and on-
cocytoma {1181) .
Localization
Most cases occur in the parotid. Onco-
cytoma may also occur in the subman-
dibular gland and minar salivary glands
{2393).
C linical features
Symptoms vary according to site of oc-
currence. Oncocytoma usually presents
as a unilateral painless swelling. Rare bi-
lateral cases have been reported {571).
Macroscopy
Oncocytomas are well-circumscribed,
lobulated , reddish-brown nodules.
Cytology
Smears show oncocytic cells with granu -
lar eosinophilic cytoplasm arranged in
sheets, papillary structures, and single
cells . Cytological atypia is minimal at
most {1417) .
Histopathology
The oncocytes are characterized by
abundant eosinophilic granular cyto-
plasm and centrally located vesicular nu -
clei, typically with a single prominent nu-
cleolus. The oncocytes are arranged in
sheets, nests, trabeculae, and duct-like
patterns, separated by thin fibrovascular
stroma. Microcysts and macrocysts may
be observed. Occasionally, the entire tu -
mour may consist of clear cells , referred
't./
. -~ >.
A ,'ef :t,,,., 1
Fig. 7.51 Lymphade~oma, · n~n-sebaceous. A The tumour is encapsulated, solid, and focally cystic, with a prominent lymphoid componen!. The nodal architecture
is evidenced by the capsule, subcapsular sinus, cortex, and hilus structure containing intranodal salivary gland inclusions. Reprinted from Weiler C et al. (2562}.
B Sebaceous lymphadenoma, biphasic, with a benign lymphoid componen! and an epithelial componen!. The epithelial cells are arranged in solid and microcystic nests with a
peripheral basaloid phenotype and show sebaceous differentiation. Clusters of histiocytes in the stroma are likely a reaction to leakage of sebum.
190 Tumours of salivary glands
to as clear cell oncocytoma {1570).
The tumour cells stain with phospho-
tungstic acid haematoxylin. Although
oncocytoma is traditionally thought of as
a neoplasm with a single cell type, a ba-
sal cell population (positive for p63 and
CK5/6) is present in all oncocytomas
{2563) .
The finding of multiple unencapsulated
nodules and residual non -oncocytic sali -
vary gland parenchyma within the nod -
ules favours nodular oncocytosis rather
than oncocytoma {831,2242). The ab-
sence of lymphoid stroma and papillary
cystic architecture distinguishes oncocy-
toma from Warthin tumour {216,2563).
Prognosis and predictiva factors
Surgical excision is the treatment of
choice. True recurrences are rare, but
additional oncocytomas may arise in re -
sidual parotid. An association between
marked clear-cell change and recurrent
and bilateral disease has been reported
{532).
Lymphadenoma
Prasad M.L.
Chiosea S.
lhrler S.
SkálováA
Definition
Lymphadenoma is a rare benign salivary
gland tumour that consists of a well -cir-
cumscribed biphasic proliferation of epi-
thelial cells and reactive lymphoid tissue .
Sebaceous and non-sebaceous forms
can be distinguished.
ICD-0 code 8563/0
Epidemiology
These are rare tumours with no sex pre-
dilection. The patient age range is 10-
78 years (median: 65 years) {2120) Non-
sebaceous cases account for one third
of lymphadenomas, and tend to affect
younger individuals (median patient age:
50 years), including children {527,1500,
1647,2562).
Localization
The parotid gland is the most common
site (affected in > 80% of cases). Tu -
mours in the minar salivary glands of
the oral cavity and in the submandibular
gland have' also been reported, as have
multiple synchronous tumours {4 ,2120).
Non-sebaceous w mphadenomas ap-
pear to occur excl'w\ sively in the parotid
gland or 1periparotid area {1442,1500,
1647,2562}.
Clinical features
Lymphadenoma presents as a painless,
slow-growing , and mobile mass of a few
months' to several years' duration {1442).
Macroscopy
The tumours measure 0.6-6 cm (median:
2 cm) . They are usually encapsulated
and have a salid or multicystic, grey to
yellow cut surface. The cyst contents are
frequently gelatinous and sebaceous
{2120).
Cytology
Preparations are hypercellular, with frag-
ments of tightly cohesive , bland epithelial
cells. Most cells appear basaloid ; how-
ever, cytoplasmic characteristics vary,
with sorne cells having abundant foamy
cytoplasm. Background polymorphous
lymphocytes are present (348) .
Histopathology
The epithelial component, which consti-
tutes 20-70% of the tumour, shows anas-
tomosing cords and nests of basaloid
cells, as well as tubuloglandular struc-
tures. Small to medium-sized cysts and
intraepithelial lymphocytes are frequently
seen and can be associated with eosino-
philic, hyaline, basement membrane-like
material. Sebaceous differentiation is
typically seen in sebaceous lymphad-
enoma. Rupture and leakage of sebum
may elicit an epithelioid granulomatous
response with foreign-body giant cells
(1442,1500,2120,2562). Squamous dif-
ferentiation with keratinization may be
seen, especially after fine-needle aspi-
ration biopsy The lymphoid component
consists of reactive lymphoid follicles with
germinal centres. lmmunohistochemistry
is generally not helpful. Lymphadenoma
can readily be distinguished from lym -
phoepithelial carcinoma and metastatic
carcinoma (1442 ,1500,2120,2562).
Prognosis and predictive factors
Lymphadenomas are benign tumours
cured by complete excision. Rarely,
malignant transformation may occur in
sebaceous cells (sebaceous lymphad-
enocarcinoma) or basal cells (basal cell
adenocarcinoma). Lymphadenocarci-
noma typically shows residual benign
lymphadenoma (497,854,2120}.
Fig. 7.52 Cystadenoma. A Low-power view showing multicystic appearance with fibrous connective tissue walls of variable thickness. B Cystic spaces with papillary projections,
surfaced by oncocytic cells; the cysts are separated by fibrous connective tissue.
Cystadenoma
Budnick S.
Simpson R.H.W.
Definition
Cystadenoma is a rare benign salivary
gland neoplasm characterized by a pre-
dominantly multicystic growth pattern,
with the cysts lined by proliferative, fre-
quently papillary epithelium that often
shows oncocytic differentiation.
ICD-0 code
Synonyms
Cystic duct adenoma; intraductal papil-
lary hyperplasia (non-neoplastic); Warthin
tumour without lymphoid component
Epidemiology
Cystadenoma accounts foras many as 4%
of all salivary gland neoplasms (2409}. The
tumour is more common in women than in
men (2591l. The average patient age is in
the fifth to seventh decade of life (2714).
Localization
The localization of the tumour varies by
study, but there appears to be a relatively
equal distribution between the minar and
majar salivary glands. The parotid is in-
volved in about 45-50% of cases, with
the minar glands of the lip and buccal
mucosa being the next most common
siles (2409}
Clinical features
In the majar salivary glands, the tumour
~- -~
presents as a slow-growing painless
mass. Minar gland tumours present as
smooth-surfaced nodules, frequently
with a cyst-like appearance. The clini-
cal differential diagnosis often includes
mucocoele.
Macroscopy
Most tumours are multicystic; the gross
appearance shows multiple small cysts,
often including normal minar salivary
gland al the periphery. lntraluminal pro-
liferation may be evident.
8440/0 Histopathology
The tumours are well circumscribed and
frequently present as multicystic lesions,
although 20% are unilocular (2714). The
cysts are separated by generally thin fi-
brous connective tissue. The lumen usu-
ally shows papillary projections lined by
columnar and/or cuboidal epithelium,
frequently with sorne degree of onco-
cytic differentiation . The oncocytic pat-
tern may predominate. Mucous cells may
be seen, and apocrine differentiation
has been reported; squamous epithe-
lium may be present focally but rarely
predominates . The lumen may contain
eosinophilic material with scattered epi-
thelial, inflammatory, or foamy cells . The
surrounding fibrous stroma often con-
tains seromucous glands . The tumours
do not show cytological atypia, mitoses,
oran invasive growth pattern.
Prognosis and predictive factors
The tumours are benign, and conserva-
tive local excision is appropriate. Recur-
rence is rare .
~
Benign tumours 191
A ..
Fig. 7.53 Sialadenoma papilliferum. A Cauliflower-like proliferation of benign cellular structures. B Variable solid cystic and glandular cellular proliferation.
Sía/adenoma papilliferum
Foschini MP.
Bell D.
Katabi N.
Definition
Sialadenoma papilliferum is an exophy-
tic lesion with an inward papillary pro-
liferation of mucosa! and salivary duct
epithelium.
ICD-0 code
Epídemíology
Sialadenoma papilliferum is rare and
mainly affects adults, with the peak inci-
dence in the eighth decade of life. Oc-
casional cases have been reported in
adolescents and children. Females and
males are equally affected.
Etiology
The etiological factors are unknown .
lnflammation and sialolithiasis have been
suggested as possible causes.
Localízatíon
The intraoral minor salivary glands are
frequently affected, with the hard pal-
ate and bucea! mucosa being the most
common sites of origin {693,1288 ,2441}.
Rare cases have been described in the
parotid {1466}.
Clínícal features
Sialadenoma papilliferum presents as a
longstanding exophytic papillary mucosa!
lesion, most often clinically diagnosed as
squamous cell papilloma. Parotid lesions
can present as ulcerated cutaneous le-
sions, simulating a malignant tumour.
192 Tumours of salivary glands
-- ~..,,,,,;¡,p: ~ - -· '•
Macroscopy Cases with malignant transformation
Sialadenoma papilliferum is usually poly- have been reported {1448,1910,2165).
poid and pedunculated, with a verrucoid
surface and well-circumscribed margins.
On cut section, cystic spaces are occa- Ductal papillomas
sionally visible.
Richardson M.
Hístopathology Bell D.
At low power, both surface and submu- Foschini M.P.
cosal components can be observed. Gnepp D.R.
The surface component displays papil- Katabi N.
lary projections that are lined by squa-
mous epithelium and extend to submu-
8406/0 cosa to form cystic-like spaces . At higher
power, acanthosis and parakeratosis of Defínítíon
the squamous epithelium can be seen. Ductal papillomas are luminal ductal
The ductal structures are lined by lu- epithelial proliferations that occur at vari-
minal cuboidal cells (luminal cells) and ous sites within the salivary duct system.
flattened myoepithelial cells (abluminal Based on their growth pattern , they can
cells) . Rare mucocytes can be present be subclassified as either intraductal
among the luminal cells. lnflammatory papilloma or inverted ductal papilloma.
infiltration may be present.
On immunohistochemistry, myoepithelial ICD-0 code 8503/0
cells (positive for SMA, S100, and GFAP)
and cells positive only for the high-mo- Synonym
lecular-weight cytokeratins CK13 and Epidermoid papillary adenoma
CK14 can be seen {1512}.
Epídemíology
Prognosis and predíctíve factors The precise incidence of ductal papil -
Surgical excision is curative. Recur- loma is unknown, but both intraductal
rences are exceedingly rare {261 ,1891). papilloma and inverted papilloma are
-
Fig. 7.54 lntraductal papilloma. A lnterlobular duct containing a delicate papillary network of cuboidal and columnar
cell-lined vascular fronds. B The surrounding ductal lining and !he columnar ductal lining cells are similar.
considered to be rare (261,2049) . The le-
sions arise in adults (patient age range:
22-77 years), with no sex predilection
(261). Rare occurrence in children has
also been reported (1747).
Etiology
The etiology of ductal papilloma remains
unknown. Masticatory trauma andan as-
soc iation with HPV have been reported
(2049).
Localization
The oral minor salivary glands are the
most common sites of occurrence. The
tumours occur most frequently in the
lower lip, followed by the cheek mucosa,
floor of the mouth, palate, and tongue.
There have been reported cases in all
major salivary glands, most commonly in
the parotid (261,1164,1747)
Clinical featu res
Both inverted and intraductal papillomas
present as painless submucosal nodules
of duration that varíes from a few weeks to
several years.
Macroscopy
The reported size range is 0.5-2.0 cm.
The tumours often presentas nodular (in-
traductal papillary) growths (1164) .
Histopathology
lntradu ctal papilloma arises in the termi-
nal portian of the salivary gland excretory
duct, at the junction with the mucosal
surface. The lesion is typically well cir-
cumscribed , with broad luminal papillary
projections composed of cylindrical or
epiderm oid cells lined by columnar gob-
let cel ls (1164). lnverted ductal papilloma
typically manifests asan unencapsulated
endophytic squamoid cell proliferation
with occasional su rface access. The
proliferative components display broad
sheets of monotonous epithelial cells
wi th central thin fibrovascular cores. Oc-
casional microcysts within the epithelium
are noted. The differential diagnosis for
intraductal papillomas includes mucoepi-
dermoid carcinoma (1287) ; however, in-
traductal papilloma lacks the multicystic,
multinodular, and infiltrative growth pat-
tern of mucoepidermoid carcinoma.
Prognosis and predictive factors
Complete excision is curative. No cases
of malignant transformation have been
reported {32,261).
Sebaceousadenoma
Gnepp D.R.
Bell D.
Hunt J.L.
Seethala R.
Definition
Sebaceous adenoma is a rare , usually
well-circumscribed tumour composed of
irregularly sized and shaped nests of se-
baceous cells without cytological atypia,
often with areas of squamous differentia-
tion and cystic change .
ICD-0 code 8410/0
Epidemiology
Sebaceous adenomas are rare, accoun-
ting for approximately 0.1% of salivary
gland neoplasms and slig htly less than
0.5% of al l salivary gland adenomas
(851). Slightly more than 30 cases have
been reported to date (88,851,2705}
The mean patient age at presentation is
59 years (range: 22-90 years). There is a
slight male predominance, with a male-
to-female ratio of 4:3. Unlike with cutane-
ous sebaceous neoplasms, there is no
increased risk of developing a visceral
carcinoma.
Localization
About 61% of cases occur in the major
sal ivary glands: 48% in the parotid gland
and 13% in the submandibular gland .
The other 39% occur in the minor sali-
vary glands, most common ly in the buc-
cal mucosa and lower molar/retromolar
regions.
Clinical features
Patients present with a painless mass.
Macroscopy
Sebaceous adenomas ran ge in size from
0.4 to 6 cm. They are typically well cir-
cumscribed to encapsu lated, and are
greyish-whi te to yel lowish-grey on cut
surface.
Cytology
Smears are cellular and show aggre-
gates of b land basaloid cells with various
numbers of cytoplasmic vacuoles {88}.
Fig. 7.56 Sebaceous adenoma. Squamoid cell nests
with sebaceous differentiation in a lymphoid stroma.
Ben ign tumou rs 193
Histopathology
Sebaceous adenomas are well circum-
scribed and do not show any invasion.
They are composed of variously sized
sebaceous cell nests, which vary in tor-
tuosity and frequently are embedded in
a fibrous stroma. The tumours can be
microcystic or may contain dilated sali-
vary ducts with foci of sebaceous differ-
entiation . Pleomorphism and cytological
atypia are minimal; necrosis and mitoses
are not usually found. Sebaceous adeno-
mas often contain areas of squamous
differentiation and occasionally show
marked oncocytic metaplasia. Histio-
cytes, foreign-body giant cells, or both
may be seen focally. The sebocytes in
salivary gland sebaceous adenomas
have an immunohistochemical staining
profile similar to that seen in sebaceous
adenomas elsewhere, staining positive
for p63, EMA, adipophilin , and perilipin.
lf there is a lymphoid background , the di-
agnosis of sebaceous lymphadenoma is
more appropriate.
Prognosis and predictive factors
These are benign tumours. lf completely
excised, they do not recur.
Canalicular adenoma and
otherductaladenomas
Bloemena E.
Katabi N.
Definition
Canalicular adenoma is a benign salivary
gland tumour composed of monomor-
phous epithelial ductal cells arranged in
anastomosing cords within cell -poor vas-
cular stroma.
ICD-0 code 8149/0
Synonyms
Ductal adenoma; striated duct adenoma
194 Tumours of salivary glands
Fig. 7.57 Canalicular adenoma. A Multiple canalicular adenomas and adenomatous changes in a minor salivary gland.
B Thin anastomosing cords and paucicellular stroma.
Epidemiology
Canalicular adenomas occur in the fourth
to seventh decades of life and rarely be-
fare the age of 50 years. Men are more
often affected than women {292,2385). In
western countries, canalicular adenoma
accounts for 0.5-12% of all minor salivary
gland tumours {292 ,1900,2524,2676). In
series from China, no canalicular ad-
enomas were reported in minor salivary
glands {2536 ,2546).
Localization
Canalicular adenoma is a tumour of the
minor salivary glands. Most cases (80%)
occur in the upper lip. The buccal muco-
sa, and rarely the palate and other sites,
may also be involved {2385).
Clinical features
Patients present with an asymptomatic,
painless swelling, or the tumour is discov-
ered incidentally during dental examina-
tion. In about 13% of cases , the tumours
present multifocally (incl uding bilaterally),
typically in the upper lip and buccal region
{518,1529,2020,2059 ,2385).
Macroscopy
Canalicular adenomas are well-circum-
scribed brown to yellowish tumours
{1055 ,2059,2385).
Histopathology
The tumours are well delineated and
lobulated. Multiple small nodules can be
found within the affected salivary gland.
Cyst formation can be present and may
be accompanied by haemorrhage and
haemosiderin-laden macrophages.
The tumour cells are uniform columnar
to cuboidal epithelial cells arranged in
anastomosing, branching , or budding
parallel cords , which are sometimes
widely separated or sometimes join and
form beaded edges. The tumour cell
nuclei are monomorphous, with finely
dispersed chromatin and inconspicuous
nucleoli. Mitoses are rare.
The cells are positive for cytokeratins.
S100 shows strong and consistent nucle-
ar and cytoplasmic staining . p63 is nega-
tive and KIT (CD117) is positive {627,628,
786,919,2385,2676,2704).
The difference between canalicular ade-
noma and reported cases of striated ad-
enoma {2572) is arbitrary, and the clinical
relevance of these variants is unknown .
The exclusive luminal differentiation of
canalicular adenoma is a distinguishing
feature from basal cell adenoma and ad-
enoid cystic carcinoma .
Prognosis and predictive factors
The prognosis is excellent, and local ex-
cision is curative. Due to the multifocal
growth of these tumours, it is difficult to
ascertain whether a recurrence of cana-
licular adenoma is a true recurrence or a
result of multinodularity.
Non-neoplastic epithelial lesions

Sclerosing polycystic Clinical features Nodular oncocytic

adenosis
Seethala R.
Gnepp D.R.
Skálová A.
Slater L.
Williams M.O.
Definition
Sclerosing polycystic adenosis is a be-
nign salivary gland lesion with close mor-
phological resemblance to fibrocystic
changes and sclerosing adenosis of the
breast {2219}.
Synonyms
Sclerosing adenosis; sclerosing polycys-
tic sialadenopathy; polycystic adenosis;
sclerosing polycystic adenoma
Epidemiology
This is a rare lesion, with about 60 re-
ported cases . The mean patient age is
about 40 years (range: 7-84 years), with
a female-to -male ratio of 1.3:1.
Localization
Most cases (> 70%) involve the parotid,
but sclerosing polycystic adenosis can
also occur in the submandibular gland,
oral cavity, and (rarely) nasal cavity
{2295}.
Sclerosing polycystic adenosis is a pain-
less slow-growing mass, usually of < 1
year in duration. Pain and tingling are rare.
Macroscopy
The tumours are firm and well delineated,
with a mean size of 3.0 cm. The cut sur-
face is pale , glistening, and multicystic.
Histopathology
Sclerosing polycystic adenosis is a well-
circumscribed lobular proliferation of
ducts with granular, vacuolated , or apo-
crine cellular features and with acini con-
taining coarse red zymogen granules em-
bedded in a fibrosclerotic stroma. Ductal
elements may be proliferative, creating a
resemblance to low-grade ductal carci-
noma in situ (858 ,1869,2196}.
Genetic profile
The occurrence of X-chromosome in-
activation, which has been detected in
certain cases by the human androgen
receptor (HUMARA) assay, suggests
that sclerosing polycystic adenosis may
be monoclonal in nature {2194}.
Prognosis and predictive factors
Sclerosing polycystic adenosis recurs in
11 % of cases that are multifocal or incom-
pletely excised {858}. One case showed
malignant transformation after 3 recur-
rences overa span of 32 years ¡321 }.
hyperplasia
Slater L.
Bell D.
Gnepp D.R.
Definition
Nodular oncocytic hyperplasia (NOH) is
a rare lesion characterized by multiple
non-neoplastic nodular proliferations
composed of cells with abundant granu-
lar eosinophilic cytoplasm (oncocytes)
and/or clear cytoplasm (clear cells) in
one or both parotid glands.
Synonyms
Multifocal nodular oncocytic hyperplasia
(MNO H); nodular oncocytosis; c lear cell
oncocytosis
Epidemiology
NOH accounts for < 1% of salivary gland
tumours. The average patient age at
presentation is approximately 57 years
(range: 39-80 years), and 85% of cases
occur in women.
Etiology
The cause of NOH remains largely un-
known. Recent evidence suggests that
HPV infection (HPV 53) and mutations
in mitochondrial DNA (m.4561TA) could
play a role in inducing the lesions {1306}.

.'
A' : . ' -
Fig. 7.58 Sclerosing polycystic adenosis. A Microcysts with granular secretory material; the lining is largely denuded, with a foamy histiocytic reaction. B Apocrine change in ductal
components is common.

Non-neoplastic epithelial lesions 195

Localization
NOH occurs exclusively in the parotid
gland. lt presents as bilateral parotid tu-
mours in approximately 40% of cases.
Macroscopy
Affected parotid glands show scattered,
well-circumscribed, brown or mahogany
to whitish-tan nodules ranging in size
from 0.2 to 2.5 cm {2435}. A large domi-
nant mass may constitute an oncocyto-
ma arising within NOH, especially if the
mass is well circumscribed and partially
encapsulated {i068,2155}.
Histopathology
There are irregularly shaped, unencap-
sulated oncocytic nodules scattered
within normal parotid architecture {1806}.
The nodules are composed of densely
packed, back-to-back acinar or tubu-
loacinar structures {882,2081}. As the
lesiona! nodules expand and coalesce,
adjacent normal parotid serous acini,
ducts, and adipocytes focally become
entrapped within nodules. This finding
may be helpful in distinguishing NOH
with clear-cell features from clear cell
Fig. 7.60 Nodular oncocytic hyperplasia. Variable
nodules scattered within !he parotid gland.
196 Tumours of salivary glands
acinic cell carcinoma or metastatic renal
cell carcinoma. The nodules are com-
posed of uniform polygonal cells with
granular eosinophilic and/or clear cyto-
plasm and centrally located uniform oval
pyknotic (dark) and/or pale nuclei with
small nucleoli.
Prognosis and predictive factors
NOH is a benign , non-neoplastic condi-
tion; malignant transformation has not
been reported.
Lymphoepithelial sía/adenitis
Bloemena E.
Bell D.
Chiosea S.
Definition
Lymphoepithelial sialadenitis is a benign
lesion characterized by acinar atrophy,
ductal hyperplasia, and epimyoepithelial
islands in lymphoid stroma.
Synonyms
Benign lymphoepithelial lesion; myoepi-
thelial sialadenitis
Epidemiology
The patients affected are predominantly
females (with a female-to-male ratio of
3:1) in their fourth to seventh decade of
life {648}.
Etiology
Lymphoepithelial sialadenitis is consid-
ered an autoimmune lesion and is one
of the cardinal components of Sjógren
syndrome. However, lymphoepithelial si-
aladenitis can also occur as an isolated
salivary gland lesion {1501}
Localization
The typical localization is the parotid
gland and less frequently the subman-
dibular glands (648}.
Clinical features
The lesions present as painless swelling
of the affected gland, either unilaterally or
bilaterally {1501}.
Cytology
Smears show polymorphous lympho-
cytes with variable amounts of benign
salivary gland epithelium and reactive
stromal tissue.
Histopathology
Lymphoepithelial sialadenitis is charac-
terized by parenchymal atrophy and
islands of epimyoepithelial cell prolifera-
tion in lymphoid infiltrate. The lobular ar-
chitecture of the gland with interlobular
fibrous septa is usually preserved {i083}.
Unlike in chronic sclerosing sialadenitis,
fibrosis and obliterative phlebitis are not
observed in lymphoepithelial sialadenitis
{830}.
Fig. 7.61 Lymphoepithelial sialadenitis in which !he
epimyoepithelial islands are highlighted by cytokeratin
(MNF116) staining; normal salivary gland parenchyma is
seen al !he left.
Prognosis and predictive factors
Patients with lymphoepithelial sialadenitis
are at risk of developing MALT lymphoma
{648l. The period from the diagnosis of
lymphoepithelial sialadenitis to the devel-
opment of malignant lymphoma is highly
variable in duration: from 6 months to
29 years {620 ,648 ,689l.
lntercalated duct hyperplasia
Chiosea S.
Seethala R.
Williams M.O.
Definition
lntercalated duct hyperplasia/lesion is a
salivary ductal proliferation resembling
intercalated ducts.
Synonyms
lntercalated duct adenoma; adenoma-
tous ductal proliferation
Epidemiology
Fewer than 80 cases have been reported
(190 ,408,418 ,575 ,1494,1642, 1713, 2570 ,
2690l, with a male-to-female ratio of 3:2.
The mean patient age at presentation is
about 52 years.
Etiology
lntercalated duct hyperplasia is consid-
ered a reactive or hyperplastic process
{1642,2570,2690l. A precursor role for
sorne salivary gland tumours has been
suggested {418,575,2570l .
Localization
The majority (85%) of cases arise in the
parotid , 11 % in the submandibular gland,
and 4% in the oral cavity {190,408,418,
575,1494,1642 ,1713,2570,2690l.
Clinical features
Most cases are incidental , detected with
other salivary gland lesions (e.g . basal
cell adenoma or epithelial-myoepithelial
carcinoma) (418 ,1642,2570).
Macroscopy
Grossly visible lesions are well circum-
scribed and tan (1713} .
Histopathology
lntercalated duct hyperplasia manifests
as a nodular formation composed of
small ductules of attenuated myoepithe-
lial and cuboidal ductal cells. lt is consid-
ered hyperplastic {2570l. lf well circum-
scribed, it must be distinguished from the
striated form of ductal adenoma.
Prognosis and predictive factors
lntercalated duct hyperp lasia is a benign
hyperplastic lesion.

. . -:.! ~-r•
. . . ?.
\ '· ~/.,....~~ .
·~
~--:-:
r;;~:.;,,,4
- ' .)> , '
~ --.. . ')· :~~
·. ·ri·r1
~-~ ,,;!JI
,: 1;. .
¡_ A J . ' ~· ,
~;,....-:"""''"')
~~_;;..¡
...~
--. - -~! ~ ~, .
Fig. 7.63 lntercalated duct lesion with adenoma-predominan! configuration. A A well-demarcated, partly encapsulated proliferation of small, slightly eosinophilic tubules.
B lntercalated duct lesion with hyperplasia configuration. Lobular proliferation of small eosinophilic tubules, slightly expanded with admixed lymphoid infiltrates.

Non -neoplastic epithelial lesions 197

Benign soft tissue lesions
Haemangioma
Flucke U.
Bullerdiek J.
lhrler S.
Definition
Haemangioma is a benign vascu lar le-
sion characterized by a proliferation of
endothelial cells and pericytes.
ICD-0 code 9120/0
Synonym
Benign haemangioendothelioma
Epidemiology
Haemangiomas are the most common
benign salivary gland tumours in infants,
and account fo r about 50% of parotid
tumours. The female -to-male ratio is 2:1
{177,1281,1385,2577).
Localization
Haemangiomas occur almost exclusively
in the parotid gland {1281 ,2577).
Clinical features
Patients present with a mass {177). Most
tumours are limited to the parotid gland,
but extensive lesions also involve the
su rrounding tissue . They can cause dis-
figurement and distortion of anatomical
structures. Shunting has been reported
as a rare complication {2577).
198 Tumours of salivary glands
Macroscopy
The neoplasm presents as a nodular,
greyish-red mass, with a usually salid cut
surface {280,1680)
Histopathology
The lesions are lobulated and com posed
of thin-walled vessels of various sizes
and shapes. Lumina may be subtle, with
densely packed endothelial cells, es-
pecially in the early stage. Larger, more
obvious lumina are a sign of maturation.
There is no nuclear atypia. Mitotic figures
may be present. The lesions surround
and replace pre-existent salivary gland
tissue {280 ,1531,1680).
On immunohistochemistry, CD34 stain-
ing highlights the endothelial cells and
SMA staining highlights the pericytic
component {280).
Fig. 7.65 Sialolipoma presenting as well-circumscribed,
homogeneous yellow mass.
Prognosis and predictive factors
lnfantile lesions grow rapidly initially, and
most involute subsequently. Successful
treatment options include propranolol,
steroid injection , endovascular sclero-
therapy, and surgery {2577)
Lipoma/sialolipoma
lhrler S.
Bullerdiek J.
Flucke U
Wenig B.M .
Definition
Salivary gland lipoma and sialolipoma
are neoplastic lipomatous growths within
majar salivary glands. Sialolipoma also
contains epithelial components, whereas
ordinary lipoma does not.
ICD-0 code 8850/0
Synonyms
Salivary lipoma; adenolipoma; oncocytic
sialolipoma; oncocytic lipoadenoma
Epidemiology
Lipoma and sialolipoma constitute ~ 0.5%
of salivary gland tumours. Ordinary lipo-
mas are about twice as common as sialol-
ipomas. Both forms manifest in patients of
middle to older age , and ordinary lipoma
shows amale predominance {18,2264f.
Localization
Most lipomas and sialolipomas (:::: 90%)
develop in the parotid glands. They de-
velop rarely in the submandibular glands
and only exceptionally in the minar sali-
vary glands {16 ,1687,2264)
Clinical features
Lipomas and sialolipomas are usually
slow-growing and clinically asymptomat-
ic {16,18,1687,2264f .

Fig. 7.66 Sialolipoma. Nests of adipose cells within !he salivary parenchyma.
Macroscopy
Lipomas/sialolipomas are well -circum-
scribed yellowish tumours .
Histopathology
Salivary gland lipomas are similar to other
lipomas and may have an incomplete rim
of atrophic salivary gland parenchyma.
Variants of ordinary lipoma (e.g. spindle
cell lipoma, angiolipoma, and pleomor-
phic lipoma) are extremely rare (16,18,
2264).
Sialolipomas can demonstrate a range of
non-oncocytic to oncocytic features (16,18,
1239) They contain lobules of parotid pa-
renchyma with evenly interspersed adipose
tissue and occasionally focal sebaceous
differentiation (18,1112,1687)
The differential diagnoses include other
salivary gland tumours with lipomatous
metaplasia (e.g. pleomorphic adenoma and
myoepithelioma (2200)) and atrophic sali-
vary gland parenchyma (16 ,18,1112,1687).
Prognosis and predictive factors
Ali cases are cured by excision, with no
reported recurrences .
Fig. 7.67 Nodular fasciitis of !he parotid gland. Proliferation of spindle cells without cellular atypia in a storiform pattern;
moderate amount of interspersed lymphocytes and extravasated erythrocytes.
Localization
Nodular fasciitis usually develops in the
parotid gland 1400,1849), with one report-
ed case in the submandibular gland (1111) .
Clinical features
Nodular fasciitis typically grows rapidly,
usually without clinical symptoms or pain.
Macroscopy
Grossly, nodular fasciitis may appear cir-
cumscribed or infiltrative, but is not en-
capsulated. lt is typically about 2-4 cm
(341,400,986 ,1111 ,2035) .
Nodular fasciitis
Histopathology
lhrler S. The neoplasm typically presents as a
Bullerdiek J. fibroblastic/myofibroblastic proliferation
Flucke U. with a tissue culture-like growth pattern
and no cellular atypia. Lesions in the
salivary glands are histologically and im-
Definition munohistochemically identical to conven-
Nodular fasciitis is a self-limiting fibrous tional subcutaneous cases. lncreased
neoplasm composed of fibroblastic/myo- mitotic activity and/or focal infiltration can
fibroblastic cells. lead to misdiagnosis as sarcoma. Misdi-
agnosis is also possible on cytological
ICD-0 code 8828/0 specimens (400 ,1849,2035).
Synonym Genetic profile
Pseudosarcomatous fasciitis Rearrangement of the USP6 gene is found
a large proportion of cases (661,1771).
Epidemiology
Only about 30 cases have been report- Prognosis and predictive factors
ed , accounting for about 1% of ali cases Conservative surgery is sufficient. Recur-
of nodular fasciitis. The lesion arises most rence is very rare, even with incomplete
frequently in the third and fourth decades excision. Spontaneous regression has
of life and rarely in children , with no sex been described in cases diagnosed by
predilection {400 ,1849). cytology using fine-needle aspiration
(3 41,986,1849).
Etiology
The etiology is unknown. Post-traumatic
development has been reported in a mi-
nority of cases {2014).
Ben ign soft tissue lesions 199
Haematolymphoid tumours

lntroduction
Cheuk W.
Ferry J.A.

Overview
Salivary gland lymphomas are uncom-
mon . They constitute 1.7-6% of all sali-
vary gland neoplasms (847,2103} and
6-26% of all extranodal lymphomas in
the head and neck reg ion (423 ,666,934,
947,1711}. Primary salivary gland lympho-
ma that manifests initially in the salivary
gland is more common than secondary
lymphoma as part of disseminated dis-
ease (1804). The parotid gland is the most
common site (affected in approximately
70% of cases), followed by the subman-
dibular gland (approximately 20%) and
the minor salivary gland (< 10%) (944,
1107,1262,2625}
The parotid gland contains intraglandular
lymph nodes, and lymphoma may arise in
glandular parenchyma (extranodal lym -
phoma) or with in the intraparotid lymph
nodes (nodal lymphoma) (2097} . lt is
often difficult to distinguish between the
two, because intraparotid lymph nodes
in turn may harbour salivary gland inclu-
sions that can undergo proliferation when enlarging masses, but sorne have pain , and there is no association between fol-
involved by lymphoma {21} . MALT lym- facial nerve paralysis, or cervical lymph licular lymphoma and autoimmune· dis-
phoma, follicular lymphoma, and diffuse node enlargement. Sorne cases present ease {1262,1692}. Morphologically, sali-
large B-cell lymphoma (DLBCL) together with features of obstructive sialadenitis vary gland follicular lymphoma is similar
account for most cases of lymphoma in {1350). B symptoms are very rare. More to follicular lymphoma occurring in other
the gland parenchyma, whereas lym- than 80% of cases present with localized parts of the body.
phoma arising from intraglandular lymph disease (stage 1or 11). DLBCLs account for 7-27% of salivary
nodes shows a much wider spectrum , gland lymphomas (6 19,1262,1692,2008},
consistent with its nodal counterparts Lymphoma subtypes and a substantial proportion of cases
elsewhere in the body (1107). MALT lymphoma is the most common pri - have a MALT lymphoma component con -
mary salivary gland lymphoma. stituting transformation (1262}. DLBCL
Clinical features The frequency of follicular lymphoma has a more aggressive clinical behaviour
Salivary gland lymphoma usually affects of the salivary gland varies significantly than do MALT lymphoma and follicular
patients in late adulthood, with a median across studies, from 0-8% in sorne se- lymphoma of the salivary gland. Accord-
patient age of 57-63 years (1262 ,1804, ries {619,1107,2008) to 22-30% in oth- ing to the lnternational Extranodal Lym-
2407). There is a slight female prepon- ers (1261 ,1262,1692}, despite the fact phoma Study Group series , salivary gland
derance, probably due to cases of MALT that strict criteria have been applied to DLBCLs, like other extranodal DLBCLs of
lymphoma arising in association with exclude nodal disease arising in intra- the head and neck region, are associated
Sjógren syndrome , which is much more glandular lymph nodes. Patients with fol- with worse survival than are their nodal
common in females. Bilateral disease is licular lymphoma are on average about counterparts of similar stage (1596}.
seen in 2.3-10% of cases (698 ,2008}. 10-15 years younger than those with Rare cases of mantle cell lymphoma,
Most patients present with painless MALT lymphoma of the salivary gland, chronic lymphocytic lymphoma, Burkitt

200 Tumours of salivary glands

lymphoma, peripheral T-cell lymphoma,
extranodal NK/T-cell lymphoma, ana-
plastic large cell lymphoma, adult T-cel l
lymphoma/leukaemia, classical Hodgkin
lymphoma, and nodular lymphocyte-
predominant Hodgkin lymphoma have
been reported in the salivary glands, with
most cases probab ly constituting nodal
disease within the salivary gland ¡21,
1267,2407,2666). The prognosis of these
lymphomas does not seem to differ from
that of lymphomas of the same type aris-
ing in other parts of the body. Rare cases
of lymphoma have been reported in the
lymphoid stroma of Warth in tumour; most
commonly follicular lymphoma, followed
by DLBCL and others 1833,1793,2086).
Most patients have disseminated lympho-
ma at diagnosis or subsequently, sug-
gestin g that this composite tumour may
constitute a nodal extension of systemic
lymphoma, which is consistent with the
hypothesis that Warthi n tumour derives
from neoplastic proliferation of salivary
gland rem nants entrapped in an intra-
glandular lymph node. Other haemato-
lymphoid tumours (e .g. myeloid sarcoma
¡313), histiocytic neoplasms 12101), and
plasmacytoma 140,1 588)) are very rare in
the salivary glands .

Extranodal marginal zone
lymphoma of mucosa-
associated lymphoid tissue
(MALT lymphoma)
Cheuk W.
Ott G.
Definition
Extranodal marginal zone lymphoma
of mucosa-associated lymphoid tissue
(MALT lymphoma) is an indolent mature
B-cell neoplasm showing architectural
and cytological similarities with reactive
mucosa-associated lymphoid tissues oc-
curring in various extranodal sites 11094).
ICD-0 code 9699/3
Epidemiology
The head and neck region is the second
most frequent site of MALT lymphoma,
following the gastrointestinal tract. MALT
lymphoma is the most common type of
lymphoma in the sal ivary glands. In the
USA, the annual incidence of salivary
gland MALT lymph oma is 0.086 cases
per 100 000 population, with no sig -
nificant change over the past two dec-
ades 12485). The median patient age is
58 years. There is a significant female
predominance (female-to-male ratio:
1.5-3:1) due to a strong association with
Sjógren syndrome 174,1033,2485).
Etiology
A well -established etiolog ical factor of
MALT lymphoma is chronic inflammation
related to infectious disease or autoim-
mune disorder, wh ich leads to the de novo
formation of lymphoid tissue in organs
otherwi se devoid of mucosa-associated
lymphoid tissue. Lymphoepithelial sialad -
enitis is the precursor lesion for salivary
gland MALT lymphoma. Among patients
with Sjógren syndrome, the risk of devel -
oping lymphoma is 5-20 times as high as
the risk in the general population (1 743 ,
2514). Monoclonal B ce lls are detected
frequently (in > 50% of cases) in tissues
from patients with Sjógren syndrome, and
selective expansion of these monoclo-
nal B cells , with the acquisition of further
mutations such as in the TNFAIP3 gene
(also called A20), has been associated
with lymphoma development 1915,1 743).
Hepatitis C infe ction may be another pre-
disposing factor in 25% of salivary gland
MALT lymphomas 191). lgG4-related
disease is an idiopathic, mass-forming
chronic inflammatory lesion that frequent-
ly involves the sal ivary gland and ocular
adnexa, and there is anecdotal evidence
of the development of MALT lymp homa in
this setting (419,1757).
Localization
MALT lymphoma arising in the head and
neck region most freq uently affects ocu -
lar adnexa (accounting for 60% of cas-
es), fol lowed by the major and minor sali-
vary glands (30-40% of cases) and less
commonly the Waldeyer ring (pharyngeal
lymphoid ring) 12303,2594). lnvolvement
of the larynx, oral cavity, or si nonasal
tract is rare (1541,1873,2363)
Clinical features
Most patients present wi th painless en-
larging masses. Sorne may have pain,
facial nerve paralysis, or cervical lymph
node en largement. Laryngeal tumours

Haematolymphoid tumours 201

A - ~--..,, _ . . _ _. ~ - !""~..:..
Fig. 7.70 Oral cavity MALT lymphoma. A Lobules of minor salivary glands in the oral cavity are expanded by lymphoma cells.
may present with hoarseness and stridor.
B symptoms are rare.
Macroscopy
The tumours are non-circumscribed,
firm , and tan-colou.red. lnterspersed
cysts formed by dilated ducts are a
common finding in sal ivary gland MALT
lymphoma.
Histopathology
The histological features of MALT lym-
phoma in the head and neck region are
similar to those of MALT lymphoma oc-
curring elsewhere, with confluent sheets
of lymphoid cells effacing the architec-
ture. In salivary glands, early lesions
consist of lymphoid cells that form so-
called collars arouno frequently oblit-
erated ducts, and often have a mono-
cytoid appearance. These collars are
not seen in lymphoepithelial sialadenitis
of Sjógren syndrome unassociated with
lymphoma, where the epimyoepithelial
islands are predominantly composed of
proliferating epithelial cells insinuated by
Fig. 7.71 Tonsil MALT lymphoma. The normal lobular architecture of the tonsil has been effaced by dense and expansile
sheets of lymphoma cells.
202 Tumours of salivary glands
small lymphocytes and accompanied by
basement membrane- like material. In
later stages , the infiltrate can be nodular,
perifollicular, and diffuse, often featuring
a mixture of cell types including small
lymphocytes, centrocyte-like cells, and
monocytoid cells. lntermediate-sized to
large blastic cells are often interspersed
in small numbers. Plasma-cell differentia-
tion occurs in one third of cases.
In the Waldeyer ring, the diagnosis of
MALT lymphoma is more difficult to
make, because the epithelium is normally
heavily infiltrated by lymphoid cells. The
diagnosis rests on the presence of dense
lymphoid infiltrates effacing the normal
architecture.
The lymphoma cells express B-lineage
markers such as CD20 , CD22, and
PAX5. They usually express lgM and
sometimes express lgG or lgA, but do
not express lgD. They are typically nega-
tive for CD5, CD10, BCL6, CD23, and
cyclin 01 . IRTA1, a marker of marginal-
zone-cell differentiation , is positive in the
majority of cases {687). Coexpression of
CD43 or T-bet can aid in the diagnosis of
lymphoma, as can the demonstration of
immunoglobulin light chain restriction in
lymphoid cells (optimally by flow cytom-
etry) and/or in plasma cells on paraffin
sections (if there is plasmacytic differen-
tiation) . A small subset of MALT lympho-
mas (< 4% of cases) that express CD5
may be associated with a more aggres-
sive behaviour {714,2593).
Genetic profile
lmmunoglobulin heavy chain (IGH) and
light chain (IGL) genes are clonally rear-
ranged, and show variable mutated re-
gions. Trisomy 3 and 18 are common in
head and neck MALT lymphomas {2356) .
Among the recurrently observed translo-
cations in MALT lymphoma, the t(14;18)
(q32;q21) (!GH-MALT1) translocation
is seen in only a small proportion of
cases , and t(11;18)(q21;q21) (BIRC3/
AP/2-MALT1) is even rarer {2291). lnacti -
vating mutations, deletions, and promot-
er hypermethylation of the TNFAIP3 gene
(also called A20) have been described
mainly in translocation-negative salivary
gland MALT lymphomas \387l
Prognosis and predictive factors
Most patients with head and neck MALT
lymphoma have localized disease at
presentation {939), and the 5-year dis-
ease-free survival and overall survival
rates, respectively, are 54% and 82-95%
in salivary gland MALT lymphoma {74,
2485). Large-cell transformation is as-
sociated wi th a more aggressive clinical
course {945).
 CHAPTER 8

Odontogenic and maxillofacial bone tumours

Odontogenic carcinomas
Odontogenic carcinosarcoma
Odontogenic sarcomas
Benign epithelial odontogenic tumours
Benign mixed epithelial and mesenchymal odontogenic tumours
Benign mesenchymal odontogenic tumours
Odontogenic cysts of inflammatory origin
Odontogenic and non-odontogenic developmental cysts
Malignant maxillofacial bone and cartilage tumours
Benign maxillofacial bone and cartilage tumours
Fibro-osseous and osteochondromatous lesions
Giant cell lesions and bone cysts
Haematolymphoid tumours
WHO classification of odontogenic and
maxillofacial bone tumours

Odontogenic carcinomas Malignant maxillofacial bone and cartil age tumou rs

Ameloblastic carcinoma 9270/3 Chondrosarcoma 9220/3
Primary intraosseous carcinoma , NOS 9270/3 Chondrosarcoma, grade 1 9222/1
Sclerosing odontogenic carcinoma 9270/3 Chondrosarcoma, grade 2/3 9220/3
Clear cel l odontogenic carcinoma 9341 /3* Mesenchymal chondrosarcoma 9240/3
Ghost cell odontogenic carcinoma 9302/3* Osteosarcoma, NOS 9180/3
Low-grade central osteosarcoma 9187/3
Odontogenic carcinosarcoma 8980/3 Chondroblastic osteosarcoma 9181 /3
Parosteal osteosarcoma 9192/3
Odontogenic sarcomas 9330/3 Periosteal osteosarcoma 9193/3

Benign epithelial odontogenic tumours Benign maxillofacial bone and cartil age tumours
Ameloblastoma 9310/0 Chondroma 9220/0
Ameloblastoma, unicystic type 9310/0 Osteoma 9180/0
Ameloblastoma, extraosseous/peripheral type 9310/0 Melanotic neuroectodermal tumour of infancy 9363/0
Metastasizing ameloblastoma 9310/3 Chondroblastoma 9230/1
Squamous odontogenic tumour 9312/0 Chondromyxoid fibroma 9241 /0
Calcifying ep ithelial odontogenic tumour 9340/0 Osteoid osteoma 9191 /0
Adenomatoid odontogenic tumour 9300/0 Osteoblastoma 9200/0
Desmoplastic fibroma 8823/1
Benign mixed epithelial and mesenchymal
odontogenic tumours Fibro-osseous and osteochondromatous lesions
Ameloblastic fibroma 9330/0 Ossifying fibroma 9262/0
Primordial odontogenic tumou r Familia! gigantiform cementoma
Odontoma 9280/0 Fibrous dysplasia
Odontoma, compound type 9281/0 Cemento-osseous dysplasia
Odontoma, complex type 9282/0 Osteochondroma 9210/0
Dentinogenic ghost cel l tumour 9302/0
Giant cell lesions and bone cysts
Benign mesenchymal odontogenic tumours Central giant cell granuloma
Odontogenic fibroma 9321 /0 Peripheral giant cell granuloma
Odontogenic myxoma/myxofibroma 9320/0 Cherub ism
Cementoblastoma 9273/0 Aneurysmal bone cyst 9260/0
Cemento-ossifying fibroma 9274/0 Simple bone cyst

Odontogenic cysts of inflammatory origin Haematolymphoid tumours

Radicular cyst Solitary plasmacytoma of bone 9731 /3
lnflammatory collateral cysts

Odontogenic and non-odontogenic developmental cysts The marphology codes are from the lnternational Classification of Diseases
far Oncology (ICD-0) 1776AI. Behaviour is coded /0 far benign tumours;
Dentigerous cyst /1 far unspecified, borderline, or uncertain behaviour; /2 far carcinoma in
Odontogenic keratocyst situ and grade 111 intraepithelial neoplasia; and /3 far malignan! tumou rs.
Lateral periodontal cyst and botryoid odontogenic cyst The classification is mod ified from the previous WHO classification, taking
into account changes in our understanding of these lesions.
Gingival cyst ·rhese new codes were approved by the IARC/WHO Committee far ICD-0.
Glandular odontogenic cyst
Calcifying odontogenic cyst 9301 /0
Orthokeratinized odontogenic cyst
Nasopalatine duct cyst

204 Odontogenic and maxillofacial bone tumours

lntroduction
In comparison with the previous edition,
the number of entities discussed in this
chapter has increased by almost 50%.
Reasons for this are the addition of the
odontogenic cysts, a group of diseases
left out before but now included given
that sorne of them may recur, and the
addition of selected bone tumours and
haematolymphoid disorders that either
have the jaws and other maxillofacial
bones as a predilection site orare impor-
tant in view of their differential diagnosis.
The emphasis in this chapter lies on the
odontogenic tumours (OGTs) OGTs are
rare, constituting < 1% of all oral tumours.
Most OGTs are benign, but sorne show
locally aggressive growth and a high rate
of recurrence. OGTs are derived from
cells of odontogenic apparatus and their
remnants. Both benign and malignant
OGTs are subclassified into epithelial
tumours, mixed epithelial and mesenchy-
mal tumours, and mesenchymal tumours.
Classification of odontogenic tumours is
in general a hotly debated subject, and
attempts have been made to simplify
the classification as much as possible,
leaving out any unproven references
to histogenesis or precursor lesions.
As a consequence, only one type of
ameloblastic carcinoma and one type
of primary intraosseous carcinoma have
been retained , leaving out adjectives or
prefixes such as primary, dedifferenti -
ated, etc. The same considerations have
led to the recognition of only one type
of odontogenic sarcoma; adjectives
such as ameloblastic and prefixes like
fibro -odonto- and fibrodentino- have no
diagnostic or clinical relevance. Amelo-
blastic fibro-dentinoma and ameloblas-
tic fibrodentinoma have been dropped
as well-defined entities deserving their
own place, because there was a general
feel ing that they in most cases represen!
developmental stages of either complex
or compound odontoma and that re -
taining them as separate entities wou ld
therefore be illogical. Odonto-ameloblas-
toma has also been dropped as available
data on this condition were considered to
be insufficient to justify its recognition as
a genuine entity, lesions reported under
th is label probably being a coincidental
mixture of an ameloblastoma or other
epithelial odontogenic tumour with an
odontoma or a developing tooth. Much
discussion has been devoted to the dis-
tinction between non -neoplastic and ne-
oplastic cystic lesions, which especially
concerned the odontogen ic keratocyst
(OKC) / keratocystic odontogenic tu mour
(KCOT) and the calcifying cystic odonto-
genic tumour (CCOT) / calcifying odonto-
Takata T.
Slootweg P.J.
genic cyst (COC) lt was concluded that
most cases of KCOT and CCOT behave
cl inically as non-neoplastic lesions and
are treated as cysts . Therefore , there was
consensus that they should be reclassi-
fied as OKC and COC , respectively, until
there is more definite evidence for clas-
sifying them as KCOT and CCOT, thus
reintroducing the time-honoured names
in use before their labelling as tumours in
the previous WHO classification.New en-
tities that have been identified since the
previous WHO classification have been
added: sclerosing odontogenic carcino-
ma, odontogenic carcinosarcoma , and
primordial odontogenic tumour. Regard -
ing the bone lesions, with in the group of
ossifying fibromas, the prefix cemento-
has been added to the variant that is
confined to the jaws and that, although
strictly speaking, should be listed among
the mesenchymal odontogenic tumours,
nevertheless has been included among
the fibro-osseous lesions in view of differ-
ential diagnostic considerations . Finally,
familia! gigantiform cementoma remains
an enigmatic cond ition evading precise
characterization but has nevertheless
been mentioned in the hope of more clar-
ity in the near future.
lntroduction 205
Odontogenic carcinomas
Ameloblastic carcinoma
Odell E.W.
Muller S.
Richardson M.
Definition
Ameloblastic carcinoma (AC) is a rare
primary epithelial odontogenic malignant
neoplasm. lt is the malignan! counterpart
ot ameloblastoma.
ICD-0 code
Synonyms
AC, secondary or dedifferentiated types;
intraoral basal cell carcinoma ot the gin-
giva (obsolete)
Epidemiology
In the USA, the overall annual incidence
of malignan! ameloblastomas (i.e. both
AC and the rarer metastasizing amelo-
blastoma) is 1.79 cases per 1O million
population, increasing with patient age
(1997}, but only about 100 cases have
been reported (1182) Males are at slight-
ly greater risk than temales , and most
cases arise in patients aged > 45 years ,
with a small incidence peak in childhood.
In China, malignan! ameloblastomas ac-
count for approximately 2% ot all amelo-
blastomas, and the mean patient age is
younger (1414).
Localization
The posterior segments of the jaws are
the most common site, with half to two
Fig. 8.01 Ameloblastic carcinoma. A very large ulcerated
tumour arising in the mandible.
206 Odontogenic and maxillofacial bone tumours
9270/3
Fig. 8.02 Ameloblastic carcinoma arising in !he right maxilla, on CT (left) and MRI (right), showing a large, expanding
mass with cortical destruction and interna! signal intensity variation.
thirds of all lesions occurring in the man-
dible {1182). Most cases arise de novo,
but sorne arise in pre-existing amelo-
blastomas. ACs are more frequent in the
mandible than in the maxilla {1182,1714).
A very small number of cases have been
described arising in peripheral amelo-
blastoma {1877). The primary and sec-
ondary types have similar histological
features and behaviour.
Clinical features
Large and longstanding lesions show
poorly defined or irregularly marginated
radiolucencies consistent with malig-
nancy, often with cortical expansion,
pertoration , and infiltration into adjacent
structures. However, sorne cases have
appeared as benign radiolucencies. A
single case with hypercalcaemia has
been reported {490}
Histopathology
AC is defined by the combination of cy-
tological teatures ot malignancy and the
histological pattern ot an ameloblastoma,
in either the primary or a metastatic le-
sion. AC can have the fo llicular or plexi-
torm patterns of ameloblastoma or can
be tormed ot sheets, nests, or broad
trabeculae of epithelium. The peripheral
cell layer shows peripheral palisading,
and reverse nuclear polarity is usually
present at least focally. There is loss ot
the organized stratification of basal cells ,
stratum intermedium, and stellate re-
ticulum that is typical ot ameloblastoma,
which is more marked in higher-grade le-
sions. The centre of epithelial sheets or
islands may be replaced by salid basa-
loid epithelium , acanthomatous epithe-
lium, or spindle cells, or may show cystic
degeneration.
Defining the borderline between amelo-
blastoma and AC is ditficult, and overdi-
agnosis is to be avoided {863). Malignan!
teatures such as pleomorphism, in-
creased N:C ratio, nuclear hyperchroma-
tism, mitotic activity, abnormal mitoses,
and vascular or perineural invasion may
all be present. Necrosis is usetul and
ranges trom subtle clusters of apoptotic
cells within islands to overt comedone-
crosis or more extensive necrosis. Mitotic
activity alone cannot be interpreted as
a feature of malignancy. Mitotic figures
are more frequent after incisional biopsy.
Cellularity and mitotic activity are also
more marked in maxillary than in man-
dibular ameloblastomas and do not by
themselves indicate malignancy. lnfiltra-
tion must also be evaluated cautiously
because benign ameloblastoma infil-
trates the medullary cavity of bone.
ACs express SOX2 {1375) and have a
higher Ki-67 proliferation index than do
benign ameloblastomas {233}, but these
teatures provide no proven additional
Fig. 8.03 Ameloblastic carcinoma. A Architectural features of ameloblastoma, a peripheral basaloid layer and stellate reticulum-like central epithelium, bu! with frequent mitotic
figures and atypia. B Marked atypia and a peripheral basal layer of palisading cells with reversed nuclear polarity. C Loss of ameloblastoma architecture and progression to higher-
grade spindle morphology. D Focus of incipient necrosis consisting of numerous clustered apoptotic cells.
diagnostic value over routine histological
features.
Occasional lesions have a partial or
completely spindle-cell morphology and
may be difficult to distinguish from od-
ontogenic carcinosarcoma or sarcoma,
because not ali reported examples have
retained keratin immunopositivity {1165,
2703). Sorne of these spindle-cell lesions
have followed an aggressive course.
lf the features of ameloblastoma are not
evident in a cytologically malignan\ odon-
togenic neoplasm, an alternative diagno-
sis of primary intraosseous carcinoma or
clear cell odontogenic carcinoma should
be considered. The distinction between
these entities is not well defined, and AC
may show both keratinization and clear-
cell change.
Genetic profile
BRAF mutations identical to those seen
in ameloblastoma have been described
in AC {283}.
Prognosis and predictive factors
Approximately one third of patients de-
velop pulmonary metastases, whereas
cervical lymph node metastases are unu-
sual {1284\. The median overall survival is
17.6 years, with maxillary lesions twice as
likely as mandibular lesions to cause death
{1997}, but many series report shorter me-
dian survivals (~5 years) {1284\.
Radical surgical excision is the primary
treatment, with a local recurrence rate of
28% {2681). Radiotherapy seems to pro-
vide little additional benefit but tends to
be used in the salvage setting. Aggres-
sive multimodality treatment from the out-
set has been recommended {1414).
Prirnaryintraosseous
carcinoma, NOS
Odell E.W.
Allen C.M.
Richardson M.
Definition
Primary intraosseous carcinoma, NOS
(PIOC) is a central jaw carcinoma that
cannot be categorized as any other type
of carcinoma. lt is assumed to arise from
odontogenic epithelium. Sorne cases
arise in odontogenic cysts or other be-
nign precursors.
ICD-0 code 9270/3
Synonyms
Primary intraosseous squamous cell car-
cinoma; primary intra-alveolar epider-
moid carcinoma; primary odontogenic
carcinoma
Epidem iology
PIOC is rare. As of 2011 , only 116 cases
arising in cysts had been reported {224)
As of 2001, 35 cases with no precursor
lesion had been reported {2379}. The
stringent diagnostic criteria for confident
diagnosis of odontogenic origin are dif-
ficult to assess with certainty, and a pre-
cursor benign lesion can be confidently
excluded or confirmed in only a minority
of cases {654). All types of PIOC (wheth-
er developing in cysts or not) show a
male predilection, with a male-to-female
ratio of almost 2:1 (reflecting the preva-
lence of cysts) and a mean patient age
Odontogenic carcinomas 207

Fig. 8.04 Primary intraosseous carcinoma. Subtle early signs of intraosseous carcinoma in the dental follicle of the
unerupted lower premolar, with slight expansion and loss of cortication (left); 2 years later, there is extensive destruction
and pathological fracture (right).
al diagnosis of 55-60 years {224 ,1049),
although the age range is broad , and
cases have been reported in children.
Localization
PIOC is more frequent in the posterior
body and ramus of the mandible than
in the maxilla. Maxillary lesions are usu-
ally in the anterior segment (224 ,2379 ,
2736). Determining origin is importan! for
diagnosis. Carcinoma arising in the oral
mucosa and infiltrating the mandible, an
antral primary, and metastatic carcinoma
must be excluded , and ulceration to the
oral cavity is normally considered to pre-
clude definitive diagnosis. PIOC in the
mandible usually arises above the inferior
dental canal , whereas metastases usu-
ally have their epicentre below it. Cases
arising in cysts are more common in the
mandible (224).
Clinical teatures
Most lesions are asymptomatic incidental
Fig. 8.05 Histological features of typical primary intraosseous carcinoma. A The same case as in Fig. 8.04, showing squamous cell carcinoma in a fibrous stroma.
B Verrucous dysplasia in an odontogenic cyst. The features are primarily architectural, with limited orno cytological atypia.
208 Odontogenic and maxillofacial bone tumours
radiographical findings . More-advanced
lesions cause non -specific signs and
symptoms suggesting malignancy:
slow-growing swelling of the jaw, pain,
ulceration, loosening ofteeth , non-healing
extraction sockets , pathological fracture,
and nerve signs. Radiographically, the
tumours produce a poorly defined, non-
corticated radiolucency, often with root
resorption and cortical perforation {2736).
Cases arising in cysts may produce an
apparently multilocular or scalloped
radiolucency. Approximately 40% of
patients have metastasis at presentation
(2736).
Radicular/residual cysts are the most
common precursors , followed by den-
tigerous cysts and odontogenic kerato-
cysts, reflecting their relative prevalence.
When the tumour is detected early, the
radiological features appear benign and
the carcinoma is an incidental histologi-
cal finding on enucleation {1217,1516).
More frequently, there is subtle loss of
cortication or tooth resorption. Advanced
lesions develop fully malignan! appear-
ances. The only evidence of the be-
nign precursor cyst may be in previous
radiographs.
Histopathology
Almos! all lesions are squamous in type
and composed of islands or small nests
of neoplastic squamous epithelium, with
prickle-cell differentiation and without
prominent keratinization {654 ,672). Many
appear cytologically bland , and most are
considered moderately differentiated .
Necrosis is unusual. Sorne show limited
peripheral palisading or a plexiform pat-
tern that suggests their odontogenic ori-
gin (654).
PIOC is a diagnosis of exclusion. This
requires histological, radiographical,
and clinical information to exclude me-
tastases (which are much more com-
mon), malignant odontogenic tumours of
specific types , carcinomas of the maxil-
lary antrum and nasal mucosa, and in-
traosseous salivary gland neoplasms.
These distinctions are often impossible
on histological grounds alone. Nega-
tive CK19 staining indicates that an od-
ontogenic epithelial origin is unlikely.
Particularly close mimics are squamous
odontogenic tumour and solid odonto-
genic keratocyst, whereas keratinizing
ameloblastoma and central high-grade
mucoepidermoid carcinoma are more
readil y distinguished.
When cases arise in odontogenic cysts,
there may be a histological transition
between the carcinoma and the benign
precursor, but the carcinoma eventually
effaces the residual benign lesion. Half
are well differentiated and half moderate-
ly differentiated . Occasionally, dysplasia
~.iif....
may be encountered in the cyst epithe-
lium, or there may be a verrucous cyst lin -
ing similar in appearance to a verrucous
dysplastic lesion of oral mucosa {93,
2442). These cases behave as dysplastic
lesion or carcinoma in situ when they are
limited to the cyst.
Squamous cell carcinoma has also been
reported to arise in ameloblastoma and
other benign odontogenic tumours.
When a carcinoma is squamous and the
histological features of specific malignan!
odontogenic carcinomas are absent, the
carcinoma is best classified as PIOC.
Prognosis and predictive factors
An insufficient number of cases has
been reported to determine outcome, but
prognosis is generally poor and is best
predicted by histological grade (1049).
Epidemiology is poorly defined radiolucency with fre -
Fewer than 10 cases have been reported quent cortical bone destruction , tooth
11061,1075,1092), with 3 cases discussed root resorption , and extension beyond ra-
in the first report 11273), but the entity diographical margins. Sinus involvement
may be underrecognized or described has been reported.
under another name 11075,2087). Males
and females are equally affected. Histopathology
SOC is characterized by single-file thin
Localization cords, nests, and strands of epithelium
The mandible is more frequently affected , in a densely sclerotic stroma. Epithelium
in the premolar and molar regions. The or stroma may dominate in different ar-
reported cases in the maxilla occurred in eas. The epithelium may be compressed
the anterior and molar regions. and only visible on immunohistochem-
istry. Cytologically, individual epithelial
Clinical features cells are bland, with infrequent mitoses.
SOC presents as swelling, sometimes Their cytoplasm may show vacuolation
with nerve signs. Radiographically there or partial clearing. There is no squamous
íJ~~!i~~~¡¡e~~~~~~-~ ~-~
.···~~:: ~~1~·~,¡:· ~~1~":'.k
.- '~\"
· '-"'''\,
~~ : ,~-\~
~\, •' :!tí."- 'i¡cl'~,,.~~~ - i.~~~~~.J.~;
: - , ~ ·\ '~ :~ -:~~ ·1'~·Jt-. _.. .:·. '~'-· \ . ' .·~x · -~· l,~- ,.(

Radi cal resection has been the primary .: ~1_.~,~ . . ~ ~~:¿.''f~~:~..; ~~ ·~·~ . ~ ~,,~i~
treatment modality (654,2736), with neck V~~\ ,~ .. .. ,~ ~~ XY~.t_·~...~) ,:~ ..; ! .,:·'-\'.~~
~~ ..~' : ,':• ,:=:-:,,~-- -.: ;,,)><,
_ . ,~ •=-,;. V. -~· . -- ;~..-.~ ~- . ~·,.... : ...;,;:: ' Q )&.'~·"...\ , ·\ ' •i
~ :--' ~ ':..' ~_¡~ ~ ~<~" ~ " ~.~.•./*~ '" ~A~ " 1...~
dissection for metastasis or reconstruc- '."~~·· ··.~ .\~
tion. Multimodality treatment provides ~~~ . -.1:..~ .,~~ .;,..~-~-..:,~;¡¿, i~
~-. - -.. :-:~".¡~~
. •. :.
added benefit and has been reported ' . '...~::-~ . ;;,-.·--~-:. i'l' ·g..~,.-.4., ~'~
• <~.,. ' , ~ ,._, ~· ... . ,; .' . ··: , ... )'
to provide a 3-year survival rate of 40%. ~ i :.-~: ~· '.. ; ; \ '~ - . ·-~ --·~:~í~;:\ ~~~
As many as 60% of lesions recur locally
(1049); in one series, patients with local
:.,:;i· \ ; tf.:g~~;::
t.f>_. ~,. .. ~ :'-. ..t " _··~¿·~t~~~~,;~~~.,:;
1

\ .• · .., - :. . . .. '~- ~'\-~·'f ....

recurrence ali died of the disease (2736). 'I l,1:·t '":, .~:~~. -·. ' ., :·: .. ·~ ~ ... ~~. ;-:.~~ -,~:·~~
Distan! metastasis is infrequent and is ~~l~ , · . ~&; · , .'· • -:·=1 ·~, ... .. ' -.-~ : ' ~-..
~~ . ...~' 1" •- , · , .... .,-,,.:•• ~ ' ~·
usually to lung 12444) As of 2001, th e
., ,, ... .
.. ~-, '1 \
·,
), . . ....
.
J\. .. - ..,, ' ' "'~, ,.. <,
-; .~H"
.·ti : !\ , 1 ·~ ' ' '-' " " ' ' .
' , ..... •' '.. ~.' , , .......
, ,'~, ..~J~ ,,
5-year survival rate of reported cases '~.. , , _ ~ ( ' ,, • • 1 • 1
~ '"" ' • '
.... ' I - '::: ' ' ,, • ~ '
was 52% 12379) ;·.... ~...~~ . , • ~ \ , l.: ' \ . \ . ~'
Cases arising in cysts often appear to ~• ' - *'
\ " ~
. - ''
~ ' ' . • ' ~ ',,. ·',,·
-.l ~ ... / , ..... . ... ' ... . ,>....: .. '

-~~ ··· ~\ •/'1 1·

... ' ... . ·..~·!f , ,,·~t~ . . • ~ ,' .. t' ·,~
be better differentiated and have a more ·~li\t
,s ..f. r~:: ~ · . .·.t.
"\ • ; 1". - .1 .. ··,:.:...- • ./ ... • ..
\.....~ ;..,,~ " ~
.. ~ · :...'' .. ...... . ' 1> •" •
prolonged course , but the 5-year survival ~-~:.~ .. "'~ :"'"" "~. . \ ' . ~?/--: ~ "':·.
~)'.1.·s;;.~~,.. . ~ .
' ... .,. . . . '"' ..... ~J'

<....~.~,.·~~'
\.: (\ L.. ...:..·:~.·.-- ~,.. ·
rate of reported cases is slightly lower, at ~~~.:~~l: . ·i~ ~- -;._~ ,' . -~~~~;.: ,,. :: .:,,,. ·e ·v ··',
40% 1224). When cysts are found to har- ~ ~ · ~~· - -~,a
·- ,~\· ·-
bour incidental dysplasia or carcinoma in '2-=\~·
situ after enucleation , conservative close ~ . . ·-,. . -'· .. · ~~."~'~~, ~-- ··-=·. ·.. .
~ "\.J"~~-= ,,~ft:ll · .¡· i w 'lp'S : '"'·-
:'°·~ --• ,~.~-
~' ..... .-.::;::~
~J..~~~'°' , -.¿• ~~
1

L- - ....... "
_ _ _...,_~11..,;._
.. :rJl.. ::...~"_..
....Jo_.-a;;...,;...:_n..1_11111
_L.._....:5<_ • . Jí,m: .'w~- - i!\, · - •.
follow-up is appropriate 1224). Fig. 8.06 Sclerosing odontogenic carcinoma. A Fine epithelial strands infiltrating around a muscle fibre. B CK19 immuno-
positivity reveals unsuspected fine strands of dispersed carcinoma cells, consisten! with an odontogenic origin.

Sclerosing odontogenic
carcinoma
Odell EW
Koutlas l.

Definition
Sclerosing odontogen ic carcinoma
(SOC) is a primary intraosseous carci -
noma of the jaws, with bland cytology,
markedly sclerotic stroma, and aggres-
sive infiltration.

ICD-0 code 9270/3

Fig. 8.07 Sclerosing odontogenic carcinoma. High-power view shows cytologically bland epithelium in a dense
collagenous stroma.

Odontogenic carcinomas 209

differentiation . Despite the benign appear-
ance, there is invasion of skeletal muscle,
and perineural infiltration is characteristic.
Necrosis is not reported {1273 ,1986)
The epithelial cells are immunopositive for
CK19, CK5/6, and p63 but are on ly focally
and subtly positive for CK7 {1092,1273,
2348) and negative for CAM5.2 {1061,
1273). Membrane staining for E-cadherin
is variable.
Diagnosis must exclude metastasis, epi-
thelium-rich central odontogenic fibroma,
calcifying epithelial odontogenic tumour,
clear cell odontogenic carcinoma {1061,
1273,2348), and desmoplastic amelo-
blastoma. This may be difficult in small
biopsies. Despite its resemblance to ep-
ithelium-rich central odontogenic fibroma
{2348) and its benign-looking epithelial
islands, SOC shows aggressive infiltra-
tion. lt is unclear whether SOC is a distinct
entity ora histopathological pattern {1074 ,
2641), but it merits recognition so that its
characteristics may be defined more fully.
Prognosis and predictive factors
SOC is a low-grade carcinoma. Resec-
tion has been the main treatment, and
only one recurrence has been reported,
following initial curettage (1092). No role
for radiotherapy is defined. Metastasis is
not described.
Clear ce// odontogenic
carcinoma
Odell E.W.
Bilodeau E.A.
Maiorano E.
Neville B.W
Definition
Clear cell odontogenic carcinoma is an
odontogenic carcinoma characterized
~ - -.,-·,,.;·~· ~:~
Fig. 8.08 Clear cell odontogenic carcinoma. A Biphasic pattern of clear cells interspersed with darker, more basaloid cells. B Rare variant of clear cell odontogenic carcinoma with
extensive dentinoid formation. C Monophasic pattern of cells with almos! complete cytoplasmic clearing or faintly eosinophilic cytoplasm with well-defined outlines. Peripheral cells
show partial palisading or reversed nuclear polarity.
210 Odontogenic and maxillofacial bone tumours
by sheets and islands of vacuolated and
clear cells .
ICD-0 code
Synonyms
Clear cell odontogenic tumour; clear cell
ameloblastoma (both obsolete)
Epidemiology
Nearly 100 well -characterized cases
have been reported. The incidence is
unknown. The carcinoma is more com-
mon in women than in men (with a male-
to-female ratio of 1:1.6), and the mean
patient age at diagnosis is 53 years. Most
cases arise in patients aged 40-70 years
(1484).
Localization
The mandible is the site of origin three
times as frequently as the maxilla, wi th
43% of ali lesions arising in the posterior
body and lower ramus {1484).
Clinical features
Clear cell odontogenic carcinoma may
cause non -specific signs and symptoms,
such as slow-growing swelling of the jaw,
pain, ulceration, loosening of teeth, nerve
signs, anda poorly defined radiolucency,
often with root resorption and sometimes
soft tissue invasion {624,1484). Many
cases are asymptomatic, and small le-
sions may appear deceptively localized
radiographically.
Histopathology
The tumour is composed predominantly
of epithelial cells that have clear to faintly
eosinophilic cytoplasm, well-demarcat-
ed cell membranes, and irregular small
dark-staining nuclei (129,935). The clear
cells are organized in lobular sheets,
islands, trabeculae, or strands, and at
their periphery there is almos! always a
9341 /3
Fig. 8.09 Clear cell odontogenic carcinoma. Resection
specimen showing a poorly defined destructive
radiolucency in the posterior body and ramus of mandible.
basaloid cell population of small dark un-
vacuolated cells (biphasic pattern). Much
less frequently, the pattern may be focal-
ly reminiscent of ameloblastoma, with an
outer layer of columnar clear cells show-
ing reversed nuclear polarity. Completely
clear-cell examples (monophasic pat-
tern) are rare. The histological appear-
ance can be bland, with only mild atypia
and few mitoses. Necrosis, overt cytolog-
ical malignancy, and perineural spread
are seen in higher-grade examples.
The clear cells are negative for mucin but
are glycogen-rich, as evidenced by di-
astase-labile periodic acid-Schiff (PAS)
positivity, although glycogen may be lost
during fixation or decalcification . The
clear cells are immunopositive for vari-
ous cytokeratins, but CK14, CK19, and
pancytokeratin AE1/AE3 are the most
useful and reliable diagnostic markers.
The cells are negative for vimentin, S100
protein, desmin , SMA, HMB45 , alpha-
1-antichymotrypsin, CD10, CD31 , CD45,
and GFAP {129,1423,1484,2711) The Ki-
67 proliferative index is highly variable.
Dentinoid has been reported in 7% of
cases {1484) but is generally a minar
inductive change. However, occasional
lesions have shown extensive dentinoid
and may be a separate entity (1658).
The appearances are distinctive but
not pathognomonic , and diagnosis re-
quires exclusion of other clear cell-rich
neoplasms, including salivary gland
neoplasms, melanoma, metastatic renal
cell carcinoma , and the clear-cel l vari-
ant of calcifying epithelial odontogenic
tumour (513). Ameloblastoma with clear-
cell differentiation and clear cell calcify-
ing epithelial odontogenic tumour can be
problematic differential diagnoses, but
clear-cell change in these lesions is usu -
ally focal.
Genetic profile
More than 80% of cases show rearrange-
ments of EWSR1 (191 ); on the basis of
fewer cases , ATF1 was confirmed as the
translocation partner (191,2667). Th is
is the same translocation found in clear
cell salivary gland carcinoma, and given
their morphological similarity, it has been
theorized that these are related tumours
(84). A single case has been reported to
harbour a BRAFV600E mutation , but this
may suggest c lear cell ameloblastic car-
cinoma (589 ). The exorne sequence of a
different single case has been published
(332).
Prognosis and predictive factors
Clear cell odontogenic carcinomas vary
in behaviour from indolent tumours to
cases that frequently recur. The tumours
have metastasized in approximately 12%
of reported cases , usually to cervical
lymph nades and lungs, and less fre-
quently to bone. Metastases at presen-
tation are rare. The outcome has been
death in 15% of cases , with a median
survival of 14 years. Recurrence and me-
tastasis may develop after many years
(624,1484)
Complete surgical resection is the pri-
mary treatment. Adjuvant radiotherapy
does not have a defined role , but may be
appropriate for cases showin g soft tissue
extension, aggressive growth, or incom-
plete surgical margins (624).
Ghost ce// odontogenic
carcinoma
Odell EW
Ledesma-Montes C.
Definition
Ghost cell odontogenic carcinoma
(GCOC) is an odontogenic carcinoma
characterized by ghost-cell aberrant
keratinization and dentinoid deposition in
variable quantities.
ICD-0 code
Synonyms
Calcifying ghost cell odontogenic carci-
noma; malignan! epithelial odontogenic
ghost cell tumour; carcinoma arising in a
calcifying odontogenic cyst; aggressive
epithelial ghost cell odontogenic tumour;
malignant calcifying odontogenic cyst;
malignant calcifying ghost cell odonto-
genic tumour
Epidemiology
GCOC is about the rarest of the ghost
cell lesions, accounting for < 3% of ali
cases (1357). Approximately 40 cases
have been reported, with more than half
occurring in Asian patients (556) . The
carcinoma is four times as common in
men as in women, with peak incidence
in patients aged 40-60 years (556). The
patient age range is 11-79 years (mean:
39.7 years) (30 ,556)
~-' ­
Fig. 8.10 Ghost cell odontogenic carcinoma. Typical admixture of malignan! epithelial cells with ghost cells.
Localization
GCOC is twice as common in the max-
illa as in the mandible. Mandibular
lesions are usually in the molar area. All
reported cases have been intraosseous.
Approximately 40% of cases have been
confirmed to arise in a benign precursor,
a calcifying odontogenic cyst, ora denti -
nogenic ghost cell tumour (OGCT) (556);
the rest arise de novo (1357)
Clinical features
GCOC causes non-specific signs and
symptoms suggesting malignancy: slow-
9302/3 growing swelling of the jaw, pain, ulcera-
tion , loosening of teeth, nerve signs , root
resorption, and sometimes soft tissue
invasion. lmaging shows a poorly demar-
cated, osteolytic radiolucency, with half
of all cases showing variable radiopaque
material l556), reflecting mineralization in
ghost cells , dentinoid formation, or resid-
ual benign precursor. Displacement and
resorption of tooth roots are common.
Macroscopy
Appearances range from salid to multi-
cystic , usually with a gritty consistency
on section.
Histopathology
GCOC, OGCT, and calcifying odonto-
genic cyst forma spectrum of histological
appearances and behaviour (1357,1373).
The diagnosis of GCOC requ ires cyto-
log ical evi dence of malignancy, including
mitotic activity; pleomorphism and hyper-
Odontogenic carcinomas 211
chromatism; necrosis; and an infiltrative
growth pattern associated with ghost
cell keratinization, dentinoid formation,
or evidence of a DGCT or calcifying od-
ontogenic cyst precursor. The malignant
epithelial cells form sheets, strands, and
islands in a fibrous or hyali nized stroma.
The cells are uniform, small basaloid cells
with round dark nuclei in most cases, but
can be larger with pleomorphic vesicu lar
nuclei. Mitoses are frequent. Ghost cells
(i.e. keratinizing cells with aberran! ter-
minal differentiation) are large, rounded
pale-staining cells with empty central nu-
clear spaces, found in varying numbers.
They may be dispersed, isolated , or in
clusters (1357, 1373, 1486, 1986). Dentinoid
may be present and the amount of ghost
cell keratinization and dentinoid are highly
variable; both can be formed by the ma-
lignan! epithelium and in one pattern are
widely and evenly dispersed. In the other
pattern, ghost cell keratinization and den -
tinoid are more localized, possibly asso-
ciated with an overgrown or residual be-
nign precursor. Small foci of ghost cells
212 Odontogenic and maxillofacial bone tumours
occur in many odontogenic tumours and
do not alone indicate malignancy or the
diagnosis. Two th irds of cases are im-
munopositive for p53 protein (556,1486,
1664). Not ali carcinomas arising in cal -
cifying odontogenic cyst and DGCT are
necessarily GCOCs; they should be di -
agnosed according to thei r predominan!
differentiation pattern.
The diagnosis of GCOC (versus DGCT)
is favoured by p53 positivity and a high
proliferative fraction. Although cut-off
values have not yet been defined (556,
868,874,1486), expression of these mark-
ers increases upon transformation (1664,
2726) Overlap lesions between GCOC
and calcifying odontogenic cyst have
been reported (94)
Genetic profile
A single case has genomic and exorne
sequencing data showing a distinc-
tive molecular profile, including (among
many changes) multiple changes in the
SHH signalling pathway, a deleted exon
in UBR5, and a novel APC mutation
{242). This APC mutation is possibly a
link between one case of GCOC and
Gardner syndrome (familia! colorectal
polyposis) (727) .
Prognosis and predictive factors
The prognosis is unpredictable dueto the
wide variety of growth patterns reported,
with the tumours ranging from slow-grow-
ing, locally invasive carcinomas to highly
aggressive and rapidly growing tumours
with local recurrence and metastasis (90).
Most are relatively low-grade. Wide sur-
gical resection is the primary treatment
and is successful in two thirds of report-
ed cases. Only a minority of cases have
been treated with adjuvant radiotherapy,
and its role remains undefined (30). Ag-
gressive multimodality therapy with im -
munotherapy has proven successful in a
case with regional lymph nade metasta-
sis (30). Death followed local recurrence
in 3 cases and distant metastasis in
2 cases among 25 reported cases (90}.
The overall 5-year survival rate in the first
16 reported cases was 73% (1486).
Odontogenic carcinosarcoma
Definition
Odontogenic carcinosarcoma is ex-
tremely rare. lt is a true malignant mixed
odontogenic neoplasm similar in pat-
tern to ameloblastic fibrosarcoma, but
in which both the epithelial and the mes-
enchymal components are cytologically
malignan! (1276).
ICD-0 code 8980/3
Synonyms
Ameloblastic carcinosarcoma; malignant
odontogenic mixed tumour
Epidemiology
Odontogenic carcinosarcoma is very
rare , with only a few single-case reports
published (558 ,1294,2205) The tumours
may be preceded by ameloblastic fib ro-
ma or ameloblastic fibrosarcoma.
Localization
The mandible is the only reported site of
occurrence.
Clinical featu res
Cases have been reported in two men
(aged 52 and 55 years) {1294,2205} and
in a 19-year-old woman (558) The size
of the lesions was 6.0-8.0 cm. The tu-
mour presents as expansion of the body
of the mandible and ramus, of several
months' duration . lt may be painless or
associated with numbness of the li p
Fig. 8.11 Odontogenic carcinosarcoma. CT shows a
large, expansive, radiolucent lesion in the left mandible.
Reprinted from Delair D et al. (558).
Radiographically, the lesions are large,
expansile radiolucencies with poorly de-
fined borders. Cortical perforation and
root resorption have been reported .
Macroscopy
The tumours are multinodu lar and tan ,
with a fleshy appearance (558)
Histopathology
The overall architecture resembles that
of ameloblastic fibroma , with budding
and branch ing ep ithelial cords widely
separated by hypercellular fibrob lastic
stroma. The ce lls in the sarcomatous
componen! are markedly pleomorphic,
with enlarged and bizarre nuclei and
El-Mofty S.K .
occas ional multinucleation and mitosis .
The epithe li al component is frankly ma-
lignan!, with large hyperchromatic nuclei
and an increased N:C ratio. The typical
ameloblastic features such as peripheral
nuclear palisading and inner stellate re -
ticulum may be lost focal ly. Ameloblastic
carcinoma associated with malignan!
spindle -cell proliferation (427,2167,2350,
2686} is best classified as sarcomatoid
ameloblastic carcinoma rather than true
odontogen ic carcinosarcoma.
In one case, p53 and Ki -67 immunostain-
ing showed p53 positivity in 90% of the
cel ls and a Ki- 67 proliferation index of
45% in high -staining areas, in both the
carcinoma and the sarcoma components
{558).
Prognosis and predictive factors
Due to the very limited number of re -
ported cases and to insufficient follow-
up, prognostic information is lacking. In
one reported case {1294), a 51 -year-old
man had mu ltiple recurrences during a
5-year period fo ll owing segmenta! re -
section; distant metastasis to lung and
bone occurred 1 year after re-resection
of the recurrent tumour. In another case,
in a 19-year-old woman (558), there was
no evidence of recurrence 2 years after
hemimandibulectomy.
Odontogenic carcinosarcoma 213
Odontogenic sarcomas
Fig. 8.13 Odontogenic sarcoma. Asymmetrical , poorly marginated radiolucency of the right posterior mandible.
Definition
Odontogenic sarcomas are a group of
mixed odontogenic tumours in which
the epithelial componen! is cytologically
benign and the mesenchymal compo-
nen! shows cytological features of malig-
nancy. Ameloblastic fibrosarcoma (AFS)
is by far the most common type, and is
generally considered to be the malignant
counterpart of ameloblastic fibroma (AF).
Sorne odontogenic sarcomas (amelo-
blastic fibrodentinosarcomas) produce
dentin/dentinoid. Others (ameloblastic
fibro-odontosarcomas) produce enamel/
enameloid and dentin .
ICD-0 code
Epidemiology
AFSs can occur in patients of any age
(reported range: 3-89 years), with an
214 Odontogenic and maxillofacial bone tumours
overall mean patient age of 27.3 years,
which is considerably older than the
mean age for AF (836). Cases in which
previous AF can be demonstrated occur
ata mean patient age of 33 years (1675),
and cases in which the benign AF cannot
be demonstrated occur 10 years earlier
(267). Males are affected about 1.5 times
as frequently as females.
Etiology
The etiology is unknown, but AFS is gen-
erally thought to arise in a pre-existing
benign AF, although this benign precur-
sor lesion is only demonstrated in about
half of all cases (1327). This finding has
9330/3 led sorne authors to speculate that sorne
AFSs arise de novo, but the lack of doc-
umentation of a pre-existing AF does
not prove a de novo origin. Addition-
ally, sorne cases have clearly benign AF
Wright J.M.
admixed with the AFS, further suggesting
an origin from AF.
Localízation
The ratio of mandibular to maxillary inci-
dence is approximately 4:1, and there is
a predilection for the posterior jaws (267).
Clinical features
The clinical features are those of any low-
grade malignancy: an expansile mass
with nerve deficit. Most odontogenic
sarcomas are poorly marginated lesions.
AFS is always radiolucent, but lesions
producing dentin (with or without enamel)
can contain opacities.
Histopathology
Odontogenic sarcomas are mixed odon-
togenic tumours in which the epithelial
component is bland and cytologically be-
nign and the mesenchymal componen!
is malignant. The epithelial componen!
ranges from lamina-like strands to larger
islands of epithelium with peripheral pali-
sading. The amount of epithelium varies,
most likely in relation to the age of the
neoplasm as the malignan! mesenchy-
mal componen! overgrows the benign
epithelial component. The stromal com-
ponent displays nuclear crowding, with
hypercellularity and variable degrees of
cytological atypia, including increased
mitoses.
Prognosis and predictive factors
Odontogenic sarcomas are considered
low- to intermediate-grade sarcomas,
although anaplastic variants have been
reported. Abou t one third of patients ex-
perience recurrence, but distan! metas-
tasis is seen in < 5% of patients, and the
overall mortality rate is about 25% (836).
Benign epithelial odontogenic tumours
Ameloblastoma
Vered M.
Muller S.
Heikinheimo K.
Definition
Ameloblastoma is a benign intraosseous
progressively growing epithelial odonto-
genic neoplasm characterized by expan -
sion and a tendency far local recurrence
if not adequately removed.
ICD-0 code 9310/0
Synonyms
Conventional ameloblastoma; classic
intraosseous ameloblastoma; solid/multi -
cystic ameloblastoma
Epidemiology
Although rare (with an estimated annual
incidence of only about 0.5 cases per
million population), ameloblastoma is the
most common odontogenic tumour, ex-
cluding odontomas {291,981 }. The peak
incidence of diagnosis is in the fourth and
fifth decades of lite, with a patient age
range of 8-92 years and no sex predi-
lection {291 ,785,980). For BRAFV600E-
mutant cases, the reported mean patient
age at diagnosis is about 34 years, com-
pared with about 54 years for BRAF-
wi ldtype cases {279)
Localization
Approximately 80% of all ameloblas-
tomas are found in the mandible; they
Fig. 8.15 Ameloblastoma. Gross specimen showing a
tumour that is partly sol id and partly cystic.
Fig. 8.16 Ameloblastoma. A The radiographical presentation is that of an extensive multilocular (so-called soap-
bubble) radiolucency involving the posterior mandible, ascending ramus , and coronoid process; root resorption and
tooth displacement are observed. B This tumour is located in the area of a missing lateral maxillary incisor and presents
as a mixed radiolucent and radiopaque lesion; histopathologically, it was diagnosed as a desmoplastic ameloblastoma.
occur most often in the posterior re - {1881 ,2313). Rarely, incipient, root-relat-
gion, followed by the anterior mandible, ed ameloblastomas can be incidentally
posterior maxilla, and anterior maxilla discovered {1078).
{291,785,980,1646,2171). Desmoplastic
ameloblastoma has a predilection for the Macroscopy
anterior region of the jaws, especially the Ameloblastomas range from entirely
maxilla {1881) Ameloblastomas of the salid to variably cystic.
sinonasal tract are rare {2090).
Histopathology
Clinical features The most common type is the follicu -
The early manifestation is of a slow, pain- lar type, which resembles the epithelial
less expansion, which can later exhibit componen! of the enamel organ within
accelerated growth {369) With increas- a fibrous stroma; the peripheral cells are
ing size, complications include loosen- columnar to cuboidal (ameloblast-like),
ing of teeth, malocclusion, paraesthesia, with hyperchromatic nuclei arranged in
pain, soft tissue invasion , facial deform - a palisading pattern with reverse polarity
ity, limited mouth opening, difficulty with {2500) The central core is reminiscent of
mastication, and airway obstruction. Un - stellate reticulum, with loosely arranged
controlled tumour growth can be fatal. angular cells that often undergo cystic
Radiographically, a corticated multilocu - change. The second most common
lar so -called soap-bubble or honeycomb type is the plexiform type , composed of
radiolucency is common (although not anastomosing strands of ameloblasto-
pathognomonic). A unilocular appear- matous epithelium with an inconspicuous
ance is less common. Buccal and lingual stellate reticulum and cyst-like stromal
expansion is often observed. Resorption degeneration . Other histopathological
of involved roots and association with an types include acanthomatous , granular,
unerupted tooth may occur. Desmoplas- and basaloid {980} The desmoplastic
tic ameloblastoma may show a mixed ameloblastoma consists of cuboidal to
radiolucent and radiopaque appearance flat peripheral cells with central spindle-
mimicking that of a fibro -osseous lesion shaped cells and densely collagenous
Benign epithelial odontogenic tumours 215
 .~~_:'A..rlii8."!::...\l~~-:~;~ ~~~I
•.
' .~~~
Fig. 8.17 Ameloblastoma. A The follicular type consists of islands of odontogenic epithelium with columnar peripheral cells ; the nuclei are hyperchromatic and show a palisading
pattern and reverse polarity. The inner cells resemble stellate reticulum and may undergo cystic change; the connective tissue is moderately to highly collagenized. B The
plexiform type consists of strands and cords that form anastomoses; the peripheral cells are less pronounced !han in the follicular type; the connective tissue is loose and often
undergoes cystic changes. C The acanthomatous type features squamous metaplasia in the stellate reticulum- like central areas. D The granular type shows granular change
in the stellate reticulum- like central areas.

stroma wi th possible metaplastic bone.

Admixed histopathological types can be
MAPK Hedgehog found in each ameloblastoma. Rarely,
pathway pathway ameloblastoma can arise in association
FGFR2 I PTCH . SMO with odontoma, and this has historically
~ ~-
¡ ~
: /--< ~ been referred to as odontoameloblasto-
ma (1655).
'
11¡ '
'
' Cell of origin
. : Ameloblastoma originates from dental

• lamina, as indicated by the expression

of early dental epithelial markers such as

-• e : • e
PITX2, MSX2, OLX2, RUNX1, and ISL1

-T · 1·-,,
T A C A G A/ T G A A A T (968,1161)

~
Genetic profile
/ : \ Mutations in genes that belong to the
MAPK pathway are present in almost
90% of ali ameloblastomas (279), with
- -· - - - _! - - ·- - - - BRAFV600E being the most common
mutation (279,589,1309,2321). Addi -
A e tional MAPK pathway mutations include
KRAS, NRAS, HRAS, and FGFR2 muta-
Fig. 8.18 Ameloblastoma. A Mutated pathways in ameloblastoma, with proteins encoded by the mutated genes
indicated in purple. B Positive immunohistochemical staining for V600E-mutant BRAF in the tumour epithelium; staining tions (279 ,2321). The high frequency and
is cytoplasmic. CSanger sequencing electropherogram of a BRAF V600E-mutant ameloblastoma. The point mutation the pattern of mutual exclusivity of these
(C 1799 T-+A) responsible for the V600 E substitution is indicated by the arrow. mutations emphasize the importance of

216 Odontogenic and maxillofacial bone tumours

Table 8.01 Prevalence of mutations in maxillary and mandibular ameloblastomas {279, 1309, 2321}
Location of ameloblastoma
Maxilla
Mandible
the MAPK pathway in the pathogenesis
of ameloblastoma (279,1309,2321). Non-
MAPK pathway mutations include SMO,
SMARCB1, CTNNB1, and PIK3CA muta-
tions, among which SMO mutations are
very common , suggesting a functional
role (279 ,2321) These non- MAPK path-
way mutations tend to co-occur with the
MAPK pathway mutations.
Prognosis and predictive factors
Current treatment is wide surgical exci -
sion, including an area of bone beyond
radiographical margins. Conservative
surgery yields a high recurrence rate
(60-80%) (1907). Histological type does
not determine prognosis (1907). More
than 50% of recurrences occur within
5 years after initial treatment Follow-up
should be at least 25 years, but lifelong
follow-up should be considered (981 ).
BRAF-targeted therapy offers a novel op -
tion to complement surgery in selected
cases of aggressive and/or recurrent
ameloblastoma (279 ,2321 ).
Ameloblastoma,
unicystic type
Vered M.
Muller S.
Heikinheimo K.
Definition
Unicystic ameloblastoma (UAM) is a vari -
ant of intraosseous ameloblastoma that
occurs as a single cystic cavity, with or
without luminal proliferation.
ICD-0 code
Epidemiology
UAM accounts for 5- 22% of ali amelo-
blastomas (1874). Approximately 50%
of cases are diagnosed in the second
decade of life, with a patient age range
of 1-79 years (12,999,1420) The mean
patient age is 16 years for cases associ-
ated with an impacted tooth and 35 years
in the absence of impaction (1345 ,
1376,1420,1874). There is a slight male
Prevalence of mutations
~
BRAF RASfamily FGFR2 SMO
20% 40% 15% 55%
72% 5% 5% 5%
preponderance overall, but UAM notas-
sociated with an impacted tooth shows a
minor female predilection (12,1345,1376,
1420,1874).
Localization
UAMs are most often located in the man-
dibular third molar area and ascending
ramus, followed by the body and sym-
physis (12 ,1368,1420,1874) Most maxil-
lary cases occur in the posterior areas.
UAMs can also be found in inter-radicular
or periapical locations and edentulous
areas (1376).
Clinical features
UAM usually occurs asan asymptomatic,
pai nless jaw expansion. Radiographical-
ly, it presents as a well-defined unilocular
Fig. 8.19 Unicystic ameloblastoma. The radiographical
presentation is that of an extensive, well-defined
unilocular radiolucency in association with an impacted
and displaced mandibular third molar.
9310/0
Fig. 8.20 Unicystic ameloblastoma. Gross specimen
showing the characteristic single cystic cavity. lntraluminal
proliferations occupy a large part of the lumen.
Benign epithelial odontogenic tumours
radiolucency, often associated with an
unerupted tooth , most often the mandib-
ular third molar. Cases unrelated to tooth
impaction may have a scalloped outline
(675,1874). Root resorption is common,
and cortical perforation is present in ap-
proximately one third of cases (2015).
Macroscopy
UAM presents as a monocystic lesion ,
occasionally with thickenings that can fill
the entire lumen.
Histopathology
The luminal type shows a simple cyst
lined by characteristic ameloblastoma-
tous epithelium (with peripheral palisad-
ing and nuclear polarization and over-
lying loosely arranged cells that may
resemble stellate reticulum). Usually, this
pattern is only focal , and in other areas
ameloblastomatous features are less pro-
nounced. The intraluminal type is charac-
terized by intraluminal extensions of the
lining epithelium , usually in a plexiform
pattern. A definitive diagnosis of UAM
can be made only after careful examina-
tion of the entire lesion. About half to two
thirds of lesions previously diagnosed
as UAM may have a mural component
(1874); and there is sorne evidence that
these behave more aggressively, like
conventional ameloblastoma (1420).
Genetic profile
In the few studies carried out to date,
BRAFV600E has been the most com-
mon mutation (279,589)
Prognosis and predictive factors
Because UAM radiographically mimics
a cyst, initial treatment often consists
of enuc leation. Further treatment is de-
termined by the pattern and extent of
the ameloblastomatous proliferation in
217
 • less, sessile, exophytic lesion with a
Fig. 8.22 Unicystic ameloblastoma. lmmunohistochemistry for V600E-mutant BRAF shows positive cytoplasmic
staining of !he neoplastic epithelium.
relation to the cyst lumen upon removal
of the entire lesion and processing of
multiple blocks . When mural involvement
is identified, the tumour may behave bio-
logically as AM and requires either addi -
tional surgery or more careful follow-up.
Any recurrence should be managed as
AM. Whether lesions with mural involve-
ment should remain a more aggressive
subtype of UAM or be reclassified as
conventional AM requires further study.
In general, UAMs require long -term fol-
low-up, because recurrence may occur
10 years or longer after initial treatment.
Ameloblastoma,
extraosseous/peripheraltype
Vered M.
Muller S.
Heikinheimo K.
Definition
Extraosseous ameloblastoma is a benign
tumour that occurs in the soft tissues
of the gingiva or edentulous alveolar
Fig. 8.23 Lymph node containing benign metastatic ameloblastoma showing a predominantly cystic tumour. Note !he
stellate reticulum-like cells and ameloblast-like cells showing reversed polarity. Reprinted from Dissanayake RK et al. {590}.
218 Odontogenic and maxillofacial bone tumours
areas, showing microscopic features of
ameloblastoma.
ICD-0 code
Synonyms
Soft tissue ameloblastoma; ameloblas-
toma of mucosal origin; ameloblastoma
of the gingiva
Epidemiology
The extraosseous type accounts for
1-10% of all ameloblastomas {1877,2478).
The mean patient age is 50-54 years, with a
range of 9- 92 years. Approximately two
thirds of ali cases occur in the fifth to sev-
enth decades of lite (1877). The male-to-
female ratio is 1.4:1.
Localization
The most common location is the soft tis-
sues in the mandibular retromolar area,
followed by the maxillary tuberosity. Most
tumours are found on the lingual aspect
of the mandible.
Clinical features
Extraosseous ameloblastoma is a pain -
smooth or papillary/granular surface; the
oral mucosa can be of normal colour or
red to dark red . The mean diameter is
about 1.3 cm. Adjacent teeth may be tilt-
ed. Duration can be as long as 20 years
{1877). The clinical impression is often of
a reactive lesion. Radiographically, a su-
perficial erosion or bony depression (cup-
ping, saucerization) may be seen.
Macroscopy
The tumour presents as a firm mass with
occasional tiny cystic spaces.
Histopathology
Ali histopathological features of intraos-
seous ameloblastoma can be encoun-
9310/0 tered (2225) . The malignant variant of ex-
traosseous ameloblastoma is extremely
rare {1877,2335). Differential diagnosis
may include basal cell carcinoma of oral
mucosal origin, extensions from skin tu-
mours (2633), or salivary gland tumours
with a peripheral palisading pattern
(1877).
Prognosis and predictive factors
Conservative removal with free margins
is expected to be curative. Recurrence is
rare, but long -term follow-up is warranted.
Merasramzmgamerobrastoma
Odell E.W
Tilakaratne W.M .
Definition
Metastasizing ameloblastoma is an
ameloblastoma that metastasizes
despite its benign histological appearance.
ICD-0 code 9310/3
Epidemiology
In the USA, the overall annual incidence
of malignant ameloblastoma (i.e. both
ameloblastic carcinoma and the rarer me-
tastasizi ng ameloblastoma) is 1. 79 cases
per 10 million population, increasing with
patient age {1997)
Localization
The primary site is more frequently the
mandible than the maxilla, and the pri -
mary lesion is usually a solid or mul -
ticystic type of ameloblastoma {590).
Metastatic deposits are most frequent
in lung (occurring in 70% of cases), fol-
lowed by lymph nodes (28%), and bone
(1 2%) (590,1296,1346,2212).
Clinical features
Metastasizing ameloblastoma is defined
by its clinical behaviour rather than its
histology; the diagnosis can be made
only in retrospect, after the occurrence of
metastatic deposits. The term "atypical
ameloblastoma" has been used to de-
note lesions with fatal outcome for vari-
ous reasons (i.e. metastasis, histological
atypia, or relentless local spread) (70},
but should be avoided. There is usually a
long latent period before metastasis, and
sorne cases occur after repeated surgi-
cal intervention (590).
Histopathology
For this diagnosis to be made, both pri-
mary and metastatic lesions must have
histological features of benign amelo-
blastoma. There are no specific features
predicting metastasis. Metastatic amelo-
blastomas with significant atypia are
ameloblastic carcinomas (1726).
Prognosis and predictive factors
The overall 5-year survival rate is 70%,
but survival depends on the site of me-
tastasis and surgical accessibility. Ra-
diotherapy and chemotherapy have no
proven benefit (590)
Squamous odontogenic
tumour
Wright J.M.
Devilliers P.
Hille J.
Fig. 8.25 Squamous odontogenic tumour.
palisading or cytological atypia.
Fig. 8.24 Squamous odontogenic tumour. Characteristic radiolucency contacting tooth roots.
Definition
Squamous odontogenic tumour (SOT) is
a benign epithelial odontogenic tumour
in which the tumour cells show terminal
squamous differentiation.
ICD-Ocode
Epidemiology
SOTs are rare neoplasms, with < 50 cas-
es published. They show a wide patient
age distribution, with a mean age of
about 38 years. The male-to-female ratio
is 1.8:1 (119)
Localization
Most SOTs presentas single intraosseous
tumours. The maxilla and mandible are
affected equally, and there is a predilec-
tion for the anterior maxilla and posterior
mandible. Rarely, multifocal and extraos-
seous tumours have been reported (1024,
1624).
Clinical features
Most patients are young and asympto-
matic. The tumours grow slowly, and the
presence of bony expansion is a function
of the duration of the tumour. Affected
teeth may become mobile.
Radiographically, most lesions present as
unilocular radiolucencies, although multi -
locularity has been reported. Most lesions
9312/0 show continuity with one or more tooth
roots. One of the more characteristic ra-
diographical presentations is a triangular
radiolucency between teeth showing root
divergence, with the base of the triangle
towards the root apices {1151}. Lesions
may or may not show cortication in their
margins. Root resorption is rare . A single
case of squamous cell carcinoma in asso-
ciation with SOT has been reported (1079)
Macroscopy
Most lesions are curetted and show non-
descript fragments of soft tissue.
Histopathology
The tumour consists of islands of bland
terminally differentiated squamous epi-
thelium of varying shape and size. The
islands are occasionally tightly packed
together in a jigsaw-puzzle architecture.
Benign epithelial odontogenic tumours 219
The peripheral layer of cells is charac-
teristically flattened. Centrally, there is a
tendency for microcystic degeneration,
individual cell keratinization, and calcifi -
cation. Mitoses are rarely encountered.
The tumour can be misdiagnosed as
ameloblastoma, acanthomatous or des-
moplastic variants , or squamous cell car-
cinoma, but it does not have peripheral
palisading with reverse nuclear polarity,
and the cytological features are bland.
Proliferations with microscopic features
similar to those of SOT have been re-
ported in the walls of odontogenic cysts,
but these proliferations do not develop
into SOTs , and have been called SOT-like
proliferations 12643).
Genetic profile
NOTCH receptors and their ligands may
play a role in the cytodifferentiation of
SOT 12172).
Genetic susceptibility
Genetic susceptibility is minimal. An iso-
lated familia! case, affecting three family
members, has been reported 11377).
Prognosis and predictiva factors
Most SOTs have been removed conserv-
atively by surgery. Recurrence is rare.
Calcifying epithelial
odontogenic tumour
Wright J.M.
Devilliers P.
Definition
Calcifying epithelial odontogenic tumour
(CEOT) is a benign epithelial odontogenic
220 Odontogenic and maxillofacial bone tumours
tumour that secretes an amyloid protein
that tends to calcify.
ICD-0 code 9340/0
Synonym
Pindborg tumour
Epidemiology
CEOT is relatively rare, accounting for
~ 1% of specimens submitted to oral
pathology laboratories. lt can occur in
patients of any age, with a predilection for
individuals in their third to sixth decade of
life. The mean patient age at diagnosis is
about 40 years. The sexes are equally af-
fected, but the peak incidence is about a
decade earlier in males than in females.
Localization
The mandible is affected twice as often
as the maxilla, and there is a predilection
for the body. Approximately 6% of cases
are extraosseous (1876).
Fig. 8.27 Calcifying epithelial odontogenic tumour.
Characteristic radiographical features of an expansile,
mixed radiolucentiopaque lesion.
Clinical features
Patients tend to be asymptomatic and the
neoplasm grows slowly, ultimately pro-
ducing bony expansion. Radiographical-
ly, about two thirds of lesions are mixed
radiolucent and radiopaque and about
one third are radiolucent, but predomi-
nantly radiopaque tumours have also
been seen. The degree of calcification
correlates with the age of the lesion. The
classic so-called driven -snow appear-
ance is not common. Lesions are most
frequently unilocular, but about one quar-
ter are multilocular. Borders tend to be
well defined, if not corticated , but about
one fifth of lesions are diffuse 11178).
About 50- 60% of lesions are associated
with unerupted teeth (1178 ,1876).
Macroscopy
There are no characteristic gross patholog-
ical features. The tumours are solid, with
variable amounts of calcification. Rarely,
cystic variants have been reported (877).
Histopathology
CEOTs display a variety of architectural
patterns, ranging from small or almost in-
conspicuous islands, cords, or trabecu-
lae to large sheets of neoplastic epithelial
cells. The cells tend to be polyhedral,
with abundant well-defined cytoplasm ;
intercellular bridges can be seen in sorne
tumours. The tumour nuclei are charac-
teristically pleomorphic, and giant nuclei
are often seen. Despite this pleomor-
phism, which might raise the possibility
of mal ignancy, the mitotic rate is very low.
The neoplastic cells secrete a unique
odontogenic amyloid protein provision-
ally called AODAM , which is encoded by
exons 5- 10 of the odontogenic amelo-
blast-associated protein (OOAM) locus
(1676,2233). As AODAM is secreted
extracellularly, it forms small rounded to
irregular homogeneous masses of lightly
eosinophilic hyaline material that stain
positively for amyloid. As more protein is
secreted, the masses tend to coalesce
and ultimately calcify, often in concentric
rings (so-called Liesegang rings). The
neoplasm will infiltrate adjacent bone.
Variations include clear-cell change indi -
cating glycogen accumulation, which can
be focal or diffuse; a clear-cell variant of
CEOT is well documented {985} Variable
numbers of Langerhans cells have been
reported in CEOT {2344). The tumours
are well documented as hybrid lesions
with other odontogenic neoplasms, par-
ticu larly with adenomatoid odontogenic
tumour {1875), but the CEOT-like areas
tend to be focal, and the hybrid tumours
behave biologically like adenomatoid od-
ontogenic tumours. CEOTs must be dis-
tinguished from CEOT-like areas found in
the follicles of unerupted teeth {110).
CEOT must be distinguished from amelo-
blastoma, but CEOT lacks peripheral pal-
isading and secretes an amyloid protein
that calcifies. The cytological atypia that
characterizes CEOT raises the possibility
of malignancy, but the lack of mitoses,
the low Ki -67 proliferation index, and
the presence of stromal amyloid protein
with calcification should allow for the dis-
tinction. However, malignant variants of
CEOT have been documented {562).
Clear-cell change raises the possibility
of clear cell odontogenic carcinoma or
metastatic clear cell carcinoma. Howev-
er, clear cell CEOT is distinct from clear
cell odontogenic carcinoma in that it se-
cretes an amyloid protein that calcifies,
and it lacks the EWSR1 and ATF1 gene
rearrangement of clear cell odontogenic
carcinoma. Metastatic clear cell carci-
nomas do not secret a calcifiable matrix
and they have a different immunohisto-
chemical phenotype.
Genetic profile
PTCH mutations have been reported in
CEOT, but the tumour is nota component
of naevoid basal cell carcinoma syn-
drome {1843) .
Prognosis and predictive factors
Although the tumours infiltrate medullary
bone, they are not as biologically aggres-
sive as ameloblastoma. Most cases are
treated with local surgical removal, and the
overall recurrence rate is about 15% {759).
Adenomatoid
odontogenic tumour
Wright J.M.
Kusama K.
Definition
Adenomatoid odontogenic tumour (AOT)
is a benign epithelial tumour that shows
duct-like structures.
ICD-0 code 9300/0
Epidemiology
AOTs account for < 5% of odontogenic
tumours {520,1875) and occur twice as
frequently in females as in males. They
have a strong predilection for individu-
als in their first three decades of life,
with about two thirds of all cases occur-
ring in teenagers and 87% of all cases
occurring in the second or third decade
of life {1880,1987). Tumours occurring in
patients older than their mid-30s are dis-
tinctly uncommon {1882} .
Benign epithelial odontogenic tumours
Fig. 8.29 Follicular adenomatoid odontogenic tumour
(asterisk) in the anterior maxilla of a 16-year-old girl.
Localization
More than 95% of AOTs are intraosseous,
but extraosseous variants have been
documented. The tumours are twice as
common in the maxilla as in the mandi-
ble and have a very strong predilection
for the anterior jaws. About three quar-
ters of cases occur in association with
unerupted teeth in a pericoronal relation -
ship, which has led sorne authorities to
subclassify the tumours as follicular or
extrafollicular. Unerupted canines are af-
fected in about 60% of cases {1875 ,1880,
1882,1987}.
Clinical features
AOTs have limited growth potential and
are considered by many to be hamar-
tomas. Patients are invariably asympto-
matic, and bony expansion may or may
not be present. On imaging, the tumours
tend to be well defined and symmetrical.
The lesions progress to produce cortical
expansion slowly, but in about two thirds
of cases, small foci of radiopacity can be
detected. AOTs can be radiographically
indistinguishable from dentigerous cysts,
unless they extend apically beyond the
cementoenamel junction of the affected
tooth. Teeth are frequently displaced but
root resorption is rare . The lesions slowly
221
progress to produce cortical expansion,
but cortical perforation is unusual. Extra-
osseous variants produce gingival swell -
ings without characteristic features.
Macroscopy
Most AOTs enucleate and are smooth,
rounded, symmetrical masses. On cut
surface, the lesions range from solid to
cystic, and fol licular lesions often contain
the affected tooth.
Histopathology
The tumours tend to be encapsulated
but produce a variety of architectural
patterns, most notably multiple, variably
sized nodules of nondescript to spin-
dled epithelial cells with minimal stroma.
Within these nodules are variably sized
rosette- or duct-like spaces, from wh ich
the tumour gets its name. These are
lined by a columnar or cuboidal epithe-
lium, with the nuclei tending to be dis-
placed away from the lumen. In sorne
tumours, the duct-like spaces can be
Benign mixed epithelial and
mesenchymal odontogenic tumours
Ameloblastic fibroma
Muller S.
Vered M.
Definition
Ameloblastic fibroma (AF) is a rare, be-
nign, true mixed tumour composed of
odontogenic mesenchyme resembling
dental papilla and epithelial tissue re -
sembling odontogenic epithelium, in
which no dental hard tissues are present.
ICD-0 code 9330/0
Epidemiology
AF constitutes 1.5-6.5% of all
odontogenic tumours 1293,1879). The
mean patient age is 14.9 years (range:
7 weeks to 57 years) 1293,1653). Most
222 Odontogenic and maxillofacial bone tumours
inconspicuous. There is frequently eosin-
ophilic material within the tumour, most
likely constituting a secretory product of
the tumour. There are often patterns of
anastomosing lamina-like cords of tu-
mour cells in a plexiform pattern, which
is more prominent at the periphery. Small
foci of calcification are frequently seen ,
and this phenomenon has been likened
to an abortive attempt at enamel matrix
secretion. Sorne tumours contain larger
areas of calcified matrix, sorne of which
has been reported to be dentinoid or
cementoid. Many tumours contain mac-
rocystic or variably sized microcystic
areas.
AOT and AOT-like areas have been
recognized with other odontogenic tu-
mours, such as odontomas, adenoma-
toid dentinoma, and calcifying epithelial
odontogenic tumour (CEOT). More than
25 cases of AOT/CEOT have been re-
ported, and sorne authors recommend
the designation "combined epithe-
lial odontogenic tumour" 11882}, but the
Fig. 8.30 Ameloblastic fibroma of !he righl mandible in a 12-year-old palien!, presenting as a multilocular radiolucency
with sclerotic border. The first molar is impacted and displaced, !he tooth bud of !he second premolar is displaced, and
!he roots of !he primary second molar are resorbed.
current consensus is that the CEOT-like
areas are simply part of the histological
spectrum of AOT 11654,1875).
lmmunophenotype
The Ki-67 index and BCL2 index are
lower in AOT than in sol id ameloblastoma
11964). The expression of amelogene-
sis-related proteins such as odontogenic
ameloblast-associated protein, amelotin,
ameloblastin, and amelogenin 1496}, as
well as TGF-beta 1 / SMADs 11185}, has
been shown to be more intense in AOT
than in ameloblastoma. Strong cytoplas-
mic expression of beta-catenin has been
demonstrated, although no molecular
anomaly within the beta-catenin gene
(CTNNB1) is evident 1941). These find-
ings may reflect the hamartomatous be-
haviour of AOT.
Prognosis and predictive factors
AOTs are encapsulated and they invari-
ably enucleate. Recurrence rates are ex-
ceedingly low.
 ... , .- .. .
......
.., '
; .....*".
_......... . ~-"'..
; 1-. "' •
.•/ . ,~
..
" ~-;
.. , .
..
,. -·..
,· ' ·'
.. .
A. .
~
Fig. 8.31 Ameloblastic fibroma. A A long strand of odontogenic epithelium showing a bilayer of ameloblastic-looking cells; the edges become thickened and rounded, imparting a
so-called drumstick appearance. B The epithelial componen! resembles the enamel organ in that the peripheral cells are columnar, have hyperchromatic nuclei in reverse polarity,
and have a palisading pattern. The peripheral cells enclose a central core that resembles the stellate reticulum; the connective tissue is cell-rich.
tumours (80%) occur in patients younger
than 22 years (i.e . before the end of
odontogenesis). The male-to-female ratio
is 1.4:1.
Localization
The ratio of mandibular to maxillary locali-
zation is 3.3:1. The posterior area of the
jaws is the most common location (affected
in 82% of cases), particularly the mandible
(74%); a minority of cases occur in either
the anterior region or both the posterior
and anterior regions (-10% each) {293)
Clinical features
AFs are usually slow-growing, painless
tumours. They can cause jaw expansion
and (rarely) reach remarkable size, with
facial deformity Radiographically, AF is an
incidental finding in 12% of cases, but the
majority (56%) present as well-defined,
usually small, unilocular radiolucencies
{293) . Multilocular tumours are frequently
associated with larger lesions. Association
with an impacted tooth (usually a first or
second permanent molar) is seen in 80%
of cases. Root resorption and cortical
perforation are uncommon.
Macroscopy
The tumour is a solid, possibly encapsu-
lated mass with a smooth outer surface.
Histopathology
The mesenchymal component is myxoid
and cell-rich and resembles the dental
papilla of the tooth bud. The epithelial
component can demonstrate a pattern
of narrow, elongated strands of two tight
and parallel-running layers of cuboidal to
columnar cells. Towards the edges, there
are occasional thickenings, with a stellate
reticulum-like area notable between the
peripheral cuboidal cells. The epithelial
component can also show a pattern re-
sembling the follicular stage of the enam -
el organ. A collagenous capsule may be
observed . On the basis of histopatho-
logical features, it is not possible to dis-
tinguish between AFs (true neoplasms)
and early-stage odontomas befare they
differentiate and mature {290,293). How-
ever, rare AFs show formation of dental
hard tissues and reach an exceptional
size.
These lesions have been referred to as
ameloblastic fibrodentinomas or amelo-
blastic fibro-odontomas {293), but are
most likely developing odontomas.
Genetic profile
lnitial investigations found BRAFV600E
mutation (in 2 cases {279)) and a low
frequency of fractional allelic loss of
tumour suppressor gene loci {805).
Prognosis and predictive factors
Small, asymptomatic tumours, especially
in young children, are removed conserv-
atively; however, ultraconservative treat-
ment might result in recurrence, which
occurs in about 16% of cases. Extensive,
destructive tumours should be treated
radically. Sarcomatous transformation is
rare, although about 50% of such cases
are reported to have developed in the
setting of a recurren! AF {38,1327).
Benign mixed epithelial and mesenchymal odontogenic tumours
Primordial odontogenic tumour
Mosqueda-Taylor A.
Neville B.W.
Definition
Primordial odontogenic tumour is a
tumour composed of variably cellular
loose fibrous tissue with areas similar to
the dental papilla, entirely surrounded
by cuboidal to columnar epithelium re-
sembling the interna! epithelium of the
enamel organ .
Epidemiology
This is a recently described tumour, with
only 7 cases reported to date. The re -
ported patient age range is 3-19 years,
with a mean patient age of 12.5 years
and no sex predilection {1659,2206).
Localization
Primordial odontogenic tumour occurs
intraosseously, with a marked preference
for the mandible; the ratio of mandibu lar
to maxillary incidence is 6:1.
Clinical features
All cases have been found as well-de-
fined radiolucencies associated with an
unerupted tooth (most commonly the lower
third molar), producing an apparent peri-
coronal relationship on radiographical im -
age. Most primordial odontogenic tumours
are asymptomatic, but they may cause
cortical expansion with displacement and
root resorption of neighbouring teeth.
223
 e
Fig. 8.32 Primordial odontogenic tumour. A,B Well-defined radiolucencies surrounding and displacing an embedded tooth; note in both cases the resorption of the roots of adjacent
molar teeth. Reprinted from Mosqueda-Taylor A et al. {1659). C Macroscopic aspee! of the tumour shown in panel B, with adjacent removed teeth; salid white mass with no evidence
of cystic changes. Note the tooth displaced towards the periphery of the tumour (top}.

, -:. ::~""> ·: -,:.~. : ":. ::. ~. ~ : :,< ;'

Fig. 8.33 Primordial odontogenic tumour. A Loase and myxoid-appearing fibrous tissue with scattered fusiform and stellate fibroblasts forming the central area of the
tumour. B Loase fibrous tissue covered over its entire surface by columnar epithelium surrounded by a fibrous capsule. Reprinted from Mosqueda-Taylor A et al. {1659).
C Tumour composed of variably cellular mesenchymatous-appearing tissue, entirely surrounded by columnar or cuboidal epithelium. Tangential sectioning shows epithelial nests
clase to the surface epithelium.

Macroscopy
The crown of the adjacent tooth was
embedded in the tumour in 3 of the
reported cases; in the other 4 cases, the
associated teeth were easily detached
from the tumours. All lesions were well
circumscribed and solid , forming multi -
lobulated whitish masses, with no cystic
spaces on sectioning .
Histopathology
The tumour is composed of loose fi-
brous tissue containing variable num -
bers of fusiform and stellate fibroblasts,
with minimal collagen production . Sorne
areas have the appearance of cell-rich
mesenchymal tissue. A characteristic
finding is that the entire periphery of the
tumour is covered by columnar or cuboi-
dal epithelium , which in sorne areas
shows scant, superficial layers of fusi -
form cells surrounded by a thin fibrous
capsule. Occasionally, epithelial islands
or cords are seen within the lesion as a
result of tangential sectioning , due to the
infolding of the surface. No evidence of
odontoblastic differentiation or dentine
has been found to date. The tumour mes-
enchymal cells are positive for vimentin
and negative for alpha-SMA , desmin,
8100, and CD34. The Ki-67 index is very
low (< 2%). The epithelial componen!
is strongly positive for pancytokeratins
(AE1/AE3), CK5, and CK14, whereas
CK19 is variably expressed by columnar
cells. Given the relatively young palien!
age al presentation of ali cases and the
apparent relationship of the lesion with
unerupted teeth, the tumoural tissue may
constitute a mesenchymal proliferation
very similar to the dental papilla of a de-
veloping tooth .
Prognosis and predictive factors
The tumours are cured by local excision ,
with no recurrences reported after follow-
up of 6 months to 20 years.
Odontoma
Vered M.
Fowler C.B.
Neville B.W.
Soluk Tekke:?in M.
Definition
Odontomas are mixed epithelial and
mesenchymal tumour-like malformations
(hamartomas) composed of dental hard
and soft tissues. They are subdivided
into compound odontoma and complex
odontoma.
ICD-0 codes
Odontoma 9280/0
Odontoma, compound type 9281/0
Odontoma, complex type 9282/0
Epidemiology
Odontomas are the most common odon-
togenic tumours. They are typically diag-
nosed during the first two decades of life
and have no sex predilection 12235}.
Etiology
The etiology is unknown, but genetic muta-
tion in a tooth germ is a possible factor (956 ,
1898,2731 }. Lesions formerly designated as
ameloblastic fibro-odontoma probably rep-
resen! immature stages of complex odon-
toma in most instances.
Localization
Although odontomas can occur in any
tooth-bearing area, compound odontomas
are mainly located in the anterior maxilla,
whereas complex odontomas are found
most often in the posterior mandible, fol-
lowed closely by the anterior maxilla 12235).

224 Odontogenic and maxillofacial bone tumours

 -.....__
\

"'---...~ ~

B
Fig. 8.34 Compound odontoma. A Compound odontoma located between the rools of the canine and second Fig. 8.37 Compound odontoma. Microscopic section
premolar; the first premolar is impacted and displaced; the radiopaque product appears as tooth-like structures. shows structures reminiscent of single-moled, small
B Macroscopic view shows numerous rudimentary teeth of various shapes and sizes. teeth.

The radiological features of compound

odontomas are frequently diagnostic,
although complex odontomas may be
confused with other highly calcified bone
lesions l2309l.

Macroscopy
Compound odontomas usually appear
as a cluster of white , tooth-like structures
or denticles of varying size and shape.
B Complex odontomas appear asan amor-
Fig. 8.35 Complex odontoma. A Complex odontoma associated with an impacted maxillary third molar; the radiopaque phous, white, bony, hard mass. Both may
product consists of a mostly homogeneous mass of calcified tissue. B Macroscopic view shows an irregular hard mass be surrounded by varying amounts of
attached to a molar tooth. capsule-like, tan-coloured soft tissue.

Clinical features Radiographically, odontoma is typically Histopathology

Odontomas are frequently associated
with an unerupted tooth and are usu -
ally detected on routine radiographs. Al-
though asymptomatic, they may become
secondarily inflamed due to trauma or
eruption , and they can cause impaction,
malposition, diastema, aplasia, malfor-
mation, and devitalization of adjacent
teeth. The diameter ranges from < 1 cm
to 6 cm, with larger odontomas produc-
ing expansion of the jaws. Multifocal od-
ontomas have been reported j2309l
located between roots or over the crown
of an impacted tooth and presents as a
well-demarcated radiopacity surround -
ed by a thin soft tissue capsule and an
adjacent corticated !ayer of bone. The
radiopaque product in compound od-
ontomas consists of numerous tooth-like
structures, whereas in complex odonto-
mas it consists of a disorganised mass
of calcified tissue. An early-stage (devel-
oping) odontoma may appear as a radio-
lucency with focal areas of calcification.
Compound odontoma consists of multi -
ple rudimentary teeth exhibiting dentin,
cementum, enamel matrix, and pulp. Ad-
jacent fibrous connective tissue consist-
ent with dental follicle is often present.
Early-stage odontomas show tissue that
resembles a developing tooth germ, with
little mineralized product. Mature com-
plex odontomas consist primarily of tubu -
lar dentin that encloses zones of enamel
matrix; reduced enamel epithelium with
occasional scattered ghost cells may

... :.-~ ~}\t.:~.. '

.-,.0·

Fig. 8.36 Complex odontoma. A Section alter decalcification shows a conglomerate of dentin admixed with small areas of enamel matrix (arrows); clefls or hollow circular structures
(asterisks) represen! the mature enamel that was removed during demineralization. B Enamel matrix (asterisk) and partially decalcified enamel (upper-right) surrounded by reduced
enamel epithelium (arrow).

Benign mixed epithelial and mesenchymal odontogenic tumours 225

surround clefts or hollow circular struc-
tures, which represent mature enamel that
was removed during demineralization.
A thin layer of cementum is often pres-
ent at the periphery of the mass. The soft
tissue capsule, if present, often includes
immature connective tissue with cords
or islands of ameloblastic epithelium - a
pattern similar to that seen in ameloblas-
tic fibroma (2235) Rarely, an ameloblas-
toma may arise in association with an
odontoma; such cases have historically
been called odontoameloblastoma, an
entity dropped now (1655)
Genetic susceptibility
Multifocal odontomas or supernumerary
teeth may occur in patients with Gardner
syndrome (familia! colorectal polyposis).
Prognosis and predictive factors
Odontomas are removed by conserva-
tive surgery, due to their low growth
potential. Recurrence after complete
removal is unusual. The prognosis is ex-
cellent (2235).
Dentinogenic ghost ce//
tumour
Carlos R.
Ledesma-Montes C.
Definition
Dentinogenic ghost cell tumour (DGCT)
is a benign but locally infiltrating neo-
plasm of odontogenic epithelium. lt has
biphasic morphology, consisting of a
predominant ameloblastomatous prolif-
eration and a less prominent component
- - -- --- - - , . ._.._,__ - - - - -
Fig. 8.39 Dentinogenic ghost cell tumour. A Tumour in a 24-year-old woman displaying a large number of ghost cells and only focal areas of dentinoid. B Tumour composed mainly
of basaloid cells, with large areas of dentinoid formation and a relatively small number of ghost cells, affecting an 11-year-old boy; for additional features of this tumour see Fig. 8.40.
226 Odontogenic and maxil lofacial bone tumours
Fig. 8.38 Dentinogenic ghost cell tumour. Unilocular radiolucent- radiopaque lesion with well-defined borders in a
60-year-old woman.
of basaloid to stellate reticulum cells . The
tumour characteristically contains aber-
rant keratinization, with a variable number
of ghost cells and material morphologi-
cally resembling dentinoid or osteodentin
(289,1648,2307).
ICD-0 code
Synonym
Calcifying ghost cell odontogenic tumour
Epidemiology
DGCT is the rarest of the ghost cel l le-
sions, accounting for < 3% of all cases
(1357). Approximately 45 cases have
been reported , with more than half occur-
ring in Asian patients (556). The tumour
is twice as common in men as in women ,
with peak incidence in patients aged 40-
60 years (556) The reported patient age
range is 11-79 years (mean: 39.7 years)
(30 ,556).
- - - ~.~¿~:te
Localization
The most frequentl y affected intraosse-
ous sites are the posterior maxilla and
mandible, and there is a slight predilec-
tion for the mandible (affected in 53% of
cases) (289). Sporadic peripheral cases
have been reported in the gingiva and al -
9302/0 veolar mucosa (323 ).
Clinical features
Most patients with DGCT present with
progressive swelling caused by cortical
bone expansion . Radiographically, 78%
of lesions are unilocu lar and 22% are
multilocular. Most lesions are mixed ra-
diolucent and radiopaque (78%) or com -
pletely radiolucent, and most (68%) have
well-defined borders. Poorly defined
borders are seen in 32% of the reported
cases with available radiological informa-
tion. Pain occurred in 52% of the cases ,
whereas the other 48% were completel y
asymptomatic. Root resorption is thought
to be present in approximately 18% of
cases; however, this figure may in fact be
-. ~
_.....,.
higher, as most reports do not mention
this finding. DGCT can occasionally be
associated with an odontoma {289,1076,
1154,1357\.

~
Macroscopy
}!~ -
The tumours are salid, with macroscopic
areas of calcification . Microcystic areas
4·:/!¡. ·P.·.("¿~ , . • . -- .
~
~/,-..jJ¡l~ . ~:.~
may be present. but they do not con -
.... ' .
1fti>~
~ ~ ~
~'l• ~~
stitute a significant area of the tumour,
generally accounting far < 5% of the re-
.. ~ •• .,; ~ ··~ .~ :~-
'I • L
Cf' • '

sected specimen.
Histopathology
The main histological componen! is od -
ontogenic epithelium, with areas closely
resembling ameloblastoma. Microcystic
spaces can be present within the epithe-
lium. Sorne tumours have a significan!
componen! of basaloid hyperchromatic
and isomorphic cells, displayed in sheets.
Mitotic figures are rare. A striking feature
is the presence of aberrant keratinization
with occasional calcification - the so-
called ghost cells, which are present in
variable numbers. When the keratinized
cells come in contact with the connective
tissue, an inflammatory fareign body re-
action with multinucleated giant cells can
be elicited. Dentinoid or osteodentin-like
material is farmed directly adjacent to the
epithelial cells, which are often trapped
in small groups within this otherwise acel -
lular material. These trapped cells may
have clear cytoplasm. Mature connec-
tive tissue may be admixed with the main
odontogenic epithelial componen! of the
tumour. Special care must be taken to
distinguish DGCT from ameloblastoma
with ghost cells, a phenomenon well de-
scribed in ameloblastomas and other od-
ontogenic lesions {289,323,1648,2307\.
The proportion of ghost cells (> 1-2%)
and the presence of dentinoid are impor-
tant features in establishing the diagnosis
of DGCT.
True dentinoid is difficult to prove as part
of this tumour, and in sorne instances it
may represent hyalinization or induction
of the adjacent connective tissues as a
result of signal ling from the odontogenic
ep ithelium. The epithelial ce lls can ex-
press CK5, CK7, CK14, and CK19. The
Ki -67 proliferation index is < 5%. CD138
(also called syndecan-1) and MMP9 pro-
tein expression have been assessed in
tumour and stromal cells, but the num-
ber of cases is limited and expression is
varied; more studies are necessary to es-
tablish the roles of CD138 and MMP9 in
the locally invasive nature and biolog ical
behaviour of this tumour {868,874\.
Prognosis and predictive factors
Due to the small number of reported
cases, conclusions cannot be drawn
regarding the optimal treatment op -
tion far DGCT. However, treatment is
known far 40 of the 45 reported cases.
·"-'"'~ . . .~
" lC~
.
. ..,,.( 1
~
'' " . ' '
In 21 cases, conservative surgery (i.e.
enucleation, curettage, or simple exci-
sion) was perfarmed, with a recurrence
rate of 73% after a follow-up period of
1-20 years. In the 19 reported cases
treated with more radical surgery (i.e.
marginal or segmenta! resection), the
recurrence rate was 33% after a follow-
up period of 2'. 1 year. There is a single
case report of malignant transformation
occurring after five recurrences. On the
basis of the limited number of cases,
the recommended surgical treatment is
segmenta! resection (i .e. wide local re -
section), perfarmed in a manner simi lar
to that recommended far ameloblasto-
mas. Long -term postsurgical follow-up
is necessary. Peripheral (extraosseous)
tumours are managed by simple exci-
sion , and recurrences are rare {289,323,
1357,2307\.

Benign mixed epithelial and mesenchymal odontogenic tumours 227

Benign mesenchymal odontogenic
tumours
Odontogenic fibroma
van Heerden W.F.P.
Kusama K.
Neville B.W.
Definition
Odontogenic fibroma is a rare neoplasm
of mature fibrous connective tissue, with
variable amounts of inactive-looking od-
ontogenic epithelium , with or without
evidence of calcification . There are two
clinical variants: intraosseous or central
odontogenic fibroma and extraosseous
or peripheral odontogenic fibroma.
ICD-0 code 9321/0
Epidemiology
Central odontogenic fibroma has a wide
patient age range and a slight female
predilection. Peripheral odontogenic fi-
broma is more common than central
odontogenic fibroma, occurs twice as
frequently in females as in males, and
has an age peak in the second to fourth
decades of life 1673,1657}
Localization
Odontogenic fibroma occurs with rela-
tively equal frequency in the maxilla
and mandible. Most maxillary central
odontogenic fibromas occur anterior to
the first molar, whereas about half of all
mandibular central odontogenic fibromas
are found posterior to the first molar 1673,
1657}. Peripheral odontogenic fibromas
tend to be more common in the anterior
gingival regions 1673}. Small radiolucen-
cies with central odontogenic fibroma-
like features sometimes occur arou nd
crowns of impacted teeth, but these
should be considered hyperplastic den-
tal follicles rather than true neoplasms.
Clinical features
Small central odontogenic fibromas are
often asymptomatic , although larger tu-
mours may present with pain, bony ex-
pansion, and loosening of teeth . Small
central odontogenic fibromas usually
228 Odontogenic and maxillofacial bone tumours
t· ., ~o~· -•\ ··';F
~
·?' - ~
". .
! \, ttthJ'l: ~
I~ ' ~
.....
Fig. 8.41 Central odontogenic fibroma . Radiograph of
left mandible showing well-defined radiolucency with
radiopacities.
present as well-defined unilocular ra-
diolucencies, but larger tumours may
become multilocular. Corticated margins
are often present. Divergence or resorp-
tion of the roots of adjacent teeth may be
noted. Peripheral odontogenic fibroma
usually develops as a slow-growing, ses-
sile gingival mass with an intact mucosa!
surface.
Histopathology
Central odontogenic fibroma is composed
of moderately cellular or collagenous
connective tissue with varying amounts
of inactive-looking odontogenic epithe-
lial islands or strands. The epithelium may
vary from being totally absent to being
a conspicuous feature. Hard tissue for-
mation may be present, with features of
mineralized dentinoid or cementum-like
calcifications associated with the odonto-
genic epithelium. A well-defined capsule
is rare. Similar features are seen in periph-
eral odontogenic fibroma.
Central odontogenic fibroma with amyloid-
like protein deposition and central odon -
togenic fibroma associated with a central
giant cell granuloma have been described
as rare variants 1673,2689}.
An unusual tumour, called granular cell od-
ontogenic tumour, has been reported and
is considered to be a variant of central od-
ontogenic fibroma. lt is composed of stro-
mal granular cells, with variable amounts
of odontogenic epithelium 12077}
Sclerosing odontogenic carcinoma may
share sorne histological features with
central odontogenic fibroma and should
be considered in the differential diag-
nosis. However, sclerosing odontogenic
carcinoma is characterized by an infil-
trative pattern and prominent perineural
infiltration.
Prognosis and predictive factors
Central odontogenic fibroma is usually
treated by enucleation and curettage,
which sometimes requires removal of
adjacent involved teeth. Recurrence is
uncommon. Peripheral odontogenic fi -
broma is treated by surgical excision,
which should probably extend down to
the periosteum, because a recurrence
rate of 50% has been reported 11994}.
Odontogenic myxoma/
myxofibroma
Odell E.W
Adebiyi K.
Definition
Odontogenic myxoma is a benign odon-
togenic neoplasm characterized by stel-
late and spindle-shaped cells dispersed
in an abundant myxoid extracellular ma-
trix. When a greater amount of collagen
is evident, the term "odontogenic myxofi-
broma" may be used.
ICD-0 code
Epidemiology
In most studies, odontogenic myxoma
is the third most frequent odontogenic
tumour (after odontoma and ameloblas-
toma) !291,1763,2332). lt has been esti-
mated to account for 2- 5% of cases in
Africa !1763}, China !1137}, and the USA
!291). The patient age range of reported
cases is 1-73 years, with most cases di-
agnosed in the second to fourth decades
of life !1549) In most series , odontogenic
myxoma is up to twice as common in fe-
males as in males !1549,1744}, but not in
all African populations !1763)
Localization
Two thirds of odontogenic myxomas are
located in the mandible, and one third in
the maxilla !1549). Odontogenic myxo-
mas are most common in the molar re-
gions. Maxillary lesions tend to obliterate
the maxillary sinuses as an early feature ,
and expansion is an early and consisten!
feature in ali. Very occasional cases have
been reported to occur extraosseously in
the gingiva !1960).
Clinical features
Odontogenic myxomas are asympto-
matic radiolucencies when small and
cause painless expansion with continued
growth. Cortical perforation may develop
when they are large. Unilateral sinonasal
obliteration may mimic nasal polyposis.
Radiographically, odontogenic myxomas
appear as unilocular or multilocular ra-
diolucencies, sometimes showing a fine
soap-bubble or honeycomb appearance,
occasionally with fine straight tennis-
racket trabeculations !1744). The margins
of the tumour appear well defined and
corticated on routine radiographs, but
these provide inaccurate representations
9320/0 of the actual anatomical limits, which
are relatively diffuse and better defined
by CT or MRI !1219). Root displacement
occurs, as does root resorption. Larger
odontogenic myxomas may present with
a periosteal reactive bone layer.
Macroscopy
Gross examination reveals a greyish-
white mass with a typical translucent
mucinous appearance. The consistency
varies from gelatinous to firm, depending
on the amount of collagen present, and
fine white bands of collagen may be vis-
ible on the cut surface.
Histopathology
Odontogenic myxoma consists of ran-
domly oriented stellate, spindle -shaped,
and round cells with long, fine, anas-
tomosing, pale or slightly eosinophilic
cytoplasmic processes. The cells are
evenly dispersed in an abundan! alcian-
ophilic myxoid ground substance that
characteristically contains minimal fine
collagen fibres. Binucleated cells, mild
pleomorphism, and mitotic figures may
occur and can mimic atypia !136). Sorne
odontogenic myxomas (designated myx-
ofibromas) produce collagen fibres, but
these lesions always retain sorne degree
of prominent ground substance on Alcian
blue staining. There is no evidence that
the myxofibromatous variant behaves
differently.
Histochemistry and immunochemistry
revea! the ground substance to be rich
in acid mucopolysaccharide, primarily
hyaluronic acid , and to a lesser degree
chondroitin sulfate. Orosomucoid 1 pro-
tein is consistently overexpressed !812).
Dispersed microscopic rests of odonto-
genic epithelium are present in about 5%
of lesions !1549) and are not required for
histological diagnosis.
Histologically, odontogenic myxoma is
almost identical to the dental papilla of
a developing tooth, normal dental fol-
licle, and myxoid enlarged or so-called
hyperplastic dental follicle. Misdiagnosis
of these entities should be avoided by
correlation with the clinical and radio-
graphical features !1227). For maxillary
cases, confusion with nasal polyps is a
risk. Because any odontogenic tumour
forming dental hard tissues can contain
areas of follicle and dental papilla-like
tissue, areas similar to myxoma can be
found as a componen! of many odonto-
genic tumours , particularly primordial
odontogenic tumour !1659).
Odontogenic myxoma permeates the
surrounding medullary spaces of bone,
driven by matrix secretion rather than
cellular infiltration. This produces a pseu-
domalignant growth pattern, so the dif-
ferential diagnosis may include myxoid
nerve sheath tumours , chondromyxoid
fibroma, low-grade myxofibrosarcoma,
and other myxoid sarcomas. However,
the histological appearance of odonto-
genic myxomas is generally distinctive.

Fig. 8.43 Odontogenic myxoma in the body of the mandible, showing thin expanded cortex and bony sepia in bone Fig. 8.44 Odontogenic myxoma. Radiograph showing
window (left) and low soft-tissue density (centre). The high proton density resulting from the high water content in the a myxoma in the posterior mandible, with characteristic
myxoid tissue gives a hyperintense signa! on T2-weighted MRI (right}. straight and criss-crossing sepia.

Benign mesenchymal odontogenic tumours 229

 '~·. ,.-~~.
M~· - ~
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-.-...' .; ·~ '·} ·
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-' ~ ~ ·~ -~ -....1....~ ::;~l ~~ · ·~ -,. ·, ~ .

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\.'+'' . :t .~ ~\ ~· - ~ ' \\~~.. "\ - - . .... "
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..... t~~· 1' .·.~ r\ ~'· ... ;é '\
·\ ,~ . ~-~-.:"-:'"":,;~
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'. I ~\ .. \ •.' \.., .
~~-- -'"'- - ~ .iJL~ ~~~ ~~~ \ ~-;-·'{- -·~' ·~--~· -:·· ~~ : .:. <~ \' . :..~;~~-~"' -~__ \ \' ~\ · l.: i\· 2~~-.~ - -.
A Typical appearance with randomly oriented stellate, spindle-shaped, and round cells with long cytoplasmic processes in a myxoid matrix.

Genetic profile Cementoblastoma mean of 20.7 years . Three quarters of

Odontogenic myxoma has been associ -
ated with tuberous sclerosis {946) and
naevoid basal cell carcinoma syndrome
{2146) in isolated cases but is not geneti -
cally related to Carney complex or other
soft tissue myxomas or their associated
syndromes {870).
Prognosis and predictive factors
The permeative margin makes effective
curettage difficult. Small lesions are usual-
ly treated conservatively by curettage, with
the expectation of low risk of recurrence,
but larger lesions require complete exci-
sion with free margins {228). Recurrence
rates in various studies average about
25%, but the prognosis is good . Recur-
rence usually follows incomplete removal
within 2 years, but may occur much later.
A single case of possible malignan! be-
haviour has been reported {1800). but
there are no accepted criteria to define
malignancy, and large benign lesions may
prove difficult to eradicate without radical
surgery.
patients are aged < 30 years {260,633).
El - Mofty S.K. The sex distribution varíes among dif-
ferent series, from male predominance
to equal distribution to female predomi -
Definition nance {633).
Cementoblastoma is a distinctive benign
odontogenic tumour that is intimately as- Localization
sociated with the roots of teeth. lt is char- The mandibular molars and premolars
acterized by the formation of calcified are the most common siles of cemento-
cementum -like tissue, which is deposited blastoma, with > 75% of the cases oc-
directly on a tooth root. curring in this location. The maxillary mo-
lars and premolars are the second most
ICD-0 code 9273/0
Synonyms
Benign cementoblastoma;
true cementoma
Epidemiology
Cementoblastoma is a relatively rare
tumour, accounting for 1-6% of ali od-
ontogenic tumours {1487,1656) . Only Fig. 8.47 Cementoblastoma. Radiograph showing
about 100 cases have been reported in a cementoblastoma associated with the roots of
the literature to date {260). The reported !he mandibular second molar and obliterating sorne
patient age range is 8-44 years, with a radiographical details of the roots .

230 Odontogenic and maxillofacial bone tumours

 -.-1
.~:!;2::~ .-:.: ¡~~¿~~: ·...;"'
1j• ZT rrc:.
Fig. 8.48 Cementoblastoma. A Thick trabeculae of cementum attached to a tooth roo!. B Radiating columns of calcified matrix rimmed with plump cementoblasts al the periphery
of the lesion.
common site. Association with primary
teeth is very rare {260,633).
Clinical features
Cementoblastoma is associated with
buccal and lingual/palatal expansion
of the affected bony cortical plates. A
characteristic feature is pain, commonly
described as sharp and similar to tooth-
ache. The tumour is slow-growing but
can attain a large size if left untreated
{633,1123) .
The radiographical appearance is char-
acteristic and almost pathognomonic.
The tumour presents as a well-defined
radiopaque mass that obliterates the ra-
diographical details of the root of the af-
fected tooth. A thin radiolucent zone sur-
rounds the central opacity. Cortical plate
expansion and deviation of the surround-
ing teeth roots occur as the tumour grows
{260,633).
Macroscopy
Grossly, cementoblastoma presents as
a calcified mass that is adherent to the
root or roots of a tooth and surrounded
;
:·
,.,/ .,
' ·1 ' .,'~~~-~í~
"' ,/1
·-"
·,- -~~_."'-' "
~: :""J~ .,~ ,~>\tt) <i,.
l"~f".~ \""~ .:-~~~~ ~ .- '
~~
~~""l , ,,,.~
~
by a grey to tan layer of irregular soft tis- they do not originate from the surface of
sue. The tumours are usually excised in- the roots and do not adhere to it.
tact with the tooth, with an average size
of 2.0 cm. Prognosis and predictive factors
lncomplete removal commonly leads to
Histopathology recurrence {1123).
Calcified cementum -like tissue is de-
posited in thick trabeculae on an intact
or partially resorbed root. The formed Cemento-ossifying fibroma
cementum is strongly basophilic and
shows numerous irregular reversa! lines Odell E.W.
resembling Paget disease of bone (os-
teitis deformans). Plump, active-looking
cementoblasts rim the trabeculae, which Cemento-ossifying fibroma (COF) is a
are present in fibrovascular stroma with distinct type of ossifying fibroma that
numerous dilated vessels and occasion- occurs in the tooth-bearing areas of the
al clusters of multinucleated osteoclast- jaws and is believed to be of odonto-
like cells. Characteristically, radiating genic origin. lt is a benign fibro-osseous
columns of uncalcified matrix surfaced lesion and is discussed in more detail in
with plump cementoblasts and inter- the Ossifying fibroma section on pages
spersed with fibrovascular tissue are 251-252.
present at the periphery of the densely
calcified mass. These peripheral micro- ICD-0 code 9274/0
scopic fields of cementoblastoma bear
significant resemblance to osteoblasto-
ma. Although osteoblastomas of the jaws
may grow to envelop the roots of teeth,
Benign mesenchymal odontogenic tumours 231
Odontogenic cysts of
inflammatory origin
Radicular cyst
Definition
Radicular cyst is an odontogenic cyst of
inflammatory origin associated with non-
vital teeth. A residual cyst is a radicular
cyst that remains in the jaws after extrac-
tion of the affected tooth.
Fig. 8.49 Radicular cyst. Typical radiographical appear-
ance of a well-demarcated radiolucency at the apex of a
non-vital tooth that has been roo! treated.
Fig. 8.50 Radicular cyst. A residual cyst appears as
corticated radiolucency at the site of previous tooth
extraction.
Synonyms
1nflammatory dental cyst; dental cyst;
periapical cyst; apical periodontal cyst
Epidemiology
Radicular cysts are the most common
cyst of the jaws and account for about
55% of all odontogenic cysts {1145 ,1149).
They occur over a wide patient age
232 Odontogenic and maxillofacial bone tumours
Fig. 8.51 Radicular cyst. A An infiamed fibrous wall lined by hyperplastic arcading epithelium; foamy histiocytes
(arrows) are seen in the infiltrate. B A nodule of cholesterol clefts .
.
:, ·
•.:.
~:r:~1~
Fig. 8.52 Radicular cyst. Focal accumulation of hyaline bodies in the epithelial lining.
range, with peak incidence in the fourth
and fifth decades of life. A slight male
predilection has been reported {1149).
Etiology
The epithelial lining derives from prolifer-
ation of the remnants of the Hertwig epi-
thelial root sheath (epithelial cell rests of
Malassez) in the periodontal ligament as
a result of inflammation following pulpal
necrosis, usually due to dental caries. A
cyst cavity is formed, which enlarges as
a result of hydrostatic pressure accom-
panied by bone resorption.
Localization
The maxilla is the most common site,
with 50% of cases arising in the anterior
region {1149). Radicular cyst is almost
always located at the tooth apex , but a
lateral rad icular cyst may be associated
with a lateral root canal.
Speight P.
Soluk Tekke~in M.
···.·;
'!: .•:·.
Clinical features
Many radicular cysts are symptomless
and discovered incidentally on radiologi-
cal examination of a carious or non-vital
tooth. Overall, radicular cyst is probably
the single most common cause of expan -
sion of the jaws. Radiographs show a
round or oval , unilocular, well-demarcat-
ed radiolucency at the apex of a tooth ,
usually about 1-2 cm in diameter. Large
lesions can also occur. Residual cysts
are found as well-defined radiolucen-
cies at a site of previous tooth extraction.
Radicular cyst is always associated with
a non-vital tooth, and this is an important
criterion for diagnosis.
Histopathology
Radicular cysts have a wall composed
of inflamed fibrous or granulation tis-
sue lined by non-keratinized stratified
squamous epithelium . The epithelium is
proliferative, with elongated rete pegs,
often forming a characteristic arcading
pattern. Mature cysts and residual cysts
are less inflamed and may show a more
regular thin epithelium. The inflamma-
tory infiltrate is mixed, and may contain
prominent foamy histiocytes or deposits
of cholesterol crystals with foreign -body
giant cells, which may form luminal nod-
ules. Hyaline or Rushton bodies are of-
ten seen and are characteristic (although
not specific) of radicular cyst (113} Other
changes include mucous metaplasia
with goblet cells, cilia, or small areas of
keratinization.
Prognosis and predictive factors
Depending on their specific clinical and
radiological features, periapical lesions
are often treated by extraction of the
tooth or apicoectomy with enucleation of
the cystic cavity, or by non-surgical root
canal treatment. Although lesions may
persist as residual cysts, recurrence is
rare (1727).
lnflammatory collateral cysts
Definition
lnflammatory collateral cysts (ICCs) arise
on the bucea! aspect of the roots of par-
tially or recently erupted teeth as a result
of inflammation in the pericoronal tissues.
There are two main types: paradental
cysts (PCs) arise on the lower third mo-
lars and mandibular bucea! bifurcation
cysts (MBBCs) arise on the lower first or
second molars.
Synonyms
lnflammatory paradental cyst
Mandibular bucea! bifurcation cyst:
mandibular infected bucea! cyst; juvenile
paradental cyst
Epidemiology
ICCs account for as many as 5% of all
odontogenic cysts {492 ,11491. The peak
incidence of PCs is among patients aged
20-40 years. The male-to-female ratio is
2:1 (492,1878)
Etiology
The etiopathogenesis is uncertain. ICCs
are of inflammatory origin , associated
with pericoronitis. Cyst formation may be
exacerbated by a down-growth of enam-
el on the bucea! aspect of the involved
tooth {492,751} or by food impaction
Fig. 8.53 lnflammatory collateral cyst. The paradental
cyst appears as well-demarcated, corticated radiolucency
al the distobuccal aspee! of a partially erupted lower third
molar. The periodontal ligamen! and lamina dura are
intact (arrows).
Fig. 8.54 lnflammatory collateral cyst. The mandibular
buccal bifurcation cyst is corticated and overlies the roots
of a lower second molar tooth.
(471). ICC may arise from proliferation of
the reduced enamel epithelium, but re-
cent studies suggest an origin from sul-
cular or junctional epithelium (15521.
Localization
More than 60% of ICCs are PCs on man-
dibular third molars. Most of the remain-
der are MBBCs. Bilateral cases are not
uncommon (1878,2151} Lesions in the
maxilla are very rare and may arise in as-
sociation with an erupting canine.
Clinical features
PCs are usually associated with a history
of longstanding pericoronitis, with asso-
ciated symptoms of pain, swelling, and
trismus. The associated teeth are vital.
PCs are well demarcated, often corti-
cated, and superimposed over the buc-
ea! aspect of the roots of the teeth. The
periodontal ligament and lamina dura are
normal (492}, and the lesion is distinct
Odontogenic cysts of inflammatory origin
Fig. 8.55 Paradental cyst appearing as an open
pocket, composed of an inflamed fibrous wall lined by
hyperplastic epithelium.
from the follicular space surrounding a
partially erupted tooth (471 l. PCs tend
to be mesially located on mesioangular
impactions, distal on distoangular impac-
tions, and bucea! on vertical impactions
(471)
MBBCs often present with painless
swelling , but infection with pain and sup-
puration may be seen. The tooth is usu-
ally tilted buccally, with deep periodontal
pockets . Radiology shows a wel l-demar-
cated bucea! radiolucency, which may
extend to the lower border of the man-
dible (18781. A periosteal reaction with
laminated new bone formation may be
visible (2151}
Histopathology
The histology is not specific , and is indis-
tinguishable from that of a rad icular cyst.
Cholesterol clefts , foamy macrophages,
and haemosiderin deposits may be seen.
The lining may be attached at the cemen-
toenamel junction or be continuous with
the epithelium of the pericoronal tissues,
forming an invagination or pocket pro-
truding down the root of the tooth (492,
539,15521.
Prognosis and predictive factors
ICCs are treated by simple enucleation.
lnvolved third molars are usually extract-
ed, but molars involved by MBBC may be
conserved.
233
Odontogenic and non-odontogenic
developmental cysts

Dentigerous cyst
Speight P
Fantasia J.E.
Neville B.W
Definition
Dentigerous cyst is an odontogenic cyst
that is attached to the cervical region
of an unerupted tooth and envelops the
crown. Eruption cyst is a variant of denti-
gerous cyst found in the soft tissues over-
lying an erupting tooth.
Synonym
Follicular cyst
Epidemiology
Dentigerous cysts account for about 20%
of all odontogenic cysts {1145,1149) and
are the second most common cyst of the
jaws . They occur overa wide patient age
range , with peak incidence in the second
to fourth decades of life. There is a male
predilection , with a male-to-female ratio
of about 3:2 {1149,2713) Eruption cysts
account for < 2% of cases and occur in
children {1149).
Etiology
Dentigerous cyst is a developmental
cyst, but the pathogenesis is uncertain.
The cyst arises due to an accumulation
of fluid between the reduced enamel
epithelium of the dental follicle and the
crown of the unerupted tooth.
Localization
About 75% of dentigerous cysts are as-
sociated with unerupted mandibular third
molars {1149,2713). Other common sites,
in descending order of frequency, are the
maxillary canines , maxillary third molars,
and mandibular second premolars (1149,
2713). Eruption cysts most commonly oc-
cur overlying mandibular deciduous inci-
sors or maxillary first permanent molars
{28,222)
Clinical features
Dentigerous cyst is usually symptomless,
and small lesions are often discovered
on radiological investigation for a miss-
ing tooth. However, the cyst may reach
a large size and present as a slowly en-
larging expansion of the jaw. lf the cyst
is infected, there may be pain and swell -
ing. Radiographs show a unilocular, well-
demarcated radiolucency, often with a
corticated margin, that surrounds the
crown of the unerupted tooth, which may
be displaced. Eruption cyst presents as a
smooth, soft swelling overlying an erupt-
ing tooth. lt is often translucen!, but trau-
ma may result in haemorrhage, imparting
the appearance of a haematoma.
Macroscopy
The cyst is attached to the cervical re-
gion of the tooth at the cementoenamel
junction and is lined in part by the crown
of the involved tooth.
Histopathology
Typical histology shows an uninflamed
wall of loose fibrous tissue , often with
a slightly myxoid appearance, lined by
thin , regular epithelium 2-4 cell layers
thick . The wall may contain small qui-
escent rests of odontogenic epithelium.
Metaplastic changes may include mu -
cous cells and cilia {1432,2345) Hyaline
or Rushton bodies are also occasionally
seen (1432). Dentigerous cyst is often in-
flamed and may exhibit epithelial hyper-
plasia, with adjacent cholesterol crystals.

B Prognosis and predictive factors

Fig. 8.56 Dentigerous cyst A Radiology shows a well-demarcated radiolucency enveloping the crown of a lower third Dentigerous cysts are treated by enucle-
molar tooth. B lntact specimen associated with a canine tooth; the cyst wall surrounds the crown of the tooth. ation , with removal of the impacted tooth.

A ? '_..,

Fig. 8.57 Dentigerous cyst A Low-power histology shows a !hin, regular lining. The cyst is attached to the tooth in the region of the cementoenamel junction (arrow).
wall is uninfiamed, with a loase myxoid appearance. C Mucous metaplasia.

234 Odontogenic and maxillofacial bone tumours

Eruption cyst can be marsupialized to al-
low the affected tooth to erupt normally.
They do not recur.

Odontogenic keratocyst
Speight P.
Devilliers P.
Li T -J.
Odell E.W.
Wright J.M.

Definition
Odontogenic keratocyst (OKC) is an od-
ontogenic cyst characterized by a thin, Fig. 8.58 Odontogenic keratocyst. A palien! with naevoid basal cell carcinoma syndrome with multiple odontogenic
regular lining of parakeratinized stratified keratocysts in !he mandible and maxilla.
squamous epithelium with palisading hy-
perchromatic basal cells.

Synonym
Keratocystic odontogenic tumour

Epidemiology
OKCs account for 10-20% of odonto-
genic cysts and are the third most com -
mon cyst of the jaws {1145,1149) They
occur over a wide patient age range,
with a peak incidence in the second
to third decades of life and a second,
smaller peak among patients aged
50-70 years {1149). Most studies find Fig. 8.59 Odontogenic keratocyst. A A unilocular radiolucency al !he angle of !he mandible extending to the posterior
a slight male predilection 12153). As aspee! of !he ramus (arrows). B An extensive multilocular lesion from !he midline, filling the body of the mandible and
many as 5% of ali OKCs occur as part extending into !he ramus; the lesions are well demarcated and mostly corticated.
of naevoid basal cell carcinoma syn-
drome (Gorlin syndrome) 11419); these . ,
'• }
cases tend to be multiple and to occur 'i. 'ti:'
.......
'·~
in younger patients {2638). J,

.,,.
o

Etiology '
OKC is a developmental cyst that aris- ....
es from remnants of the dental lamina.
There is an association with mutation or 4
" { ' . l. .
-- •,. . , .\· .' "": • .
;...
inactivation of the PTCH1 gene, which \ ~

activates the SHH signalling pathway r "' -- ~ D

'\
' ,._: •
,.-~

and results in aberrant cell proliferation of . : '· 4' ......

...1.:~,~ - .' ..,,.. ¡ 13
¡,, ~ ....
.\ . "
"" >
\

the OKC epithelium {1419,2153) .

Localization
OKCs are most frequently (in 80% of
cases) found in the mandible, with as
many as half of ali lesions located in the
posterior body and ramus {1149,2153) . ..
, _

~:~¿~~~:: 1~;;;:?~¿-y~:i '

Cysts found in the posterior maxilla are
more often associated with naevoid ba-
sal cell carcinoma syndrome 12639).
Clinical features
OKCs are frequently large at first presen-
·~
·~~
Fig. 8.60 Typical histology of odontogenic keratocyst. A The parakeratin layer is corrugated and the basal cells are
palisading, with hyperchromatic nuclei. B Focal areas may show reversa! of nuclear polarity of !he basal layer. C Basal
cell budding. D Satellite cysts and islands in !he wall.

Odontogenic and non-odontogenic developmental cysts 235


·"""~
Fig. 8.61 Odontogenic keratocyst. Enucleated specimens are often fragmented, bu! show a typical uninfiamed fibrous
wall with !hin, regular, folded epithelial lining.
tation. Most lesions present as painless
rad iolucencies and are found inciden-
tally during radiographical examination
for other reasons. Large lesions may
cause displacement of teeth . Maxillary
lesions may displace the orbit and are
more often infected . Radiology shows a
well-demarcated radiolucent lesion, of-
ten with a corticated margin. The lesions
may be unilocular (with or without a scal-
loped margin) or may be multilocular.
The posterior body and lower ramus of
the mandible is the most common site,
and lesions often surround the crown of
the third molar, resulting in an appear-
ance similar to that of dentigerous cyst.
Lesions tend to grow in a posteroante-
rior direction, resulting in large lesions
with relatively little swell ing or cortical
expansion.
About 10% of patients have multiple
OKCs (either metachronous or synchro-
nous), and half of these patients have
naevoid basal cell carcinoma syndrome
!2153,2639} In addition to multiple
OKCs, patients with naevoid basal cell
carcinoma syndrome have multiple ba-
sal cell carcinomas and other develop-
mental anomalies.
Histopathology
Typical histology shows an uninflamed
fibrous wall lined by a folded, thin, regular
parakeratinized epithelium 5-8 cell layers
thick, without rete ridges. The parakeratin
surface is typically corrugated, and the
basal !ayer is well defined and often
palisaded, with hyperchromatic nuclei
and focal areas showing reversed nuclear
polarity. These features are diagnostic
and distinguish OKC from other jaw
cysts that can show keratinization .
236 Odontogenic and maxillofacial bone tumours
~
' Aj~\~.'.-~:~?·\
l'J).~ "· ""' ·-·, """' .-
- support a neoplastic origin of OKC . lt is
. - (
~
···-:: ....
.
. currence after resection was rare (occur-
~.'.
' be dueto incomplete removal or the pres-
Mitotic figures are often seen, but these
are normal. lnflamed lesions lose these
typical features and are lined by non -
specific stratified squamous epithelium
with sorne degree of hyperplasia.
OKCs may show small satellite cysts
or solid islands in the wal l, or may have
budding of the basal layer. These fea-
tures are more commonly seen in cysts
associated with naevoid basal cell car-
cinoma syndrome l2637f. Occasionally,
OKCs are of the so-called solid variant:
composed of multiple small cysts and
epithelial islands in a dense collagenous
stroma !2493). Careful examination is
essential to differentiate this lesion from
squamous cell carcinoma or acanthoma-
tous ameloblastoma. The true nature of
this variant and its relationship to conven-
tional OKC is uncertain, and further re-
search is needed.
Genetic profile
A variety of molecular and genetic altera-
tions have been identified in OKC !871,
1419}, the most notable of wh ich are al-
terations in the PTCH1 gene. Naevoid ba-
sal cell carcinoma syndrome and basal
carcinomas are associated with muta-
tions and inactivation of the PTCH1 gene,
and similar changes are found in as many
as 80% of both syndromic and sporadic
OKCs !1419,1938). Loss of heterozygo-
sity (LOH) on the 9q22.3 region (where
the PTCH1 gene has been mapped) has
been found in other developmental cysts ,
including dentigerous cyst !1394, 1841},
but this work needs confirmation, and
sequencing data on these lesions has
not yet been presented. Further research
is needed, but at the present time there
appears to be insufficient evidence to
felt therefore that OKC remains the most
appropriate name for this lesion.
Prognosis and predictive factors
Treatment is most often by enucleation, or
by surgical resection for large lesions. Re-
currences were more frequent in the past
but are dramatically reduced with meticu-
lous treatment. A systematic review found
an overall recurrence rate of about 25%,
but the recurrence rate after enucleation
with Carnoy's solution was 8% !1144). Re-
ring in < 2% of cases). Recurrences may
ence of persistent daughter cysts. Large
lesions can be marsupialized followed by
enucleation l1906l, and meta-analysis
suggests that this approach is associated
with lower recurrence rates than surgery
!2649). There is no evidence of any dif-
ference in behaviour between syndromic
and sporadic OKCs and the management
is the same !718).
Lateral periodontal cyst
and botryoid odontogenic cyst
Speight P.
Fantasia J.E.
Neville B.W.
Definition
Lateral periodontal cyst (LPC) is a de-
velopmental odontogenic cyst lined by
non-keratinized epithelium, occurring on
the lateral aspect or between the roots of
erupted teeth . Botryoid odontogenic cyst
(BOC) is the multicystic variant of LPC
!2556}.
Epidemiology
LPCs/BOCs account for < 1% of odonto-
genic cysts !1149,2150). They occur over
a wide patient age range, with peak inci -
dence in the sixth and seventh decades
of life !1953} A slight male predilection
has been noted in most series {2150).
Etiology
LPC/BOC arises from odontogenic
epithelial remnants, but the source is
controversia!. Origin from dental lamina,
reduced enamel epithelium, or rests of
Malassez has been proposed.
Localization
LPCs/BOCs most frequently occur in the
t · .~,~~j·~ ~; .
' '1 .. ::,
mandible, with < 20% arising in the max-
illa. Almost all lesions have been reported
to arise anterior to the molars, in particular
in the premolar regían (2150l . Multifocal
occurrence has been reported (2188l.
Clinical features
LPCs/BOCs are usually asymptomatic,
and most are identified incidentally on
radiographs. lnfrequently, there is ex-
pansion of bone, usually on the buccal
aspect. On radiographs, LPC is a well -
demarcated, often corticated unilocular
radio lucency juxtaposed to the lateral
surface of the tooth root. Most lesions are
~ 1 cm in size. BOC often has a multi loc-
ular radiographical appearance {2068l.
Fig: 8.63 Lateral periodontal cyst. Radiography shows
a corticated radiolucency between the roots of the
mandibular left second incisor and canine.
Macroscopy
LPC is unicystic and may contain clear
fluid. BOC may show a bosselated sur-
face dueto the presence of multiple cyst-
ic compartments.
Histopathology
LPC has a characteristic histopathology
that is similar to that of gingival cyst
of the adult. lt exhibits a thin lining of
non-keratinized epithelium, typically
consisting of a single or double layer
of cells, with focal plaque-like epithelial
thickenings (1953l. These often have
a whorled appearance, and the cells
may have clear cytoplasm due to
accu mulation of glycogen. Separation of
Odontogenic and non -odontogenic developmental cysts
the epithelial lining from the connective
tissue wall is a common finding. The
fibrous wall is uninflamed, but may show
a hyalinized band immediately beneath
the cyst lining .
The microscopic appearance of BOC is
similar to that of LPC , except there are
mu ltiple cystic spaces.
Prognosis and predictive factors
LPC can be treated by enucleation , with-
out the removal of the adjacent tooth or
teeth. Recurrence of simple unilocular
cysts is rare, but recurrence is document-
ed in as many as 20% of BOCs, probably
dueto the multicystic nature of the lesion
(1953 ,2068l.
237
 ..

;..; 2-~~¡pjf I!:' __:~...-.._:.:..... .::::____._- .

Fig. 8.65 Gingival cyst of !he adult presenting as a Fig. 8.66 Gingival cyst of !he adult. A Plaque-like lhickenings have a whorled appearance; note !he basilar clear cells
blister-like lesion (arrow). in !he adjacent !hin epithelial lining. B There is a thin epithelial lining with focal thickenings.

Gingival cyst
Speight P.
Kessler H.
Definition
Gingival cysts are odontogenic cysts
found in the alveolar mucosa. They can
arise in adults and in infants.
Synonyms
Alveolar cyst; Bohn nodules (in infants)
Epidemiology
Gingival cyst of the adult is rare, ac-
counting for < 0.5% of odontogenic
cysts {1149). lt occurs in adults aged
40-60 years, with a slight female predi-
lection {1149,2519). Gingival cyst of the
infant is common . lt is found in as many
as 90% of neonates, but is rare in infants
aged > 3 months.
Etiology
The etiology is unknown . Gingival cysts
are thought to be developmental cysts
that arise from remnants of the dental
lamina in the gingival or alveolar soft tis-
sues (rests of Serres).
Localization
In adults, most gingival cysts (as many
as 75%) occur in the mandible in the
,,
premolar/canine region {2150,2519) . In
the maxillary gingiva, gingival cysts may
be seen in the incisor and premolar/ca-
nine areas. They are found on the buc-
ea! surface of the alveolus in almost ali
cases . In infants, the cysts occur on the
edentulous alveolar ridge of the mandible
or maxilla.
Clinical features
Gingival cysts of the infant present as
small (< 2 mm) white nodules on the alve-
olar mucosa, and are often multiple. Gin-
gival cysts of the adult typically present
as a painless, small , dome-shaped eleva-
tion of the attached gingiva, resembling
a blister. Occasional lesions are found in
the moveable mucosa, at its junction with
the attached gingiva. Lesions often have
a light-blue to bluish-grey, translucent
appearance, but may appear clear. Ra-
diographs fail to revea! the lesion in most
cases, although superficial erosion of the
underlying bone cortex may occasionally
be seen radiographically.
Histopathology
The cyst lies just below the normal oral
epithelium and is typically uninflamed
and lined by thin epithelium composed
of a single or double !ayer of cuboidal
to squamous cells without rete ridges.
Focal, abrupt thickening is often pres-
ent, producing plaques that protrude
into the lumen or into the connective tis-
sue wall. Clear cells are often present.
Occasionally, the cyst lining is thicker and
appears stratified squamous in character.
The connective tissue wall may contain
islands of epithelium resembling epithe-
lial plaques. Gingival cysts of the infant
are rarely seen histologically, but most
appear to be lined by thin keratinized
epithelium {2149).
Prognosis and predictive factors
In adults , simple excision is the treatment
of choice and is typically curative. Recur-
rence has not been reported. Gingival
cysts of the infant undergo involution or
resolve spontaneously and do not need
to be treated.
Glandular odontogenic cyst
Speight P.
Fowler C.B.
Kessler H.
Definition
Glandular odontogenic cyst (GOC) is a
developmental cyst with epithelial fea-
tures that simulate salivary gland or glan-
dular differentiation.

., ·'

.,- -:.,.
'

" ' z:
A~ .- -
:=:::.\~~~ ~ ~~~~•• ~........,_i ;/)h.. . ~
""
Fig. 8.67 Glandular odontogenic cyst. A The epithelial lining is of variable thickness, with a prominent luminal layer of columnar cells (so-called hobnail cells). B Microcysts and
duct-like structures are commonly seen. C An area showing ducts and prominent cilia.

238 Odontogenic and maxillofacial bone tumours


Fig. 8.68 Glandular odontogenic cyst. Radiography shows an extensive multilocular lesion crossing the midline and
filling the body of the mandible.
Synonym
Sialo-odontogenic cyst
Epidemiology
GOC is rare, accounting for < 0.5%
of ali odontogenic cysts {1149). lt oc-
curs over a wide patient age range,
with an incidence peak in patients aged
40-70 years. There is no sex predilection.
Etiology
The etiology is unknown . GOC is thought
to be a developmental cyst that arises
from remnants of the dental lamina.
Localization
GOC occurs exclusively in the jaws, with
the mandible involved in about 75% of
cases. Lesions in the maxilla tend to oc-
cur anteriorly j752)
Clinical features
The most common presentation is painless
swelling. Radiographs revea! a well-de-
fined unilocular or multilocular radiolucent
lesion, which may have a scalloped border.
GOC is typically associated with the roots
of multiple teeth, and tooth displacement
or root resorption is common {813). Asso-
ciation with an impacted tooth is extremely
rare, and extreme caution should be exer-
cised in diagnosing GOC when the lesion
is in a dentigerous relationship. Mandibu -
lar lesions may reach a large size and can
cross the midline {813,1176).
Histopathology
Statistical analysis has shown that a
confident diagnosis of GOC can be
made when at least 7 of 10 specific cri-
teria are present {752,1177). Sorne crite-
ria are present in ali cases : (1) variable
thickness of the epithelium lining the
Calcifying odontogenic cyst
Speight P.
Ledesma-Montes C.
Wright J.M.
Definition
Calcifying odontogenic cyst (COC) is a
simple cyst lined by ameloblastoma-like
epithelium, which contains focal accu-
mulations of ghost cells.
ICD-0 code 9301/0
Synonyms
Calcifying cystic odontogenic tumour;
cyst, from 2- 3 cell layers of flattened calcifying ghost cell odontogenic cyst;
squamous or cuboidal cells to thicker, Gorlin cyst
stratified squamous epithelium, and (2)
a luminal !ayer of cuboidal to low colum- Epidemiology
nar cells, sometimes referred to as hob- COC is rare, accounting for < 1% of ali
nail cells, present at leas! focally. Other odontogenic cysts {1149). lt occurs over
criteria are present in most cases: (3) a wide patient age range, with a mean
intraepithelial microcysts, (4) apocrine patient age of about 30 years {288,1357).
metaplasia of the luminal cells, (5) clear
cells in the basal and parabasal layers,
(6) papillary projections (tufting) into the
lumen , and (7) mucous cells . The other
three microscopic criteria for diagnosis
are (8) epithelial spheres similar to those
seen in lateral periodontal cyst, which
are frequently identified; (9) cilia, which
are occasionally seen; and (10) multiple
cystic compartments, which are some-
times present. GOC may share sorne
features with central mucoepidermoid
carcinoma, and great care must be taken
in the interpretation of incisional biopsies.
However, GOCs have been found to be
consistently negative for MAML2 gene
rearrangements {209). This suggests
that the two are separate entities, but the
number of cases tested is small, and this
finding does not preclude the possibility
that central mucoepidermoid carcinoma
could develop from a pre-existing GOC.
Prognosis and predictive factors
Enucleation is the most common treat-
ment for GOC, but is associated with a
high recurrence rate (30-50%) {1179) .
Recurrence can be late, with one study
reporting a mean time to first recurrence
of 8 years {752). For this reason, resec -
tion has been advocated, particularly for
large or multilocular lesions {1179).
Fig. 8.69 Calcifying odontogenic cyst. Typical
radiology shows a well-demarcated unilocular
radiolucency. A Tooth resorption may be seen.
B Many cases show foci of calcified tissue.
Odontogenic and non -odontogenic developmental cysts 239
 genic ghost cell tumour and ghost cel l
odontogenic carcinoma (1357). There has
been considerable debate as to whether
it is a neoplasm or a developmental cyst
{1021 ,1357,2410) On the basis of its be-
haviour and clinicopathological features,
COC is now thought to be a developmen -
tal cyst that arises from the dental lamina
{1021 ,1422,1973,2148,241 O).

Localization
COC can arise in either jaw, usually in
the anterior regions {288 ,1357). Lesions
associated with odontomas have a pre-
dilection for the anterior maxilla (1357).
Occasional lesions (as many as 10%) are
extraosseous and are found in the ante-
rior regions of either jaw (1021)

Clinical features
The most common presentation is a
painless swelling of the jaws Radio-
graphs revea! a wel l-defined radiolu -
cent lesion, which is usually unilocular
and may have a scalloped border. Tooth
displacement and root resorption are
common {288 ,2357). About half of all
cases have amounts of calcified tissue
{288) oran associated odontoma {1001,
1357). Extraosseous lesions present as
gingival swellings , sometimes with pain
or tenderness .

Histopathology
COC is unicystic and is lined by epithe-
lium of variable thickness. Sorne areas
may be only a few cells thick or may
show squamous change. However, the
key diagnostic feature is the presence
of a well-defined basal layer of palisad -
ing columnar cells and a thick overlying
layer resembling the stellate reticu lum of
the enamel organ , with focal accumula-
tions of ghost cells, which may calcify.
Many lesions show luminal projections of
ghost cells or of ameloblastoma-like epi-
thelial proliferations. Small satellite cysts,
islands of epithelium, or ghost cells may
be seen in the fibrous capsule. A vari -
able amount of dentinoid is sometimes
laid down adjacent to the epithelial lining
Fig. 8.70 Calcifying odontogenic cyst. A The lining varies in thickness from only a few cell layers (top) to thick and (288,1021). In about 20% of cases, den-
ameloblastoma-like (bottom). There is a palisading basal layer and focal accumulations of ghost cells can be seen in the tal hard tissues resembling an odontoma
wall (arrow); small squamous areas are also noted. B Focal accumulations of ghost cells can be seen throughout the
are found (1001 ,1021,13571. Occasion-
epithelial lining, and small sheets of dentinoid are visible in the wall (top right). C Ghost cells accumulate in the lining
and form luminal nodules; note the areas of calcification. ally, areas resembling ameloblastic fi-
broma, ameloblastic fibro -odontoma, or
COC associated with odontoma has a Etiology adenomatoid odontogenic tumour can
peak incidence in the second decade of COC is one of a group of ghost cell le- be detected (1357)
life (288,1021). There is no sex predilection. sions of the jaws, along with dentina-

240 Odontogenic and maxillofacial bone tumours

Prognosis and predictive factors
Enucleation is the treatment of choice.
Recurrence is rare and has been report-
ed to occur in< 5% of cases (288l.
Orthokeratinized
odontogenic cyst
Speight P
Fantasia J.E.
Neville B.W.
Definition
Orthokeratinized odontogenic cyst (OOC)
is an odontogenic cyst that is entirely or
predominantly lined by orthokeratinized
stratified squamous epithelium.
Synonym
OOC was originally referred to as an
orthokeratinized variant of odontogenic
keratocyst (2153 ,2644l. However, this
terminology should be avoided , be-
cause OOC is a distinct entity.
Epidemiology
Oue to changes in terminology, the true
prevalence of OOC is uncertain, al -
though it is known to be rare . In most
series of keratinizing odontogenic cysts,
OOCs account for about 10% of cases
(499,2644l Therefore, OOCs probably
account for about 1% of ali odontogenic
cysts overa!!. They occur over a wide
patient age range, with peak incidence
in the third and fourth decades of lite
(2644l Most studies show a male predi-
lection (598,2644¡.
Etiology
OOC is a developmental odontogenic
cyst, but its pathogenesis is uncertain.
An origin from remnants of the dental
lamina is most likely (1421l.
Localization
OOCs are most frequently found in the
mandible (accounting for 90% of cases),
with about 75% of ali lesions found in the
posterior regions (499,598,1421l . Multi -
ple and bilateral cases have been report-
ed (410,1892}.
Clinical features
OOC usually presents as a painless
swelling (499,5981, but many are found
incidentally during radiograph ical ex-
amination for other reasons. Radiology
Fig. 8.71 A Orthokeratinized odontogenic cyst. Radiology
shows a well-demarcated unilocular radiolucency
associated with an unerupted third molar.
shows a well-demarcated unilocular ra-
diolucent lesion , often with a corticated
margin. Occasional cases are multilocu-
lar (597,598l. The posterior body of the
mandible is the most common site, and
about half of ali lesions are associated
with an impacted tooth, often resulting in
an appearance similar to that of dentiger-
ous cyst (499,598l. Rare cases of multi-
ple cysts have been reported , but there
is no evidence of any association wi th
naevoid basal cell carcinoma syndrome
(Gorlin syndrome) (410l.
Histopathology
Histology shows an uninflamed fibrous
wall lined by !hin, regular epithelium
5-8 cell layers thick, but without rete ridg-
es. The surface exhibits orthokeratiniza-
tion, with a prominent granular cell !ayer.
Unlike in odontogenic keratocyst, the ker-
atin surface is not corrugated, but is thick
and lamellated. The basal cells are flat or
cuboidal , but do not show palisading or
hyperchromatic nuclei (2644l . Focal ar-
eas may be non-keratinized or parakerati-
nized, but these areas constitute a minar
componen! of the lining and are often as-
sociated with inflammation (2644).
Prognosis and predictive factors
Treatment is by enucleation. Recurrence
is rare and has been reported in < 2% of
cases (499 ,597,598l.
Nasopalatine duct cyst
Speight P.
Wright J.M.
Definition
Nasopalatine duct cyst (NOC) is a non-od-
ontogenic cyst of developmental origin that
arises in the midline of the anterior maxilla.
Odontogenic and non -odontogenic developmental cysts
. . .
.. . -.
- - . ..., ..-
....' .,~...., o~~\, )
. . . : . -----...:,
. . ~~- ~ ~ ·--....·......~¡~- -
:
Fig. 8.71 B Orthokeratinized odontogenic cyst. A thin,
regular, epithelial lining with a thick keratin layer that is
lamellated and extends into the lumen.
Synonym
lncisive canal cyst
Epidemiology
NOC accounts for about 5% of ali cysts
of the jaws, and for as many as 80%
of ali non-odontogenic cystic lesions
(520,1150l lt occurs most frequently in
patients aged 30-60 years, with a male-
to-female ratio of about 3:1 (2152).
Etiology
NOC is a developmental cyst, thought to
arise from epithelial remnants of the na-
sopalatine duct within the incisive canal.
Localization
NDCs are found exclusively in the midline
of the anterior hard palate.
Clinical features
Most lesions present towards the oral
cavity and present as a sessile swelling
just posterior to the incisors. Occasion-
ally, a lesion may arise deeper within the
Fig. 8.72 Nasopalatine duct cyst. An anterior occlusal
radiograph shows a typical nasopalatine duct cyst; the
lesion is in the midline of the anterior hard palate and
has a well-demarcated, corticated margin. The anterior
incisor teeth appear normal and the lamina dura and
periodontal ligamen! are intact (arrow).
241

incisive canal and present as a swelling
on the labial alveolus oras bulging of the
floor of the nose (362,2152).
NDCs are often traumatized and may
become infected . Radiology is almost
always diagnostic and shows a well -de -
marcated, often corticated radiolucency
242 Odontogenic and maxillofacial bone tumours
in the midline of the hard palate, between
the roots of the incisors, which may be
displaced but are vital. The lamina dura
of the teeth is intact.
The average cyst diameter is about
18 mm {2320), and lesions may have a
characteristic heart shape.
On radiology, the normal incisive ca-
nal can be as large as 6 mm; therefore,
small radiolucencies of ~ 6 mm that are
asymptomatic and with vital teeth can be
considered to be within normal anatomi -
cal limits and only need to be followed
radiographically {2152,2320)
Histopathology
In > 90% of cases, NDCs are lined by
stratified squamous epithelium, with fo -
cal areas of cuboidal, columnar, or cili -
ated change. About half of ali cases con -
tain areas of respiratory epithelium, but
< 10% of cases are lined entirely by res -
piratory epithelium (2152,2320). The cyst
walls contain prominent neurovascular
bundles and occasionally contain small
mucous glands or cartilage. Traumatized
cysts are inflamed.
Prognosis and predictive factors
NDCs can be enucleated and do not
normally recur.
Malignant maxillofacial bone and
cartilage tumours
Chondrosarcoma
Baumhoer D.
Casiraghi O.
Coleman H.
Hunt J.L.
Triantafyllou A.
Definition
Chondrosarcoma, NOS, is a malignant
bone tumour that produces cartilaginous
matrix.
ICD-0 codes
Chondrosarcoma
Chondrosarcoma , grade 1 9222/1
Chondrosarcoma , grade 2/3 9220/3
Synonyms
Chondrosarcoma, grade I; atypical carti -
laginous tumour
Epidemiology
These tumours are rare in the jaw and
facial bones, and account for approxi-
mately 3-4% of all chondrosarcomas
(2045,2446). Patients of any age can be
affected , but there is a slight predilection
for middle-aged men (1254).
Etiology
Chondrosarcomas in the maxillofacial
ske leton generally develop sporadically;
manifestations of Ollier disease and Maf-
fucci syndrome with malignant transfor-
mation are exceed ingly rare (1067).
Localization
The maxilla and the nasal septum seem
to be more frequently involved than the
mandible; however, chondrosarcoma
can occur in any maxillofacial bone
(1254,2045)
Clinical features
The symptoms are non -specific and de-
pend on the site of origin . lnvolvement of
the nose can resu lt in nasal obstruction;
in all other sites, asymptomatic or painful
swellings are the most common finding.
Fig. 8.74 Chondrosarcoma (T) involving the lower part
of the nasal septum and nasal fossa , showing a ver¡ high
signal on axial T2-weighted MRI.
Macroscopy
Chondrosarcomas often exhibit a lobular
architecture, with a glistening bluish-grey
or white solid cut surface.
Histopathology
Chondrosarcoma generally shows oste-
odestructive growth, with entrapment of
pre-existing trabecular bone and/or corti-
cal permeation. Because chondromas in
the maxillofacial bones are exceptionally
rare, tumours with pure cartilaginous dif-
ferentiation should always be assumed
to be chondrosarcoma until proven oth-
erwise. Chondroblastic osteosarcoma
is far more common than chondrosar-
coma, especially in the jawbones, re-
quiring a thorough histological search
to exclude neoplastic osteoid deposits.
In the temporomandibular joint, synovial
Fig. 8.75 Chondrosarcoma. Cartilaginous tumour cells and matrix encasing !amellar bone as a sign of osteodestructive growth.
Malignan! maxillofacial bone and cartilage tumours
chondromatosis should be ruled out, es-
pecially if the tumour shows a lobular ar-
chitecture and no unequivocal signs of
infiltrative growth. Well-d ifferentiated
tumours resemble hyaline cartilage and
show oval to polygonal cells within !acu-
nar spaces surrounded by a cartilagi-
nous matrix. The nuclei are small and
uniform , with round to oval outlines and
evenly distributed dense chromatin. Bi-
and multinucleation frequently occurs.
With increasing grade, the nucleoli be -
come discernible due to open chroma-
tin. Nuclear atypia, increased cellularity,
decreased volume of cytoplasm , myxoid
background, and mitoses are also asso-
ciated with higher tumour grade. High-
grade lesions usually show :::>: 2 mitoses
per 1O high-power fields and marked
cellular pleomorphism. lmmunohisto-
chemistry is of limited diagnostic value;
however, the tumour cells usually stain
with antibodies against S100, SOX9, and
podoplanin (1756).
Genetic profile
Chondrosarcomas harbour IDH1/2 muta-
tions in 49-61% of cases (65,66,1216}.
Genetic testing might be useful to ex-
clude chondroblastic osteosarcoma, par-
ticularly on small needle-core biopsies.
243
Prognosis and predictive factors
Histological grade and complete resec -
tion with clear surgical margins are the
most important prognostic factors.
Mesenchymal
chondrosarcoma
Baumhoer D.
Casiraghi O.
Hunt J.L.
Triantafyllou A.
Definition
Mesenchymal chondrosarcoma is a bi-
phasic malignant tumour composed of
small round blue cells and islands of dif-
ferentiated hyaline cartilage.
ICD-0 code 9240/3
Epidemiology
Mesenchymal chondrosarcomas are
very rare. They generally develop in the
second to fourth decade of lite. There is
no sex predilection {768,1696,1845).
Localization
The tumours can develop in bones (ac-
counting for 65- 79% of cases) and adja-
cent soft tissues. The craniofacial bones
(especially the jaws) are most commonly
affected {1696,2280,2341,2490)
Clinical features
The symptoms are non-specific and de -
pend on the site of origin.
Fig. 8. 76 Sinonasal mesenchymal chondrosarcoma.
The tumour involves !he maxillary sinus, nasal cavity,
and elhmoidal sinus, and shows central calcifications, as
shown on axial bone-window CT.
244 Odontogenic and maxillofacial bone tumours
Macroscopy
The tumours are often well defined and
have a grey to pink cut surface. Foci of
calcifications and/or necrosis can be
prominent.
Histopathology
Although the proportions vary, mesen-
chymal chondrosarcomas always show
small round blue cells with intermingled
islands of highly differentiated carti -
lage. The small round blue tumour cells
have ovoid and hyperchromatic nuclei
and scant cytoplasm . Mitoses , includ-
ing atypical forms, are common. Occa-
sionally, the round cells develop a more
spindle-shaped morphology, and there
is generally a prominent , haemangioper-
icytoma-like vascular pattern. lmmuno-
histochemically, the tumour cells express
SOX9 {690 ,2558).
Genetic profile
Mesenchymal chondrosarcomas typi-
cally show HEY1 -NCOA2 fusions {1699,
1751,2539) IDH1 and IDH2 mutations
are absent {522) .
Prognosis and predictive factors
Because distant metastases can occur
after years to decades, long-term follow-
up is necessary. However, tumours of the
jaws seem to have a favourable outcome
{2490) .
Osteosarcoma
Baumhoer D.
Lopes M.
Raubenheimer E.
Definition
Osteosarcoma constitutes a group of
malignant bone tumours whose neo-
plastic cells produce bone. Conventional
osteosarcoma is an aggressive high-
grade tumour, periosteal osteosarcoma
is of intermediate grade, and low-grade
central and parosteal osteosarcomas are
low-grade subtypes.
ICD-0 codes
Osteosarcoma, NOS 9180/3
Low-g rade central osteosarcoma 9187/3
Chondroblastic osteosarcoma 9181/3
Parosteal osteosarcoma 9192/3
Periosteal osteosarcoma 9193/3
Synonyms
Osteogenic sarcoma; intraosseous well -
differentiated osteosarcoma (9187/3)
Epidemiology
Osteosarcoma is rare, with an overall an-
nual incidence of approximately 4 cases
per 100 000 population . Most cases are
high -grade tumours that affect the meta-
physis of long bones in children and ado-
lescents , with a particular predilection for
the femur, tibia, and humerus. The fourth
most common site of origin is the jaw-
bones, accounting for about 6% of cas-
es. Osteosarcomas in this location tend
Fig. 8.78 High-grade osteosarcoma of !he mandible. CT
shows a heavily mineralized tumourwith osteodestructive
growth and an aggressive-appearing periosteal reaction .

Fig. 8.79 High-grade osteosarcoma of the maxilla. Low-
magnification view showing a polypoid osteosarcoma
attached to the alveolar bone and in close contact with
the gingival surface and the palatal mucosa.
to develop 10-20 years later than do their
peripheral counterparts , and affect men
and women equally {160,13691 Similar
to the proportion seen in the peripheral
skeleton, 2-8% of ali maxillofacial osteo-
sarcomas are low- or intermediate-grade
tumours, with a predominance of the low-
grade central subtype {160,13691.
Etiology
Most cases develop spontaneously;
however, prior radiotherapy or underlying
Paget disease of bone (osteitis defor-
mans) increases the risk for developing
secondary osteosarcoma {411,2145) .
Localization
There is a predilection for the jawbones
(particularly the mandible), but any cranio-
facial bone can be involved {160,24611.
Clinical features
The symptoms, which are non-specific,
include pain, swelling, and loosening of
teeth. Radiographically, osteosarcomas
presentas mixed radiolucencies correlat-
ing with the amount and kind of neoplas-
tic matrix. Aggressive features , including
cortical permeation and periosteal re-
action, generally reflect the histological
grade. With gnathic tumours, widening
of the periodontal ligamen! space of the
involved teeth may be observed.
Macroscopy
Oepending on the type , amount, and
mineralization of the lesiona! matrix, oste-
osarcoma can present with tan-white and
solid or more grey, glistening, and soft
cut surfaces. Areas of haemorrhage, ne-
crosis, and cystic change are frequently
observed.
Histopathology
Conventional osteosarcoma is defined
by highly atypical cells producing neo-
plastic osteoid. High-grade osteosar-
comas consist of anaplastic and highly
pleomorphic cells with a broad spectrum
of morphologies. Osteoblastic differ-
entiation is evidenced by polygonal or
epithelioid cells, whereas the cells in
chondroblastic and fibroblastic variants
resemble highly atypical chondrocytes
and fibroblasts, respectively. Low- and
intermediate-grade subtypes generally
demonstrate more subtle atypia; mitotic
activity can be scarce. The extent of ma-
trix can vary significantly, ranging from
focal, immature, and lace-like osteoid to
heavily mineralized sclerotic bone. The
tumours generally show an aggressive
and osteodestructive growth replacing
the marrow spaces. As a result, pre-
existing trabeculae become surrounded
and eroded by tumour infiltrates and en-
cased by neoplastic bone. Frequently,
fibroblastic components and/or neoplas-
tic cartilage can also be found, and the
predominant matrix defines the tumours
as osteoblastic, chondroblastic, and fi-
broblastic subtypes. Chondroblastic
osteosarcoma is proportionally more
common in the jawbones and can histo-
logically mimic chondrosarcoma, which

' . ~
.
1
is far less frequent in the maxillofacial
bones {455). Small-cell and telangiec-
tatic variants have been reported but are
exceptionally rare. Low-grade central
and parosteal osteosarcomas consist of
irregular woven bone trabeculae embed-
ded in a fibroblastic stroma with only min-
imal atypia. The stromal component can
predominate and is of low to moderate
cellularity. Rarely, scattered foci of atypi-
cal cartilage can be present. Positive
staining with antibodies against MOM2
and COK4 might aid in distinguishing
low-grade osteosarcoma from benign
fibro-osseous mimics {615,2684) Peri-
osteal subtypes generally demonstrate
a predominant chondroblastic differen-
tiation, with intermediate-grade atypia.

Genetic profile
. Peripheral osteosarcomas have highly
. ... complex karyotypes, with abundant struc-
. '·.. . tural and numerical aberrations frequently
o•

•,.
...
/1: : •

: . •.
caused or influenced by chromothripsis
B .
., " CJ•
... ..,IJ...
n.
~
{1167). Whether the favourable outcome of
Fig. 8.80 High-grade chondroblastic osteosarcoma. A Highly pleomorphic tumour cells producing neoplastic lace-like gnathic osteosarcomas is associated with
osteoid. B Highly pleomorphic tumour cells producing neoplastic cartilage. C Spindle-cell proliferation showing only differences in their genomic landscapes
minor atypia and immature deposits of bone. is yet to be determined. Low-grade central

Malignant maxillofacial bone and cartilage tumours 245

and parosteal osteosarcomas show am-
plifications of the MDM2 gene in as many
as 29% and 79% of cases, respectively
{1820,2056}, whereas MDM2 amplifica-
tion is found in only 12% of conventional
osteosarcomas (1582).
Genetic susceptibility
The risk of osteosarcoma is increased in
severa! rare tumour syndromes, includ-
ing Li-Fraumeni syndrome, retinoblas-
toma, Werner syndrome (adult progeria),
and Rothmund-Thomson syndrome (poi -
kiloderma atrophicans with cataract) .
Benign maxillofacial bone and
cartilage tumours
Chondroma
Toner M.
van Heerden W.FP.
Definition
Chondroma is a benign neoplasm of hya-
line cartilage that arises within the medul-
lary cavity of bone.
ICD-0 code 9220/0
Synonym
Enchondroma
Localization
Chondromas are very rare in the head
and neck region, with only isolated cases
described (1088)
Clinical features
This is a slow-growing painless tumour. lt
is usually radiolucent, with central areas
of radiopacity.
Histopathology
The tumour consists of mature bland
cartilage with a circumscribed edge,
without atypia or cellularity. Because
benign chondromas are so rare in the
craniofacial region, malignancy must be
considered in ali cartilaginous lesions in
this area.
246 Odontogenic and maxillofacial bone tumours
Prognosis and predictive factors
Osteosarcomas of the jaws metastasize
far less frequently (in 6-21 % of cases),
and later on in the course of disease, than
do their peripheral counterparts, which is
why resection with clear margins is the
most important prognostic factor - re -
sulting in 10-year survival rates of > 80%
(160,455,895). The role of (neo)adju -
vant treatment for osteosarcomas of the
jawbones is controversia!, especially for
cases in which a complete resection is
surgically feasible (160,1118,1828,2220,
2374) Low-grade osteosarcomas can
Osteoma
Toner M.
Allen C.M.
Castle J.
Definition
Osteoma is a benign neoplasm com -
posed of mature bone, limited almost ex-
clusively to the craniofacial bones.
ICD-0 code 9180/0
Epidemiology
Most osteomas occur in the third to fifth
decades of lite, with a male predomi-
nance (1336).
Localization
Both surface and central osteomas are
more common in the mandible than in
the maxilla, with the mandibular condyle
being a common site (1180). Central os-
teomas are usually mandibular or sino-
orbital in location. Sino-orbital cases
occur in the nasal cavity, orbit, and para-
nasal sinuses (most commonly the frontal
sinus) (1571)
Clinical features
Surface osteomas can present as a
painless swelling on the surface of the
bone, whereas central lesions are often
typically be cured by complete resection
without additional treatment modalities
(160) These prognostically favourable
characteristics are restricted to tumours
of the jaws only. Extragnathic osteosar-
comas of the skull or facial bones behave
as aggressively as tumours of the periph-
eral skeleton and are generally treated
accordingly (by chemotherapy and sur-
gery) {1118).
asymptomatic (1691 ). Radiographically,
osteoma presents as a well-demarcated
radiopaque mass, usually < 2 cm in size .
Sino -orbital osteomas may present with
pain, headache, or visual changes.
Histopathology
Osteomas are composed of !amellar
bone (compact, trabecular, or a com -
bination of both) that merges with and
may protrude from the surface of the
bone (1180). Sorne examples have more
abundan! fibrous stroma and sorne con -
tain osteoblastoma-like areas, which are
thought to represen! remodelling within
the lesion rather than constituting a tu-
mour subtype. This is more common in
sino-orbital osteomas but is not associat-
ed with a more aggressive clinical course
{1571).
Genetic susceptibility
Multiple osteomas may be a manifesta-
tion of familia! adenomatous polyposis
(Gardner syndrome), an autosomal domi -
nant disorder characterized by mutation
of the APC gene {1359) . In this setting,
the osteomas may increase in size over
time.
Prognosis and predictive factors
Recurrence is rare after surgical excision.
Melanotic neuroectodermal
tumour of infancy
Prasad M.L.
Nelson B.
Tilakaratne W.M.
Definition
Melanotic neuroectodermal tumour of in-
fancy (MNTI) is a locally aggressive, rap-
idly growing tumour consisting of a bipha-
sic population of small neuroblast-like and
larger melanin-producing epithelioid cel ls.
ICD-0 code 9363/0
Synonyms
Melanotic progonoma; retinal anlage
tumour (both synonyms are obsolete and
not recommended)
Epidemiology
MNTI is rare. More than 90% of
patients are infants, with a median age of
5 months, although exceptional cases at
birth or in adults have also been report-
ed. There is a slight male predilection
(394,1173,1285,1944).
Localization
More than 90% of cases occur in the
craniofacial regions, most commonly in
the maxilla (accounting for > 60 % of cas-
es), followed by the skull , mandible (6% of
cases), and brain (1285 ,1944,2031} Out-
side the head and neck, the most com-
mon siles are the testis and epididymis.
Rare cases occur in the ovary, uterus ,
mediastinum , scapula, and bones and
soft tissues of the extremities (130,2445)
Fig. 8.81 Melanotic neuroectodermal tumour of infancy.
A 6-month-old infant presented with a rapidly growing
mass in the maxillary alveolar ridge. The mass is well
defined, with focal dark-brown discolouration and a tooth
bud protruding from its surface.
Clinical features
The tumour presents as a sessile , pain-
less, rapidly enlarging mass in the up-
per alveolus, causing facial deformity
and feeding disruption. lt may be bluish-
black in colour, due to its melanin con -
tent. lmaging shows a mass that destroys
the maxillary bone; may extend into the
sinus , nasal cavity, or orbit; and may en-
trap developing tooth buds. A subset of
tumours produce vanillylmandelic acid
(394,1944).
Macroscopy
The median tumour size is 3.5 cm (range:
1-20 cm) (1173 ,1944). The tumours are
smooth , firm , unencapsulated , generally
non-ulcerated , and pigmented.
Histopathology
The tumour consists of a biphasic
population of small neuroblast-like cells
and larger melanin-producing epithelioid
cells arranged in an alveolar architecture,
Benign maxillofacial bone and cartilage tumours
with cords and trabeculae intersected by
dense fibroblastic stroma. The melanotic
epithelioid cells generally surround nests
of small cells, but may form solid and
tubuloglandular structures. The intracy-
toplasmic melanin corresponds to mela-
nosomes ultrastructurally {553,1872).
lnfiltration of bone and entrapped odon-
togenic tissue is frequently present. Mi -
toses and necrosis are generally absent
but may be seen (147).
The presence of characteristic clini -
cal and histological features may obvi-
ate the need for immunohistochemis-
try. Both small and large tumour cells
express vimentin , synaptophysin, and
neuron-specific enolase. The epithelioid
cells are also positive for pancytokeratin
markers and HMB45, but negative for
other melanoma markers. The tumour
cells are typically negative for chro -
mogranin , neurofilaments, S100 protein,
and desmin , although focal rhabdomyo-
blastic and glial differentiation has been
rarely reported (652 ,1872).
MNTI must be distinguished from other
malignant small round blue cell tumours ,
which have worse prognoses (e.g.
Ewing sarcoma/ primitive neuroecto-
dermal tumour, rhabdomyosarcoma,
and lymphoma). These tumours do not
have the characteristic biphasic mor-
phology of MNTI, and have distinctive
immunohistochemical profiles. In MNTI,
abundan! melanin pigment is usually
apparent at low magnification , or can
be demonstrated by Fontana-Masson
staining if necessary. CD99 may show
membranous expression in the small
and large tumour cells of sorne MNTls
(147).
247
 .......... .,,...
'

.. _
!

~
Fig. 8.83 Chondroblastoma. B Chondroblasts stain positive with cytokeratins.

Genetic profile Chondroblastoma Histopathology

Most MNTls are diploid but sorne are The tumour cells are polygonal, with well -
aneuploid (1173,1872). BRAFV600 E Baumhoer D. defined borders and nuclear grooves.
mutation has been reported in one case van Heerden W. F.P. lntermingled multinucleated giant cells,
(869) chondro-osteoid matrix, and co-called
chicken-wire calcifications can be found
Prognosis and predictive factors Definition in varying amounts. The tumour cel ls
Despite rapid growth and local destruction, Chondroblastoma is a benign chon - at least focally express S100, SOX9,
most MNTls are cured by complete exci- droid -producing neoplasm composed of cytokeratins (CK8, CK18, and CK19), and
sion . Recurrence occurs in approximately chondroblasts . p63 (1008,2126).
20% of cases, usually within 6 months of
treatment (1285,2031). The risk of recur- ICD-0 code 9230/1 Genetic profile
rence appears to correlate with patient H3F3B point mutations are highly spe-
age at diagnosis; it is highest in patients Epidemiology cific for chondroblastoma (172) .
diagnosed within 2 months of birth, low- Chondroblastoma of the maxillofacial
est in those diagnosed after 4.5 months of bones is exceptionally rare, with < 100 Prognosis and predictive factors
age, and intermediate in those diagnosed cases reported in the literature (957, As many as 50% of cases recur, and me-
at 2-4.5 months of age (1944). The tu- 2263). tastasis has rarely been reported (180) .
mours rarely (in -3% of cases) behave in a
malignan! fashion, with distant metastases Localization
consisting of small neuroblast-like cells The tumours develop almost exclusively
(553,1285,1872,2031}. No histological fea- around the temporoma ndibular joint,
tures or biological markers are known to particularly in the squamous part of the
predict behaviour. temporal bone (185,957,1269,2263).

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Fig. 8.84 Chondromyxoid fibroma. A Tumour cells arranged in lobules with hypocellular centres and hypercellular peripheries. B Higher magnification shows stellate and ~·
eosinophilic tumour cells with cytoplasmic extensions.

248 Odontogenic and maxillofacial bone tumours

Chondromyxoid fibroma
Baumhoer D.
van Heerden WF.P.
Definition
Chondromyxoid fibroma is a benign car-
tilaginous bone tumour with a character-
istic lobular architecture and a chondro-
myxoid background.
ICD-0 code 9241 /0
Epidemiology
Chondromyxoid fibroma is rare , and
tumours of the maxillofacial bones ac-
count for only 5% of all cases {2646).
Localization
There is a slight p redilection for the jaw-
bones , but ali bones can be affected
{111 ,715 ,927,1504,1566).
Histopathology
The spindle-shaped to stellate tumour
cel ls general ly show abundant eosino-
philic cytoplasm , grow in lobules with
hypocellular centres and more hypercel-
lular peripheries, and are surrounded by
a chondromyxoid matrix. Hyperchromatic
nuclei , mu ltinucleated giant cells , calcifi-
cations , and/or hyaline cartilage can com-
mon ly be observed (2646)
Osteoid osteoma
Toner M.
Allen C.M.
Castle J.
Definition
Osteoid osteoma is a benign bone-
forming tumour characterized by limited
growth potential.
ICD-0 code 9191 /0
Epidemiology
Osteoid osteoma is very rare in the maxil -
lofacial bones.
Clinical features
Osteoid osteoma typicall y presents with
pain disproportionate to the tumour size.
The pain is often nocturnal and relieved
by aspirin, although relief with aspirin
is less common for jaw tumours {1147).
.-- ~~-
Radiographicall y, cortical sclerosis sur-
rounds a radiolucent nidus. In gnathic le-
sions, the nidus may be more radiopaque
(2280). Most osteoid osteomas do not
grow beyond 20 mm in diameter (73).
Histopathology
Histologically, osteoid osteoma is essen-
tially identical to osteoblastoma. Osteoid
osteoma is distinguished from osteoblas-
toma only on the basis of tumour size
(=::; 20 mm) and the presence of a sur-
rounding zone of sclerotic bone (1733).
Prognosis and predictive factors
Recurrence after treatment is very rare.
Osteoblastoma
Toner M .
Allen C.M.
Castle J.
Definition
Osteoblastoma is a benign bone-forming
tumour with prominent osteoblastic rim-
ming, forming a mass > 20 mm in size.
ICD-0 code 9200/0
Epidemiology
This is a rare tumour occurring mostly in
the second to third decades of life, with a
slight male predominance (1147)
Localization
About 10% of osteoblastomas are found
in the craniofacial bones , most common -
ly the posterior mandible (328).
Clinical features
Osteoblastomas can be asymptomatic
Benign maxillofacial bone and cartilage tumours
but more commonly present with
localized swelling and pain that may
mimic toothache, not relieved by aspirin.
Plain radiography shows a circumscribed
round to oval lesion varying from radio-
lucent to radiopaque, without a sclerotic
border or periosteal reaction . Root re-
sorption is rare (328), but the tumour may
mimic malignancy radiologically.
Histopathology
The tumour is composed of haphazard
mineralized trabeculae of bone and oste-
oid rimmed by osteoblasts and with a cel-
lular vascular fibrous stroma and occa-
sional osteoclasts. Sorne of the bone may
be strongly haematoxophilic, resulting in
the characteristic so-called b lue-bone
appearance. Mitoses are rare. In sorne
cases, the osteoblasts appear epithe-
lioid, with admixed immature bone, which
raises concern of malignancy. These tu-
mours have been called aggressive or
epithelioid osteoblastoma. Although this
morphology can be associated with a
clinically aggressive course, this is not al-
ways the case. Tumour size > 40 mm and
an anatomical site that makes removal
difficult are better predictors of behaviour
for such lesions (942,2280). The absence
of nuclear atypia, permeative growth into
surrounding bone, and atypical mitoses
distinguish osteoblastoma from osteo-
sarcoma (1489). Cementoblastoma is a
tumour that arises from and is fused to
dental roots. The histology of osteoblas-
toma and cementob lastoma are identical
except that the blue-bone appearance is
uncommon in cementoblastoma (see Ce -
mentoblastoma, p. 230) (1963)
Prognosis and pred ictive factors
Recurrence may occur after incomplete
removal.
249
 Desmoplastic fibroma
Flucke U.
Coleman H.

Definition
Desmoplastic fibroma is a locally aggres-
sive (myo)fibroblastic lesion of bone.

ICD-0 code 8823/1

Synonym
Desmoid tumour of bone

Epidemiology
Most patients are aged < 30 years
(mean: 16 years) {2634).

Localization
Approximately 86% of gnathic cases oc-
cur in the mandible, with a predilection
for the ramus and angle region {2352,
2634).

Clinical features
The lesions are slow-growing and com-
monly painless {2634). They are radio-
graphically well defined, without minerali-
zation {1089) .

Macroscopy
The lesions are firm and white, with a
B~ ... - ~­ coarse cut surface and focal myxoid
Fig. 8.86 Osteoblastoma. A Characteristic, so-called blue-bone appearance in a mandibular osteoblastoma. areas. Cortical perforation with extension
B Epithelioid osteoblasts in a mandibular osteoblastoma. into soft tissue may occur {738) .

Histopathology
Histology shows an infi ltrative/permeative
lesion composed of fascicles of uniform
(myo)fibroblasts with slender tapering
nuclei . Mitoses are occasionally present,
but are never atypical. The background
stroma is collagenous, but may have
myxoid areas. Coarse keloid-like colla-
gen bundles are occasionally observed.
There are small capillaries with parallel
alignment to the fascicles. Perivascu-
lar oedema is typical {738,2043} The
tumour cells are variably SMA-positive,
and nuclear beta-catenin expression has
been reported in rare cases {738,959) .
Fig. 8.87 Desmoplastic fibroma composed of long fascicles of monomorphous (myo)fibroblastic cells; bone is seen
below. Reprinted from Flucke U et al. {738}. Genetic profile
Activating CTNNB1 hotspot mutations or
APC mutations are driving events {738,
1029).

Prognosis and predictive factors

Recurrence may occur {2634).

250 Odontogenic and maxillofacial bone tumours

Fibro-osseous and
osteochondromatous lesions

Ossifying fibroma
El-Mofty S.K.
Nelson B.
Toyosawa S.

Definition
Ossifying fibromas are benign fibro -
osseous neoplasms affecting the jaws
and the craniofacial skeleton. The three
c linicopathological variants that have
been identified are ossifying fibroma of
odontogenic origin - also called cemen-
to-ossifying fibroma (COF) - and two dis-
tinct juvenile ossifying fibromas: juvenile
trabecular ossifying fibroma (JTOF) and
juvenile psammomatoid ossifying fibro-
ma (JPOF) {632,2208\ .
ICD-0 code
Ossifying fibroma
Synonyms
Cemento-ossifying fibroma: central os-
sifying fibroma; cementifying fibroma;
periodontoma
Juvenile ossifying fibroma: juvenile active
ossifying fibroma; juvenile aggressive os-
sifying fibroma
Epidemiology
COF is rare. The peak incidence is in the
third and fourth decades of life. There
is a definite female predilection, with a
female-to-male ratio as high as 5:1 {638 ,
674).
JTOF is a rare bone tumour. lt predo-
Fig. 8.89 Juvenile trabecular ossifying fibroma.
CT showing a circumscribed, expansive lesion of the
maxilla; cortical thinning is observed.
minantly affects children and adoles-
cents, with a mean patient age of 8.5-
9262/0 12 years {632). The sexes are equally
affected.
JPOF is a rare tumour. The reported
mean patient age ranges from 16 to 33
years. However, the overall patient age
range is wide; cases have been reported
in patients as young as 3 months and as
old as 72 years {632 ,638 ,2214\. There is
no sex predilection.
Localization
COF occurs exclusively in the tooth-
bearing areas of the mandible and max-
illa. The mandible is far more commonly
involved than the maxilla. The mandibu -
lar premolar and molar area is the most
common site.
Fig. 8.91 Juvenile psammomatoid ossifying fibroma.
CT shows an expansile, well-defined, bu! incompletely
corticated lesion with ground-glass appearance al the
ethmoid area.
JTOF occurs in the maxilla and mandible,
with the maxilla being a more common
site. Extragnathic occurrence is extreme-
ly rare.
JPOF may occur in the jaws but it pre-
dominantly affects the extragnathic cra-
niofacial bones , particularly the periorbi -
tal frontal and ethmoid bones {632).
Clinical features
CO Fs present as a painless expansion of
the buccal and lingual plates of the af-
fected bone. Large lesions can expand
the inferior border of the mandible or the
floor of the maxillary sinus. Radiographi-
cally, early lesions are typically radiolu-
cent. Over time, the tumour becomes
progressively more radiopaque {638 ,
676,2208). JTOFs are characterized by

Fig. 8.88 Cemento-ossifying fibroma. Radiography

showing a well-defined, expansive radiolucent lesion with
radiodense areas present in the mandibular molar area.

Fibro-osseous and osteochondromatous lesions 251

Fig. 8.92 Juvenile trabecular ossifying fibroma.
B Aggregates of osteoclast-like cells.
progressive and sometimes rapid expan-
sion of the affected bone. In the maxilla,
obstruction of the nasal passages and
epistaxis can occur. Radiographically,
the tumour is expansile and fairly well de-
marcated. lt may be radiolucent or may
show various degrees of opacification.
Cortical thinning and perforation can oc-
cur !632,2213).
JPOFs present as bony expansions that
may involve the orbit or nasal bones and
sinuses. Tumour expansion can result in
proptosis, visual symptoms, and nasal
obstruction. The rapid tumour growth
that has been observed in sorne cases
is most likely caused by secondary an-
eurysmal bone-cyst formation !632,638).
Macroscopy
An important feature of COF is that it
is wel l defined and can be shelled out
relatively easily from the surrounding tis-
sue. Grossly, the tumour is submitted in
one piece or in large fragments that are
yellowish -tan and may be haemorrhagic
and feel gritty when cut with a scalpel
!638,676). On cut surface, JTOF shows
curvilinear haemorrhagic strands not
seen in other types of ossifying fibroma
¡2210).
Histopathology
COF is well defined and may be en-
Fig. 8.93 Cut surface of specimen of juvenile trabecular
ossifying fibroma. Curvilinear haemorrhagic strands
create a distinct pattern typical for this lesion.
252 Odontogenic and maxillofacial bone tumours
capsulated. lt is composed of hyper-
cellular fibroblastic stroma containing
variable amounts of calcified structures.
The stromal cells have hyperchromatic
nuclei but no marked atypia. Mitosis is
not easily found. The calcified structures
are composed of variable amounts of os-
teo id or bone and lobu lated basophilic
masses of cementum-like tissue. These
structures may coalesce and form curvi-
linear trabeculae, wh ich may be acellular.
The ratio of bone to cementum-like tissue
varies from lesion to lesion; in sorne tu-
mours, one type of calcified tissue may
dominate. Osteoblastic rimming of the
bone trabecu lae is evident. Polarized
light microscopy shows both woven and
!amellar bone. The cementum-like tissue
is often woven, and may show a charac-
teristic quilted pattern.
JTOF is unencapsulated but neverthe-
less maintains a well -del ineated border.
lt has a characteristic loase architecture,
with hypercellular stroma composed of
spindle cells with little collagen produc-
tion. Osteoid develops directly from the
fibrous stroma and forms long slender
strands that have been likened to paint
brush strokes. Irregular mineralization
takes place at the centre of the strands,
resulting in the production of immature
bone trabecu lae that are devoid of osteo-
blastic rimming and show no evidence
of maturation. Aggregates of osteoclas-
tic giant cells are typically found in the
stroma. Occasional mitoses may be ob-
served in the stromal cells. Aneurysmal
bone-cyst formation has been reported
in sorne cases !632,2208,2213).
JPOF is unencapsulated and is charac-
terized by multiple small uniform ossi-
cles (psammomatoid bodies) embedded
in cellular stroma composed of spin-
dled and stel late cells {632,638 ,2214).
The psammomatoid bodies are baso-
philic and bear sorne resemblance to
dental cementum. At the periphery of the
lesion, these structures may coalesce
and form bone trabeculae. Cystic degen-
eration and aneurysmal bone-cyst forma-
tion may occur.
Genetic profile
Mutations in CDC73 (also called HRPT2)
have been reported in sporadic cases
!537,1890} COF lacks the GNAS gene
mutation that is characteristic of fibrous
dysplasia.
Genetic susceptibility
Multiple ossifying fibromas may be as-
sociated with hyperparathyroidism-jaw
tumour syndrome, which is caused by
COC73 (also called HRPT2) mutations
!340). Lesions with similar histological
features have been reported in a familia!
setting as gigantiform cementoma (see
next section) !634).
Prognosis and predictive factors
COF is a slow-growing benign neoplasm.
lt can be surgically excised conservative-
ly, with no recurrence in most cases. Un-
treated tumours can attain a massive size
and may require en bloc resection. Sar-
comatous transformation has not been
documented !633,638,674).
Multiple recurrences have been reported
following conservative excision of both
JTOF and JPOF. Malignan! transforma-
tion has not been reported !632}
Familia/ gigantiform
cementoma
El-Mofty SK

Definition
Familia! gigantiform cementoma (FGC)
is a rare form of fibro -osseous lesion of
the jaws characterized by early onset of
mu ltifocal/mu ltiq uadrant prog ressively
expansive lesions that may be massive
and cause remarkab le facial deformity.
No other bones are affected. Autoso-
mal dominan! inheritance is seen among
sorne cases whereas others are familia!.
Sporadic cases wi thout known heritable
features have also been described .
and extensive involvement of the jaws.
Simple cosmetic recontouring proce-
dures result in recurrences, which may
be multiple and occasionally at a more
accelerated rate {3A ,634,676,2138A}
Fibrous dysplasia
El-Mofty S.K.
Nelson B.
Toyosawa S.
Definition
Fibrous dysplasia (FO) is a skeletal
anomaly in which normal bone is re-
placed and distorted by poorly organized
and inadequately mineralized immature
bone and fibrous tissue . lt may involve a
single bone (monostotic FO) or multiple
bones (polyostotic FO) A variety ofendo-
crinopathies accompany polyostotic FO
in McCune-Albright syndrome. Although
FO occurring in multiple adjacent cranio -
facial bones is considered to be monos-
totic, the term "craniofac ial fibrous dys-
plasia" is preferred for such cases {2523) .

Fig. 8.95 Familia! gigantiform cementoma in a 3-year-

old female patient. CT sean showing bilateral, massive
expansive masses of the maxilla and mandible with well-
circumscribed borders presenting as radiolucent areas
containing radiopaque calcifications.

Histopathology
The microscopic features of FGC are
analogous to those of cemento-ossifying
fibroma characterized by hypercel lular fi-
broblastic stroma with monomorphic ap - Fig. 8.97 Fibrous dysplasia. A Waters' (occipitomental) view of craniofacial fibrous dysplasia involving the right maxilla,
showing ground-glass appearance, with indistinct borders. B Polyostotic fibrous dysplasia involving the maxilla and
pearing spind le shaped fibroblasts and
base of the skull, with obliteration of the maxillary sinus. Frontal (coronal) bone-window CT.
co llagen fibres. Oispersed throughout
the stroma are mineralized structures of
immature bone trabeculae and cemen -
tum-like tissue. The latter is formed of
hypocellular basophilic and curvilinear
structures resembling cementicles that
are normally seen in the periodontal liga-
ment. Under polarized light, Sharpey's
fibres are seen to project radially from
these spheroidal deposits.
·,¡~;~'
Prognosis and predictive factors Fig. 8.98 Fibrous dysplasia. A lrregularly shaped trabeculae of woven bone, without osteoblastic rimming in a
Surgical management of FGC is a chal- fibroblastic cell- rich stroma. B Progressive maturation to lamellar bone in a longstanding maxillary lesion of 30 years'
lenge due to rapid regrowth of the lesions duration; !amellar bone with osteoblast rimming is present.

Fibro-osseous and osteochondromatous lesions 253

Synonym
Craniofacial fibrous dysplasia
Epidemiology
FO accounts for approximately 7% of al l
benign bone tumours {618) . lt appears
to be a disorder of growing bones; most
cases are initially identified in children
and adolescents. Monostotic FO is 6-1 O
times as common as polyostotic FO
{735).
Etiology
FO is caused by postzygotic activating
missense mutations in the GNAS gene,
which encades the alpha subunit of the
stimulatory G protein (G 5 -alpha) {186 ,
2158,2575). Constitutively active G5 -
alpha stimulates adenylyl cyclase activ-
ity, resulting in overexpression of cAMP
and subsequent changes in the proper-
ties of bone osteoprogenitor cells, lead-
ing to abnormal bone formation {1989,
1990,1991).
Localization
The milder forms of FO affect only a few
bones (usually asymmetrically), localized
to one region of the body. The cranio-
facial bones and the femur are the two
most common siles of both monostotic
and polyostotic FOs, but any bone can
be affected {735). In the gnathic bones,
FO occurs more often in the maxilla than
in the mandible, and may extend to in-
volve adjacent bones such as the zygo-
matic and sphenoid bones {2523).
Clinical features
The initial presentation usually consists of
painless swelling of the jawbones, often
leading to facial asymmetry. The disease
is typically diagnosed with in the first two
decades of life {2523} Jaw involvement
may lead to displacement of teeth and
malocclusion, although the dental arch
is generally maintained {35}. Cases af-
fecting the paranasal sinus, orbits, and
foramina of the base of the skull can pro-
duce a variety of symptoms, including
nasal obstruction, visual loss, headache,
and hearing loss {634} In McCune-
Albright syndrome, café-au-lait skin pig-
mentation and endocrine abnormalities
are present {618).
The radiographical appearance of FO
depends on the stage of development.
Early lesions may appear radiolucent,
whereas later lesions may appear scle-
rotic. Classic lesions typically have a
254 Odontogenic and maxillofacial bone tumours
ground-glass appearance, with indistinct
borders that blend imperceptibly with the
surrounding uninvolved bone {596}. In af-
fected jaws , narrowing of the periodontal
ligament spaces and effacement of the
lamina dura surrounding the teeth are
suggestive of FO.
Macroscopy
The affected bone is rubbery, compress-
ible, and greyish-white, with a gritty tex-
ture when cut with a scalpel.
Histopathology
The lesions consist of fibrous and osseous
tissue in varying proportions depending
on the disease stage. The fibrous tissue
consists of bland fibroblastic cells. Mitotic
figures are uncommon. The osseous tis-
sue is composed of irregularly shaped tra-
beculae of immature woven bone without
osteoblastic rimming {41}. These trabecu-
lae often assume curvilinear forms, which
have been likened to Chinese characters
in appearance. The lesiona! bone fuses
with the adjacent normal bone {41 ,2209}.
Unlike FO in long bones , craniofacial le-
sions may undergo progressive matura-
tion to !amellar bone {2209,2523}. A small
proportion of cases contain nodules of
hyaline cartilage. Cases with abundan!
cartilage have been termed fibrocartilagi-
nous dysplasia {1098}.
Genetic profile
Activating missense mutations in the
GNAS gene have been detected in mon-
ostotic and polyostotic FOs, as well as in
McCune-Albright syndrome.
Prognosis and predictive factors
In most cases, the lesions seem to sta-
bilize with skeletal maturation; therefore ,
surgical intervention in younger patients
Fig. 8.99 Cemento-osseous dysplasia. Radiography shows lesions of mixed radiolucent and radiopaque fiorid
cemento-osseous dysplasia in both quadrants of the mandible.
should be delayed foras long as possible
{2523} Simple contouring of the affected
facial or skull bones to normal dimension
has proven to be adequate. Very rarely,
spontaneous malignant transformation
occurs {2027}
Cemento-osseous dysplasia
El-Mofty S.K .
Nelson B.
Toyosawa S.
Wright J.M.
Definition
Cemento-osseous dysplasia (COO) is a
non-neoplastic fibro-osseous lesion of
the tooth-bearing regions of the gnathic
bones.
Synonyms
Osseous dysplasia; cementa! dysplasia;
cementoma
Epidemiology
COO is the most common benign fibro-
osseous lesion of the jaws. There is a
strong predilection for middle-aged
Black women; an age-adjusted preva-
lence rate of 5.5% among Black females
has been reported {62,529,2127).
Localization
COO occurs exclusively in the tooth-
bearing regions of the jaws.
Clinical features
COO has traditionally been divided into
three variants (largely on the basis of ana-
tomical location): periapical COO is asso-
ciated with the apical areas of mandibular
anterior teeth ; focal COO is associated

with a single tooth; and florid COD has
multifocal (multiquadrant) involvement.
The lesions are usually asymptomatic
and may only be discovered on routine
dental radiograp hs (1791). COD is as-
sociated with vital teeth; however, it may
also be found in edentulous areas. The
lesions are generally non-expansive, but
florid cases are the exception; they may
be expansile an d present with pain and
discharge secondary to infection {529 ,
1316)
Radiographical evaluation of COD is es-
sential. ldeally, these lesions shou ld be
identified clinically and radiographically,
without the need for biopsy. The lesions
may be radiolucent, radiodense , or mixed .
Serial radiographs may show increased
density and calci fi cation as a lesion ma-
tures. A focus of COD is generally well de-
fined and demonstrates a thin rad iol ucent
rim. The periodontal lig ament should ap-
pear intact, and the lesion should not be
fused to the roots (529 ,634,1316)
Macroscopy
The lesions are grossly fragmented, grit-
ty, and tan and brown.
Histopathology
Ali the variants of COD have analogous
microscopic features, characterized by a
variably cellu lar fibrous stroma with areas
of swirling and/or loose collagen. Within
the stroma are mineralizin g tissues con-
sisting of osteoid, bone, and cementum-
like material. As the lesions mature, they
become increasingly calcified {1316).
Dense hypocellular sclerotic masses
may form , especially in florid COD. Os-
teoblastic rimming is generally rare. The
vascularity is pronounced and results in
free blood within biopsied specimens.
No capsule is identified. lnflammation
may be seen in cases of florid COD that
become infected {634). Cystic changes
resembling simple bone cyst may occur
in florid cases.
Prognosis and predictive factors
Once a diagnosis of periapical and focal
COD has been established, patients re-
quire no treatment and can be monitored
during routine dental appointments. lndi-
viduals with florid COD may require close
clinical follow-up for complications of os-
teomyel itis (529,1316).
Osteochondroma
Toner M.
van Heerden WFP.
Definition
Osteochondroma is a cartilage-capped
bony projection arising on the externa!
surface of bone, continuous with under-
lying bone. Categorization as a benign
neoplasm rather than a reactive lesion is
favoured {2023)
ICD-0 code 9210/0
Synonym
Osteochondromatous exostosis
Epidemiology
Osteochondroma is one of the most
common lesions of the axial skeleton but
is much rarer in the maxi llofacial bones,
because it occurs at sites of endochon-
dral ossification, which are limited in this
region. Less than 1% of all osteochon-
dromas occur in the head and neck.
Osteochondromas in the maxillofacial
bones occur in the fourth to fifth dec-
ades of life, which is later than elsewhere
in the body
Etiology
Trauma may be an etiological factor
{2023). An association with externa! ra-
diation therapy in childhood has been
suggested.
Fibro-osseous and osteochondromatous lesions
Localization
The reported sites are the skull base,
maxillary sinus, zygoma, and mandible
(condyle and coronoid processes).
Clinical features
The symptoms are related to tumour lo-
cation. Asymmetry, malocclusion, pain,
and lim ited mouth opening are the most
common features of cases in the mandi-
ble (2023). lmaging reveals a lobulated
bony outgrowth in continui ty with the
cortex and medulla of the bone of origin ,
with a thin cartilaginous cap (although
the cap is not always visible).
Macroscopy
Osteochondromas can be sessile or pe-
dunculated.
Histopathology
The tumour consists of perichondrium
covering a hyaline cartilaginous cap and
bony stalk (2010). The cartilaginous cap
is typically < 2 cm in thickness. The oste-
ochondral junction resembles the growth
plate, and the zone of endochondral os-
sification matures into cancellous bone.
There is minimal atypia, and binucleated
forms are rare. The cortex and medulla
are continuous with the underlying bone.
Absence of BCL2 expression may be
helpful in distinguishing osteochondroma
from chondrosarcoma {925).
Genetic profile
Homozygous deletion of the EXT1 gene,
located at 8q22-24.1, occurs in chon-
drocytes in sporadic osteochondromas.
Abnormalities of both EXT1 and EXT2 are
associated with hereditary multiple os-
teochondromas {201 O).
Genetic susceptibility
About 15% of patients with osteochon-
dromas have hereditary multiple osteo-
chondromas/exostoses, but this condi-
tion rarely involves the maxillofacial
bones {2010}.
Prognosis and predictive factors
Excision is curative, although recurrence
is possible following incomplete removal.
Malignant transformation is very rare.
255
Giant cell lesions and bone cysts
Central giant ce// granuloma
Raubenheimer E.
Jordan R.C.
Definition
Central giant cell granuloma (CGCG) is a
localized, benign but sometimes aggres-
sive osteolytic lesion of the jaws charac-
terized by osteoclast-type giant cells in a
vascular stroma.
Synonyms
Central giant cell lesion; reparative giant
cell granuloma (obsolete)
Epidemiology
CGCGs account for 10% of benign gnath-
ic tumours. Most cases occur in females
and in patients aged < 20 years 1729}.
Localization
The lesions are more frequent in the ante-
rior jaws , in particular the mandible. Mul-
tiple lesions should raise suspicion for
Noonan syndrome, LEO PARO syndrome,
or neurofibromatosis type 1 12492).
Clinical features
CGCGs generally present as slow-
growing, asymptomatic, expansile, well-
defined radiolucencies, without tooth
Fig. 8.101 Central giant cell granuloma presenting as a
well-circumscribed radiolucency in the anterior mandible.
256 Odontogenic and maxillofacial bone tumours
Fig. 8.102 Central giant cell granuloma. Occlusal
radiograph showing mandibular expansion and
tooth displacement in a multilocular central giant cell
granuloma.
resorption. More advanced lesions may
be multilocular. About 30% of cases fol-
low an aggressive clinical course char-
acterized by pain , tooth resorption and
displacement, cortical perforation, and
invasion of perignathic tissues 12492).
MRI and PET-CT are helpful in delineat-
ing soft tissue involvement and multicen-
tricity, respectively 11572).
Macroscopy
The lesion has a fleshy, reddish-brown,
haemorrhagic appearance.
Histopathology
CGCG is characterized by an unencap-
sulated proliferation of mononuclear
spindle-shaped and polygonal cells with
-- ~- · - ----------
Fig. 8.103 Central giant cell granuloma. Osteoclast-like giant cells and mononuclear cells in a vascular stroma with
reactive osteoid formation.
osteoclast-type multinucleated giant cells
in a vascular background, with haemor-
rhage and haemosiderin pigment. The
lesion may have a lobular architecture
separated by fibrous septa with osteoid
and woven bone. Other giant cell lesions
with similar features (such as cherubism ,
hyperparathyroidism , and aneurysmal
bone cyst) must be excluded. The gi-
ant cells in CGCGs show reactivity for
osteoclast and macrophage markers
1729,2413 ,2492) The mononuclear stro-
mal ce ll is the proliferative component.
Genetic profile
CGCG does not have a defined genetic
profile, and lacks the point mutations in
the histone H3F3A gene that character-
ize giant cell tumour of bone 11922).
Genetic susceptibility
Most CGCGs have no genetic asso-
ciation , but a minority of cases (most
commonl y cases associated with neu-
rofibromatosis type 1, Noonan syn-
drome, or LEOPARD syndrome) arise in
patients with germline mutations in the
genes encoding specific proteins of the
RAS/MAPK pathway 1729,1723).
Prognosis and predictive factors
Most CGCGs respond favourably to lo-
cal curettage. A higher recurrence rate
is associated with an aggressive clini-
cal course 12492) and association with
Noonan syndrome or neurofibromatosis
type 1 1729). To limit the extent of resec-
tion of large lesions, intralesional or sys-
temic pharmacological agents such as
steroids, calcitonin, interferon, and the
RANK ligand inhibitor denosumab may
be considered 154,2492).
B
Fig. 8.104 Peripheral giant cell granuloma. A Manifesting as a broad-based, non-ulcerated polyp on the alveolar
Peripheral giant ce// granuloma mucosa of the right mandible. B Cut surface of an excision specimen, showing a fieshy reddish-brown appearance.

Raubenheimer E.
Jordan R.C.

Definition
Peripheral giant cell granuloma is a re-
active localized proliferation of mononu-
clear cells and osteoclast-type giant cells
in a vascular stroma outside bone. lt oc-
curs in the gingiva or alveolar mucosa.

Synonym
Giant cell epulis

Epidemiology
Peripheral giant cell granuloma is the
most common giant cell lesion affecting
the oral tissues 12136).
Etiology
The lesion occurs as a result of local ir-
ritation of the mucoperiosteum or the cor-
onal part of the periodontal ligamen! by
dental calculus deposits or other types of
chronic irritation j388}.
Localization
Peripheral giant cell granuloma is more
common in the gingiva and edentulous
alveolar ridge of the mandible, but can
also affect the maxilla 12136}.
Clinical features
The proliferation presents as a sessile or
pedunculated soft-pink to purplish -blue
lump with a smooth, ulcerated, or papil-
lomatous surface 12136} A shallow in-
dentation of the adjacent alveolar bone
may be present 1388).
Macroscopy
Oue to vascularity, the cut surface of the
specimens often has a fleshy reddish-
brown appearance.
Histopathology
Histology shows an unencapsulated
proliferation of mononuclear spindle-
shaped and polygonal cells with giant
cells in a vascularized background. Foc i
of haemorrhage, haemosiderin pigment,
and scattered deposits of immature bone
are frequent.
Prognosis and predictive factors
Surgical removal is advised, and the
recurrence rate is low. The lesions may
even regress alter removal of the irritant.
Cherubism
Jordan R.C.
Raubenheimer E.
Definition
Cherubism is an autosomal dominant in -
herited condition characte rized by sym-
metrical expansion of the maxilla and
mandible as bone is replaced by cyst-like
and giant cell lesions 1729) .
Synonyms
Famil ia! fibrous dysplasia; juvenile fibrous
dysplasia (both terms are obsolete)
Epidemiology
The incidence of cherubism is unknown,
but the condition is rare 1367). Cherub-
ism presents in childhood or preadoles-
cence and is most often followed by par-
tial or complete regression in adulthood.
Most cases are familia!, with variable
penetrance and expressivity. De novo
cases from sporadic mutations can also
occur.
Etiology
Mutations of the SH3BP2 gene, located
on chromosome 4p16.3, have been iden-
tified in about 80% of cases of cherub-
ism 11523). The majority of mutations
occur in exon 9, within a proline-rich se-
quence 6 amino acids long , resulting in a
constitutively active form that increases
the activity of osteoclasts 12443)
Localization
Both jaws are affected bilaterally, with
the mandible affected more extensively
than the maxilla. The condition appears
to start around the first molars, but typi-
cally spares the condyles. In the maxilla,
cherubism begins in the tuberosity and
subsequently affects other areas.

Giant cell lesions and bone cysts 257

Fig. 8.106 Cherubism. A A child showing bilateral maxillary and mandibular bone expansion, with malpositioned and
displaced teeth. B Panoramic rad iograph showing multifocal rad iolucent lesions of the maxilla and mandible, with
missing and displaced teeth.
C linical features
Slow, symmetrical expansion of the jaws
occurs before the age of 6 years . Expan -
sion of the maxilla may cause retraction
of the facial skin, including the eyelids,
leading to scleral exposure and the char-
acteristic so-called heavenly gaze, which
is similar to the facial appearance of putti
(angelic children) in Renaissance paint-
ings (incorrectly referred to as cherubs
in the Baroque period of art). Females
are typical ly more severely affected than
males {1921). Bone expansion leads to
tooth displacement, altered tooth erup-
tion, loosening of teeth , speech altera-
tion , and visual impairment {1921). Ra-
diographically, the affected bones have
a multiloculated, so-called soap -bu bble
radiolucent quality (1967} The cortices
may be thinned, and with time the fibrous
tissue is replaced by new bone, leading
to sclerosis.
Macroscopy
Similar to the appearance of other
giant cell lesions , the tissue may be red
and haemorrhagic with areas of cystic
change.
Histopathology
The histology is not specific, and may re -
semble that of other giant cell lesi ons of
the jaws , such as giant cell granuloma,
__, ~,:
Fig. 8.107 Aneurysmal bone cyst. A Low-power image showing blood-filled sinusoidal spaces. B High-power image showing blood-filled sinusoidal spaces lined by multinucleated
giant cells. C Salid type. Salid area containing clusters of multinucleated giant cells set in fibrovascular stroma.
258 Odontogenic and maxillofacial bone tumours
Noonan syndrome (1723), and the bone
lesions of hyperparathyroidism. Variably
cellular mesenchymal tissues contain fo-
cally aggregated clusters of multinucle-
ated giant cells. Eosinophilic cuff-like
perivascular deposits can be seen, but
are nota consistent finding.
Genetic susceptibility
The condition occurs in families and is
inherited in an autosomal dominant man-
ner {729)
Prognosis and predictive factors
Most cases regress after puberty (1921),
but sorne cases show continued growth
with little regression {345) Before pu-
berty, surgery shoul d be performed only
in severe cases , where it will provide a
functional benefit.
Aneurysmal bone cyst
Jordan R.C.
Koutlas l.
Raubenheimer E.
Definition
Aneurysmal bone cyst (ABC) is a cystic
or multicystic expansile osteolytic neo-
plasm composed of blood-filled spaces
Fig. 8.108 Aneurysmal bone cyst. Panoramic radiograph
showing the features of an aneurysmal bone cyst
involving the right mandible of an 8-year-old boy.
separated by fibrous septa containing
osteoclast-type giant cells.
ICD-0 code 9260/0
Ep idemiology
ABC is rare , with an estimated annual in-
cidence of approximately 0.15 cases per
1 million population {1381 }. About 1.5%
of all cases occur in the jaws. All age
groups are affected , but > 80% of cases
occur in younger patients, usually within
the first two decades of life. The sexes
are equally affected overall, but a male
predilection has been reported for cases
of the jaws (1663}
Localization
More than 60% of cases occur in the
mandible; more frequently in the poste-
rior regions (1663}. Maxillary lesions have
a more uniform anatomical distribution.
Other sites in the craniofacial complex
can also be affected .
Clinical features
There is enlargement, which is frequently
painful {1663) The teeth remain vital ,
but tooth mobility and displacement are
common. Maxillary tumours can extend
to the sinuses, nose, and orbits and can
result in exophthalmos . Radiographically,
there is expansion with well-deli neated
unilocular or multilocular radiolucencies.
Perforation of the cortex can occur with
extension to the adjacent soft tissues .
Root resorption is seen. CT may reveal
bone septa compartmentalizing the le-
sion. CT and MRI demonstrate fluid-fluid
levels that are characteristic of (but not
specific for) ABC l2427l.
Macroscopy
The cysts are haemorrhagic and multi -
cameral , featuring fibrous septa of vari-
able thickness. Solid areas may be iden-
tified; these constitute either the solid
portion of the primary tumour ora portion
of tumour that has undergone second-
ary ABC-like changes. Rarely, the entire
lesion is solid.
H istopathology
ABC is composed of blood -filled or
empty sinusoidal spaces that are lined
by macrophages and fibroblasts and
are separated by fibrous sepia contain-
ing scattered multinucleated osteoclast-
like giant cells. Woven bone can appear
prominently basophilic (the so-called
blue-bone appearance), but this is not
diagnostic. The solid variant can feature
cellular areas (which may be mitotically
active) and few inconspicuous cystic
spaces. ABC-like areas (secondary ABC)
can occur in a variety of other disorders
of bone, including osteoblastoma , fibrous
dysplasia, and ossifying fibromas.
Simple bone cyst
Raubenheimer E.
van Heerden W.F.P.
Wright J.M.
Definition
Simple bone cyst (SBC) is an intraosse-
ous cavity that is devoid of an epithelial
lining and is either empty or filled wi th se-
rous or sanguineous fluid.
Synonyms
Traumatic bone cyst; haemorrhagic bone
cyst; unicameral bone cyst; solitary bone
cyst
Epidemiology
SBCs have an equal sex distribution
and occur in young patients (in the sec-
ond or third decades of life) 11025). One
third are associated with florid osseous
dysplasia in populations where florid os-
seous dysplasia is common 1368). An
older average palien! age and a female
predominance have been reported for
SBCs associated with florid osseous
dysplasia 1368)
Etiology
The etiology is unknown. Trauma does
not seem to play a role; the incidence
in patients with a history of trauma is the
same as that in the general population
12301).
Localization
SBCs are usually solitary and typically
affect the metaphysis of long bones. In
the head and neck region, they occur
mostly in the mandible, with a predilec-
tion for the body of the mandible 11025).
Multiple SBCs account for 13% of cases
12301).
Clinical features
Although a small number of cases mani-
fest with a pathological fracture, SBCs
are generally asymptomatic, and are
usually found incidentally during rou-
tine examination. Radiologically, they

Genetic profile
Rearrangements of CDH11 and/or USP6 Fig. 8.109 Simple bone cyst cavity in the left mandible. A Note the scalloping between the roots of the associated teeth.
are seen in 69% of primary ABCs 11772) B Florid osseous dysplasia with a multilocular simple bone cyst cavity in !he right mandible.
but not in secondary ABCs. Other fusion
partners for CDH11 include COL1A1,
OMD, THRAP3 (also called TRAP150),
and CNBP (also called ZNF9). Fusion
resu lts in the upregulation of USP6. Al -
though the mechanism is not well under-
stood, USP6 upregulation may affect ac-
tin remodelling and vesicular trafficking,
which regulate cell motility and invasive-
ness j1550). Familia! cases have been
described 11380), but not in the jaws or
skull.

Prognosis and predictive factors

ABC can be treated with curettage, but
en bloc resection may be necessary for
large, destructive tumours. The recur-
rence rate is approximately 10%, with
soft tissue extension.
Fig. 8.110 Simple bone cyst. Curettings of !he wall of a simple bone cyst cavity showing connective tissue, lace-like
osteoid, and !amellar bone.

Giant cell lesions and bone cysts 259

are well -defined radiolucencies that
frequently extend between the roots
of associated teeth , without resorption
or displacement {1025). Larger exam-
ples may be multilocular. A minority of
cases (17.6%, 2.9% , and 11 .8% , respec-
tively) show bone expansion, loss of the
periodontal ligament space , and efface-
ment of the lamina dura. Expansion of
the cortical plates and loss of the lamina
dura are more frequent in cases associ-
ated with osseous dysplasia (368)
Macroscopy
Upan surgical exploration , the cavity
is either empty or filled with serous or
Haematolymphoid tumours
Solitary plasmacytoma of bone
Definition
Solitary plasmacytoma of bone (SPB) is
a localized proliferation of monoclonal
plasma cells involving bone. No other
bony lesions are present on imaging
studies, and there are no diagnostic clini -
cal features of plasma cell myeloma. Min-
imal bone marrow involvement (< 10%
plasma cells) may be seen in a subset of
patients.
ICD-0 code 9731/3
Synonyms
Plasmacytoma of bone; osseous plasma-
cytoma
Epidemiology
SPB is rare, accounting far 3-5% of all
plasma cell neoplasms. There is a male
predominance, with a male-to-female
ratio of 2:1, and the median patient age is
55 years {1087).
Localization
SPB presents as a solitary bone lesion,
with the axial skeleton (in particular the
vertebrae) involved more frequently than
the appendicular skeleton {1087). In the
head and neck region, this lesion occurs
much more frequently in the mandible
260 Odontogenic and maxillofacial bone tumours
sanguineous fluid. The inferior alveolar
nerve is often visible inside the cavity
(2038)
Histopathology
The term "simple bone cyst " is in fact
somewhat of a misnomer, because the
specimens never have an epithelial lin-
ing. Compressed connecti ve tissue is
often seen lining the cavity, sometimes
with myxomatous change and often with
immature lace-like osteoid or spiky col-
lagen deposits {161).
Prognosis and predictive factors
Surgical exploration and curettage are
Fig. 8.111 Solitary plasmacytoma involving the mandible
of a 73-year-old man. The tumour is composed of sheets
of plasma cells.
than in the maxilla, most commonly in the
bone marrow-rich areas of the body, an-
gle, and ramus {24).
Clinical features
The most common symptoms of head
and neck SPB are pain in the jaws and
teeth, migration of teeth , haemorrhage,
and swelling {1901). A monoclonal serum
or urine paraprotein (M protein) may be
present, but hypercalcaemia, renal insuf-
ficiency, and anaemia are absent {1087,
1950). On imaging studies, multifocal
bone involvement is absent (582,1667).
Two types of SPB have been defined:
one with no bone marrow involvement
and the other with minimal involvement
(< 10% clonal plasma cells in the bone
marrow) (992 ,1803,1950) A solitary
often sufficient to stimulate bleeding and
facilitate osteogenesis. Spontaneous heal-
ing has been reported. One quarter of soli-
tary SBCs recur. Cases of multiple lesions
have a higher recurrence rate {1025). Lack
of bone formation can usually be demon-
strated within the first year after treatment ,
and regular follow-up is recommended
(2038). Curettage is not recommended far
c ases associated with uncompl icated ma-
ture florid osseous dysplasia, due to the
likelihood of inducing sequestration of the
hypovascular mineralized masses .
Feldman A.L.
Ott G.
p lasmacytoma with ¿ 10% clonal plasma
cells in the bone marrow qualifies instead
as plasma cell myeloma.
Histopathology
The histopathological features are similar
to those of plasma cell myeloma. Typical-
ly, the plasma-cell nature of the tumour is
readily apparent, although far sorne poor-
ly differentiated (e.g. anaplastic) cases ,
immunohistochemistry or additional stud-
ies may be required to confirm lineage.
The immunophenotype of SPB is also
similar to that of plasma cell myeloma.
lmmunohistochemistry for the kappa
and lambda immunog lobulin light chains
can be helpful to support plasma cell
clonality.
Prognosis and predictive factors
Most patients achieve local control with
radiotherapy. Median overall survival
is about 10 years {1087). About 10% of
cases with no bone marrow involvement
and 60% of cases with minimal involve-
ment progress to plasma cell myeloma
within 3 years {1950). Adverse prognos-
tic factors include older age , lesion size
> 5 cm , monoclonal free light chains
in urine, an abnormal serum free light-
chain ratio, and persistence of M protein
1-2 years after diagnosis {585 ,588,1087,
1426,2429 ,2608) .
 CHAPTER 9

Tumours of the ear

Tumours of the externa! auditory canal
Tumours of the middle and inner ear
WHO classification of tumours of the ear

Tumours of the externa! auditory canal Vestibular schwannoma 9560/0

Squamous cell carci noma 8070/3 Meningioma 9530/0
Adenocarcinoma 8420/3 Middle ear adenoma 8140/0
Ceruminous adenocarcinoma 8420/3
Adenoid cystic carcinoma 8200/3
Mucoepidermoid carcinoma 8430/3
Ceruminous adenoma 8420/0

Tumours of the middle and inner ear
Squamous cell carcinoma
Aggressive papil lary tumour
Endolymphatic sac tumour
Otosclerosis
Cholesteatoma
The morphology codes are from the lnternational Classification of Diseases
for Oncology (ICD-0) 1776AI. Behaviour is coded /O for benign tumou rs;
8070/3 /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in
8260/1 situ and grade 111 intraepithelial neoplasia; and /3 for malignant tumours.
8140/3 The classification is modified from the previous WHO classification, taking
into account changes in our understanding of these lesions.

262 Tumours of the ear

Tumours of the ear
lntroduction
Slootweg PJ
Takata T.
Tumours of the ear can be subdivided
into those of the externa! auditory canal,
the middle ear, and the inner ear. In this
edition, the number of entities included
has been reduced, by omitting tumours
that can occur at these sites but have
Tumours of the external auditory canal
Squamous ce// carcinoma
Sandison A.
Thompson L.D.R.
Definition
Squamous cell carcinoma (SCC) of the
externa! auditory canal is a malignant
neoplasm of squamous epithelium ari-
sing within the externa! auditory canal.
ICD-0 code 8070/3
Fig. 9.01 Squamous cell carcinoma of the externa!
auditory canal. Subtotal pinnectomy specimen showing
an ulcerated tumour occluding the ear canal; this tumour
extended into the adjacent parotid gland.
been extensively discussed elsewhere
and have no specific site-related fea-
tures requiring further consideration. For
tumours of the externa! auditory canal ,
site-specific features of squamous cell
carcinoma are briefly mentioned, the
main discussion being devoted to lesions
from the ceruminous glands, which are
specific to this site. For practica! reasons,
tumours of the middle and inner ear are
listed together, because their site of ori-
gin cannot always be determined beyond
Synonyms
Epidermo id carcinoma, squamous
carcinoma
Epidemiology
The annual incidence of SCC of the ex-
terna! auditory canal is about 1 case per
1 million population (1787). Patients are
usually aged 55-65 years, and there is
a female predominance, in contrast to
the male predominance seen with pinna
tumours (1142).
Tumours of the externa! auditory canal
doubt in a given patient. Otosclerosis has
been added as a new entity, because
there are sorne indications of a poten -
tially neoplastic behaviour of this lesion.
Several refinements have been made in
the classification and nomenclature of
adenoma and adenocarcinoma. Mid-
dle ear paraganglioma, also known as
glomus jugulare tumour, is discussed in
Chapter 10.
Etiology
Whereas actinic overexposure and frost-
bite are suggested etiologies for pinna
carcinomas, chronic inflammation and
radiation are suggested etiologies for
carcinomas of the externa! auditory ca-
nal and middle ear (730,1461,1787,2169).
Rarely, papilloma may transform into
scc {1595).
Localization
Tumours usually arise on the pinna; few
cases affect the externa! auditory canal
(2162,2595,2624).
263
Clinical features
An excoriated or ulcerated mass affec-
ting the pinna. Otitis media, otitis externa ,
pain , hearing changes , cholesteatoma ,
and stenosis are common presenting
symptoms (456,1031,2595), with nerve
symptoms noticed later (1979,2715).
Macroscopy
The gross appearance is that of a warty,
exophytic mass, possibly occluding the
externa! auditory canal and invading the
tympanum.
Histopathology
The histology is similar to that of SCC
occurring elsewhere. Spindle-cell and
acantholytic morphologies may be seen,
as well as (rarely) verrucous SCC. Des-
moplastic stroma and inflammation are of-
ten present (456,1031 ,1563,1787,2260).
Prognosis and predictiva factors
Externa! auditory canal SCC is aggres-
sive , often with local recurrence and
lymph node metastases, and frequently
involving vital structures. Poor prognostic
factors include high clinical stage, tumour
depth > 8 mm, and lymphovascular inva-
sion {456,730,1563,1752,1787,2595).
Ceruminous adenocarcinoma
Sandison A.
Stenman G.
Thompson L.D .R.
Definition
Ceruminous adenocarcinoma is a
malignan! neoplasm derived from the
264 Tumours of the ear
ceruminous glands of the externa! audi-
tory canal.
ICD-0 codes
Adenocarcinoma 8420/3
Adenoid cystic carcinoma 8200/3
Mucoepidermoid carcinoma 8430/3
Synonyms
Ceruminal adenocarcinoma;
cylindroma (to be discouraged)
Epidemiology
Ceruminous adenocarcinoma is rare , ac-
counting for < 2.5% of all externa! audi -
tory canal neoplasms (493,1865,2390)
Localization
The tumours occur in the outer half of the
externa! auditory canal , excluding direct
extension from parotid gland (493,1110,
1865).
Clinical features
Women are more often affected, with
a female-to-male ratio of 1.5:1. The
average patient age is 50 years (range:
21-92 years). Patients present with pain,
hearing loss, and tinnitus (493,552,1498,
1605). lmaging defines tumour extent
and excludes direct extension from the
parotid gland or nasopharynx.
Macroscopy
The tumours can be as large as 3 cm ,
with a mean size of 1.4 cm.
Histopathology
The unencapsulated cellular tumour in-
filtrates soft tissue and bone, showing
variable salid, cystic, cribriform, glandu-
lar, and sing le-cell patterns. Perineural
invasion and comedonecrosis are often
present. Cytoplasmic apocrine features
are common. There is nuclear pleomor-
phism , with prominent nucleoli easily
identified along with increased mitoses.
Ceroid pigment is absent. Adenocarci-
nomas are subclassified as adenocar-
cinoma, adenoid cystic carcinoma, and
mucoepidermoid carcinoma. Adenoid
cystic carcinoma and mucoepidermoid
carcinoma are histologically identical to
their salivary gland counterparts. There
is a biphasic immunohistochemistry: lu-
minal cells are positive for CK7 and KI T
(CD117); basal cells are positive for p63 ,
S100 protein , and CK5/6 (493 ,1102,1478).
Genetic profile
Adenoid cystic carcinomas are charac-
terized by a t(6;9) chromosomal translo-
cation resulting in a MYB-NFIB gene fu-
sion , similar to that seen in adenoid cystic
carcinomas of the salivary glands (1861 ,
1862). No genetic data are avail able on
ceruminous adenocarcinoma or mucoepi-
dermoid carcinoma.
Prognosis and predictive factors
Recurrences are common, associated
with positive margins or high-grade his-
tology. Death results from the destruction
of local vital structures or distan! blood-
borne metastases (to the lungs) (493 ,
1110,1528,1865).
 \ .
Fig. 9.04 Ceruminous adenoma. A A variety of growth patterns are seen in ceruminous adenoma; glandular structures are separated by fibrous stroma.
B The glandular epithelium is bilayered, with !he outer layer being myoepithelial, but this may no! be obvious in all parts of the neoplasm. Abundan! cytoplasm is seen in the luminal
cells, which show focal decapitation secretion and contain ceroid pigment.

Ceruminous adenoma pleomorphic adenoma, and cerumi-

Sandison A.
Thompson L.D.R.
Definition
Ceruminous adenoma is a benign tumour
of the wax-producing glands of the exter-
na! aud itory canal.
ICD-0 code
Synonyms
Ceruminoma; ceruminal adenoma;
ceruminous pleomorphic adenoma;
ceruminous syringocystadenoma
papilliferum
Epidemiology
There is a wide patient age range
(12-85 years), with a mean patient age in
the fifth decade of life. There is an equal
sex distribution 12390), and children are
rarely affected 11510).
Localization
These tumours are confined to the skin
over the cartilaginous externa! auditory
canal (the outer half)
Fig. 9.05 Ceruminous adenoma. lmmunostaining for
8420/0 CK5/6 highlights the basal cells.
Clinical features
Symptoms include hearing loss and
otorrhoea; pain is rare, unless associated
with inflammation (1090).
Macroscopy
The tumour presents as a superficial ,
skin-covered , non-ulcerated mass as
large as 4 cm in size.
Histopathology
Histology shows unencapsulated, cir-
cumscribed , regular bilayered glands in
fibrous stroma. The growth pattern is vari-
able, and the tumour may be pseudo-infil-
trative . Three histological types are recog-
nized: ceruminous adenoma, ceruminous
nous syringocystadenoma papilliferum.
The histological features of these sub-
types are similar to those of the named
variant (i.e. pleomorphic adenoma), but
there are concurrent histological fea-
tures of ceruminous differentiation . lnner
cuboidal cells are positive for CK7, pan-
cytokeratin , and CD117 and may show
decapitation secretion and acid-fast
fluorescent yellow ceroid pigment 1324,
2390,2600). Neuroendocrine markers
are negative 11340,2390). Differential
diagnoses include middle ear adeno-
ma and ceruminous adenocarcinoma.
Prognosis and predictive factors
Recurrence is unlikely after complete
excision (1340).

Tumours of the externa! auditory canal 265

Tumours of the middle and inner ear
Squamous ce// carcinoma
Sandison A.
Thompson L.D .R.
Wenig B.M.
Definition
Squamous cell carcinoma (SCC) of the
middle ear is a malignant neoplasm of
squamous epithelium arising within the
middle ear.
ICD-0 code 8070/3
Epidemiology
SCC is rare in the middle ear. The mean
patient age at presentation is 60 years
(range: 21-89 years) . There is a reported
predilection for the left ear of elderly men
1834).
Etiology
The etiology is unknown, but chronic
otitis media is a predisposing factor in
75-85% of cases 11043).
Localization
SCC of the middle ear can originate in
the middle ear or can extend from an
externa! auditory canal SCC. lt does not
arise from the epidermoid formation (an
Fig. 9.06 Squamous cell carcinoma of !he middle ear.
Axial slice from a CT of left temporal bone showing the
tumour (arrow) causing cortical bone breach posteriorly
with extension into a few mastoid air cells.
266 Tumours of the ear
Fig. 9.07 Squamous cell carcinoma of the middle ear. Al
surgery, !he well-differentiated tumour (indicated by the
arrow in Fig. 9.06) was found to be extensively infiltrating
!he middle ear and surrounding structures.
embryonic epithelial rest associated with
congenital cholesteatoma). lntracranial
spread occurs with erosion through the
thin bony plate overlying the carotid ca-
nal in the medial wall of the middle ear
at the junction with the Eustachian tube.
Direct spread into the inner ear (via peri-
neural invasion along the eighth cranial
nerve) is uncommon 11603).
Clinical features
Patients report aural discharge and con-
ductive hearing loss. Otalgia, bleeding,
and facial palsy are common 1701,834,
1389}.
Macroscopy
A plaque-like or polypoid mass may
be seen or palpated in the ear canal.
Tumour may fill the middle ear and ex-
tend into the mastoid air space.
Histopathology
The histology is similar to that described
at other siles. There may be associated
carcinoma in situ of cuboidal middle ear
epithelium.
Prognosis and predictive factors
The prognosis is generally poor, due to
advanced disease at presentation and
delayed diagnosis. Outcome is related
to stage at presentation 1115}, with a
wide range of reported 5-year survival
rates (25-83%) following surgery and ra-
diotherapy 1701,1341,1389,1557). Death
usually results from direct intracranial
extension. Nodal metastases, which are
unusual, affect neck levels 11 and 111
1834). Distant metastases are rare . SCC
may be mistaken for chronic otitis media.
Aggressive papillary tumour
Sandison A.
Definition
Aggressive papillary tumour is a locally
invasive, papillary epithelial neoplasm .
ICD-0 code 8260/1
Synonym
Papillary adenocarcinoma of the middle
ear
Epidemiology
The mean patient age at presentation
is 34 years (range: 16-55 years), with
patients often symptomatic for severa!
years befare diagnosis. The tumour is
rare, with relatively few cases reported in
the literature, but there appears to be a
female predominance .
Localization
The tumour can be found in any area of
the middle ear, including the mastoid pro-
cess and air cells, and may fill the tym-
panic cavity. In all but 3 of the described
cases 1510,1084,2268}, there was exten-
sive invasion outside the middle ear, in-
volving the apical portian of the petrous
bone in most cases. In a few cases, the
tumour reached the cerebellopontine
ang le and the cerebellum . In cases with
widespread involvement of the temporal
bone, origin from the endolymphatic sac
has been suggested 1964).
Clinical features
Patients present with clinical and audio-
logical features that suggest a tumour
in the middle ear. In almost all reported
cases, there has been extensive inva-
sion outside the middle ear 1614,793,794,
1908,2285).
A ...
Fig. 9.08 Aggressive papillary tumour of the middle ear. A The tumour shows a papillary glandular pattem, with complex papillae lying loase or infiltrating loose fibrous connective
tissue. B The papillae are lined by peripheral basal and inner cuboidal to columnar epithelial cells with uniform nuclei and eosinophilic cytoplasm.
Macroscopy
The middle ear cleft (including the mas-
toid air cells) is usually filled with a papil-
lary tumour. Bone invasion is often seen .
Histopathology
A papillary glandular pattern is present,
with complex interdigitating papillae ly-
ing loosely or infiltrating fibrous con-
nective tissue . The papillae are lined
by basal and low cuboidal to colum-
nar epithelial cells with uniform nuclei ,
eosinophilic cytoplasm, and indistinct
cell borders. Thyroid follicle-like areas
may be present, resembling endolym-
phatic sac tumour.
The tumours express cytokeratin, EMA,
and 8100. Metastatic papillary carci-
noma of the thyroid can be excluded by
immunostaining for thyroglobulin.
Cell of origin
Both the endolymphatic sac and the
middle ear epithelium have been con-
sidered as possible sites of origin
l1673,2174l.
Genetic susceptibility
Sorne cases of aggressive papillary
tumour of the middle ear have been asso-
ciated with von Hippel-Lindau disease.
Prognosis and predictive factors
Complete surgical excision is the treat-
ment of choice. However, surgery
carries the risk of high morbidity, because
resection may necessitate the sacrifice
of cranial nerves. Various treatment mo-
dalities may be employed (depending on
the stage at presentation), including ra-
diotherapy alone and the combination of
-~- -
surgery and postoperative radiotherapy
l614l.
Endolymphatic sac tumour
Sandison A.
Definition
Endolymphatic sac tumour (ELST) is a
low-grade malignant epithelial tumour
arising from the endolymphatic sac in the
temporal bone.
ICD-0 code
Synonyms
Low-grade papillary adenocarcinoma of
endolymphatic sac origin; Heffner tumour
Epidemiology
ELST is rare. lt occurs mostly in adults,
over a wide age range; it has been
described in a 4-year-old child l1305l.
There may be a slight female predomi-
nance. About one third of cases are as-
sociated with von Hippel-Lindau disease
(VHL), an autosomal dominant familia!
cancer syndrome !1527).
Etiology
About 10% of patients with VHL develop
ELST, of which about 30% of cases are
bilateral l1527,1578l. The prevalence of
VHL is approximately 1 case per 39 000
population l1470l.
Localization
Early-stage tumours are confined to
the endolymphatic sac in the inner ear
l955,1600l As tumours grow, they may
destroy petrous temporal bone and ex-
tend into the middle ear and the middle
and posterior cranial fossae and into the
cerebellopontine angle !150,964).
Correlation with imaging helps distin-
guish ELST from middle ear adenoma,
meningioma, and choroid plexus papil-
loma. Jugular glomus tumours and mid-
dle ear paraganglioma involve the jugular
foramen and the middle ear rather than
extending into the retrolabyrinthine tem-
poral bone. Schwannoma is usually well
circumscribed and centred on the jugu-
lar foramen, and does not involve the ret-
8140/3 rolabyrinthine temporal bone.
Clinical features
Non-specific presenting symptoms in-
clude hearing loss, tinnitus, aural fullness,
and vertigo l1470,1527l. As the tumour
spreads, patients may develop facial nerve
paralysis and/or cerebellar disorders.
Histopathology
The architecture is variable; the tumour
can be both papillary and cystic. There is
usually a single layer of tumour cells, but
the tumour may appear bilayered. The
tumour cells may be flattened, attenuated,
and cuboidal or columnar, with bland , ec-
centrically located nuclei and pale eosin-
ophilic or clear cytoplasm. Small glands
and follicular structures may be present,
containing deeply eosinophilic colloid-
like secretions that give a strongly posi-
tive periodic acid-Schiff (PAS) reaction
and resembling thyroid tissue. PAS may
demonstrate intracytoplasmic inclusions
in tumour cells. Mucin stains are negative.
Mitoses and necrosis are not seen.
Tumours of the middle and inner ear 267

Fig. 9.09 Endolymphatic sac tumour. On axial
postcontrast MRI, the tumour presents as a large
heterogeneous mass centred on the left cerebellopontine
angle cistern; fluid levels are seen in cystic components.
There is distortion and mass effect on the left cerebellar
hemisphere.
The tumour is poorly defined, and
diagnosis may be obscured by adjacent
vascular granulation tissue in subsurface
tissue, associated with haemosiderin
deposition, chronic inflammation, cho-
lesterol clefts, and dystrophic calcifica-
tion. ELST may be misdiagnosed as a
reactive or inflammatory process, es-
pecially if biopsies are small and not
representative.
The differential diagnosis includes me-
tastases. lmmunostaining for CD10,
CAIX , and PAX8 is positive in renal cell
carcinoma, but negative in ELST. Meta-
static thyroid carcinoma can be exclud-
ed with TTF1 and thyroglobulin immu-
nostains. Metastatic prostate carcinoma
expresses prostate-specific antigen and
P504S.
Cell of origin
The tumour is thought to arise from papil-
lary epithelium of the endolymphatic sac.
268 Tumours of the ear
Genetic profile
The VHL gene, mapped to chromosome 3
(3p25-26) l2124l, is a tumour suppressor
gene !1342). lts product forms a multipro-
tein complex with a role in oxygen sens-
ing . The VHL gene regulates VEGF. ln-
activation results in upregulation of VEGF
and angiogenesis. A loss-of-function mu-
tation results in overexpression of HIF1 ,
promoting angiogenesis and tumori-
genesis. Genetic analysis of the heredi-
tary form of ELST has shown inherited
(germline) mutations together with dele-
tion of the wildtype VHL allele, supporting
Knudson's hypothesis of the sequence of
events required for tumorigenesis !1253,
2197) and supporting the clinical j1527}
and genetic !2512) association of the
tumour with VHL.
Genetic susceptibility
Screening for ELST by audiologi-
cal testing and MRI with gadolinium
is recommended for individuals who
have been diagnosed w ith or who
have a family history of VHL j1578}
Patients with sporadic ELST should be
screened for VHL.
Prognosis and predictive factors
Complete surgical excision may be
curative !1470). However, surgery car-
ries the risk of high morbidity, because
it may require resection of petrous tem-
poral bone and mastoid, necessitating
sacrifice of cranial nerves. Advanced
tumours may be treated by radiotherapy
alone or by a combination of surgery
and postoperative radiotherapy. The
prognosis depends on the tumour size
at presentation and the adequacy of
surgical excision. Rarely, distant metas-
tases have been described !2365).
/i: ·;~ /,::~~;;··. :· ,.,,
~~ ~.~, ~ ;~:::~ ~'
: · :'./~}]¡ >:-~··:'
Otosclerosis
Sandison A.
Definition
Otosclerosis is a bone lesion that devel-
ops in the otic capsule and may affect
hearing and balance.
Synonym
Otospongiosis
Epidemiology
Otosclerosis affects about 3 in 1 000
White adults !2025); it is rare in Asians
and Africans . The reported incidence
is higher in patients with hearing loss
(5-9%) and higher still in patients with
conductive hearing loss in particu lar
(18- 22%) ¡550,1188). Hearing loss usu-
ally develops in the third to fifth decade
of life, and there is a female-to-male
ratio of 2-3:1. Although < 0.5% of affected
people develop symptoms, an autopsy
study has shown that silent, so-called
histological otosclerosis may have a
much higher incidence j549}.
Etiology
The etiology is not understood. Otoscle-
rosis has been considered to be a disor-
der of bone remodelling of the otic cap-
sule possibly associated with abnormal
collagen synthesis , aberran! expression
of inflammatory mediators, or viral in-
fection !1188,2025). However, the argu-
ment has recently been made that oto-
sclerotic plaques behave like low-grade
neoplasms, in that pre-existing normal
structures in the cochlear and vestibular
otic capsules are invaded and replaced
!1602). Autopsy studies have also shown
 as 50% of recorded cases are sporad-
Otic capsule ic {2025). Multiple gene loci have been
identified that may be associated with
otosclerosis, but the mechanism is un-
known (1188\. A recent systematic litera-
ture review determined that the available
data are insufficiently robust to guide ge-
netic counselling {212\.

Prognosis and predictive factors

The prognosis is good. Untreated, oto-
sclerosis leads to very significant hearing
loss, but total deafness is rare. Medical
treatment options are available, but the
best treatment is surgery, and the aim is
to improve the conductive hearing loss
{2025). Complications include a low risk
of sensorineural hearing loss, which can-
not be improved, and facial nerve injury.
Tinnitus may become worse.

Cholesteatoma
Sandison A.

Definition
Vestibule Cholesteatoma is a cystic or open mass
of keratin izing squamous epithelium
Fig. 9.11 Otosclerosis. Otosclerotic plaque in !he cochlear part of !he clic capsule. The lesion appears to arise from in air-filled spaces of temporal bone.
periosteum and infiltrates into cochlea, vestibular region , and stapes joint. The basophilic front contains primitive
Although not neoplastic, it has a propen-
osteoblasts and Volkmann canals (perforating holes), whereas there is more mature, spongiform bone behind this,
closer to !he origin. Adapted from Michaels L and Soucek S (1602}. sity to erode local structures and to recur
after excision.
that, like neoplasms, the lesions continue conductive hearing loss, which is bilat-
to grow and expand throughout life {1602\. eral in 80% of cases {2025\. Epidemiology
The reported annual incidence of
Localization Macroscopy cholesteatoma is 3-15 cases per
Disease is usually bilateral and sym- Biopsy is seldom performed . Morpho- 100 000 children and 9-13 cases per
metrical. A bony plaque develops in the logy is based on analysis of temporal 100 000 adults. A male predominance
otic capsule (predominantly in the region bones examined at autopsy. Stapedec- has been reported.
posterior to the cochlea), which then tomy specimens may contain otosclerotic Congenital cholesteatoma affects infants
involves the stapes footplate, resulting in plaque tissue, which is usually associat- and young children. In one large series ,
conductive hearing loss {1601,2025\ The ed with the anterior part of the footplate. 72% of cases occurred in males {1912\.
lesion broadly expands in all directions Acquired cholesteatoma affects older
into the otic capsule. lt passes through Histopathology children and young adults.
the stapedovestibular joint and along the Otosclerosis presents as well-demarcat- Cholesteatoma is more prevalent in de-
stapes footplate. lnferiorly and laterally, ed tumour-like masses of predominantly veloping countries, but there does not
it may involve branches of the vestibulo- immature trabecular bone and vascular appear to be an association with socio-
cochlear nerve (eighth cranial nerve) to stroma forming in the otic capsule. Le- economic status (1212,1481 ,1779\. There
the saccule. Anterior cochlear plaques of siona! cellularity varies , and active bone is an ethnic predilection, with the disease
otosclerosis may also be present. These remodelling may be identified, with cyto- seen most commonly in White people,
have a wide area of contact with the peri- logical atypia of osteocytes (1601,2025\ followed by Africans; it is rarely seen in
osteum bordering the canal for the inter- One study reported histological changes non- lndian Asians (1299,1724\.
na! carotid artery. Occasional plaques in patients' stapes bone suprastructure
have been described in other locations {344\. Etiology
within the otic capsule. Congenital cholesteatoma develops be-
Genetic profile hind the intact eardrum and is believed
Clinical features There is a strong familia! link (-60%) in to originate from an embryonic rest (the
Patients usually present with progressive clinical otosclerosis cases , but as many epidermoid formation) {1598\. Acquired

Tumours of the middle and inner ear 269


Fig. 9.12 Cholesteatoma. Non-echoplanar imaging
diffusion study showing high signa! in the left petrous
apex, characteristic of cholesteatoma.
Fig. 9.13 Cholesteatoma of the externa! ear canal.
Otoscopy shows drum retraction, ulceration, and
haemorrhage.
cholesteatoma is associated with a per-
forated eardrum. Most cases are associ-
ated with recurrent infection resulting in
squamous epithelium growing down into
the middle ear from the tympanic mem-
brane {2583}. Acquired cholesteatoma is
also known to occur following tympanic
membrane retraction, due to deep in-
growth of squamous epithelium from the
fundus of the retraction pocket into the
middle ear. Cholesteatoma may also de-
velop following a blast injury that causes
perforation of the tympanic membrane
11282). Cytokines and inflammatory me-
diators have been implicated in the de-
velopment of cholesteatoma 1424,1298).
Localization
Congenital cholesteatoma arises in the
anterior superior quadrant of the meso-
tympanum. Acquired cholesteatoma
most commonly arises in the superior
posterior middle ear 11599). Rarely, cho-
lesteatoma is diagnosed in the externa!
ear canal , where it must be distinguished
from infection and other inflammatory
conditions 1969,1821).
270 Tumours of the ear
-
Fig. 9.14 Cholesteatoma. Strips of keratinizing squamous
epithelium with abundan! keratin fiakes are usually seen;
there may be associated chronic infiammation and foreign
body-type reaction in underlying stroma, as shown.
Clinical features
Patients typically report hearing loss
associated with foul-smelling aura! dis-
charge. The mass can remain unde-
tected and grow large, with a risk of in-
tratemporal or intracranial complications.
Destruction of the bone overlying the
semicircular canals can result in dizzi-
ness and balance disorders, and facial
paralysis may result if the facial nerve ca-
nal is affected 11299}.
Macroscopy
Cholesteatoma presents as a pearly-
wh ite mass in the middle ear cavity.
Cholesteatoma of the ear canal may be
difficult to distinguish from other inflam-
matory/infective disorders or squamous
neoplasia 1969,1821).
Histopathology
Biopsied cholesteatoma material typical-
ly consists of abundant anucleate keratin
squames that make up the cornea! !ayer
of the squamous epithelium , together
with otherwise normal keratinizing squa-
mous epithelium. There may be evidence
of increased proliferation of the deeper
epithelial layers of the cholesteatoma ma-
trix , with down-growths into the underly-
ing stroma. The granular !ayer is usually
prominent and a helpful diagnostic find-
ing. The epithelium lacks atypia and of-
ten lacks rete pegs , yielding an atrophic
appearance. There is usually an inflamed
fibrous connective tissue stroma, a help-
ful finding for the diagnosis. Concurrent
disorders (otic polyp, cholesterol granu-
loma, encephalocoele) may be present.
Genetic profile
Clinically, cholesteatoma behaves as a
low-grade neoplasm, and recent stud-
ies have shown altered expression in
cholesteatoma of severa! genes associ-
ated with intercellular signalling and cell-
growth control. These alterations include
upregulation of EGFR , TGF-alpha, and
metalloproteinases, as well as downregu-
lation of tumour suppressor genes and
altered expression of proto-oncogenes
11298,1299). The mechanisms involved
in the development of cholesteatoma are
unclear.
Prognosis and predictive factors
Treatment is surgery. The risk of recur-
rence is high, and follow-up is by surgery
and direct observation. Follow-up scans
with diffusion-weighted MRI may be
effective for detecting disease recur-
rence 11136}. Long-term follow-up is
required, because late recurrence can
occur. Rare complications of surgery
include complete neurosensory hearing
loss in the affected ear and damage to
the facial nerve (the risk is usually < 1%).
Vestibular schwannoma
Sandison A.
Thompson L.D.R.
Wenig B.M .
Definition
Vestibular schwannoma is a benign pe-
ripheral nerve sheath tumour arising with-
in the interna! auditory canal or within the
labyrinth.
ICD-0 code 9560/0
Synonyms
Acoustic neuroma; vestibular neuroma;
neurilemmoma
Epidemiology
Vestibular schwannoma is the most com-
mon tumour of temporal bone, account-
ing for 5-10% of ali intracranial tumours
and 80-90% of ali cerebellopontine angle
tumours; however, it is found incidentally
in < 1% of adult autopsies performed for
otherreasons{250,1386} Overall , patients
typically present in their fifth to sixth dec-
ade of life, but patients with neurofibroma-
tosis type 2 (NF2) present significantly
younger 11701 ).

Fig. 9.15 Vestibular schwannoma. On coronal slice from
postcontrast MRI, the well-circumscribed lesion in !he
right cerebellar pontine angle can be clearly seen; !he
tumour is bright in comparison with !he adjacent brain
tissue and contains cystic hypointense areas.
unsteady gait, and balance alterations
may also occur.
Facial pain, weakness, and loss of taste
are more common with brain stem com-
pression by the tumour {250). A funnel -
shaped widen ing of the interna! audi -
tory canal or a mushroom-shaped mass
(with the stalk in the canal and the flange
within the cerebellopontine angle) can
be seen as a hyperintense area on T2-
weighted MRI {1525) . The tumours are
radiographically staged on the basis of
location, size, and extent {2125).
Macroscopy
A smooth, lobulated tumour mass creates
a globular, eccentric mass, frequently
attached to the eighth cranial nerve,
which may be stretched or compressed.
The tumours are usually < 2 cm (due to
anatomical confines), with a firm, yellow-
ish-tan, solid to cystic appearance.
greater risk of recurrence or malignant
transformation {167,2559). However, a
watchful waiting approach (vs surgery)
may be employed, because the tumours
grow 1-4 mm per year {1449,1738).
Meningioma
Sandison A .
Thompson LO.R.
Definition
Meningioma is a benign neoplasm of
meningothelial (arachnoid) cells .
ICD-0 code 9530/0
Epidemiology
Meningiomas constitute about 20-36%
of intracranial neoplasms. Primary

Fig. 9.16 Vestibular schwannoma. High-power view
showing palisaded, elongated nuclei.
Etiology
For most cases the etiology is unknown,
but trauma dueto extended occupational
exposure to excessively loud noise may
be a potential risk factor, whereas mobile
phone use is not a demonstrated risk fac-
tor {1651 ). lnherited cases (associated
with NF2) are uncommon {1701).
Localization
Most cases are unilateral and sporadic
cerebellopontine angle tumours arising
within the vestibular division of the eighth
cranial nerve, rarely affecting the cochle-
ar division {1717,2012) . When the tumours
are bilateral or multicentric, there may be
association with NF2 {1701 ). Rarely, the
interna! auditory meatus may be involved
{250,2651 ).
Clinical features
The most common clinical manifesta-
tions, usually present for many years,
are unilateral progressive sensorineu-
ral hearing loss (occurring in > 90% of
cases) and tinnitus (in 70% of cases)
{2237,2261,2456) . Headache, vertigo,
Histopathology
The histological features are characteristic
of a schwannoma, with cellular (Antoni A)
areas of closely packed spindle cells with
nuclear palisading, adjacent to microcyst-
ic or loosely reticular (Antoni B) areas. The
cells are fusiform, with fibrillary cytoplasm
and buckled nuclei. They lack significant
pleomorphism, with limited mitoses and
no necrosis. Perivascular hyalinization of
medium-sized vessels is characteristic.
Ancient change (nuclear degeneration)
is usually only focal, whereas significant
pleomorphism, necrosis, and increased
mitoses suggest malignant peripheral
nerve sheath tumour {135).
The tumour cells are strongly positive for
8100 protein and SOX10; GFAP staining
is weak to absent; and CD34, NFP, BCL2,
and EMA are negative {1608,2416). The
Ki-67 proliferation index is higher in NF2-
associated tumours than in sporadic
lesions {25) The tumours should be dis-
tinguished from meningioma, neurofi -
broma, solitary fibrous tumour, paragan-
glioma, and malignant peripheral nerve
sheath tumour.
Genetic profile
NF2 gene mutations (usually resulting in
loss of merlin) are identified in < 5% of
tumours, most commonly in patients
< 21 years of age {913). Fig. 9.17 Meningioma ofthe middle ear. AThe characteristic
whorled architecture of meningothelial meningioma is noted
beneath an intact squamous epithelium. B Lobules and
Prognosis and predictive factors nests of bland epithelioid tumour cells are seen in syncytial
Larger tumour size (> 18 mm) and NF2 architecture. C There is strong CAM5.2 reactivity in a pre-
association are features associated with psammomatous pattern, quite characteristic of meningioma.

Tumours of the middle and inner ear 271

extracranial (i .e. ectopic or extracalva-
rial) meningiomas of the ear and tem-
poral bone are rare, accounting for only
about 2% of all meningiomas and about
10% of ear and temporal bone tumours
{2029,2386). Meningioma affects wom-
en more often than men, with a female-
to-male ratio of 2:1. The mean patient
age at presentation is 50 years (range:
10-90 years). The average patient age
is older among women than among men
{1920,2279,2386}.
Etiology
The roles of radiation exposure and
sex hormones in the genesis of ear
and temporal bone meningiomas are
unproven. Composite tumours as a
result of a schwannoma merging with a
meningioma may be seen in the setting
of neurofibromatosis type 2 {1701}.
Localization
The tumours involve subsites in the tem -
poral bone, in order of frequency: the
middle ear, interna! auditory meatus, jug-
ular foramen, and roof of the Eustachian
tube {1920,2029,2386).
Clinical features
Patients present clinically with hearing
loss, tinnitus, otitis media, pain, head-
aches, dizziness, and/or vertigo, with
symptoms usually having been present
for years {2029,2279). Direct extension
from the CNS must be radiographi -
cally or clinically excluded {2029,2386).
En plaque tumours must be excluded .
lmaging usually shows bone erosion ,
sclerosis, and hyperostosis with temporal
air cell opacification {2163,2279 ,2647).
Macroscopy
Macroscopically, there is a gritty, granu-
lar mass infiltrating bone. The mass is
usually < 1.5 cm in size , due to the ana-
tomical confines of the region.
Histopathology
Microscopically, the tumour infiltrates
bone and soft tissues of the region, show-
ing a well-developed meningothelial and
whorled architecture. Lobules and nests
of bland epithelioid tumour cells are
seen in a syncytial architecture. Nuclei
are round to oval , with delicate nuclear
chromatin distribution and frequent in-
tranuclear cytoplasmic inclusions. Psam-
moma bod ies or pre-psammoma bodies
may be seen. The most common types
272 Tumours of the ear
are meningothelial, psammomatous, and
fibroblastic. Lesiona! cells express EMA,
CAM5.2, and pancytokeratin as well as
CK7 (pre-psammoma-body pattern),
but S100 protein (weakly) , claudin 1,
progesterone receptor, and vimentin are
also positive. lmmunostaining for GFAP,
SMA, synaptophysin, and chromogranin
is negative.
Genetic susceptibility
Meningiomas are well described in
neurofibromatosis type 2, with chromo-
some 22 deletions being the most con-
sistent cytogenetic finding .
Prognosis and predictive factors
The prognosis is good, with a 5-year
survival rate of about 85% , although re-
current or persistent tumour is common
(seen in 20% of cases). Mastoiditis and
meningitis are the most common com-
plications of surgery {2029 ,2279,2386,
2647).
Middle ear adenoma
Sandison A.
Bell D.
Thompson L.D.R.
Definition
Middle ear adenoma is a benign neo-
plasm of the middle ear showing cyto-
morphological and immunohistochemi-
cal evidence of dual neuroendocrine and
mucin -secreting differentiation.
ICD-0 code 8140/0
Synonyms
Neuroendocrine adenoma of the middle
ear; middle ear adenomatous tumour;
carcinoid of the middle ear; middle ear
adenoma with neuroendocrine differen-
tiation; amphicrine adenoma
Epidemiology
This is a rare tumour of the middle ear,
accounting for < 2% of ear tumours. lt
has an equal sex distribution and has
been reported over a wide patient age
range (13-80 years), with a mean patient
age at presentation of 45 years {19,593 ,
1846,2414).
Localization
These tumours can arise anywhere in
the middle ear cavity, including in the
tympanic membrane, and occasionally
extend into the mastoid , Eustachian tube,
or externa! auditory canal {19,99,2055,
2414).
Clinical features
The most common presenting symptom
is unilateral hearing loss (of the conduc-
tive type if the ossicular chain is involved)
{19,614,2055,2414). Pressure, fullness,
tinnitus, discharge, bleeding, and otitis
media are uncommonly seen. Otoscopic
examination shows a soft tissue mass
behind a usually intact tympanic mem-
brane. Nerve compression is uncommon
{1371) and serological evidence of neu-
roendocrine function is rare . CT (without
contrast) or MRI visualizes tumour ex-
tent and exact location. There is usually
no temporal bone destruction , although
ossicular encasement is common {593,
1846,2414).
Macroscopy
The tumour is white, grey, or redd ish
brown. lt is unencapsulated , frequently
entrapping and destroying the ossicles.
Most tumours are < 1 cm in size {19,
2055,2414).
Histopathology
The tumours lack a surface origin, show-
ing an infiltrative, unencapsulated , mod-
erately cellular growth of a variety of pat-
terns, including glandular, trabecular,
solid , acinar, cribriform , pseudoalveolar,
organoid , nested , diffuse, and sing le-
cell. The duct-like structures show a
loosely cohesive back-to-back appear-
ance, and are often separated by a fi-
brotic to desmoplastic stroma. The neo-
plastic cells show a dual cell population
of inner, luminal , slightly flattened eosino-
philic cells frequently associated with a
secretion, subtended by a basal, cuboi-
dal to columnar cell population {19,1478 ,
2414). The cells may have an eccentric
(plasmacytoid) placement of a round
to oval nucleus, showing delicate, fine ,
salt-and-pepper nuclear chromatin distri-
bution. The nucleoli are small {99,1984,
2554). Mitoses are sparse , and there is
no necrosis, perineural invasion, or lym-
phovascular invasion . lsolated pleomor-
phism may be seen, but is not profound.
Concurrent cholesteatoma or cholesterol
granuloma may be seen.
There is variable but consistently present
reaction with pancytokeratin, CAM5.2,
~ ,.,

. - - - - -- - - - -- - ----- -- - - - -

Fig. 9.18 Middle ear adenoma. A The duct-like structures show a loosely cohesive back-to-back appearance, separated by a fibrotic stroma. B The neoplastic cells show
slightly fiattened eosinophilic cells frequently associated with a secretion, subtended by a basal, cuboidal to columnar cell population. A myoepithelial layer is absent.
C Cords and trabeculae of bland tumour cells are seen infiltrating around bone trabeculae. D There is strong nuclear immunoreactivity for ISL 1, an aberran! neuroendocrine marker.

CK7 (luminal cells), CK5/6 and p63
(abluminal cells), synaptophysin , chro-
mogranin, and CD56, along with various
polypeptides (e.g. human pancreatic
polypeptide) and transcription factors
(e.g. ISL1). 8100 protein, SMA, TTF1 ,
CDX2, and PAX8 are negative !19,1478,
2414). Sorne cases may not show immu-
nohistochemical neuroendocrine mark-
ers, but these do not require a separate
designation. Ultrastructural examination
shows two distinct cell types: type A api-
cal cells with microvilli and secretory mu-
cus granules and type B cells with sol id,
dense-core neurosecretory granules.
There are also transitional forms of both
types , confirming the dual differentiation
!2554). Mucoprotein luminal and cyto-
plasmic secretions are highlighted with
periodic acid-Schiff (PAS) and Alcian
blue staining, and neurosecretory gran-
ules are highlighted by Grimelius stain
{2414,2554) . Although it is not wrong to
consider these tumours carcinoids !572,
1643,1954,2055}, it is appropriate to refer
to these tumours as adenoma with neu-
roendocrine features, in line with curren!
tumour taxonomy.
Prognosis and predictive factors
The tumour usually peels away easily, but
if middle ear bones are not included in
the resection , recurrence or persistence
is seen in about 15% of cases !614,1846,
2414). Parotid gland involvement via
direct extension from a widely infiltrative
tumour does not constitute metastatic
disease !1371,1643,1954). A metastatic
potential may exist; there is no indisput-
able evidence and further investigation is
required.

Tumours of the middle and inner ear 273

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WHO classification of paraganglion tumours

Carotid body paraganglioma 8692/3* The morphology codes are from the lnternational Classification of Oiseases
Laryngeal paraganglioma for Oncology (ICD-0) (776A}. Behaviour is coded /0 for benign tumours;
8693/3*
/ 1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in
Middle ear paraganglioma 8690/3* situ and grade 11 1 intraepithel ial neoplasia; and /3 for malignan! tumours.
Vaga! paraganglioma 8693/3* The classification is modified from the previous WHO classification , taking
into account changes in our understanding of these lesions.
*These new codes were approved by the IARC/WHO Committee for ICD-0 .

Paraganglion tumours

lntroduction
Chan J.K .C.
There have been remarkable advances
in our knowledge of the molecular ge-
netics of paragangliomas since publica-
tion of the 3rd edition of the WHO clas-
sification ¡304,722l. Paraganglioma has
been shown to have the highest degree
of heritability among human neoplasms,
with as many as 40% of ali cases be-
ing associated with germline mutation
in a known susceptibil ity gene (512,
722l. As a result, the Endocrine Soci-
ety guidelines recommend referrin g ali
patients with paraganglioma (including
patients with an apparently sporadic tu-
mour) for clinical genetic testing {1383l
In this 4th edition of the WHO classifi-
cation , head and neck paragang liomas
are classified as in the previous edition ,
with one change in terminology, from
"jugulotympanic paraganglioma" to "m id-
dle ear paraganglioma".
The term "malignant paraganglioma", tra-
ditionally used to refer to tumour compli -
cated by metastasis, is no longer used
in this classification because it is now
recognized that ali paragangliomas have
sorne potential for metastasis (albeit vari -
able). Tumours previously referred to as
"malignant paraganglioma" can be de-
scribed as "metastasizing paragang lio-
ma" or "paraganglioma with metastasis" .

276 Paraganglion tumours

Carotid body paraganglioma Kimura N.
Capella C.
Lam A.KY
Tischler A.S .
Gill A. Williams M.O.
Komminoth P.

Definition produce catecholamines are rare (ac- Histopathology

Carotid body paraganglioma is a neu-
roendocrine neoplasm arising from
the carotid body paraganglia near the
carotid bifurcation.
ICD-Ocode 8692/3
Synonyms
Carotid body tumour; chemodectoma;
non-chromaffin paraganglioma
Epidemiology
Carotid body paragangliomas account
for the majority (60%) of head and neck
paragangliomas. They present in adults
in their fifth or sixth decade of lite (or
about a decade younger in metastatic
cases) (389 ,1576l. There is a female-to-
male ratio of 2:1 , and this female pre-
dilection is even more pronounced in
populations living at high altitudes, where
the female-to-male ratio is 8:1 (1365,
2006). Bilateral paragangliomas occur in
as many as iü- 25% of cases, with 4-6%
of cases being metastatic (67,1332,1753,
1937,2047).
counting for < 5% of cases) (67,1332,
1753,1937,2047), but are more common
in metastatic tumours {1576l. lmaging
with contras! confirms a hypervascu-
lar, well-defined mass at the carotid
bifurcation.
Macroscopy
Paragangliomas are firm, rubbery, and
often well circumscribed. The tumour
size range is 2- 6 cm, which may include
a portian of the arterial wall with lumen.
Cytology
Aspirates are usually bloody, with low
to moderate cellularity, showing single
or clusters of cells with poorly defined
borders and basophilic cytoplasm. Nu-
clei are round to elongated, with mild to
moderate pleomorphism and prominent
nucleoli. Redd ish cytoplasmic granules
may be identified on Giemsa-stained
preparations {931).
The organoid (Zellballen) pattern of the
normal paraganglion is typically seen.
However, a wide range of variant mor-
phology may be observed , including
trabecular, spindled, and angioma-like
patterns, as well as a sclerosing pat-
tern characterized by extensive colla-
gen deposition with features mimicking
those of an invasive malignan! neoplasm
{1321) The tumours are composed of
two cell types: chief cells, which have
abundan! pale eosinophilic cytoplasm
with slightly to moderately atypical nu-
clei , and sustentacular cells, which are
slender, spindled , and located peripher-
ally in the nests. A prominent vascular
network separates the tumour nests. Mi-
totic figures are usually rare. There is no
cellu lar polarity within the nests, which
helps to distinguish these tumours from
other neuroendocrine tumours, such as
carcinoid.
The chief cells express synaptophysin,
chromogranin A, CD56, and somatostatin

Etiology
Carotid body paragangliomas are pre-
dominately parasympathetic , with genet-
ic factors identified in one third of cases.
Chronic hypoxia, including that due to
living at high altitudes, is a risk factor
(2006).

Localization
Carotid body paragangliomas arise at
the bifurcation of the common carotid ar-
tery. They may be associated with the ex-
terna! or interna! carotid branch and may
grow circumferentially around the vessel
(Shamblin class 111) {2141) .

Clinical features
The usual presentation is an asympto-
matic or pulsatile high neck mass near
the anterior border of the sternocleido-
mastoid muscle near the mandible. Pain , Fig. 10.01 Carotid body paraganglioma. A Circumscribed bilateral carotid body paragangliomas (arrows) on coronal
syncope, and Horner syndrome (oculo- contrasted CT. B Angiography of the larger, right paraganglioma shows the highly complex vascular network of vessels
sympathetic palsy) are rare manifesta- (arrow) that often necessitates embolization prior to resection. C On cut surface, the tumour has a homogeneously
tions. Clinically functional tumours that tan-pink, elastic, firm appearance, with areas of fibrosis .

Carotid body paraganglioma 277

receptor 2A {653,1232}, and are typi-
cally negative for cytokeratin, carci-
noembryonic antigen, and calcitonin.
Approximately 30% express tyrosine hy-
droxylase, which is required for catecho-
lamine synthesis {1786}, but staining is
often only focal {2408}, consistent with
the typical lack of clinical function. The
sustentacular cells express S100 protein
and GFAP, but are negative for epithelial
and neuroendocrine markers. The Ki-67
(MIB1) proliferation index is generally
< 1%, consistent with the slow growth of
carotid body paragangliomas {555l . The
loss of immunohistochemical staining of
neoplastic chief cells for the SDHB pro-
tein has recently been found to be signifi -
cantly correlated with germline mutation
of any of the SDH complex genes, but is
not seen in sporadic or non-SDH -mutant
cases {2472l . This immunohistochemical
test can therefore be used as a screening
method to guide genetic testing.
Tumours that should be distinguished
from paragangliomas include carcinoid
and well-differentiated neuroendocrine
tumour, medullary thyroid carcinoma, hy-
alinizing trabecular tumour of the thyroid
gland, and (rarely) haemangiopericytoma
278 Paraganglion tumours
and glomus tumour. The combination of
positive immunostaining for chromogra-
nin A, synaptophysin, GFAP, S100 pro-
tein, and tyrosine hydroxylase and the
absence of cytokeratin is helpful for dis-
tinguishing paragangliomas from these
tumours.
Genetic susceptibility
Collectively, phaeochromocytomas, sym-
pathetic paragangliomas, and head and
neck (parasympathetic) paragangliomas
are the most hereditarily driven of all hu-
man tumours, with at least 19 suscepti-
bility genes identified to date {1798l (see
Table 10.01). Tumour location , multiplic-
ity, biochemical function, metastatic risk,
and syndromic associations depend on
the specific gene involved . A predis-
posing germline mutation is present in
;:>:30% of all patients and in 7-13% of
those presenting with an apparently spo-
radic tumour {272l. Most mutated genes
causing hereditary paragangliomas have
an autosomal dominant mode of inher-
itance, with loss or inactivation of the
wildtype allele in a tumour. Exceptions
are the RET proto-oncogene and EPAS1
(also called HIF2A), wh ich exhibits
gain-of-function mutations not requiring
a second hit, although allelic imbalance
can occur (1256l. lnheritance of three
genes (SOHO, SDHAF2, and MAX) in-
volves a parent-of-origin effect, such that
transmission can occur from either par-
ent, but an affected child usually devel-
ops paraganglioma only if the mutated
gene was received from the father (164l.
This may lead to generation skipping of
tumour susceptibility in affected families,
which must be considered when family
history is examined. To date, genomic
imprinting at the disease gene locus has
not been unequivocally identified as the
mechanism of this parent-of-origin effect,
and several other mechanisms have also
been proposed (164l.
The highest rates of head and neck para-
ganglioma are associated with germline
mutations in SDHD or SDHC, followed by
SOHAF2 and SDHB (Table 10.01) (176 ,
1060l These genes, along with SDHA,
are collectively known as the SDH genes.
Most head and neck paragangliomas in
SOHO-mutation carriers are multiple,
and approximately 85% are carotid body
paragangliomas (307,18241. In contrast,
SOHC mutation is usually associated with

single head and neck paragangliomas.
SDHB mutation is associated mainly
with extra-adrenal abdominal and pelvic
paragangliomas 1227}, although tumours
can also be found in the head and neck
1844). Most hereditary paragangliomas
have syndromic associations with other
endocrine and/or non-endocrine tumours
that have only recently been recognized
1512,1798 ).
These tumours can present befare, after,
or simultaneously with paraganglioma,
making it difficult to recog nize index
patients. The identification of an associa-
tion of germline SDH gene defects with
the development of pituitary adenoma,
paraganglioma, and phaeochromocy-
toma, called the 3P association , has ex-
panded the spectrum of tumours consid-
ered to be SDH-associated 12650).
The familia! occurrence of combined gas-
trointestinal stromal tumour and paragan-
glioma has been termed Carney-Stra-
takis syndrome (or paraganglioma and
gastric stromal sarcoma) ¡339). Since
the initial description of this association
in 2002, it has been demonstrated that
most of these patients harbour mutations
in one of the SDH genes 11823,2289}, in-
dicating that Carney-Stratakis syndrome
and paraganglioma syndromes overlap
or are part of the same disease. Another
condition in which paraganglioma can
be found is Carney triad 1338). Affected
individuals (mostly females) present with
paraganglioma, gastrointestinal stromal
tumour, and pulmonary chondroma. To
date, no inherited trait has been estab -
lished , although Carney triad can rarely
be allelic to Carney-Stratakis syndrome
1231 ). Deletions within the 1pcen13-q21
region (which harbours the SDHC gene)
and aberrant DNA hypermethylation of
SOHC have been proposed as possible
mechanisms of tumour development in
Carney triad 1924,1560).
Somatic mutations of hereditary suscepti -
bility genes are found in as many as 20%
of truly sporadic phaeochromocytoma/
paraganglioma cases without indication
of heritable disease {512). SDH genes
are seldom or never mutated in the non-
familial, sporadic tumours , whereas so-
matic NF1 mutations are common {512}
(see Table 10.01) However, these driver
gene mutations alone are not sufficient
far tumorigenesis in either hereditary or
sporadic tumours , and the complete set
of requirements remains unknown.

Table 10.01 Major mutated genes causing- hereditary head and neck paraganglioma
- (HNPGL)

Frequency Thoraco- Other

Numberof Risk of
Gene Syndrome Chromosome lnheritance of HNPGL in PCC abdomi- syndromic References
tumours metastasis
gene carriers nal PGL lesions

SDHO ~GL1/CSS 1 11q23 1 AD-PT 79-89% Multiple 4% 14- 53% 1 12- 39% RCC, GIST, PA
{1762,1798,
1824}
- -
SOHAF2 PGL2/CSS 11q12.2 AD-PT 73-86% Multiple Low - - None reported {1762,1798}
-
SDHC PGL3/CSS 1q23.3 AD 88% Single 3% <3% Very rare RCC, (GIST) {1798,1824}

{227,1762,
SOHB PGL4/CSS 1 1p36.3 AD 27-62% Multiple 23% 18-28% 52-84% RCC, GIST, PA
1 1798,1824}
-
(RCC), GIST,
SDHA PGL5/CSS 5p15.33 AD ? Single Low __Rare .l +
PA
{303,1798}
1
1 - - ·-
VHL VHL 3p25-26 AD 0.5% Single 4% 10-34% Rare RCC, HB {1762,2527}
MTC, HPT,
RET MEN2 10q1 1.2 AD Very rare Single < 5% 50% Rare {488,2526}
(GNM)
-
Café-au-lait
spots, NF,
NF1 NF1 17q11.2 AD Very rare Single 12% 1-5% Rare PNST, SOM, {488,1739}
Lisch nodules,
GIST
TMEM127 Non-syndromic 2q11 .2 AD 1-2% Multiple Low + + None reported {1762}
Parentheses within the column "Other syndromic lesions" indicate that the lesion is not obligatory and/or is a rare componen! of the syndrome. AD, autosomal dominan!; AD-
PT, autosomal dominan! with paternal transmission (disease is inherited only from paternal carrier); CSS, Carney- Stratakis syndrome (paraganglioma and gastric stromal
sarcoma); GIST, gastrointestinal stromal tumour; GNM, ganglioneuromatosis; HB, haemangioblastoma; HPT, hyperparathyroidism; MEN2, multiple endocrine neoplasia type
2; MTC, medullary thyroid carcinoma; NF, neurofibroma; NF1 , neurofibromatosis type 1; PA, pituitary adenoma; PCC, phaeochromocytoma; PGL, paraganglioma; PGL1-5,
paraganglioma_syndrome types 1-5; PNST, peripheral nerve sheath tumour; RCC, renal cell carc}noma; SOM , duodenal somatostatinoma; VHL, von Hippel-Lindau disease.

Carotid body paraganglioma 279

A variety of other changes, including mu- Table 10.02 Phaeochromocytoma/paraganglioma susceptibilily genes
tations of additional genes, copy-number
changes reflected in chromosomal gains
Types of mutations
Germline only -Genes
SDHA, SDHAF2, SDHC, KIF18, TMEM127, FH
or losses, and epigenetic modifica-
Germline and somatic NF1, RET, VHL, SDHD, SDHB, MAX
tions, have been identified . SDH-mutant
tumours show frequent combinations Somatic only HRAS, ATRX
of - 1p and +1q, whereas VHL-mutant Somatic and somatic mosaicism EPAS1 (also called HIF2A)
tumours have combined deletions at 3pq MEN1, EGLN1 {also called PDH2), EGLN2(also called POH1),
and llp. Gains of genomic material oc- Single palients or families
MOH2, /OH1
cur less frequently, and amplifications
have not been reported . SDH genes (in
Table 10.03 The most importan! somatic mutations in sporadic phaeochromocytoina/¡iaraganglioma
particular SOHB) in SDH -mutant para-
gangliomas are hypermethylated, lead - Gene Frequency of mutation References
--
ing to silencing of genes involved in neu- NF1 21-41% {305,2581}
roendocrine differentiation {353,1390} In ATRX 12.6% {723}
contrast, sporadic tumours and tumours
HRAS 5-10% {498,1491 ,1788}
with mutant RET, NF1, MAX, TMEM127,
or HRAS are associated with widespread VHL 9.2% {308}
hypomethylation outside of CpG islands EPAS1 (also called HIF2A) 5-7.4% {475,2580}
{1390). lt has been suggested that DNA COKN2A 7% {355}
methylation profiling might be useful to
RET 5% {308}
predict tumour aggressiveness {536).
The expression profiles of microRNAs are TP53 2.35-10% {355,1491}
reported to be differentially expressed in MET 2.5% {355}
genetic subtypes of paraganglioma and BRAF 1.2% {1491}
to correlate with transcriptome-based
MAX 1.65-2.5% {306,308}
classifications {355 ,1080).
More recently, a refined classification IOH1 Very rare {788}
based on integrated genomic analyses, K/F18 Very rare {2096}
including chromosomal changes, micro- SDH family Very rare {162,501 ,1824,2473}
RNA profiles, and epigenetic alterations
{354,355 ,740}, has been proposed .
resection occurs in < 10% of cases, but the cervical nodal metastasis and distan! me-
Prognosis and predictive factors rate may exceed 50% among patients with tastasis) is 88%. Patients with distan! me-
Carotid body paragangliomas are slow- SOHB mutations, suggesting that treat- tastases and patients with SDHB-mutant
growing tumours . The most common ment strategies can be tailored according paragangliomas have the lowest 5-year
treatment is surgery with or without adju- to genotype {651A). There are no validated survival rates: 11% and 36.5% , respectively
vant radiation, although more conserva- histological criteria to predict metastasis at {302,1365,2133).
tive approaches have been suggested present. The overall 5-year survival rate for
{2133,651A) . Overall, recurrence after metastasizing paraganglioma (including

280 Paraganglion tumours

Laryngeal paraganglioma
Definition
Laryngeal paraganglioma is a neuroen-
docrine neoplasm derived from either the
superior or the inferior paragang lia of the
larynx.
ICD-0 code
Synonyms
Chemodectoma; non -chromaffin
paraganglioma
Epidemiology
True laryngeal paragangliomas are very
rare. Sorne cases previously reported as
laryngeal paraganglioma may in fact be
misidentified carcinoid tumours, and only
76 definite cases of laryngeal paragangli -
oma had been reported by 2004 (1678).
Unlike other neuroendocrine tumours of
the larynx, paraganglioma is more com-
mon in females, with a female -to-male
ratio of 3:1 (1678,1893) . Most tumours
present in the fourth to sixth decades
of life, but a wide patient age range has
been reported (5-83 years) (1678).
Localization
The larynx contains two pairs of paragan-
glia: superior and inferior (140) . Supra-
glottic paragangliomas (82% of cases)
appear to arise from the superior pair of
laryngeal paraganglia, and present as
a submucosal mass in the region of the
Fig. 10.04 Laryngeal paraganglioma. A Contrast-enhanced sagittal CT shows an enhancing heterogeneous mass
(arrow) filling the left supraglottic region. B Nests of paraganglion cells (arrow), called Zellballen, are noted beneath the
squamous mucosa, accompanied by prominent vasculature.
aryepiglottic fold (140) . Subglottic para-
gangliomas (15% of cases) arise from the
inferior pair of laryngeal paraganglia, and
may extend laterally to present as thy-
roid masses (1678). Right-side laryngeal
paragangliomas are more common; the
8693/3 ratio of right-side to left-side incidence is
2.3:1 (140) .
Clinical features
Paragangliomas may present with dys-
phagia, dyspnoea, or stridor, but the
symptoms Jargely depend on location;
supraglottic tumours more commonly
present with hoarseness, whereas sub-
glottic tumours more commonly present
as a mass (often in the thyroid) (1678,
2223). Symptoms due to catecholamine
production occur rarely, if ever {140,
1678), and most tumours reported as
functional laryngeal paraganglioma are
probably misidentified atypical carci-
noids {1097,1160,2498) .
Macroscopy
Laryngeal paragangliomas are usually
well-circumscribed submucosal masses
(140) .
Histopathology
The morphology and immunohistochemi-
cal profile are similar to those of paragan-
gliomas at other sites (see Carotid body
paraganglioma, p. 277). Particular care
Kimura N.
Capella C.
Komminoth P.
Lam A.K.Y.
Gill A. Tischler A.S.
Williams M.O.
should be taken to avoid misdiagnosis of
laryngeal carcinoid tumours or neuroen-
docrine carcinomas as paragangliomas
(140,1678).
Genetic susceptibility
In head and neck paragangliomas,
germline mutations of the succinate
dehydrogenase genes (SDHA, SDHB,
SDHC, and SOHO) are particularly com-
mon {163,814,837,2024), and these muta-
tions have been reported or presumed in
laryngeal paragangliomas (814,2024).
Prognosis and predictive factors
Surgical excision is the treatment of
choice {705) . Recurrence after surgery
has been reported in as many as 17% of
patients, 1-16 years after excision {140).
However, given the frequent association
with germline mutation, many such ca-
ses may in fact constitute second prima-
ry tumours rather than true recurrence .
Metastasis is exceptional; the few cases
previously reported as "malignant" la-
ryngeal paraganglioma were in fact mis-
identified atypical carcinoids (140). The
best estimate of the rate of metastasis is
2% {533,705,2026).
Laryngeal paraganglioma 281
Middle ear paraganglioma
Definition
Middle ear paraganglioma is a neuro-
endocrine neoplasm arising from the
paraganglia in the adventitia of the jugu-
lar bulb or on the medial promontory wall
of the middle ear.
ICD-0 code 8690/3
Synonyms
Jugulotympanic chemodectoma; glomus
jugulare tumour; glomus tympanicum
tumour
Epidemiology
Middle ear paragangliomas account for
about 29% of ali head and neck para-
gangliomas {660 ,2721). About 66-90%
of middle ear paragangliomas occur
in women. The patient age range is
26-79 years (mean: 55 years), and bi-
modal incidence peaks are seen in the
fourth and seventh decades of life {336).
In men , the tumour presents ata younger
age and the familia! type occurs more
frequently.
Localization
Most middle ear paragangliomas are jug-
ular neoplasms, originating from a para-
ganglion in the adventitia of the jugular
bulb . Less commonly, they are tympanic
neoplasms, arising from a paraganglion
associated with the tympanic nerve
(nerve of Jacobson). Jugular neoplasms
invade petrous bone, whereas tympanic
neoplasms occupy the middle ear cavity.
Middle ear paragangliomas can be bilat-
eral and associated with paragangliomas
of other sites (e.g. carotid body and vagal
paragangliomas) {336} They can also
coexist with phaeochromocytoma.
Clinical features
Patients commonly present with pulsa-
tile tinnitus, subjective hearing loss, and
aural fullness. Otalgia and symptoms
suggestive of lower cranial neuropathy
282 Paraganglion tumours
Kimura N.
Capella C
Lam A.KY
Tischler A.S.
GillA. Williams M.O.
Komminoth P.
B
Fig. 10.05 Middle ear paraganglioma. A Typical appearance on axial contrast-enhanced T1-weighted MRI. The
contrast-enhanced jugular foramen neoplasm (arrows) has !he typical salt-and-pepper appearance, due to !he
combination of foci of haemorrhage (!he sal!) and flow voids (!he pepper). B On otoscopy, !he tumour is recognizable
as a vascular mass appearing behind !he intact tympanic membrane.
Histopathology
The histology and immunoprofile are similar
to !hose of carotid body paraganglioma
(see Carotid body paraganglioma,
p. 277). Lack of immunoreactivity for
cytokeratins and p63 is useful in the
differential diagnosis from middle ear
adenoma {1478).
'?V~~-·~~-=-~ Genetic susceptibility
Fig. 10.06 Middle ear paraganglioma showing Hereditary syndromes such as neurofi-
tumour cells with rich vascular network. bromatosis and phaeochromocytoma-
paraganglioma syndrome have been
(e.g. dysphonia and dysphagia) may be reported in patients with middle ear
noted. On otoscopic examination, the paraganglioma {226 ,548,2091 }. Mid-
tumour is recognizable as a red , vascular dle ear paraganglioma can occur in
mass either appearing behind the intact familia! settings, typically with multiple
tympanic membrane or protruding through tumours and together with carotid body
the tympanic membrane into the externa! paraganglioma.
canal. Neurosecretory function is rare.
Prognosis and predictive factors
Macroscopy Metastasis has been reported in as many
The neoplasm presents as an irregular, as 5% of cases {1526). In older patients,
red, fleshy mass. The jugular variety in- the tumour often remains stable for many
vades the petrous portion of the tempo- years and may have slow growth with
ral bone as well as the middle ear cavity. progressive cranial neuropathy; there-
Massive middle ear paragangliomas with fore , observation can be a reasonable
extensive erosion of the petrous bone management strategy {337). Lack of im-
and intracranial impingement are rare . In munostaining for SDHB is associated
exceptional cases, the tumour extends with an increased risk of metastasis.
intravenously. The tumour appearance
can be modified by preoperative tumour
embolization and/or radiotherapy.

Vagal paraganglioma
Definition
Vagal paraganglioma is a neuroendo-
crine neoplasm arising from paraganglia
in the vagal trunk near its exit from the
brain stem. Paragangliomas associated
with peripheral vagus nerve branches
are usually defined by their anatomical
site (e.g. laryngeal paragangliomas) .
ICD-0 code 8693/3
Synonyms
Glomus vagale tumour; chemodectoma;
non-chromaffin paraganglioma
Epidemiology
Vagal paragangliomas account for ap-
proximately 13% of all head and neck
paragangliomas. They are the third most
common paragangliomas in this body
site, after carotid body and middle ear tu-
mours {660,2721) They usually present
in middle-aged patients (mean patient
age: 41-47 years {660)) but have also
been reported in children and in elderly
patients. Most series show a female
predominance (with 50-85% of cases
occurring in females) {188,1618,1722,
2226) . Multicentric tumours are seen
in 17-37% of cases overall and in as
many as 80% of cases in patients with a
pos itive family history {327) . Vagal para-
gangliomas can occur bilaterally and in
combination with other paragangliomas
{2721).
Localization
Vagal paragangliomas arise from micro-
scopic variably distributed paraganglia
within or adjacent to the vagal nerve and
its ganglia. Most tumours occur within the
first 2 cm of the nerve, at the level of the
inferior (nodose) ganglion, but sorne are
more rostral or more caudal. Anatomical
imaging typically shows tumours supe-
rior to the carotid bifurcation, displacing
the bifurcation anteriorly and medially
but not enlarging it. These findings dis-
tinguish vagal paragangliomas from their
carotid body counterparts.
Fig. 10.07 Vagal paraganglioma. MR angiogram showing
a vagal paraganglioma on the left (red arrow) and a
carotid paraganglioma on !he right (white arrow). The
vagal tumour is located well above the carotid bifurcation,
displacing it anteriorly and medially.
Clinical features
The signs and symptoms depend on the
tumour location in relation to the vagus
nerve, the consequent location within
the parapharyngeal space {970}, tumour
size, and the presence or absence of
infiltration. Cranial nerve palsies can be
caused by direct involvement of the va-
gus nerve or compression of nerves IX,
XI, and XI l. Other reported manifestations
include Horner syndrome (oculosympa-
thetic palsy) caused by damage to the
cervical sympathetic chain and slow-
growing masses that displace or infiltrate
adjacent tissues {970). Historically, many
patients presented with palpable masses
in the neck or pharynx and intracranial
extension with damage to multiple cra-
nial nerves {970,2448) In recent studies,
vagal paragangliomas are sometimes
first detected by imaging of patients with
a personal or family history of paragangli-
omas or as incidentalomas, and as many
as 70% of these patients are asympto-
matic {1332).
Less than 4% of vagal paragangliomas
are clinically functional, producing nor-
epinephrine or dopamine {660,893). In
suspected functional cases, care must
be taken to rule out the possibility that the
hormone is being produced by a second
primary tumour.
Komminoth P
Kimura N.
Capella C. Lam A.KY
GillA. Tischler A.S.
Macroscopy
Most vagal paragangliomas are globoid
or elongated tumours, partially or com-
pletely surrounded by a fibrous capsule .
The most rostral examples can be cone-
shaped because of adhesion to the skull
base, or dumbbell -shaped because of
intracranial extension through the jugu-
lar foramen {970) . The cut surface is
variably pinkish -grey, pinkish -tan, or
yellowish -tan, with areas of fibrosis and
haemorrhage.
Histopathology
Vagal paragangliomas are morphologi-
cally and immunohistochemically similar
to other paragangliomas in the head and
neck (see Carotid body paraganglioma,
p. 277).
Genetic susceptibility
The predisposing mutations usually
involve one of the genes encoding suc-
cinate dehydrogenase subunits. Rare
cases involve mutations of SDHAF2,
the gene encoding the flavination factor
for SDHA {1295) . In a series of 37 vagal
paragangliomas with an inherited basis,
33 cases (89%) harboured mutations
in SDHO, 3 cases (8%) in SDHB, and
1 case (3%) in SDHC {2334).
Prognosis and predictive factors
The prognosis depends on tumour
location, size, and genotype, as well as
comorbidities, including other paragan-
gliomas. Currently, the major treatment
options are external-beam radiotherapy
and stereotactic radiosurgery, which
are sometimes used in combinations
that may include chemotherapy {327).
Although the surgical cure rate is > 90%,
almost all surgically treated patients have
severe vagal nerve deficits, and as many
as 61 % have postoperative neurologi -
cal complications caused by damage to
other cranial nerves {327) . In contrast,
two series that monitored vagal and other
head and neck paragangliomas for peri-
ods of 1-17 years showed that untreated
tumours usually grow very slowly or re-
main stable for long periods {1114,1332},
Vagal paraganglioma 283
indicating that close observation without
treatrnent can be an option {252} .
In sorne series, vagal paragangliornas
have been reported to have a higher fre-
quency of rnetastasis than other head
and neck paragangliornas, with rnetasta-
sis occurring in as rnany as 16% of vagal
284 Paraganglion turnours
turnours versus in 2-6% of carotid body
and rniddle ear turnours {327} . However,
in sorne cases, the possibility of a sec-
ond prirnary rather than rnetastasis rnay
not have been ruled out. The rnost corn-
rnon site of rnetastasis is the cervical
lyrnph nodes (accounting for as rnany as
73% of cases) , followed by bone, lung,
and liver {970}. Because rnetastases rnay
occur after years or decades, long -terrn
follow-up is required . Overall survival
with distant rnetastases varies, but can
exceed 1O years even without treatrnent.
Contributors

Dr Kehinde ADEB IYI Dr Elizabeth A. BILODEAU Dr Steve BUDNICK

Department of Oral Pathology and Department of Diagnostic Sciences Atlanta Oral Pathology
Oral Medicine University of Pittsburgh 1209 Springdale Road
Lagos State University College of Medicine School of Dental Medicine Decatur GA 30033
Lagos 3501 Terrace Street, G135 Salk Annex USA
NIGERIA Pittsburgh PA 15261 USA Tel . + 1 678 592 3386
Tel. +234 8033 447 558 Tel.+ 1 412 383 7949 sbudnic@gmail.com
kenad@justice.com elizabeth .bilodeau@dental.pitt.edu

Dr Carl M. ALLEN Dr Justin A. BISHOP Dr Jorn BULLERDIEK

Division of Oral & Maxillofacial Pathology & Radiology Department of Pathology University of Bremen
College of Dentistry, The Ohio State University Johns Hopkins University Leobenerstrasse, ZHG
Central Ohio Skin & Cancer, lnc. School of Medicine 28359 Bremen
300 Polaris Parkway, Suite 3300 401 North Broadway, Weinberg 2249 GERMANY
Westerville OH 43082 Baltimore MD 21231 Tel. +49 42121861501
USA USA Fax +49 421 218 61505
Tel. +1614823 5597 Tel. + 1 41 O 955 8116 bullerd@uni-bremen .de
Fax +1614823 5468 Fax +1410955 0115
drcarlallen@cohskin.com jbishop@jhmi.edu

Dr Ade l ASSAAD Dr Elisabeth BLOEMENA Dr Cario CAPELLA

Virginia Mason Medical Center Department of Oral and Maxillofacial Surgery, Department of Surgical and
1100 9th Avenue Department of Pathology Morphological Sciences
Seattle WA 98101 VU University Medical Center, University of lnsubria - Varese
USA Academic Centre for Dentistry Via O. Rossi 9
Tel. +1206624 1144 De Boelelaan 1117 21100 Varese
a del. assaad@vi rg in iamason .org 1081 HV Amsterdam ITALY
THE NETHERLANDS Tel. +39 332 270 601
Tel. +31 20 444 40 14 Fax +39 332 270 600
e.bloemena@vumc.nl carlo.capella@uninsubria.it

Dr Daniel BAUMHOER* DrSonjaBOY Dr Antonio CARDESA

Department of Pathology Unit of Oral Pathology Department of Anatomic Pathology
University Hospital Basel School of Oral Health Sciences Faculty of Medicine, University of Barcelona
Schoenbeinstrasse 40 Sefako Makgatho Health Sciences University August Pi i Sunyer Biomedical Res. lnstitute
4031 Basel Molotlegi Street Villarroel, 170
SWITZERLAND 1 Ga-Rankuwa, Pretoria 08036 Barcelona
Tel. +41 61 328 68 92 SOUTH AFRICA SPAIN
Fax +41 6126535 13 Tel . +27 82 654 3256 Tel. +34 93 227 5450
daniel .baumhoer@usb.ch Fax +27 12 521 427 4 Fax +34 93 227 5717
son ja. iaop@gmail.com acardesa@clinic.ub .es

Dr Diana BELL* Dr Margaret BRANDWEIN-GENSLER* Dr Roman CARLOS

Department of Pathology Department of Pathology & Anatomical Sciences Oral Pathology, Clínico de Cabeza y Cuello
University of Texas State University of New York at Buffalo Hospital Herrera-Llerandi
MD Anderson Cancer Center Erie County Medica! Center 6a. Avenida 7-39 Zona 10
1515 Holcombe Boulevard, Unit 0085 462 Grider Street Edificio 1-as Brisas of. 501
Houston TX 77030 Buffalo NY 14215 01010 Guatemala City
USA USA GUATEMALA
Te l. +1713792 2041 Tel. +17168983114 Tel. +502 2362 6001 ext.
Fax +1713745 8610 Fax +1716898 3090 Fax +502 2362 6003
diana.bell@mdanderson.org mgensler@buffalo.edu monchorcb@yahoo.com

*lndicates participation in the Working Group Meeting on the WHO Classification of Head and Neck Tumours that was held in Lyon, France,
14- 16 January 2016.
# lndicates disclosure of interests .

Contributors 285
Dr Odile CASIRAGHI Dr Hedley COLEMAN Dr Hanadi A. FATANI
Gustave Roussy, Université Paris-Saclay Tissue Pathology & Diagnostic Oncology Pathology and Clinical Laboratory
Département de Biolog ie et Patholog ie lnstitute for Cli nical Pathology and Med ic ine Administration
Médicales Medical Research King Fahad Medical City
114 Rue Édouard-Vaillant Sydney Westmead, Locked Bag 9001 Riyadh
94805 Villejuif NSW, 2145 Sydney SAUDI ARABIA
FRANCE AUSTRALIA Tel. +966 11 288 9000 ext. 11540
odile.casiraghi@gustaveroussy.fr Tel . +61 2 9845 7772 emsaffana@yahoo.com
Fax +61 2 9687 2330
hedley .coleman@health. nsw. gov .au

Dr James CASTLE Dr Patricia DEVILLI ERS Dr Andrew L. FELDMAN#

Department of Oral & Maxillofacial Pathology Department of Anatomic Pathology Department of Laboratory
Naval Postgraduate Dental School, NMPDC Dynamic Pathology Medicine and Pathology
Walter Reed National Military Medica! Center 14730 Second Avenue Circle Northeast Mayo Clinic
8955 Wood Road Bradenton FL 342 12 200 First Street Southwest
Bethesda MD 20889-5628 USA Rochester MN 55905
USA Tel. + 1 205 790 5866 USA
Tel. + 1 301 295 5373 dynamicpathology@gmail.com Tel. + 1 507 284 4939
Fax + 1 3012951216 Fax +1 507 284 5115
james.t.castle4.mil@mail.mil feldman.andrew@mayo.edu

Dr John K.C . CHAN* Dr Silvana DI PALMA Dr Judith A. FERRY*

Department of Pathology Department of Histopathology Department of Pathology
Queen Eli zabeth Hospital Royal Surrey County Hospital Massachusetts General Hospital
Gascoigne Road, Kowloon Egerton Road 55 Fruit Street
Hong Kong SAR Gui ldford, Surrey GU2 7XX Boston MA 02114
CHINA UN ITED KINGDOM USA
Tel. +852 3506 6830 Tel. +441483 571 122 ext. 2371 Tel. + 1 617 726 4826
Fax +832 2385 2455 Fax +44 1483 452 718 Fax +1617726 9312
jkcchan@ha.org.hk sdipalma@nhs.net jferry@partners.org

DrWah C HEUK Dr Samir K. EL-MOFTY* Dr Uta FLUC KE

Department of Pathology Department of Pathology and lmmunology Department of Pathology
Queen Elizabeth Hospital Washington University School of Medicine Radboud University Nijmegen Medical Center
Gascoigne Road, Kowloon Campus Box 81 18, 660 South Euclid Avenue PO Box 9101
Hong Kong SAR Saint Louis MO 6311 O 6500 HB Nijmegen
CHINA USA THE NETHERLANDS
Tel. +852 3506 5739 Tel. +1314362 2681 uta.flucke@radboudumc.nl
Fax +852 2385 2455 Fax + 1 314 747 4392
cheuk_wah@hotmail. com elmofty@path. wustl. edu

Dr Simon CHIOSEA Dr Adel K. EL- NAGGAR* Dr Isabel FONSECA

Department of Pathology University of Texas Faculdade de Medicina, Universidade de
UPMC Presbyterian Hospital MD Anderson Cancer Center Lisboa & Instituto Portugués de Oncolog ia
200 Lothrop Street, PUH A610.3 1515 Holcombe Boulevard, Unit 0085 Francisco Gentil - Lisboa
Pittsburgh PA 15213 Houston TX 77030 Avenida Professor Egas Moniz
USA USA 1649-028 Lisbon
Tel. +1 412647 5565 Tel . + 1713 792 3109 PORTUGAL
Fax + 1 412647 7799 Fax+ 1 713 745 1105 Tel. +351 21 722 9825
chioseas i@upmc.edu anaggar@mdanderson.org Fax +351 21 720 0475
ifonseca@medicina.ulisboa.pt

Dr Shih-Sung CHUANG# Dr John Edward FANTASIA Dr Ma ria Pia FOSCHINI

Department of Pathology Department of Dental Medicine Dipartimento di Scienze
Chi Mei Medica! Center Long lsland Jewish Medica! Center Biomediche e Neuromotorie
901, Chung Hwa Road Hofstra Northwell School of Medicine University of Bologna
71004 Tainan 270-05 76th Avenue Via Altura3
Taiwan New Hyde Park NY 11040 40123 Bologna
CHI NA USA ITALY
Tel. +886 6 281 2811 ext. 53686 Tel . + 17184707116 Tel. +39 051 6225523
Fax +886 6 251 1235 Fax + 1516470 5644 Fax +39 051 6225759
cmh5301@mail.chimei.org.tw jfantasia@northwel l.edu mariapia.foschini@unibo.it

286 Contributors
Dr Craig B. FOWLER Dr Maura GILLISON Dr Jennifer L. HUNT
Department of Oral and Division of Medical Oncology Department of Pathology
Maxillofacial Pathology The Ohio State University University of Arkansas for Medical Sciences
University of Kentucky College of Dentistry 420 West 12th Avenue, Room 690 4301 West Markham Street, Mail Slot #517
800 Rose Street, MN528 Columbus OH 43210 Little Rock AR 72205
Lexington KY 40536-0297 USA USA
USA Tel. +1614247 4589 Tel. + 1 501 686 5170
Tel.+ 1 859 323 5515 Fax+ 1 614 688 4245 Fax+ 1 501 296 1184
Fax + 1 859 323 2525 maura.gillison@osumc.edu; gillison .3@osu.edu jlhunt@uams.edu
craig.fowler@uky.edu

Dr Alessandro FRANCHI Dr Douglas R. GNEPP* Dr Keith HUNTER

Dipartimento di Chirurgia e Medicina Department of Head and Neck Pathology Department of Oral & Maxillofacial Pathology
Traslazionale (DCMT) University Pathologists Diagnostics University of Sheffield
Universitá degli Studi di Firenze 1030 Presiden! Avenue, Suite 213 19 Claremont Crescent
c/o Anatomia Patologica - Largo Brambilla Fall River MA 02720 Sheffield S10 2TA
350134 Firenze USA UNITED KINGDOM
ITALY Tel. + 1 401 996 3981 Tel. +44 1104 271 7956
Tel. +39 55 447 8102 Fax+ 1 508 235 6310 Fax +44 1104 271 7863
Fax +39 55 275 1731 douglasgnepp@gmail.com k.hunter@sheffield .ac.uk
alessandro.franchi@unifi.it

Dr Christopher A. FRENCH# Dr Jennifer R. GRANDIS* Dr Stephan IHRLER

Department of Pathology Department of Otolaryngology Labor für Dermatohistologie und
Brigham and Women's Hospital Head and Neck Surgery Oralpathologie
Harvard Medical School University of California, San Francisco Bayerstrasse 69
77 Avenue Louis Pasteur, Room 630G 550 16th Street, Box 0558 80335 Munich
Boston MA 02115 San Francisco CA 94143 GERMANY
USA USA Tel . +49 89 9788 0450
Tel. + 1 617 525 4415 Tel.+1415514 8899 Fax +49 89 3402 327 4
Fax +1617525 4422 jennifer.grandis@ucsf.edu ihrler@dermpath-muenchen.de
cfrench@partners.org

Dr Nina GALE* Dr Kristiina HEIKINHEIMO Dr Hiroshi INAGAKI#

lnstitute of Pathology Department of Oral Diagnostic Sciences Department of Pathology and
Faculty of Medicine, University of Ljubljana lnstitute of Dentistry Molecular Diagnostics
Korytkova 2 University of Eastern Finland Nagoya City University
1000 Ljubljana Yliopistonranta 1, Box 1627 1 Kawasumi Mizuho-ku Aichi Prefecture
SLOVENIA 70211 Kuopio 467-8601 Nagoya
Tel. +386 1 543 7151 FINLAND JAPAN
Fax +386 1 543 7104 Tel. +358 50 564 2669 Tel. +81 52 853 8005
nina.gale@mf.uni-lj.si krihei@uef.fi hinagaki@med .nagoya-cu.ac.jp

Dr Philippe GAULARD Dr Tim HELLIWELL Dr Elaine S. JAFFE#

Department of Pathology Molecular and Clinical Cancer Medicine Laboratory of Pathology, Center for Cancer
Henri Mondor Hospital, INSERM U841 University of Liverpool Research, National Cancer lnstitute
51 Avenue du Maréchal de Lattre de Tassigny Duncan Building, Daulby Street Building 10, Room 3S 235, 10 Center Orive
94010 Créteil Liverpool L69 3GA MSC-1500
FRANCE UNITED KINGDOM Bethesda MD 20892-1500
Tel. +33 1 49 81 27 43 Tel. +44 151 706 4492 USA
Fax +33 1 49 81 27 33 Fax +44 151 706 5859 Tel. + 1 301 480 8040
philippe.gaulard@hmn .aphp.fr trh@liv.ac.uk Fax+ 1 301 480 8089
ejaffe@mail.nih.gov

Dr Anthony GILL DrJos HILLE Dr Robert JAKOB*

Department of Anatomical Pathology Department of Oral & Maxillofacial Pathology Data Standards and lnformatics
Royal North Shore Hospital University of the Western Cape & National lnformation, Evidence and Research
Reserve Road Health Laboratory Service World Health Organization (WHO)
NSW 2065 St Leonards Tygerberg, Cape Town 20 Avenue Appia
AUSTRALIA SOUTH AFRICA 1211 Geneva 27
Tel. +61 2 9926 4399 Tel. +27 21 938 4041 SWITZLERAND
Fax +61 2 9926 4084 Fax +27 21 938 6559 Tel. +41 22 791 58 77
affgill@med.usyd.edu.au jhille@sun.ac .za Fax +41 22 791 48 94
jakobr@who.int

Contributors 287
Dr Richard C. JORDAN Dr loannis KOUTLAS Dr limo LEIVO
Department of Oral Pathology Division of Oral and Maxillofacial Pathology Department of Pathology
Pathology & Radiation Oncology University of Minnesota School of Dentistry University of Turku
University of California, San Francisco 16-1168 Moas Tower Kiinamyllynkatu 10
1701 Divisadero Street, Room 280 515 Delaware Street Southeast 20520 Turku
San Francisco CA 94115 Minneapolis MN 55455 FINLAND
USA USA ilmo.leivo@utu.fi
Tel. +1415608 9378 Tel. +161 2624 8607
Fax +1415353 7553 Fax + 1 612 626 3076
richard .jordan@ucsf.ed u koutl001@umn.edu

Dr Nora KATABI Dr Kaoru KUSAMA Dr James S. LEWIS#

Department of Pathology Division of Pathology, Department of Department of Pathology,
Memorial Sloan Kettering Cancer Center Diagnostic and Therapeutic Sciences Microbiology, and lmmunology
1275 York Avenue Meikai University School of Dentistry Vanderbilt University Medical Center
New York NY 10065 1-1 Keyakidai , Sakado 1211 Medica! Center Orive, Room 30200
USA 350-0283 Saitama Nashville TN 37232
Tel. +1212639 3349 JA PAN USA
katabin@mskcc.org Tel . +81 49 279 2773 Tel. +1615343 0233
Fax +81 49 286 6101 Fax +1615322 1303
kusama@dent.meikai.ac.jp james.lewis@vanderbilt.edu

Dr Harvey KESSLER# Dr Hans Michael KVASNICKA Dr Jean E. LEWIS

Department of Diagnostic Sciences Senckenberg lnstitute of Pathology Department of Pathology
Texas A&M University Baylor College of University of Frankfurt Mayo Clinic
Dentistry Theodor-Stern-Kai 7 200 First Street Southwest
3302 Gastan Avenue 60590 Frankfurt am Main Rochester MN 55905
Dallas TX 75246 GERMANY USA
USA Tel. +49 69 6301 4900 Tel. + 1 507 288 6878
Tel.+ 1 214 828 8116 Tel. +49 69 6301 3903 Fax + 1 507 284 1599
Fax +1214828 8306 hans-michael.kvasnicka@kgu.de lewis. jean2@mayo.edu
hkessler@bcd.tamhsc.edu

Dr Noriko KIMURA* Dr Sunil R. LAKHANI* Dr Jiang LI

Clinical Research , Pathology Division Department of Molecular & Cellular Pathology Department of Oral Pathology
National Hospital Organization Hakodate University of Queensland 9th People's Hospital , Shang hai Jiao Tong
Hospital The Royal Brisbane & Women's Hospital University, School of Medicine
18-16 Kawahara Leve! 6, Building 71/918 639 Zhi -Zao-Ju Road
041-8512 Hakodate QLD 4069 Brisbane Herston 200011 Shanghai
JA PAN AUSTRALIA CHINA
Tel. +81 138 51 6281 Tel. +61 7 3346 6052 Te l. +86 136 1179 1235
Fax +81 138 30 1020 Fax +61 7 3346 5596 Fax +86 21 5331 5687
kimura-path@hnh.hosp.go.jp s. lakhani@uq.edu.au lijiang 182000@yahoo.com

Dr Young-Hyeh KO Dr Alfred King Yin LAM Dr Tie-Jun LI

Department of Pathology School of Medicine Department of Oral Pathology
Samsung Medical Center, Sungkyunkwan Griffith University Peking University School of Stomatology
University Gold Coast Campus 22 South Avenue
50 lrwondong Gangnamgu QLD 4222 Gold Coast Zhonguancun Haidian District
135-710 Seoul AUSTRALIA 100081 Beijing
REPUBLIC OF KOREA Tel. +61 7 5687 6543 CHINA
Tel. +82 2 3410 2762 Fax +61 7 5687 6797 Tel. +86 106 217 9977 ext. 2203
Fax +82 3 341 O 0025 a.lam@griffith.edu.au Fax +86 106 217 3402
yhko310@skku.edu litiejun22@vip.sina.com

Dr Paul KOMMINOTH Dr Constantino LEDESMA-MONTES Dr Xiao-Qiu LI

lnstitute of Pathology Laboratorio de Patología Clínica Department of Pathology
Stadtspital Triemli Facultad de Odontología Fudan University Shanghai Cancer Center
Birmensdorferstrasse 497 National Autonomous University of Mexico 270 Dong-An Road
8063 Zurich Circuito Institutos S/N 200032 Shanghai
SWITZERLAND Ciudad Universitaria Col Copilco CU CHINA
Tel. +41 44 466 21 22 MEXICO Tel. +86 21 3477 8242
Fax +41 44 466 21 38 Tel. +52 55 5622 5562 Fax +86 21 6417 0067
paul.komminoth@triemli.stzh.ch Fax +52 55 5550 3497 leexiaoqiu@hotmail.com
cledezma@unam.mx

288 Contributors
Dr Lisa LICITRA# Dr Adalberto MOSQUEDA-TAYLOR Dr Brad W . NEVILLE#
Department of Head and Neck Cancer Departamento de Atención a la Salud Oral Pathology, Department of Stomatology
Medical Oncology, Fondazione IRCCS Universidad Autónoma Metropolitana Medica! University of South Carolina College
lstituto Nazionale dei Tumori Xochimilco of Dental Medicine
Vía G. Venezian 1 Calzada del Hueso 1100, Col. Villa Quietud 173 Ashley Avenue, Room 539
20133 Milan 04960 DF Mexico City Charleston SC 29403
ITALY MEXICO USA
Tel. +39 2 2390 2150 mosqueda@correo.xoc.uam.mx Tel.+ 1 843 792 4495
Fax +39 2 2390 3769 Fax + 1 843 792 3697
lisa.licitra@istitutotumori.mi .it nevilleb@musc.edu

Dr Mark UNGEN Dr Susan MULLER Dr Piero NICOLAI

Department of Pathology Department of Otolaryngology Department of Otorhinolaryngology -
University of Chicago School of Medicine Head and Neck Surgery Head and Neck Surgery
5841 South Maryland Avenue, MC6101 Emory University University of Brescia - Spedali Civili Brescia
Chicago IL 60637 1209 Springdale Road Piazzale Spedali Civili 1
USA Atlanta GA 30306 25123 Brescia
Tel. + 1 773 702 5548 USA ITALY
Fax + 1 773 834 7644 Tel. +1404501 7445 Te l. +39 303 995 319
mark.lingen@uchospitals .edu Fax + 1 404 501 7460 Fax +39 303 995 212
smullerdmd@gmail.com pieronicolai@virgilio.it

Dr Scott LIPPMAN Dr Alfons NADAL Dr Karin NYLANDER

Moores Cancer Center Department of Anatomic Pathology Department of Medical Biosciences
University of California, San Diego Medical Facu lty, University of Barcelona Umea University
3855 Health Sciences Orive, MC 0658 August Pi i Sunyer Biomedical Res . lnstitute 2 Sjukhusomradet
La Jol la CA 92093 Casanova, 143 901 85 Umea SE
USA 08036 Barcelona SWEDEN
Tel. +1858822 1222 SPAIN Tel. +46 90 785 15 91; +46 70 558 05 23
Fax + 1 858 822 0207 Tel. +34 93 227 5450 karin.nylander@umu .se
slippman@ucsd edu Fax +34 93 227 5450
anadal@clinic.ub.es

Dr Thomas LOENING Dr Toshitaka NAGAO* Dr Edward W. ODELL*

Gerhard Seifert Reference Centre Department of Anatomic Pathology Department of Head and Neck/Oral Pathology
Hansepathnet Tokyo Medical University King's College London, Guy's and St Thomas'
Papenreye 23 6-7-1 Nishishinjuku, Shinjuku-ku NHS Foundation Trust
22453 Hamburg 160-0023 Tokyo Floor 4 Tower Wing, Guy's Hospital
GERMANY JAPAN London SE1 9RT
Te l. +49 40 554 952 83 Tel. +81 3 3342 6111 UNITED KINGDOM
Fax +49 40 554 952 60 Fax +81 3 3342 2062 Tel . +44 207 188 4378
loening@hansepathnet.de nag ao-t@tokyo-med.ac .jp edward.odell@kcl.ac.uk

Dr Marcio LOPES Dr Shigeo NAKAMURA Dr Hiroko OHGAKI*

Oral Diagnosis, Piracicaba Dental School, Department of Pathology and Laboratory Section of Molecular Pathology
State University of Campinas (UNICAMP) Medicine lnternational Agency for Research on Cancer
Cidade Universitária 'Zeferino Vaz', Barao Nagoya University Hospital 150 Cours Albert Thomas
Geraldo - Campinas 65, Tsurumai-cho, Showa-ku 69372 Lyon Cedex 08
13083-970 Piracicaba, Sao Pau lo 466-8560 Nagoya FRANCE
BRAZIL JAPAN Tel. +33 4 72 73 85 34
Tel. +55 19 3412 5319 Tel. +81 52 744 2896 Fax +33 4 72 73 86 98
Fax +55 19 3412 5218 Fax +81 52 744 2897 ohgakih@iarc.fr
malopes@fop. unicamp .br snakamur@med.nagoya-u .ac.jp

Dr Eugenio MAIORANO Dr Brenda NELSON Dr Andre M . OLIVEIRA

Department of Emergency and Organ
Transplantation, Pathological Anatomy
Un iversity of Bari Aldo Moro
Policl inico , Piazza G. Cesare, 11
70124 Bari
ITALY
Tel. +39 080 547 8292
Fax +39 080 547 8263
eugenio.maiorano@uniba.it
Department of Anatomic Pathology Departments of Laboratory Medicine and
Naval Medical Center San Diego Pathology and Anatomic Pathology
34800 Bob Wilson Orive Mayo Clinic
San Diego CA 92134-5000 200 Second Street Southwest
USA Rochester MN 55905
brenda.l.nelson24.mil@mail.mi l USA
Tel. + 1 507 284 2511
Fax + 1 507 285 1599
oliveira.andre@mayo.edu

Contributors 289
Dr German OTT Dr Jesper RE IBEL Dr Ann SANDISON*
Department of Clinical Pathology Department of Odontology Department of Histopathology
Robert Bosch Hospital University of Copenhagen Charing Cross Hospital
Auerbachstrassse 11 O 20 Noerre Alié Fulham Palace Road
70376 Stuttgart 2200 Copenhagen N London W6 8RF
GERMANY DENMARK UNITED KINGDOM
Tel. +49 711 8101 3394 Tel. +45 353 26720 Tel. +44 20 33 11 7139
Fax +49 71 1 8101 3619 jrei@sund.ku.dk Fax +44 20 33 11 1364
german.ott@rbk.de ann .sandison@imperial .nhs .uk

Dr Bayardo PEREZ-ORDONEZ* Dr Mary RICHARDSON Dr Sulen SAR IOGLU

Department of Laboratory Medicine and Department of Pathology and Department of Pathology
Pathobiology, University of Toronto Laboratory Medicine Dokuz Eylül University Faculty of Medicine
Toronto General Hospital Medical University of South Carolina Mithatpasa Cad. No:1606 Saglik Yerleskesi
200 Elizabeth Street, Room 11 E-444 Children's Hospital 35340 lnciralti-Balcova
Toronto ON M5G 2C4 165 Ashley Avenue, Room EH30304 TURKEY
CA NADA Charleston SC 29425 Te l. +90 232 412 3408 ext. 3408
Tel. +1416340 3852 USA Fax +90 232 277 7274
Fax + 1 416 340 5517 Tel . + 1 843 792 1994 sulen.sarioglu@deu.edu.tr
bayardo.perez-ordonez@uhn.ca richardm@musc.edu

Dr Bengt Fredrik PETERSSON DrJae Y. RO Dr Mary R. SCHWARTZ

Department of Pathology Department of Pathology & Genomic Department of Pathology and
National University of Singapore Medicine, Houston Methodist Hospital Genomic Medicine
Yong Loo Lin School of Medicine Weill Medica! College of Cornell University Houston Methodist Hospita l
NUHS Tower Block Kent Ridge Road , (S), 6565 Fannin Street 6565 Fannin Street, M227
119228 Houston TX 77030 Houston TX 77030
119077 Singapore USA USA
SINGAPORE Tel. + 1713441 2263 Te l. +1713441 6482
Tel. +65 6772 4304 Fax + 1 713 793 1603 mschwartz@houstonmethodist.org
bengt_fredrik_petersson@nuhs.edu .sg jaero@houstonmethodist.org

Dr Stefano A . PILER I# Dr Brian ROUS* Dr Raja SEETHALA *

Haematopathology Unit National Cancer Registration Service , Department of Anatomic Pathology
European lnstitute of Oncology Eastern Office UPMC Presbyterian Hospital
40121 Milano, ITALY Victoria House , Capital Park 200 Lothrop Street, Room A6 14
Tel. +39 02 57489521; stefano.pileri@ieo.it Fulbourn, Cambridge CB2 1 5XB Pittsburgh PA 15213
UNITED KING DOM USA
Un iversity of Bologna School of Medicine Tel. +44 122 321 3625 Tel . +14 12 647 9051
40138 Bolog na, ITALY Fax +44 122 321 3571 Fax +1412647 7799
Tel. +39 051 636 3044; stefano .pi leri@unibo.it brian.rous@phe.gov.uk seethalarr@upmc.edu

Dr Manju Lata PRASAD Dr Nasser SAID-AL-NAIEF Dr Roderick H.W. SI MPSON*

Department of Pathology OM FP Laboratory Departm ent of Anatomical Pathology
Yale University School of Medicine OHSU School of Dentistry University of Calgary
310 Cedar Street, PO Box 208023 2730 Southwest Moody Avenu e, CLSB 5N008 1403 29th Street Northwest, Foothills Medical
New Haven CT 06520-8023 Portland OR 9720 1 Centre, 11th Floor
USA USA Calgary AB T2N 2T9
Tel. + 1 203 785 4479 Te l. + 1 503 494 0041 CANA DA
Fax + 1 203 737 2922 saidalna@ohsu .edu Te l. + 1 403 944 8506
manju .prasad@yale.edu Fax +1403944 4748
roderick.simpson@doctors .org.uk

Dr Erich RAUBENHEIMER Dr Tuula SALO Dr Alena SKÁLOVÁ *

Oral Pathology Department of Oral and Maxil lofacial Diseases Department of Pathology
Sefako Makgatho Health Sciences University University of Helsinki Charles University in Prague
Molotleg i Street Box 41 (Mannerheimintie 172) Faculty of Medicine in Plzen
Ga-Rankuwa 0208 00014 Helsinki Faculty Hospital , Ed. Benese 13
SOUTH AFRICA FIN LAND 305 99 Pilsen
Te l. +27 12 521 4839 Tel. +358 40 544 1560 CZECH REPUBLIC
ejraub@fox5.co.za tuula.salo@helsinki.fi Tel. +420 377 402 545
Fax +420 377 402 634
skalova@fnplzen.cz

290 Contributors
Dr Leland SLATER Dr Edward B. STELOW* Dr Arthur S. TISCHLER
Scripps Oral Pathology Service Department of Pathology, Division of Surgical Department of Pathology
5190 Governor Orive, Suite 106 Pathology and Cytopathology Tufts Medical Center
San Diego CA 92122 University of Virginia School of Medicine 800 Washington Street, Box 802
USA PO Box 800214 Boston MA 02111
Tel. + 1 858 784 0600 Charlottesville VA 22908-0214 USA
Fax + 1 858 784 0604 USA Tel. + 1 617 636 1038
lee.slater36@sbcglobal.net Tel. +14349824185 Fax + 1 617 636 8302
Fax+ 1 434 982 6130 atischler@tuftsmedicalcenter.org
es7yj@virginia.edu

Dr Philip SLOAN# Dr Góran STENMAN* Dr Mary TONER

Department of Cellular Pathology Department of Pathology and Genetics Departm ent of Histopathology, CPL
Newcastle University Sahlgrenska Cancer Center Trinity College
New Victoria Wing, RVI University of Gothenburg St. James's Hospital
Newcastle upon Tyne NE1 4LP SE-405 30 Gothenburg Dublin 8
UNITED KINGDOM SWEDEN IRELAND
Tel. +44 191 2821517 Tel. +46 31 786 6733 mtoner@tcd .ie
Fax +44 191 282 5892 goran.stenman@gu.se
philip.sloan@ncl.ac.uk

Dr Pieter J. SLOOTWEG* Dr Stina SYRJANEN# Dr Satoru TOYOSAWA

Department of Pathology Department of Oral Pathology, lnstitute of Department of Oral Pathology
Radboud University Nijmegen Medical Center Dentistry, Faculty of Medicine, University of Osaka Un iversity Graduate School of Dentistry
Geert Grooteplein Zuid 10, Route 812 Turku and University Hospital Turku 1-8 Yamada-Oka, Suita
PO Box 9101 Lemminkaisenkatu 565-0871 Osaka
6500 HB Nijmegen 20520 Turku JAPAN
THE NETHERLANDS FINLAND Tel. +81 6 6879 2891
Te l. +31248186232; +31657595780 Tel. +358 2 333 8349 Fax +81 6 6879 2895
piet.slootweg@radboudumc .nl Fax +358 2 333 8399 toyosawa@dent.osaka-u.ac.jp
stina.syrjanen@utu.fi

Dr Merva SOLUK TEKKE$iN Dr Takashi TAKATA* Dr Asterios TRIANTAFYLLOU

Department of Tumour Pathology Department of Oral & Maxil lofacial Pathobiology Department of Oral and
lnstitute of Oncology, lstanbul University lnstitute of Biomedical & Health Sciences Maxillofacial Pathology
Capa/Fatih Hiroshima University School of Dentistry, University of Liverpool
34093 lstanbul 1-2-3 Kasumi, Minami-ku Pembroke Place
TURKEY 734-8553 Hirosh ima Liverpool, Merseyside L3 5PS
Tel. +90 212 414 2434 JAPAN UNITED KINGDOM
Fax +90 212 534 8078 Tel. +81 82 257 5631 Tel. +44 151 706 5243
msoluk@istanbu l.edu .tr Fax +81 82 257 5619 a.triantafyllou@liverpool.ac.uk
ttakata@hiroshima-u.ac.jp

Dr Paul SPEIGHT*# Dr Lester D.R. THOMPSON* Dr Willie F.P. VAN HEERDEN

Unit of Oral & Maxi llofacial Pathology Department of Pathology, Southern California Department of Oral Pathology & Oral Biology
School of Cl inical Dentistry Permanente Medical Group School of Dentistry, University of Pretoria
University of Sheffield Woodland Hills Medical Center PO Box 1266
19 Claremont Crescent 5601 De Soto Avenue 0001 Pretoria
Sheffield S10 2TA Woodland Hills CA 91365 SOUTH AFRICA
UNITED KINGDOM USA Tel. +27 12 319 2320
Tel. +44 7774 704 869 Te l. +1818719 2613 Fax +27 12 321 2225
p.speight@sheffield.ac.uk Fax +1 818 719 2309 willie.vanheerden@up .ac.za
lester .d.thompson@kp.org

Dr Stefan STEENS Dr Wanninayake M . TILAKARATNE Dr Annemieke VAN ZANTE

Department of Radiology and Department of Oral Pathology, Facu lty of Department of Pathology
Nuclear Medicine Dental Sciences University of California, San Francisco, School
Radboud University Nijmegen Medica! Center University of Peradeniya of Medicine
Geert Grooteplein Zuid 10, Route 766, Room 17 Peradeniya 1600 Divisadero Street, MZ Building B
6525 GA Nijmegen SRI LANKA San Francisco CA 94143
THE NETHERLANDS Tel. +94 81 239 7435 USA
Tel. +31 24 361 44 99 Fax +94 81 238 8948 Tel. +1415885 7256
stefan.steens@radboudumc .nl wmtilak@pdn.ac.lk annemieke.vanzante@ucsf.edu

Contributors 291
 Dr Marilena VERED Dr llan WEINREB Dr John M . WRIGHT*
Department of Oral Pathology & Department of Laboratory Medicine and Department of Diagnostic Sciences
Oral Medicine Pathobiology, University of Toronto Texas A&M University Baylor
School of Dental Medicine, Tel Aviv University Toronto General Hospital College of Dentistry
Room 246 200 Elizabeth Street, Room 11E-444 3302 Gaston Avenue
IL-69978 Tel Aviv-Yafo Toronto ON M5G 2C4 Dallas TX 75246
ISRAEL CANADA USA
Tel. +972 3 640 9305 Tel. +14163405146 Tel . +1214828 8118
Fax +972 3 640 9250 Fax + 1 416 340 55 17 Fax + 1 214 828 8306
mvered@post.tau .ac. il ilan.weinreb@uhn.ca jwright@bcd .tamhsc.edu

Dr Philippe VIELH* Dr Bruce M. WENIG* Dr Wendell G . YAR BROUGH

Département de Pathologie Moffitt Cancer Center Department of Surgery
Laboratoire National de Santé Section Head , Head and Neck, and Yale University Medica! Center
1 Rue Louis Rech Endocrine Pathology Senior Member Yale Otolaryngology, PO Box 208041
L-3555 Dudelange Anatomic Pathology Department of Pathology New Haven CT 06520-8041
LUXEMBOURG 12901 Magnolia Orive USA
philippe.vielh@lns.etat. lu Tampa, FL 33612 USA Te l. + 1 203 785 4862
Fax+ 813-632-1708 Fax + 1 203 200 2028
bruce.wenig@moffitt.org wendell.yarbrough@yale.edu

Dr Nadarajah VIGNESWARAN Dr William H. WESTRA* Dr Rosnah Binti ZAIN*

Department of Oral & Maxillofacial Pathology Department of Pathology Department of Oral Cancer
University of Texas Health Science Center at Johns Hopkins School of Medicine Research & Coordinating Centre
Houston School of Dentistry 401 North Broadway Faculty of Dentistry, University of Malaya
7500 Cambridge Street, Suite 1210 Balti more MD 21287 50603 Kuala Lumpur
Houston TX 77054 USA MALAYSIA
USA Tel. +1410614 3964 Tel. +601 2609 5428
Tel. +1713486 4410 Fax+14109550115 Fax +603 7954 7301
nadarajah. vigneswaran@uth. tmc. ed u wwestra@jhmi.edu rosnahmz@um .edu .my

Dr Paul E. WAKELY, Jr Dr Michelle D. WILLIAMS Dr Nina Z IDAR

Department of Pathology Department of Pathology lnstitute of Pathology
The Ohio State Un iversity University of Texas Faculty of Medicine
Wexner Medical Center MD Anderson Cancer Center University of Ljubljana
405 Doan Hall, 410 West 10th Avenue 1515 Holcombe Boulevard Unit 0085 Korytkova 2
Columbus OH 43210 Houston TX 77030 1000 Ljubljana
USA USA SLOVENIA
Tel. + 1 614 293 9235 Tel. +1713794 1765 Tel. +386 1 543 7149
Fax+ 1 614 293 7626 Fax +17 13563 1848 nina zidar@mfuni-lj.si
paul.wakely@osumc.edu mdwillia@mdanderson.org

Declaration of interests

Dr Chuang reports having received travel
support from Millennium : The Takeda Oncol-
ogy Company.
Dr Feldman reports holding intellectual prop-
erty rights for a patent held by the Mayo Clinic
on the activity of interferon regulatory factor
4 (IRF4) in T-cell lymphomas. Dr Fel dman re-
ports being part of a pending patent applica-
tion, with the Mayo Clinic, for detecting trans-
locations of TBL 1XR1 and TP63 nucleic acid.
Dr French reports receiving personal consul -
tancy lees from GlaxoSmithKline.
Dr lnagaki reports having received personal
consu ltancy lees from Kyowa Hakko Kirin.
Dr lnagaki reports having received personal
speaker's lees from Kyowa Hakko Kirin and
Zenyaku Kogyo.
Dr Jaffe reports rece ivi ng royalties from Elsevier.
Dr Kessler reports receiving personal con-
sultancy lees for medicolegal work from two
law firms representing defendants in tobacco
litigation.
Dr J.S. Lewis reports having received per-
sonal research support, through Washington
University in St. Lou is, from Advanced Cell
Diagnostics .
Dr Licitra reports receiving personal consu l-
tancy lees from Eisai, Bristol-Myers Squibb ,
MSD, Merck Serono, Boehringer lngelheim,
Debiopharm, Sobi, Novartis , AstraZeneca,
Bayer, and Roche. Dr Licitra reports that the
Fondazione IRCCS lstituto Nazionale dei
Tumori receives research support from Ei-
sai, MSD , Merck Serono, Boehringer lngel-
heim , Novartis, AstraZeneca, and Roche .
Dr Licitra reports receiving travel support
from Merck Serono, Debiopharm, Sobi, and
Bayer.
Dr Neville reports receiving royalties from
Elsevier.
Dr Pileri reports receiving personal consul-
tancy lees from Takeda.
Dr Sloan reports having received personal
consultancy lees from Navidea Biopharma-
ceuticals. Dr Sloan reports having provided
expert testimony to the European Medicines
Agency for Navidea Biopharmaceuticals.
Dr Speight reports receiving royalties from
Blackwell Munksgaard .
Dr Syrjanen reports receiving personal con -
sultancy fees from Bionit. Dr Syrjanen reports
receiving travel support from EHNS/AXON .

292 Contributors
IARC/WHO Committee for the lnternational Classification of
Diseases for Oncology (ICD-0)

Dr Freddie BRAY Dr Hiroko OHGAKI

Section of Cancer Surveillance Section of Molecular Pathology
lnternational Agency for Research on Cancer lnternational Agency for Research on Cancer
150 Cours Albert Thomas 150 Cours Albert Thomas
69372 Lyon Cedex 08 69372 Lyon Cedex 08
FRANCE FRANCE
Tel. +33 4 72 73 84 53 Te l. +33 4 72 73 85 34
Fax +33 4 72 73 86 96 Fax +33 4 72 73 86 98
brayf@iarc.fr ohgakih@iarc.fr

Dr Adel K. EL- NAGGAR Dr Ma rion PIÑEROS

Un iversity of Texas Section of Cancer Surveil lance
MD Anderson Cancer Center lnternational Agency for Research on Cancer
1515 Holcombe Boulevard , Unit 0085 150 Cours Albert Thomas
Houston TX 77030 69372 Lyon Cedex 08
USA FRANCE
Tel. +1713792 3109 Tel. +33 4 72 73 84 18
Fax +17137451105 Fax +33 4 72 73 80 22
anaggar@mdanderson.org pinerosm@iarc.fr

Mrs April FRITZ Dr Brian ROUS

A. Fritz and Associates, LLC National Cancer Registration Service ,
21361 Crestview Road Eastern Office
Reno NV 89521 Victor ia House, Capital Park
USA Fulbourn, Cambridge CB21 5XB
Tel. +1 775 636 7243 UNITED KINGDOM
Fax+ 1 888 891 3012 Tel . +44 122 321 3625
april@afritz.org Fax +44 122 321 3571
brian. rous@phe.gov.uk

Dr Robert JAKOB Dr Pieter J. SLOOTWEG

Data Standards and lnformatics Department of Pathology
lnformation, Evidence and Research Radboud University Nijmegen Medical Center
World Health Organization (WHO) Geert Grooteplein Zuid 10, Route 812,
20 Avenue Appia PO Box 9101
1211 Geneva 27 6500 HB Nijmegen
SWITZERLAND THE NETHERLANDS
Tel. +41 22 791 58 77 Tel. +31248186232; +31657595780
Fax +41 22 791 48 94 piet.slootweg@radboudumc.n l
jakobr@who.int

Dr Paul KLEIHUES Dr Leslie H. SOBIN

Faculty of Medicine Frederick National Laboratory for Cancer
University of Zurich Research , Cancer Human Biobank
Pestalozzistrasse 5 National Cancer lnstitute
8032 Zurich 611 O Executive Boulevard, Su ite 250
SWITZERLAND Rockville MD 20852
Tel. +41 44 362 21 10 USA
kleihues@pathol.uzh.ch Te l. + 1 301 443 7947
Fax + 1 301 402 9325
leslie sobin@nih .gov

ICD-0 Committee 293

Sources of figures and tables

molecular genetic analysis of 3.01A-C Zidar N

Sources of figures 39 cases. Diagn Pathol. 9: 131 . 3.02A-D Zidar N
1.42A,8 Thompson LDR 3.03 Zidar N
1.01 8ishop JA 1.43A,8 Thompson LDR 3.04 Zidar N
1.02A-C 8ishop JA 1.44A,8 Thompson LDR 3.05A-C Zidar N
1.03A-C 8ishop JA 1.45A,8 Thompson LDR 3.06A-C Lewis JS
1.04A,8 8ishop JA 1.46A,8 Thompson LDR 3.07A El-Mofty SK
1.05 Lewis JS 1.47 Wenig 8M 3.078 Thompson LDR
1.06A,8 8ishop JA 1.48 McDermott M 3.08 Thompson LDR
1.07A-C Thompson LDR Paediatric Laboratory Med icine 3.09A-C 8ishop JA
1.08A,8 8ishop JA Our Lady's Children's Hospital , 3.10 8ishop JA
1.09A-D French CA Crumlin, Dublin , lreland 3.11 Thompson LDR
1.10 French CA 1.49A,8 Chuang S-S 3.12 8ishop JA
1.11A-D Thompson LDR 1.50A,8 Chan JKC 3.13 Gale N
1.12A-D Stelow E8 1.51A-C Chuang S-S 3.14 Gale N
1.13A,8 Nicolai P 1.52A,8,D Chan JKC 3.15A,8 Gale N
1.14 Stelow E8 1.52C Chuang S-S 3.16 Gale N
1.15A,8 Stelow E8 1.53 Chan JKC 3.17A Gale N
1.16A,8 Stelow E8 1.54 Chan JKC 3.178 Attwood R
1.17A Franchi A 1.55A,8 Feldman AL Division of Otorhinolaryngology,
1.178 Wen ig 8 M 1.56A Slootweg PJ Head & Neck Surgery
1.17C,D Thompson LDR 1.568 Wenig 8M Stellenbosch University and
1.18A,8 Hunt JL 1.57 8ell D Tygerberg Academic Hospital
1.19A,8 Hunt JL 1.58 Ginsberg LE Cape Town, South Africa
1.20 Hunt JL Division of Diagnostic lmaging 3.18 Richardson M
1.21 A-C Wenig 8M MD Anderson Cancer Center 3.19A,8 Richardson M
1.22A Perez-Ordonez 8 Houston (TX), USA 3.19C Gale N
1.228 EusebiV 1.59 8ell D 3.20A,8 Slootweg PJ
University of 8ologna, ltaly 1.60A,8 Thompson LDR 3.21 Perez-Ordonez 8
1.23A,8 8el l D 1.61 Wil liams MD 3.22A,8 Thompson LDR
1.24 Franchi A 1.62 Williams MD 3.23 Thompson LDR
1.25 Franchi A 1.63A-D Williams MD 3.24 Perez-Ordonez 8
1.26 Flucke U 1.64A,8 Williams MD 3.25A,8,D 8ishop JA
1.27A Franchi A 3.25C Thompson LDR
1.278-D Thompson LDR 2.01 Reproduced with permission 3.26 Perez-Ordonez 8
1.28 Thompson LDR from the Census and Statistics 3.27 81oemena E
1.29 Thompson LDR Department, Department of 3.28 Flucke U
1.30 Thompson LDR Health , Hong Kong Cancer 3.29 Wenig 8M
1.31 Thompson LDR Reg istry, Hospital Authority, 3.30A-C Wenig 8M
1.32A,8 Lewis JE http//www.chp.gov.hk/en/ 3.31 Gale N
1.33A-D Lewis JE content/9/25/54.html. 3.32 Gale N
1.34A-D Reprinted from Wang X, 2.02 Lee AWM 3.33A,8 Gale N
81edsoe KL, Graham RP, et al. Department of Clinical 3.34 Chan JKC
(20 14). Recurren! PAX3-MAM L3 Oncology, University of Hong 3.35 Ferry JA
fusion in biphenotypic sinonasal Kong , Hong Kong SAR , Ch ina
sarcoma. Nat Gene!. 46:666-8. 2.03A,8 Chan JKC 4.01A,8 Reprinted from Ferlay J,
With permission from Macmillan 2.04A-C Chan JKC Soerjomataram 1, Ervik M, et al.
Publishers Ud. 2.05A-C Chan JKC (2013) GL080CAN 2012 v1 .O,
1.35 8ell D 2.06A-C Chan JKC Cancer lncidence and Mortality
1.36A,8 8ell D 2.07 Chan JKC Worldwide: IARC Cancer8ase
1.37A Flucke U 2.08A,8 Chan JKC No. 11 [Internet] . Lyon, France:
1.378 Wenig 8 M 2.09 Stelow E8 IARC; Available from:
1.38A,8 Thompson LDR 2.10A Chiosea S http ://g lobocan. iarc. fr,
1.39 Thompson LDR 2.108 Skálová A accessed on 3 March 2016.
1.40A Thompson LDR 2.1 1 Thompson LDR 4.02 Sloan P
1.408 Wenig 8M 2.12A-D Thompson LDR 4.03 Sloan P
1.41A Flucke U 2.13 Mahajan A 4.04A,8 Vigneswaran N
1.418 Reprinted from Flucke Diagnostic Radiology 4.05A-C Reibel J
U, Vogels RJ , de Saint Yale University School of 4.06A,8 Reibel J
Aubain Somerhausen N, Medicine 4.07A Odell EW
et al. (2014). Epithelioid New Haven (CT), USA 4.078 MullerS
hemangioendothelioma: 2. 14A-D Prasad ML 4.08A,8 MullerS
clinicopathologic, 2.15A,8 8aumhoer D 4.09 Vigneswaran N
immunhistochemical , and 4.10A,8 MullerS

294 Sources of figures

4.11 Takata T Korea University Anam Hospital 7.45A,B Li J
4.12 Odel l EW Seou l, Republic of Korea 7.46A-D Li J
4.13 Allen CM 6.09 Cho KJ 7.47 Nagao T
4.14 van der Waal 1 Asan Medical Center 7.48A,B Nagao T
Department of Pathology University of Ulsan College of 7.49 El-Naggar AK
VU Un iversity Medical Center Medicine 7.50 El-Naggar AK
Amsterdam, The Netherlands Seoul , Republic of Korea 7.51A Rep rinted from Weiler C,
4.15 Allen CM 6.10A,B Wake ly PE Agaimy A, Zengel P, et
4.16A-D Bishop JA 6.11A,C Ro JY al. (2012) . Nonsebaceous
4.17 Allen CM 6.118 See above (6.09) lymphadenoma of salivary
4.18A-D Allen CM 6.12A,B Prasad ML glands: proposed development
4.19A,B Thompson LDR 6.13 Katabi N from intraparotid lymph nades
4.20 Flucke U 6.14 Chiosea S and risk of misdiagnosis.
4.21A,B Wenig BM 6.15 Chiosea S Virchows Arch. 460:467- 72.
4.22A,B Thompson LDR 7.518 Prasad ML
4.23 Flucke U 7.01A,B,C Brandwein-Gensler M 7.52A,B Budnick S
4.24 Will iams MD 7.02A,C Bell O 7.53A,B Bell D
4.25A,B Wi lliams MD 7.028 El-Naggar AK 7.54A,B Richardson M
4.26 Ferry JA 7.03 Stenman G 7.55A,B Richardson M
4.27 Feldman AL 7.04A,B Stenman G 7.56 Nagao T
4.28A,B Feldman AL 7.05A,B van Zante A 7.57A Bloemena E
4.29 Boy S 7.05C Stenman G 7.578 El-Naggar AK
4.30A,B Chan JKC 7.06 El-Naggar AK 7.58A,B Seethala R
4.31A,B Pileri SA 7.07A-D Simpson RHW 7.59A,B Slater L
4.32A,B Li X-Q 7.08 Simpson RHW 7.60 Bell O
7.09A,B Fonseca 1 7.61 Bloemena E
5.01A-D Westra WH 7.10 Fonseca 1 7.62 Bell D
5.02 Reprinted from Bishop JA, 7.11A,B Skálová A 7.63A,B Seethala R
Ma XJ , Wang H, et al . (2012). 7.12A,B Wenig BM 7.64 Bullerd iek J
Detection of transcriptional ly 7.13A,B Wenig BM 7.65 El-N aggar AK
active high-risk HPV in patients 7.13C Seethala R 7.66 Bullerdiek J
with head and neck squamous 7.14A,B Fonseca 1 7.67 Flucke U
ce ll carcinoma as visualized 7.14C Williams MD 7.68A-C Cheuk W
by a novel E6/E7 mRNA in situ 7.140 Seethala R 7.69A-C Cheuk W
hyb rid ization method. Am J 7.15A We inreb 1 7.70A,B Cheuk W
Surg Pathol. 36:1874- 82. 7.158 Loening T 7.71 Cheuk W
With permission from Wolters 7.15C Leivo 1
Kluwer Health. 7.16A Leivo 1 8.01 Mul lerS
5.03A,B Bell D 7.168-D Loening T 8.02 Odell EW
5.04A Reprinted from Li J, 7. 17 Leivo 1 8.03A-D Odell EW
Perlaky L, Rao P, et al. 7.18A-C Nagao T 8.04 Odell EW
(2014) . Development and 7.19A-C Nagao T 8.05A,B Odell EW
characterization of sal ivary 7.20A,B Nagao T 8.06A,B Kout las 1
adenoi d cystic carcinoma cel l 7.21 Nagao T 8.07 Odell EW
line. Oral Oncol. 50:991-9, with 7.22A Skálová A 8.08A,B Odel l EW
permission from Elsevier. 7.228,C Bel l D 8.08C Bang G
5.048 Bel l D 7.23 Seethala R c/o Bang AK ·
5.05 Skálová A 7.24A,B Seethala R Dept. of Archaeology, History,
5.06A,B Jaffe ES 7.24C ,D Fonseca 1 Cu ltural Stud ies and Re ligion
5.07 Jaffe ES 7.25A Wil liams MD Un iversity of Bergen
5.08A,B Pileri SA 7.258 lhrler S Bergen, Norway
5.09 Pileri SA 7.26 Williams MD 8.09 Odell EW
5.10 Ott G 7.27 A-F Skálová A 8.10 Takata T
5.11 KoY-H 7.28A,B Ro JY 8.11 Repri nted from Oral Surg
5.12A,B Ohgami RS 7.29A Will iams MD Oral Med Oral Pathol Oral
Department of Pathology 7.298 Nagao T Radial Endod. 103. DeLair D,
Stanford University 7.30A,B Wi lliams MD Bejarano PA, Peleg M, et al.
Stanford (CA), USA 7.31A-C Chiosea S Ame loblastic carcinosarcoma
5.12C Chan JKC 7.32 Lewis JS of the mandible arising in
5.13 Chan JKC 7.33 Lewis JS amelob lastic fibroma: a case
5.14A-C Chan JKC 7.34 Lewis JS report and review of literature.
5.15A-C Chan JKC 7.35 Bell D Pages 516-20 (2007) With
7.36A,B Nagao T permission from Elsevier.
6.01 MD Anderson Cancer Center 7.37A,B Brandwein-Gensler M 8.12A,B See above (8.11)
©'89 MDACC 7.38A,B Brandwein-Gensler M 8.13 WrightJM
6.02A,B Lewis JS 7.39A,B Bell D 8.14A Wrig htJM
6.03 Chan JKC 7.40 Bell O 8.148 Odel l EW
6.04 Lewis JS 7.4 1A,B Bell D 8.15 Slootweg PJ
6.05A,B Lewis JS 7.42A-C Bell D 8.16A Ve red M
6.06 Perez-Ordonez B 7.43 Bell D 8.168 Muller S
6.07A,B Perez-Ordonez B 7.44A Fonseca 1 8.17A-D Vered M
6.08 KimCH 7.448 Bishop JA 8.18A-C Heikinheimo K
Department of Pathology 7.44C Bel l D 8.19 Vered M

Sources of figures 295

8.20 MullerS 8.62A Neville 6W 9.03A,6 Thompson LDR
8.21 WrightJM 8.626 Speight P 9.04A,6 Thompson LDR
8.22 Heikinheimo K 8.63 Neville 6W 9.05 Thompson LDR
8.23 Reprinted from Dissanayake 8.64 Neville 6W 9.06 Sandison A
RK, Jayasooriya PR, 8.65 Kessler H 9.07 Sandison A
Siriwardena DJ, et al. (2011) 8.66A Speight P 9.08A,6 Sandison A
Review of metastasizing 8.666 Kessler H 9.09 Sandison A
(malignan!) ameloblastoma 8.67A-C Speight P 9.10A,6 Sandison A
(METAM): pattern of metastasis 8.68 Speight P 9.11 Adapted with permission
and treatment. Oral Surg Oral 8.69A Speight P from Michaels L, Soucek S.
Med Oral Pathol Oral Rad iol 8.696 Wright JM Atypical mature bone in the
Endod. 111 :734-41. 8.70A,6 Speight P otosclerotic otic capsule
With permission from Elsevier. 8.70C WrightJM as the differentiated zone
8.24 Wright JM 8.71A-6 Neville 6W of an invasive osseous
8.25A,6 WrightJM 8.72 Speight P neoplasm. Acta Otolaryngol .
8.26A,6 WrightJM 8.73 Speight P 2014; 134: 118-23.
8.27 WrightJM 8.74 Casiraghi O 9.12 Madani G
8.28A,6 WrightJM 8.75 6aumhoer O lmaging
8.29 Kusama K, lde F 8.76 Casiraghi O Charing Cross Hospital
Division of Pathology 8.77A Slootweg PJ Imperial College Healthcare
Department of Diagnostic & 8.776 6aumhoer O London , United Kingdom
Therapeutic Sciences 8.78 Lopes M 9.13 Sandison A
Meikai University School of 8.79 Slootweg PJ 9.14 Sandison A
Dentistry, Saitama, Japan 8.80A,C 6aumhoer O 9.15 Sandison A
8.30 MullerS 8.806 Lopes M 9.16 Thompson LDR
8.31A,6 Vered M 8.81 Manojlovié S 9.17A-C Thompson LDR
8.32A,6 Reprinted with permission Department of Pathology 9.18A-D Thompson LDR
from Mosqueda-Taylor A, Pires University of Zagreb School of
FR, Aguirre-Urízar JM , et al. Medicine 10.01A,6 Williams MD
(2014). Primordial od ontogenic Zagreb, Croatia 10.01C Kimura N
tumour: clinicopathological 8.82A,6 Prasad ML 10.02A-D Kimura N
analysis of six cases of a 8.83A,6 6aumhoer O 10.03A,6 Kimura N
previously undescribed entity. 8.84A,6 6aumhoer O 10.04A,6 Williams MD
Histopathology. 65:606-12. 8.85 6aumhoer O 10.05A,6 Capella C
8.32C Pires FR 8.86A Toner M 10.06 Lam AKY
Department of Oral Pathology 8.866 6aumhoer O 10.07 Tischler AS
Rio de Janeiro State University 8.87 Reprinted with permission
Rio de Janeiro - RJ, 6razil from Flucke U, Tops 66,
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8.34A Fowler C6 of the head and neck region Top left Jordan RC (see Fig. 8.106A)
8.346 Neville 6W in the paediatric population: Top centre Mahajan A (see Fig. 2.13)
8.35A Fowler C6 a clinicopathological and Top right Gale N (see Fig . 3.31)
8.356 Soluk Tekke~in M genetic study of seven cases . Middle left Stenman G (see Fig. 7 046)
8.36A Neville 6W Histopathology. 64:769-76. Middle centre Leivo 1 (see Fig . 7.17)
8.366 Vered M 8.88 Toyosawa S Middle right Kimura N (see Fig. 10.02C)
8.37 Vered M 8.89 El-Mofty SK 6ottom left Pileri SA (see Fig. 5.09)
8.38 Carlos R 8.90A,6 El-Mofty SK 6ottom centre Ferlay Jet al. (see Fig . 4.01)
8.39A,6 Carlos R 8.91 El-Mofty SK 6ottom right Stenman G (see Fig . 7.03)
840 Carlos R 8.92A,6 El-Mofty SK
841 van Heerden WFP 8.93 Slootweg PJ
842 van Heerden WFP 8.94 El-Mofty SK
843 Odell EW, Nortje CJ, van 8.95 El-Mofty SK
Rensburg LJ c/o Odell EW 8.96A,6 El-Mofty SK
844 Thompson LDR 8.97A,6 Toyosawa S
845A,6 Odell EW 8.98A,6 Toyosawa S
846A,6 Odell EW 8.99 Nelson 6
847 El-Mofty SK 8.100A,6 Nelson 6
848A,6 El-Mofty SK 8.101 Raubenheimer E
849 Soluk Tekke~in M 8.102 Jordan RC
8.50 Soluk Tekke~in M 8.103 6aumhoer O
8.51A,6 Speight P 8.104A,6 Raubenheimer E
8.52 Speight P 8.105 Raubenheimer E
8.53 Speight P 8.106A,6 Jordan RC
8.54 Speight P 8.107A-C Koutlas 1
8.55 Speight P 8.108 Koutlas 1
8.56A,6 Neville 6W 8.109A Wright JM
8.57A-C Speight P 8.1096 van Heerden WFP
8.58 Li T-J 8.110 Raubenheimer E
8.59A,6 Li T-J 8.111 Feldman AL
8.60A,6,D Speight P
8.60C Li T-J 9 01 Sandison A
8.61 Speight P 9.02 Sandison A

296 Sources of figures

Sources of tables

1.01 Lewis JS
1.02 Reprinted from Neurosurgery
Clinics of North Ameri ca,
Volume 24, lssue 1, January
2013, OwTJ, Bell D,
Kupferman ME, et al., pages
51-65, copyright (2013), with
permission from Elsevier .
1.03 Bell D
1.04 Williams MD

2.01 Chan JKC

2.02 Chan JKC

3.01 Cardesa A, Prasad ML

3.02 Gale N
3.03 Gale N

4.01 Sloan P
4.02 Consensus group
4.03 Consensus group
4.04 Consensus group
4.05 Adapted with permission
from Warnakulasuriya S,
Ariyawardana A (2016) .
Malignan! transformation of
oral leukoplakia: a systematic
review of observational studies.
J Oral Pathol Med. 45:155-66.
4.06 Adapted from Barnes L, Eveson
JW, Reichart P, et al. , eds
(2005) . WHO Classification
of Tumours . Pathology and
Genetics of Head and Neck
Tumours. Lyon: IARC Press;
and Fletcher DCM, Bridge JA,
Hogendoorn PCW, Mertens
F (2013). WHO Classification
of Tumours of Soft Ti ssue and
Bone. Lyon : IARC Press

6.01 Schwartz MR
6.02 Schwartz MR

8.01 Heikinheimo K

10.01 Komminoth P
10.02 Komminoth P
10.03 Komminoth P

Sources of tables 297

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References 339
Subject index
A Ameloblastoma of mucosal origin 218
ABC See Aneurysmal bone cyst
Abrikossoff tumour 100, 121
AC See Ame loblasti c carcinoma
ACC See Adenoid cystic carcinoma
Accessory tissue-associated carcinoma 152
Acinic cel l carcinoma 160, 166
Ackerman tumour 84
Acoust ic neuroma 270
ACTB-GLl1 fusio n 45
Adenocarcinoma 12, 160, 171, 172, 264
Adenoid cystic carcinoma 71 , 99 , 139, 164
Adenolipoma 198
Adenolymphoma 188
Adenoma in laryngocoele 99
Adenomatoid odontogen ic tumour 204, 22 1
Adenomatous ductal prol iferation 197
Adenomyoepithelioma 175
Adenosquamous carcinoma 78, 89, 11 O
Adult neuroblastoma 56
Adult-type fibrosarcoma 34
AE1 19, 22 , 32,49, 88, 110, 210, 224
AE1 /AE3 19, 224
AE3 19, 22, 32,49, 88, 110, 210, 224
Aesthesioneuroblastoma 57
Aesthesioneurocytoma 57
Aesthesioneuroepithelioma 57
AF See Ameloblastic fibroma
AFS See Ame loblastic fibrosarcoma
Aggressive epithelial ghost cell odontogen ic
tumour 211
Aggress ive fibromatosis 43
Aggressive papillary tumour 262 , 266 , 267
AIM 1 53
AKT 1 123
Alcohol consumption 28 , 65, 81, 86-90,
93, 109, 11 2, 114
ALK-positive large B-cell lymphoma 129
Alpha-fetoprotein 27
Alveo lar cyst 238
Alveolar rhabdomyosarcoma 12, 18, 36
Ameloblastic carcinoma 204, 206, 207, 213
Ame loblastic carcinosarcoma 213
Ameloblastic fibroma 204, 213, 214 , 222,
223 , 226, 240
Ame loblastic fib rosarcoma 214
Amelob lastoma 204, 21 1, 215-218
Ame loblastoma, extraosseous 218
Ameloblastoma, peripheral type 218
340 Subject index
Ame loblastoma of the gingiva 218
Ameloblastoma, unicystic type 217 , 218
Amph icrine adenoma 272
Anaplastic large ce ll lymphoma 75
Anaplastic/und ifferentiated carcinoma 180
Androgen receptor 74, 75, 173, 17 4, 178,
195
Aneurysmal bone cyst 204, 258
Ang iocentric lymphoma 52
Angiofibroma 74
Angiosarcoma 12, 38
Anti -ad ipophilin 178
Antoni A / Anton i B 124
AODAM 220
AOT See Adenomatoid odontogenic tumour
APC 43 , 212 , 246, 250
Apical periodontal cyst 232
ARAF 131
ARID1A 143
ASC See Adenosquamous carcinoma
ATF1 169, 211 , 221
ATG5 53
ATI C 102
ATM 36, 144
Atyp ical carc inoid 96
Atypical cartilaginous tumour 243
AURKA 42
B
BAC See Basal cel l adenocarc inoma
Basal ce ll adenocarcinoma 160, 169, 170
Basal cell adenoma 160, 187, 188
Basaloid salivary gland adenoma 187
Basaloid squamous cell carcinoma 18, 64,
65, 68, 69 , 78, 85, 86
BCA See Basal cel l adenoma
BCL2 42 , 44, 50, 59 , 143, 144, 168, 222 ,
255, 271
Beckwith-Wiedemann syndrome 37
Benign cementob lastoma 230
Benign haemang ioendothelioma 198
Benign lymphoepithelial lesion 196
Benign mixed tumour 33, 99, 127, 139, 185
Benign peripheral nerve sheath tumour 48,
49, 123, 270
Ben ign soft tissue tumours 12, 47
Biphenotypic sinonasal sarcoma 12, 40 , 41
BOC See Botryoid odontogen ic cyst
Bohn nodule 238
Botryoid odontogenic cyst 236 , 237
Botryoid rhabdomyosarcoma 36
Branchial cleft cyst 148, 155
BRCA 165
BRD4 21
Brooke-Spiegler syndrome 170, 188
BSCC See Basaloid squamous cell
carc inoma
BSNS See Bi phenotypic sinonasal sarcoma
Burkitt lymphoma 52, 75, 128, 134, 141 , 142,
143
e
CA See Condyloma acuminatum
CA15-3 178
CAIX 26, 268
Calcifying cystic odontogen ic tumour 239
Calcifying epithelial odontogenic tumour 204,
220-222
Calcifying ghost cell odontogenic carcinoma
211
Calcifying ghost cell odontogenic cyst 239
Calc ifying ghost cel l odontogen ic tumour 226
Calcifying odontogenic cyst 204, 239, 240
Calpon in 17, 32 , 126, 172, 175, 187
CAM5.2 22, 32 , 59 , 86, 89, 21 O, 272 , 273
CAMTA1 46
Canalicular adenoma 160, 194
Cancer of unknown primary 150
Capillary haemangioma 47, 48
Carcinoid 95
Carcinoid of the midd le ear 272
Carcinoma arising in a calcifying odontogen ic
cyst 211
Carcinoma ex pleomorphic adenoma 160,
176
Carcinoma of unknown primary 148, 150 ,
151
Carcinosarcoma 26, 88, 160, 179, 204, 205,
207, 213
Carotid body paragangl ioma 277-279 ,
28 1-283
Carotid body tumour 277
Cartilage tumours 78, 102
Cavernous haemangioma 47
CCC See Clear ce ll carcinoma
CCND1 144 Chloroma 131 CUP See Carcinoma of unknown primary
CC NF 143 Cholesteatoma 262, 269 , 270 CXCL13 146
CD 1a 131 , 145 Chondroblastic osteosarcoma 204, 244 CYLD 170, 188
CD4 53, 125, 129, 142, 145 Chondroblastoma 204, 248 Cylindrical ce ll carcinoma 16
CDS 53, 144, 202 Chondroma 78, 102, 103, 204, 246 Cylindrical cel l papilloma 29
CDS 53, 129, 145 Chondromesenchymal hamartoma 12, 51 , 52 Cyl indroma 169, 264
CD10 26, 130, 143-145, 200, 202, 210, 268 Chondromyxoid fibroma 204, 248, 249 CYP2E1 69
CD20 37, 55, 130, 142-1 44, 202 Chond rosarcoma 78, 102, 103, 204 , 243 Cystaden ocarcinoma 153, 162, 170-172
CD21 146 Chordoma 76 Cystadenolymphoma 188
CD23 144, 146, 202 Choristoma 152 Cystadenoma 160, 191
CD30 27 , 53, 106, 128-130, 142, 155 CIC-DUX4 fusion 57 Cystic dermoid 157
CD30-positive T-cell lymphoproliferative CK1 /2/10/11 29 Cystic duct adenoma 191
disorder 129 CK8 19, 82, 248 Cystic teratoma 157
CD31 38, 44, 46 , 48, 75, 123, 125, 210 CK10 29
CD33 131 CK10/ 13 29 D
CD35 146 CK 14 187 , 192, 210, 224, 227
0 2-40 38, 104, 123, 125, 146
CD43 131 , 202 CK17 32
Dandy- Walker syndrome 72
CD44 186 CK18 19, 51, 59, 82, 172, 248
DDX3X 53
CD45 19,83, 130, 210 CK 19 32, 70, 76, 208-21 0, 224, 227, 248
Dental cyst 232
CD57 53 , 100, 120, 121 CK20 22 , 24, 26, 32, 69, 89, 152, 172, 180
Denti gerous cyst 204, 234
CD68 100, 121, 131 Classical Hodgkin lymphoma 134, 141 , 142
Dentinogenic ghost ce ll tumour 204, 211,
CD79a 55, 130, 142 Classic intraosseous ameloblastoma 215
212, 226 , 227
CD99 37 , 42,56,57 , 59, 247 Claudin 5 38
Dermoid cyst 157
CD138 55, 130, 227 Clear cell ameloblastoma 210
Dermoid polyp 72
CD163 131 Clear ce ll carc inoma 160, 168, 169
Desmoid tumour 43 , 250
CD207 130, 131 Clear ce ll odontogenic carcinoma 204, 210
Desmoid tumour of bone 250
CDC73 252 Clear cell odontogenic tumour 210
Desmoid-type fibromatosis 12, 43
CDH11 259 Clear ce ll oncocytosis 195
Desmop lastic fibroma 204, 250
CDK2N A 36 CLTC 102
DGCT See Dentinogeni c ghost cell tumour
CDK4 101, 245 Clusteri n 146
DICER 1 52
CDKN2A 24, 83, 92, 111 , 115, 145, 181, 280 CN8P 259
Diffuse large 8-cell lymphoma 52, 61, 64, 75,
CDX224, 26, 32,172,273 COC See Calcifying odontogenic cyst
104, 128, 141 , 154, 200
Cementa! dysplasia 254 COD See Cemento-osseous dysplasia
DL8CL See Diffuse large 8-ce ll lymphoma
Cementifying fibroma 251 COF See Cemento-ossifying fibroma
DLX2 21 6
Cementoblastoma 204, 230 , 231, 249 COL1A1 259
DOG1 26, 166 , 172, 178
Cementoma 204, 205, 230, 252-254 Colloid -type adenocarcinoma 23
Ductal adenoma 194
Cemento-osseous dysplasia 204, 254, 255 Colonic-type adenocarcinoma 23
Ductal carcinoma/ad enocarcinoma 171
Cemento-ossifying fibroma 204, 231 , 251 , Columnar ce ll papilloma 29
Ductal papil loma 192
253 Condyloma acuminatum 106, 116
DUSP22- IRF4 rearrangement 129
Central giant cel l gran uloma 204, 256 Congenita l basal cel l adenoma 183
Dysp lasia 91
Central giant cell lesion 256 Congenital epulis 119
Central odontogenic fibroma 228 Congenital ging ival granular cel l tumour 119
E
Central ossifying fibroma 251 Congenital granular cel l epul is 106, 119
CEOT See Calcifying epithelial odontogenic Congenital hybrid basal cell adenoma- E6 28, 29, 137, 138
tumour adenoid cystic carcinoma 183 E7 28, 29, 137, 138
Ceruminal adenocarcinoma 264 Congenital pleomorph ic adenoma 71 EBV-encoded small RNA 18, 22 , 53, 54, 68,
Ceruminal adenoma 265 Conventional ameloblastoma 215 128, 130, 142, 143, 181 , 182
Ceruminoma 265 Conventional squamous cell carcinoma 81 Ectomesenchymal chond romyxoid tumour
Ceruminous adenocarcinoma 262, 264 Costel lo syndrome 37 106, 119, 120, 127
Ceruminous adenoma 262, 265 Cran iofacial fibrous dysplasia 254 Ectopic pituitary adenoma 64, 72 , 73
Ceruminous pleomorphic adenoma 265 Craniopharyng ioma 64, 73 ELST See Endolymphatic sac tumo ur
Ceruminous syringocystadenoma papilliferum Cribriform adenocarcinoma 140, 167 Embryoma 183
265 Cribriform cystadenocarcinoma, low-grade Embryonal rhabdomyosarcoma 12, 36
Cervical lymphoepithelial cyst 155 170 EMC See Epithe lial- myoepithelial carc inoma
CGCG See Central giant cell granuloma CRTC1 -MAM L2 gene fusion 164 EMCMT See Ectomesenchymal
Ch emodectoma 277 , 281-283 CRTC3-MAML2 gene fusion 164 cho ndromyxoid tumour
Cherub ism 204, 257 , 258 CTNN 8 143, 44, 73 , 75, 186, 217, 222, 250 Enchondroma 246

Subject index 341

Endolymphatic sac tumour 262, 267 , 268
ENKTL See Extranodal NK!T-cell lymphoma
Enteric-type adenocarcinoma 23
Eosinophilic granuloma 130
EPAS1 278,280
Epidermoid carcinoma 14, 81, 263
Epidermoid papillary adenoma 192
Epiphora 38
Epithelial hamartoma 32
Epithelial- myoepithelial carcinoma 160, 175
Epithelioid haemangioendothelioma 12, 38,
45,46
ER-alpha 72
ERBB2 /H ER2 173, 174, 177
ERG 38, 46, 123, 125
ESR1 69
ETV6 177, 178
ETV6-NTRK3 gene fusion 177, 178
Everted papilloma 30
Ewing sarcoma/primitive neuroectodermal
tumour 56 , 61
EWSR1-ATF1 gene fusion 169
EWSR1-FLl1 gene fusion 57
EWSR1 gene rearrangement 175
EWSR1-POU5F1 gene fusion 164
Exophytic papilloma 30, 31
EXT1 255
EXT2 255
Extracranial pituitary adenoma 72
Extracutaneous Merkel cell carcinoma 151
Extramedullary myeloid sarcoma 52, 64, 75,
104, 106, 131
Extramedullary plasmacytoma 54, 55
Extranodal marginal zone lymphoma of
mucosa-associated lymphoid tissue
See MALT lymphoma
Extranodal NK!T-cell lymphoma 12, 52-54,
75 , 141
Extranodal NK!T-cell lymphoma, nasal-type
52
Extraosseous ameloblastoma 218
Extraosseous plasmacytoma 12, 52, 54, 55,
64, 75, 104
Extrasel lar pituitary adenoma 72
F H3F3A/H3F3B point mutation 248, 256
Faciocutaneoskeletal syndrome 37
Familia! adenomatous polyposis 43, 246
Familia! fibrous dysplasia 257
Familia! gigantiform cementoma 253
Familial/multiple cylindromatosis syndrome
170
FANCA 36
Fanconi anaemia 111, 112
FO See Fibrous dysplasia
342 Subject index
FDC See Follicular dendritic cel l sarcoma
FDG-PET 103
FGC See Familia! gigantiform cementoma
FGFR2 216, 217
Fibroblastic osteosarcoma 34
Fibroneuroma 49
Fibrosarcoma 12, 34
Fibrous dysplasia 204, 253
FL11 38,46, 48, 56,57, 59, 125
FNCLCC 36
Focal epithelial hyperplasia 117
Foll icu lar cyst 234
Follicu lar dendritic cell sarcoma 145
Follicular lymphoma 134, 143, 154, 200
FOX01 37, 41
FOX03 53, 165
Fungiform papilloma 30
G HMGA2 174, 176, 177, 186
Gardner syndrome 43, 212, 226, 246
GATA2 72
GCOC See Ghost cell odontogenic
carc inoma
Ghost cell odontogenic carcinoma 204, 211,
212
Giant cell angiofibroma 45
Giant cell epulis 257
Gigantiform cementoma 204, 205, 252, 253
Gingival cyst 204, 238
Glandular hamartoma 31, 32
Glandular odontogenic cyst 204, 238, 239
Glomus jugulare tumour 282
Glomus tympanicum tumour 282
Glomus vagale tumour 283
GLUT1 123
GNAS 252, 254
GOC See Glandular odontogenic cyst
Gorlin cyst 239
Granular cell myoblastoma 100, 121
Granular cell neurofibroma 100, 121
Granular cell schwannoma 100, 121
Granular cell tumour 78, 100, 106, 121
Granulocytic sarcoma 131
GSTM1 69
H lgG 55, 67, 202
HACE1 53
Haemangioblastoma 38, 279
Haemangioma 12, 47, 106, 123, 160, 198
Haemangiopericytoma 45
Haemangiosarcoma 38
Haemorrhagic bone cyst 259
Hairy polyp 64, 72
Hand-Schül ler- Christian disease 130
Heck disease 117
Heffner tumour 267
HER2 173, 174, 177
Hereditary multiple osteochond romas 255
Heterotopia-associated carcinoma 152, 153
HEY1-NCOA2 gene fusion 244
High-grade non-IT AC See High-grade
non-intestinal-type adenocarcinoma
HHF35 175
HHV8 124, 125, 130, 143
HIF2A 278, 280
High-grade ductal carcinoma 173
High-grade myxofibrosarcoma 35
High-grade non-intestinal-type
adenocarcinoma 24-26
Histiocytosis X 130
HIV 52, 115, 117, 124, 125, 128, 130, 142
HL See Hodgkin lymphoma
HMB45 34, 47, 61, 82, 210, 247
Hodgkin lymphoma 68, 75, 129, 134, 141,
142, 144, 154, 201
Horner syndrome (oculosympathetic palsy)
48, 277, 283
HPV 6 28, 29, 93-95
HPV 11 94
HPV 16/18 28, 29
HPV 32 117
HPV-negative sinonasal squamous cell
carcinoma 17
HPV-positive sinonasal squamous cell
carcinoma 17
HPV 16, 17, 21, 25, 28, 29,69, 86, 136-138,
149, 151
HRAS 37, 111, 168, 186, 216, 280
Human papilloma virus 16
Hyperparathyroidism jaw tumour syndrome
252
ICC See lnflammatory collateral cyst
103 143
IDH1/2 mutation 243, 244, 280
lgA 54, 55, 67, 202
IGF2 186
lncisive canal cyst 241
lnfantile fibromatosis (desmoid variant) 43
lnfectious mononucleosis 141
lnflammatory col lateral cyst 204, 233
lnflammatory dental cyst 232
lnflammatory myofibroblastic tumour 78, 101,
102
lnflammatory paradental cyst 233
lnflammatory pseudotumour 101
INSRR 165
lntercalated duct adenoma 197
lntercalated duct hyperplasia 160, 197
lntestinal-type adenocarcinoma 12, 14, 15,
23-26, 171, 172
lntraductal carcinoma 160, 170, 171
lntraductal papillary hyperplasia
(non-neoplastic) 191
lntraoral basal cell carcinoma of the ging iva
206
lntraosseous well-differentiated osteosarcoma
244
lnverted Schneiderian papilloma 28
lnverting papilloma 28
ISL 1 216, 273
ITAC See lntestinal-type adenocarcinoma
J Liposarcoma 78, 100
JAK3 53
JAK/STAT 53
JPOF See juvenile psammomatoid ossifying
fibroma
JTOF See Juvenile trabecular ossifying
fibroma
Jugulotympanic chemodectoma 282
Juvenile active ossifying fibroma 251
Juvenile aggressive ossifying fibroma 251
Juvenile angiofibroma 74
Juvenile fibrous dysplasia 257
Juvenile nasopharyngeal angiofibroma 74
Juvenile ossifying fibroma 251
Juvenile paradental cyst 233
Juveni le psammomatoid ossifying fibroma
251, 252
Juvenile trabecular ossifying fibroma
251, 252
K Lymphocyte-depleted class ical Hodgkin
Kaposi sarcoma 106, 124, 125, 143
Kaposi sarcoma-associated herpesvirus 124
Keratinizing squamous cell carcinoma 12,
14, 29, 64, 65,68, 138
Keratocystic odontogenic tumour 235
KIF18A 42
KIT SeeCD117
K-NPC See Keratinizing nasopharyngeal
carcinoma
KRAS 24, 216
KSCC See Keratinizing squamous cell
carcinoma
KSHV See Kaposi sarcoma-associated
herpesvirus
L
Langerhans cell histiocytosis 106, 130
Large ce ll neuroendocrine carcinoma 12, 21,
22, 78, 97, 98, 160, 180, 181
Laryngeal granular cell tumour 100
Laryngeal paraganglioma 275, 276, 281
Lateral neck cyst 155
Lateral periodontal cyst 204, 236, 237
LCNEC See Large cell neuroendocrine
carcinoma
LEC See Lymphoepithelial carcinoma
Leiomyoma 12, 47
Leiomyosarcoma 12, 34, 35, 47
LEOPARD syndrome 256
Lethal midline granuloma 52
Letterer- Siwe disease 130
LG non-ITAC See Low-grade
non-intestinal-type adenocarcinoma
Li- Fraumeni syndrome 37, 111, 246
Lipoma 101, 198, 199
LMP1 53, 69
Lobular capi llary haemangioma 47, 48
LOH 29, 83, 92, 113, 236
Low-grade adenocarcinoma 24, 30, 70, 140
Low-grade central osteosarcoma 204, 244
Low-grade non-intestinal-type adenocarci-
noma 24-26
Low-grade papillary adenocarcinoma of
endolymphatic sac origin 267
Low-grade papillary tumour 24
Low-grade salivary duct carcinoma 170
Low-grade sinonasal sarcoma 40
Low-risk HPV 28
LPC See Lateral periodontal cyst
LTA See Lymphotoxin alpha gene
Lymphadenoma 160, 190, 191
Lymphangioep ithelioma 122
Lymphangioma 106, 122, 123
Lymphangiomatous polyp 122
lymphoma 142
Lymphocyte-rich classical Hodgkin
lymphoma 142
Lymphoepithelial carc inoma 12, 18, 65, 78,
90, 110, 160, 181, 182
Lymphoepithelial sialadenitis 160, 196, 197,
201
Lymphoepithelioma-like carcinoma 18, 90,
137, 181
Lymphotoxin alpha gene 54
Lysozyme 32, 131
LYVE1 123, 125
M Midline carc inoma of children and young
Malignan! angioendothelioma 38
Malignant calcifying ghost cell odontogenic
tumour 211
Malignan! calcifying odontogenic cyst 211
Malignant epithelial odontogenic ghost cell
tumour 211
Malignan! fibrous histiocytoma 35
Malignant haemangioendothelioma 38
Malignan! lymphoepithelial lesion 181
Malignan! midline reticulosis 52
Malignan! myoepithelioma 174
Malignant neurilemmoma 39
Malignant oncocytoma 182
Malignant peripheral nerve sheath tumour
39, 40
Malignant rhabdomyoma 36
Malignan! schwannoma 39
Malignant surface epithelial tumours 77, 78 ,
81, 105, 109
Malignant teratoma 26
MALT lymphoma 52, 54, 55, 75 , 104, 128,
141, 160, 197, 200, 201, 202
MAML2 89, 164, 239
MAML3 40, 41
Mammary analogue secretory carcinoma 177
Mandibular buccal bifurcation cyst 233
Mandibular infected buccal cyst 233
Mantle cell lymphoma 75, 128, 134, 141,
144, 154,200
MAP2K1 131
MAPK 216, 217, 256
MCC See Merkel cell carcinoma
McCune-Albright syndrome 253, 254
MDM2 101, 177, 186, 245, 246
MEC See Mucoepidermoid carcinoma
MED12 36
Melanoma 12, 18, 34, 35, 60, 61, 82, 105,
106, 126, 127, 149, 180, 211, 247
Melanotic neuroectodermal tumour of infancy
204, 247
Melanotic progonoma 247
Membranous adenoma 187
Meningioma 12, 50, 262, 271, 272
Merkel cell carcinoma 148, 151, 152, 180
Mesenchymal chondrosarcoma 204, 244
Mesenchymoma 51
Metastasizing ameloblastoma 204, 218, 219
MFEH See Mu ltifocal epithelial hyperplasia
MIB1 278
Microglandular adenosis of nose 32
Midd le ear adenoma 262, 272, 273
Middle ear adenomatous tumour 272
Middle ear adenoma with neuroendocrine
differentiation 272
Middle ear paraganglioma 263, 276, 282
adu lts with NUT rearrangement 20
MIR143-NOTCH fusion 44
Mixed cellularity classical Hodgkin lymphoma
142
MMP9 227
MNOH See Multifocal nodu lar oncocytic
hyperplasia
Subject index 343
MNTI See Melanotic neuroectodermal
tumour of infancy
Moderately differentiated neuroendocrine
carcinoma 96
Monomorphic adenoma 187
Monostotic fibrous dysplasia 253
MPNST See Malignan! peripheral nerve
sheath tumour
MSA 36 , 37, 41, 44,47, 168, 187
MSX2 216
MUe2 24, 26
Mucinous cystadenocarcinoma 171
Mucocoele 156
Mucoepidermoid carcinoma 127, 163
Mucoepidermoid tumour 127, 163
Mucosal melanoma 12, 60
Multifocal adenomatous oncocytic
hyperplasia 195
Multifocal epithelial hyperplasia 106, 117,
118
Multifocal nodular oncocytic hyperplasia 195
Multiple familia! trichoepithelioma 170, 188
Neuroectodermal/ melanocytic tumours
12, 56
Neuroendocrine adenoma of the middle ear
272
Neuroendocrine carc inoma 12, 21, 83, 95-97
Neuroendocrine tumours 78, 95
Neurofibroma 12, 49, 50, 106, 123, 124
Neurofibromatosis type 1 37, 39, 40, 49, 50,
124, 256, 257, 279, 280
Neurofibromatosis type 2 51 , 124, 270-272
Neurofibrosarcoma 39
NF1 See neurofibromatosis type 1
NF2 See neurofibromatosis type 2
NFP 49 , 50, 56 , 271
NK-cell lymphomas 128
NKSee See Non-keratinizing squamous cell
carcinoma
NK/T-cell lymphoma 75
Nodal Merkel cell carcinoma 151
Nodular fasciitis 160, 199
Nodular oncocytic hyperplasia 160, 195, 196
Nodular oncocytosis 190, 195
Odontogenic myxoma 204, 229, 230
Odontogenic sarcoma 203, 204, 21 4
Odontoma 204, 224
OED See Oral epithelial dysplasia
OGG1 69
OKe See Odontogenic keratocyst
Olfactory neuroblastoma 12, 18, 57-59
Olfactory placode tumour 57
OMD 259
OMP 59
ONB See Olfactory neuroblastoma
Oncocytic adenocarcinoma 182
Oncocytic adenoma 189
Oncocy1ic adenomatous hyperplasia 99
Oncocytic carcinoma 160, 182, 183
Oncocytic cyst 99
Oncocytic lipoadenoma 198
Oncocytic papillary cystadenoma 78, 99,
100
Oncocytic papillary cystadenomatosis 99
Oncocytic papilloma 29 , 30
Oncocytic Schneiderian papilloma 29

MUM1 /IRF4 55, 130, 144 Nodular sclerosis classical Hodgkin Oncocytic sialolipoma 198
MYB 17, 71, 164, 165, 264 lymphoma 142 Oncocytoma 99 , 160, 182, 189, 190, 196
NOH See Nodular oncocytic hyperplasia ooe See Orthokeratinized odontogenic cyst
MYBL 1 165
Non-chromaffin paraganglioma 277, 281, OPMDs See Oral potentially malignan!
MYB-NFIB gene fusion 71, 164, 165, 264
disorders
MYe 130, 142-144 283
OPSee See Orophary ngeal squamous cel l
MYe-IGH fusion 130 Non-intestinal type adenocarcinoma 14, 24
carcinoma
MYeL 69 Non-ITAe See non-i ntestinal type
Oral condyloma acuminatum 116
MYF4 37 adenocarcinoma
Oral epithelial dysplasia 106, 112-114
MYOeO 36 Non-keratinizing carcinoma 65
Oral mucosal melanoma 106, 126
MYOD1 37, 41 , 122 Non-keratin izing squamous cell carcinoma
Oral potentially malignan! disorders 108, 112
Myoepithelial carcinoma 160, 174 12, 15, 18, 64-69, 136
Oral potentially malignan! disorders and oral
Myoepithelial sialadenitis 196 Noonan syndrome 256-258
epithelial dysplasia 112
Myoepithelioma 119, 160, 186, 187 Notch 41 , 145, 220
Oral squamous cell carc inoma 109-111
Myofibroblastic sarcoma 106, 125, 126 NOTeH1 /NOTeH2 165, 181
Oropharyngeal squamous cell carcinoma
Myofibrosarcoma 125 NPe See Nasopharyngeal carc inoma
136-138
Myoglobin 37, 122 NPM1 131
Orthokeratinized odontogen ic cyst 204, 241
Myosarcoma 36 NRAS 61, 216
osee See Oral squamous cell carcinoma
Myosin 37, 122 NTRK3 177, 178
Osseous dysplasia 254
NUT carcinoma 12, 14, 17, 18, 20-22, 61
N Osseous plasmacytoma 260
NUTM1 20, 21
Ossifying fibroma 204, 231 , 251
NAB2-STAT6 gene fusion 44, 45 NUT midline carcinoma 20
Osteoblastoma 204, 249, 250
Nasal chondromesenchymal hamartoma 51
Nasal dermoid sinus cyst 157
o Osteochondroma 204 , 255
Osteochondromatous exostosis 255
Nasopalatine duct cyst 204, 241 , 242 Oat cell carcinoma 97 Osteogenic sarcoma 244
Nasopharyngeal angiofibroma 74 ODAM See Odontogenic Osteoid osteoma 204, 249
Nasopharyngeal carcinoma 18, 64, 65, 67, ameloblast-associated protein Osteoma 204, 246
69, 90 Odontogenic amelob last-associated Osteosarcoma 204, 244
Nasopharyngeal papillary adenocarcinoma protein 220 Otosclerosis 262, 263, 268, 269
64 , 70 Odontogenic carcinosarcoma 204, 213 Otospongiosis 268
NeOA2 37, 244 Odontogenic cyst 204, 208, 211 , 212, 232 , Oxyph ilic adenoma 99, 189
NDe See Nasopalatine duct cyst 234-241
Neumann tumour 119 Odontogenic fibroma 204, 228
Neurilemmoma· 39, 48, 123, 270 Odontogenic keratocyst 204, 235 , 236
Neurinoma 123 Odontogenic myxofibroma 229

344 Subject index

p Polymorphous low-grade adenocarcinoma
p14ARF/p161NK4a 115, 145
PA See Pleomorphic adenoma
PAe See Polymorphous adenocarcinoma
Papillary adenocarcinoma of the midd le ear
266
Papi llary cystadenocarcinoma 171
Papillary cystadenoma lymphomatosum 188
Papillary squamous cell carc inoma 78, 87
Papil loma 106, 115
Paragangl ioma 162, 263, 267, 271, 276-280,
28 1-283
Paranasal sinus tumours 38, 58
Paranasal tumours 52
Paraneoplastic syndromes 58
Parosteal osteosarcoma 204, 244
PAX3 37,40 , 41
PAX7 37
PAX8 26, 268, 273
PBL See Plasmablastic lymphoma
Periapical cyst 232
Periodontoma 251
Periosteal osteosarcoma 204, 244
Peripheral giant cel l granu loma 204, 257
Peripheral neuroblastoma 56
Peripheral neuroectodermal tumour 56
Peripheral neuroepithel ioma 56
Peripheral T-ce ll lymphoma 52, 53, 75 , 141,
201
Phaeochromocytoma- paragangl ioma
syndrome 282
PIK3eA 69, 83, 111, 138, 165, 217
Pindborg tumour 220
PIOe See Primary intraosseous carcinoma
PIT1 72
Pitu itary adamantin oma 73
PITX2 216
PLAG1 174, 176, 185, 186
PLAP 27
Plasmablasti c lymphoma 106, 129, 130
Plasma ce ll granuloma 101
Plasmacytoma 12, 52, 54, 55, 64, 75 , 104,
128, 141, 201, 204, 260
Pleomorphic adenoma 12, 33, 78, 99, 106,
127, 134, 139, 160, 185, 186
Pleomorphic liposarcoma 35
Pleomorphic rhabdomyosarcoma 12, 36
Pleomorphic rhabdomyosa rcoma, adu lt type
36
Podoplanin 123, 125, 146, 243
Poikiloderma atrophicans with cataract
See Rothmund-Thomson syndrome
Polycystic adenosis 160, 163, 195
Polymorphic reticulos is 52
Polymorphous adenocarcinoma 134, 140 ,
160, 167, 168
ROR2 36
140, 167 Rothmund-Thomson syndrome 246
Polyostotic fibrous dysplasia 253, 254 RRP See Recurren! respiratory
Polytetraf luoroethylene (Teflon) injection 103 papi llomatosis
Poorly differentiated carcinoma 160, 165, RUNX1 216
180
Poorly differentiated neuroendocrine
s
carcinoma 21, 22, 78 , 97 S45F/S45P 43
PRDM1 53 , 130 Salivary duct carcinoma 160, 173, 174
Primary intra-alveolar epidermoid carc inoma Salivary gland adenocarcinoma 171
207 Salivary gland anlage tumour 64, 71
Primary intraosseous carcinoma 204, Sal ivary type tumours 127
207-209 Sarcomatoid carc inoma 17, 34, 88, 179
Primary intraosseous squamous cell SBe See Simple bone cyst
carcinoma 207 see See Squamous cell carcinoma
Primary odontogenic carcinoma 207 Schneiderian carcinoma 16
Primordial odontogenic tumour 204, 223, 224 Schneiderian papi lloma 28-30, 40
PRKD1, PRKD2, PRKD3 168 Schneiderian papi lloma, inverted type 28
Proliferative verrucous leukoplakia 47, 106, Schwannoma 12,48, 106, 123, 124, 267
113-115, 123 Sclerosing adenosis 195
PROX1 123, 125 Sclerosing odontogenic carcinoma 204, 209,
PSee See Papillary squamous ce ll 228
carcinoma Sclerosing polycystic adenoma 195
Pseudosarcomatous fasci itis 199 Sclerosing polycystic adenosis 160, 195
PTeH 221 Sclerosing polycystic sialadenopathy 195
PTeH159 ,1 22,235, 236 sesee See Spindle ce ll squamous ce ll
PTEN 36,111, 181 carci noma
PTGS2 83 soe See Salivary duct carcinoma
PTPRK 53 SDH 278-280
PVL See Prol iferative verrucous leukoplakia SDHA 278-281 , 283
Pyogen ic granuloma 47, 123 SDHAF2 278-280, 283
SDHB 278-283
R
SDHe 278-281, 283
Rad icular cyst 204, 232 SDHD 278-281 , 283
RANBP2 102 Sebaceous adenocarcinoma 160, 178
Ranula 148, 156, 157 Sebaceous adenoma 160, 193
RAS 26, 127, 217,256 Secretory carc inoma 160, 177, 178
RB1 36, 180 Septal papi lloma 30
RBL2 143 Seromucinous adenocarcinoma 24
REAH See Sinonasal respiratory epithelia l Seromucinous hamartoma 12, 32
adenomatoid hamartoma SF1 72
Recurren! respiratory papi llomatosis 93-95 SH3BP2 257
Renal cel l-like carcinoma 24, 26 SHH signal ling pathway 59, 212, 235
Reparative giant ce ll granuloma 256 Sialadenoma papilliferum 160, 192
Respiratory epithelial adenomatoid Sialoblastoma 160, 183, 184
hamartoma 3 1 Sialolipoma 160, 198
RET 278-280 Sialo-odontogenic cyst 239
Retention cyst 156 Simple bone cyst 204, 259
Retina! anlage tumour 247 Sinonasal ameloblastoma 12, 51
Retinoblastoma 57, 246 Sinonasal ang iosarcoma 38
Rhabdomyoma 106, 122 Sinonasal Burkitt lymphoma 52
Rhabdomyosarcoma 12, 36, 37, 57 Sinonasal cavity tumours 38
Rhabdosarcoma 36 Sinonasal exophytic papi lloma 30
RHOA 143 Sinonasal fibrosarcoma 34
Rle8B 59 Sinonasal g lomangiopericytoma 12, 44
Ringertz tumour 30 Sinonasal haemangiopericytoma- like tumour 44
Subject index 345
Sinonasal keratinizing squamous cel l ssx 41, 42 u
carcinoma 14 STAT3 53
Sinonasal mucosa! melanoma 60, 61 STAT6 44, 45,51 UAM See Unicystic ameloblastoma
Sinonasal neuroendocrine carcinoma 21 , 22 Striated duct adenoma 194 UBR5 212
Sinonasal neurofibroma 49 Sturge-Weber syndrome 48 Unclassified adenocarcinoma 171
Sinonasal non-intestinal-type Swed ish snuff 109 Undifferentiated carcinoma 65, 160, 180,181
adenocarcinoma 24 Synovial sarcoma 12, 34, 41 , 42 Undifferentiated pleomorphic sarcoma
Sinonasal papil loma 12, 28 Synovioma 41 12, 34, 35
Sinonasal oncocytic papilloma 29 Unicameral bone cyst 259
T Unicystic ameloblastoma 217, 218
Sinonasal papilloma, exophytic type 30
Sinonasal papil loma, inverted type 28 t(6;22)(p2 1;q12) translocation 164 Unknown primary Merkel cell carcinoma 151
Sinonasal papilloma, oncocytic type 29 t( 11 ; 18)(q21 ;q21) (BIRC3/AP l2-MALT1) USP6 199, 259
Sinonasal respiratory epithelial adenomatoid translocation 202
hamartoma 31 , 32 t( 11; 19}(q21 ;p 13) translocation 164
V
Sinonasal rhabdomyosarcoma 36 t( 12;15}(p13;q25) translocation 178 Vagal paraganglioma 276 , 283
Sinonasal schwannoma 48 1( 14;18}(q32;q21) (IGH-MALT1) VC See Verrucous squamous cell carcinoma
Sinonasal teratocarcinosarcoma 26 translocation 202 VEGF 83, 268
Sinonasal tract meningioma 50 t(15;19) carcinoma 20 VEGFA 83
Sinonasal tract tumo urs 56 t(X; 18}(p11;q11) translocation 41, 42 VEGFR3 123, 125
Sinonasal undifferentiated carcinoma 12, 14, T41A 43 Venereal condyloma 116
16, 18, 19, 26, 30 T-ce ll lymphoproliferative disorder 128, 129
Verruca vu lgaris 106, 117
Small cell neuroendocrine carcinoma 12, 21 , TCF3 143
Verrucous squamous cell carcinoma 29, 78,
22, 78, 97 , 98, 160, 180, 181 Teratocarcinosarcoma 26, 27
84, 85, 116
SMARCB 1 16, 17, 19-21, 39, 61, 217 Teratoid cyst 157
Vestibular neuroma 270
SmCC See Small cell neuroendocrine Teratoid polyp 72
Vestibular schwannoma 262, 270, 271
TERC 69
carcinoma VHL See Von Hippel- Lindau disease
Terminal duct carcinoma 140, 167
SMO 217 Von Hippel-Lindau disease 48, 267, 268,
Terminal tubulus adenocarcinoma 24
SN UC See Sinonasal undifferentiated 279, 280
TFE3 46
carcinoma VV See Verruca vulgaris
TGD cyst See Thyroglossal duct cyst
SOC See Sclerosing odontogenic carcinoma
Soft tissue ameloblastoma 218
TGF-alpha 270
TGF-beta 1 / SMAD 222
w
Solid/multicystic ameloblastoma 215
THRAP3 259 Warthin tumour 160, 163, 188-191 , 201
Solitary bone cyst 259
Thyroglossal duct cyst 156 Well -differentiated liposarcoma 101
Solitary fibrous tumour 12, 45
Thyroglossal duct remnant 156 We ll-differentiated neuroendocrine carcinoma
Solitary plasmacytoma of bone 204, 260
Thyroid-like low-grade nasopharyngeal 78, 95 , 96
SOT See Squamous odontogenic tumour
papillary adenocarcinoma 70 Werner syndrome 246
SOX2 20, 206
T-LBL/L See T-l ymphoblastic leukaemia/ WHSC1L1 21
SOX11 144
lymphoma WWTR1-CAMTA1 fusion 46
SPB See Solitary plasmacytoma of bone
TLE1 41, 42
Spindle cell melanoma 34 TLPD See T-cell lymphoproliferative disorder X
Spindle cel l rhabdomyosarcoma 12, 34, 36, T-lymphoblastic leukaemia/lymphoma 134,
37 144 XBP1 130
Spindle cell squamous cell carc inoma 12, TMEM127 279, 280 XRCC1 69
17, 78, 87 , 88, 102 TNFAIP3 201 , 202
Squamous ce ll carc inoma 109, 182, 263,
y
Tobacco 14, 65, 81 , 84, 86, 87 , 91 , 93, 95 ,
266 96, 109, 110, 112, 114, 136 YAP1-TFE3 fusion 46
Squamous cell carcinoma, HPV-negative TPIT 72
138 TPM3 102
Squamous cel l carcinoma, HPV-positive 136 TPM4 102
Squamous ce ll papilloma 78, 85, 93 , 106, TRAF3 138
115, 116 Transitional cell carcinoma 16
Squamous cell papillomatosis 78 , 93 Transitional cell papilloma 30
Squamous intraepithelial lesion 91 , 112, 316 Traumatic bone cyst 259
Squamous intraepithelial neoplasia 91, 92 True cementoma 230
Squamous odontogenic tumour 204, 219 TIF1 21 , 70, 96-98, 146, 152, 268, 273
SS18 41 , 42 Tubulopapi llary low-grade adenocarcinoma
SS18-SSX fusion 41 24

346 Subject index

List of abbreviations

30 Three-dimensional
AJCC American Joint Committee on Canear
BCL2 B-cell lymphoma 2 protei n
BCL6 B-cell lymphoma 6 protein
cAMP Cyclic adenosine monophosphate
CDK4 Cycli n-dependent kinase 4
CNS Central nervous system
CT Computad tomography
DNA Deoxyribonucleic acid
EBER Epstein- Barr virus- encoded small ribonucle ic acid
EBV Epstein- Barr virus
EGFR Epidermal growth factor receptor
EMA Epithelial membrane an ti gen
FDG-PET 18F-Fluorodeoxyglucose positron emiss ion tomography
FISH Fluorescence in situ hybridization
FLAIR Fluid-attenuated inversion recovery
GFAP Glial libril lary acidic protein
H&E Haematoxylin and eosin
HHVB Human herpesvirus 8
HIV Human immunodeficiency virus
HPV Human papillomavirus
ICD-0 lnternati onal Classification of Diseases for Oncology
lg lmmunoglobulin
LOH Loss of heterozygosity
MAPK Mitogen-activated protein kinase
MDM2 Mouse double minute 2 homologue
MRI Magnetic resonance imaging
mRNA Messenger ribonucleic acid
N:C ratio Nuc lear-to-cytoplasmic ratio
NKcell Natural killer cell
PAS Periodic acid-Schiff
PCR Polymerase chain reaction
PET Positron emission tomography
PET-CT Positron emission tomography- computed tomography
RB Retinoblastoma protein
RNA Ribonu c leic acid
RT-PCR Reverse transcriptase polymerase chain reaction
SDHA ~ Succinate dehydrogenase [ubiquinon e] flavoprotein subunit, mitochondrial
SDHB Succinate dehydrogenase [ubiquinon e] iron-sulfur subunit, mitochondrial
SEER Surveillance, Epidemiology, and End Results
SMA Smooth muscle actin
SMARCB1 SWl/SNF-related matrix-associated actin-dependent regulator of chromatin subfami ly B member 1
STAT6 Signal transducer and activator of transcription 6
TdT Terminal deoxynucleotidyl transferase
TNM Tumour, nade, metastasis

List of abbreviations 347