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Edited by
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Günter Burg
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Alain Sarasin
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Pathology and genetics of skin tumours/ edited by Philip E. LeBoit... [et. al.].
I. LeBoit, P.E.
II. Series
Contributors 295
References 301
Keratinocytic Tumours
__________
1
Morphology code of the International Classification of Diseases for Oncology (ICD-O) {786} and the Systematized Nomenclature of Medicine (http://snomed.org).
Behaviour is coded /0 for benign tumours, /3 for malignant tumours, /2 for in situ carcinoma and /1 for borderline or uncertain behaviour.
__________
1
{894,2219}.
2
A help desk for specific questions about the TNM classification is available at www.uicc.org/index.php?id=508 .
10 Keratinocytic tumours
Keratinocytic tumours: Introduction D. Weedon
R. Marks
G. F. Kao
C.A. Harwood
The keratinocytic tumours are a clinically may be precursors of squamous cell car- genes and/or inactivation of tumour sup-
and histopathologically diverse group of cinoma. These include actinic keratosis pressor genes in the human skin ker-
lesions derived from the proliferation of and Bowen disease (intraepidermal car- atinocytes. NMSCs are caused by genet-
epidermal and adnexal keratinocytes. At cinoma/squamous cell carcinoma in- ic abnormalities, most often induced by
one end of the spectrum the prolifera- situ). UVB exposure. Actinic keratoses, which
tions are benign (acanthomas) and usu- Actinic keratoses are erythematous, lead to SCCs, have gene mutations in K-
ally of cosmetic importance only, while at scaling lesions occurring on heavily sun- ras {2235}. H-rasV12 and cyclin depend-
the other there are malignant tumours, light exposed areas that increase in ent kinase 4 (CDK4) produce human epi-
which uncommonly may be aggressive prevalence with increasing age in fair dermal neoplasia. Therefore, a combina-
with metastatic potential, as seen with skinned people. Histologically, they tion of these genetic abnormalities might
some squamous cell carcinomas. demonstrate confluent keratinocytic be crucial to the carcinogenesis at least
Included in the spectrum are the epider- atypia involving predominantly the ker- in a subset of SCCs {1336}.
mal dysplasias (actinic keratosis, arseni- atinocytes in the basal layer of the epi- High doses of ultraviolet light can also
cal keratosis and PUVA keratosis) and dermis {2475}. lead to skin cancers by inducing reactive
intraepidermal carcinomas (Bowen dis- It is difficult to determine the incidence of oxygen species (ROS) that play an
ease and bowenoid papulosis). actinic keratoses as they come and go important role in tissue injury. Increased
Ackerman and others have proposed over time {788}. Longitudinal studies production of ROS and/or decreased effi-
that solar keratoses should be regarded suggest that they are likely to be a pre- ciency of antioxidant defence system
as squamous cell carcinoma de novo cursor of squamous cell carcinoma, contribute to a number of degenerative
and not as pre-malignancies or pre-can- although the malignant transformation processes including cancer {1161}. UV
cers that evolve into squamous cell car- rate is small, certainly less than one in a induces pyrimidine dimers and loss of
cinoma {994,1443,1701}. hundred per year {1517}. Data suggest, heterozygosity (LOH). TP53 and PTCH,
also, that remission of these lesions will two tumour suppressor genes, have LOH
Epidemiology occur if sunlight exposure can be which lead to basal cell carcinoma
Keratinocytic tumours are an important reduced. Thus the majority of lesions do (BCC) {1265}. LOH in TP53 is related to
public health problem, despite their com- not progress to squamous cell carcino- elevated microsatellite instability at
paratively low mortality rate {2484}. The ma {1516,2349}. selected tetranucleotide repeats {587}.
lifetime risk for the development of skin Bowen disease demonstrates ker- LOH at 9q22 loci in PTCH genes causes
cancer in the USA is now 1 in 5 {1937}. It atinocyte atypia involving the full thick- non-melanoma skin cancer tumours
is much higher in subtropical Australia. ness of the epidermis. There is also {1265}. The type of mutations for TP53
There is an increasing incidence of squa- involvement of the hair follicle and rarely and PTCH are predominantly UV-signa-
mous cell carcinoma of the skin in some the sweat duct. Although Bowen disease ture transitions, C->T and CC->TT at
countries {2462}. Keratinocytic tumours has been classified as a full thickness in- dipyrimidine sites {1265}. SCCs have
account for approximately 90% or more situ squamous cell carcinoma, there are mutations of H-Ras gene and the INK4a
of all skin malignancies, of which approx- no longitudinal studies published on the locus whereas BCC has missense muta-
imately 70% are basal cell carcinomas. frequency of malignant transformation. tions leading to rasGTPase activating
The latter exceed squamous cell carci- Even if invasive squamous cell carcino- protein {168}. Further, mutations have
nomas in frequency by a factor of ma does occur within one of these been found in both TP53 tumour sup-
approximately 5:1 although in lower lati- lesions, it is believed that the in-situ pressor gene and ras in patients with
tudes the incidence of squamous cell phase may be very prolonged, lasting xeroderma pigmentosum (XP), a disease
carcinoma increases and this ratio many years {1203}. of DNA repair deficiencies {1717}.
becomes 3:1. If solar keratoses are Common exogenous carcinogenic
regarded as squamous cell carcinomas Etiology agents in addition to UV radiation include
(see above), then squamous cell carci- Findings regarding the genetic basis of 1) tobacco use {2457}, 2) human papillo-
noma becomes the more common non-melanoma skin cancer (NMSC) have ma viruses {1703}, 3) arsenic {2184}, 4)
tumour {300}. confirmed that UV radiation, especially industrial chemicals such as vinyl chlo-
UVB (290-320 nm in the solar spectrum), ride {1362}, polycyclic aromatic hydro-
Precursor lesions contributes to the formation of squamous carbons {1086}, 5) MNNG (N-methyl-N’-
There are no known precursor lesions to {1336} and basal cell carcinomas {602}. nitro-N-nitrosoguanidine), an alkylating
basal cell carcinoma. On the other hand, Squamous cell carcinomas (SCCs) of the agent {335}, and 6) exposure to gasoline
there are a number of intra-epidermal skin develop through a multistep process or gasoline vapours {1567}.
proliferative disorders (dysplasias) that that involves activation of proto-onco-
Introduction 11
Clinical features ciated keratinocytic lesions detected by of non-melanoma skin cancer develop-
Keratinocytic tumours vary in their clini- ligation mediated PCR assay. The lower ing in an individual diagnosed with SCC
cal appearance depending on the type level of TIG-3 mRNA expression in SCC is 35-60% and the risk of melanoma is
of lesion and stage of development. is visualized by immunohistochemistry or also increased {1507}. Five-year cure
by in situ mRNA hybridization. Upre- rates for BCC of up to 99% are obtain-
Histopathology gulation of S100 protein subtypes in spe- able with surgical techniques {1617,
The histopathologic changes noted in cific keratinocyte disorders is confirmed 1984}, and metastasis is extremely rare,
keratinocytic proliferative lesions involve by immunohistochemistry. occurring in approximately 0.05% of
disturbance of normal surface matura- cases {1440}. As with SCC, patients with
tion. The degree and extent of ker- Prognosis and predictive factors BCC are at high risk of further primary
atinocytic atypia vary in these lesions. Most patients with primary cutaneous BCCs; in patients with one lesion the 5-
The atypical keratinocytes show non-melanoma skin cancer (NMSC) have year risk is 27%, and in those with 10
enlarged nuclei with hyperchromasia, an excellent prognosis. The overall mor- lesions the risk is 90% {1208}, and the
dyskeratosis and mitoses in any layer of tality rates are generally low, on average risk of SCC and malignant melanoma is
the epidermis. In lesions of epidermal approximately 0.1% of the incidence also increased {1208,1430}.
dysplasias (AK, arsenical, and PUVA ker- rates, but significantly higher for SCCs
atoses), surface keratinocytic maturation than BCCs {2483}. Invasive SCC has the
is present, i.e. a granular cell layer is usu- potential to recur and metastasize with
ally noted. an overall 5-year rate of recurrence for
In intraepidermal carcinomas (Bowen primary tumours of 8%. With the excep-
disease, bowenoid papulosis), there is tion of lip tumours, sqamous cell carcino-
full-thickness involvement of the epider- mas arising in actinic keratoses have a
mis by the atypical keratinocytes. frequency of metastatic spread of 0.5-3%
{1459,1630}. For those with metastatic
Molecular markers disease the long-term prognosis is poor;
A number of potentially useful molecular 10-year survival rates are <20% for
markers or tests have been proposed. patients with regional lymph node
These include the demonstration of a dif- involvement and <10% for patients with
ferent pattern of basic fibroblast growth distant metastases {50}. More than 70%
factor expression in neoplastic ker- of SCC recurrences and metastases
atinocytes by in situ hybridization and the develop within 2 years of treatment of the
persistence of integrated HPV sequen- primary tumour {635}, and 95% within 5
ces in the host cell genome of HPV asso- years {1985}. The 3-year cumulative risk
12 Keratinocytic tumours
Basal cell carcinoma S. Kossard
E.H. Epstein, Jr.
R. Cerio
L.L. Yu
D. Weedon
Definition Australia. The rate of basal cell carcino- growth, or superficial erythematous
A group of malignant cutaneous tumours mas has increased in the older age patches that appear as a dermatitis or
characterised by the presence of lob- groups. Older men have a higher inci- tumours complicating vaccination scars,
ules, columns, bands or cords of basa- dence of basal cell carcinoma than rhinophyma or a venous ulcer. The clini-
loid cells (“germinative cells”). women, but women have been found to cal capacity to differentiate some basal
outnumber men in younger age groups. cell carcinomas from squamous cell car-
ICD-O code 8090/3 The latter may be due to increased sun cinoma or even melanoma may be
exposure in younger women in associa- impossible without skin biopsy. In coun-
Synonyms tion with tanning bed use as well as tries with a high incidence of basal cell
Basal cell epithelioma, trichoblastic car- smoking {293}. carcinomas it is not unusual to have indi-
cinoma. viduals with multiple basal cell carcino-
Clinical features mas, and regular review is required to
Epidemiology Basal cell carcinomas typically have a deal with new skin tumours. Incomplete
Basal cell carcinomas (BCC) develop pearly appearance with telangiectasia removal of basal cell carcinoma may
predominantly in sun-damaged skin in that may appear as a papule or nodule result in delayed recurrences that may
individuals who are fair skinned and that can be eroded or ulcerated. These not be recognized for years, particularly
prone to sunburn {330,888,889}. features may be more subtle in the if the tumour recurrence is deep or
Migration of such individuals particularly superficial forms that appear as erythe- masked by skin grafts.
as children, to countries with high UV matous patches resembling an area of
radiance is associated with increased dermatitis. Pale scar-like lesions may Genetics
rates of skin cancer. Although basal cell also be a presentation of basal cell car- Genetic analysis of sporadic basal cell
carcinomas typically occur in adults, the cinoma and these slowly grow over carcinoma {2024} has been propelled by
tumours also develop in children {1873}. years. Pigmented basal cell carcinomas the identification of mutations in PTCH1
Arsenic exposure {924} and ionizing may masquerade as melanomas but (chromosome 9q22.3) as the cause of
radiation may also induce basal cell car- usually can be distinguished by the pres- the basal cell nevus syndrome (BCNS), a
cinomas. ence of a pearly component. Derma- rare autosomal dominant disorder {110,
Nodular basal cell carcinomas occur at a toscopy is also helpful in analysing pig- 1146,2395}. These patients develop mul-
later age than superficial basal cell car- mented basal cell carcinoma and distin- tiple basal cell carcinomas which may
cinomas and are more frequently on the guishing these from melanocytic tumours appear in childhood (see Chapter 2).
head whereas the trunk is the most fre- {1587}. Erosive lesions on the lower limbs PTCH1 encodes a protein that functions
quent site for superficial tumours {1550, may be mistaken for slowly healing trau- as an inhibitor of the hedgehog signaling
2121}. matic wounds. Delays in clinical diagno- pathway, and BCCs, whether sporadic or
Basal cell carcinomas are very frequent sis may occur for basal cell carcinomas occurring in BCNS patients, all have
tumours particularly in light-skinned indi- that are localized within non-sun abnormalities of this signaling pathway
viduals living in countries at low latitudes. exposed sites {225} such as the perianal {110,1146,2272,2395}. In most sporadic
Incidences of 2000 per 100,000 popula- area {1312} or between the toes, young BCCs this is due to somatically-acquired
tion have been recorded in Queensland, age of onset, tumours with very slow mutations in PTCH1 {802}, and in many
A B C
Fig. 1.1 Basal cell carcinoma, nodular type. A and B The epidermis is raised with flattening of the rete ridges overlying solid and cystic groups of atypical basaloid
cells with peripheral palisading showing invasion of the deep dermis in a nodular pattern. C High power view of nodular basal cell carcinoma showing focal cys-
tic change, peripheral palisading and cleft between tumour nests and stroma.
C D
Fig. 1.2 A Basal cell carcinoma, superficial type. A solid group of atypical basaloid cells is present at the dermo-epidermal junction showing peripheral palisading
and cleft formation between tumour nest and dermis. The dermis shows fibrosis and a patchy lymphocytic infiltrate which frequently accompany basal cell carci-
noma of the superficial type. B Basal cell carcinoma, nodular type, pigmented. The appearances are those of typical nodular basal cell carcinoma with the addi-
tional feature of melanin pigmentation of the tumour nests. C Basal cell carcinoma, cystic type. There is extensive cystic change in an otherwise nodular basal
cell carcinoma. The cystic space contains connective tissue type mucin. In the purely cystic variant, tumour cells may be compressed to only 1 to 2 cell layers thick.
D Basal cell carcinoma, micronodular type. The tumour cell nests are tightly packed, with a diameter of 3 to 10 cells across with deep dermal invasion. In this exam-
ple, there is also tumour-associated amyloid in the stroma.
tumours the type of PTCH1 mutations are BCCs and either spontaneously or in mis {475}. Apoptosis is usually apparent.
those expected from UV-mutagenesis response to environmental mutagens The release of keratin into the stroma as
{108,1265}. Approximately 10% of spo- (i.e. UV or ionizing radiation) develop a result of apoptosis may lead to the for-
radic BCCs have mutations in BCCs and adnexal basaloid tumours. mation of amyloid deposits {2067}.
SMOOTHENED which encodes the pro- Mucinous cystic degeneration, focal vac-
tein whose function is inhibited by the Histopathology uolation with lipid or ductular differentia-
PATCHED1 protein {2553}. Thus it The multiple variants of basal cell carci- tion, and in rare cases, sebocytes or fol-
appears that the relevant dysfunction noma are connected by the common his- licular differentiation with squamous
driving BCCs is abnormal hedgehog sig- tological feature of lobules, columns, eddies, trichohyaline granules and blue-
naling, irrespective of which gene con- bands and cords of basaloid cells (“ger- grey corneocytes may be seen.
trolling that signaling is mutated. The minative cells”) associated with scant Melanocytes may proliferate within some
identification of hedgehog signaling cytoplasm and a characteristic outer pal- tumours and produce pigmentation by
abnormalities as crucial to BCC forma- isade of cells associated with a sur- melanin production that can be stored in
tion has stimulated the development of rounding loose fibromucinous stroma tumour cells or in surrounding
genetically-engineered mice with hedge- {2147,2282}. Artefactual retraction melanophages {1365}.
hog signaling abnormalities {109,708, spaces between the tumour and stroma Problematic lesions include tumours that
1716,2163}. Unlike previously studied are often present. The tumour-stromal merge with squamous cell carcinoma
mouse carcinogenesis models, which interaction is weakened by the charac- (basaloid squamous cell carcinoma) or
uniformly produce tumours of the squa- teristic lack of the hemidesmosomes that those that share adnexal differentiation
mous cell lineage, these mice develop anchor the normal epidermis to the der- demonstrating trichilemmal or seba-
14 Keratinocytic tumours
ceous areas. Some examples of mor- less than 1 in 10,000 tumours {1440, deeply infiltrating and recurrent {70}. The
phoeic or sclerotic basal cell carcinoma 1950,2443}. Morbidity is increased with risk of further primary BCCs is increased
may resemble desmoplastic trichoep- deeply invasive tumours which may by male gender, age over 60 years and
ithelioma or microcystic adnexal carcino- extend into the deep tissue to bone and truncal site {1208,1378}.
ma particularly when a small sample is follow fusion planes particularly on the Rarely, extensive perineural invasion is
obtained for analysis. The growth pattern face where they follow nerves through seen in infiltrative primary BCCs of the
of the basal cell carcinoma should be bony channels. Morbidity also increases face, presenting life-threatening compli-
included in the pathology report as well with neglected tumours that may meas- cations of CNS extension {317,946}.
as the presence of perineural involve- ure more than 10 cm in diameter and Distance to the closest resection margin
ment and excision margins particularly if have been described as giant basal cell is an important predictor of BCC recur-
less than 1 mm. Although the majority of carcinomas {1502,2009}. Multiple recur- rence {639}.
basal cell carcinomas can be classified rences with deep residual tumour on the
into the nodular, micronodular, superfi- head may be associated with particular
cial, sclerosing/morpheic or infiltrative morbidity as basal cell carcinomas can Superficial basal cell
subtypes, it is not unusual to have a ultimately penetrate the cranium. carcinoma
mixed pattern. Increased recurrences are associated
with infiltrative, morphoeic and micron- ICD-O code 8091/3
Immunoprofile odular basal cell carcinomas as surgical
Occasionally in curette specimens, dif- margins may be underestimated {639, Clinical features
ferentiation from small cell melanoma 1940}. The possibility of the BCNS This variant appears as erythematous
may require the use of a combination of should be considered in children who patches that are often multiple and may
light-weight keratin markers and S100 develop BCCs. Families can be vary from a few millimetres to over 10 cm
acidic protein to differentiate the screened for mutations of the PTCH1 in diameter. A fine pearly border or cen-
tumours. BerEP4, a keratin marker, has gene. Low bcl-2 protein expression has tral superficial erosions with a history of
been used to differentiate basal cell car- been found to correlate with clinically contact bleeding may be present. Areas
cinoma from squamous cell carcinomas aggressive basal cell carcinomas with of regression may appear as pale patch-
{2334}. CK20, a marker for Merkel cells, infiltrative, sclerosing/morphoeic pat- es or fibrosis. This variant makes up 10-
has been used to differentiate some terns as compared to superficial and 30% of basal cell carcinomas and occurs
forms of trichoblastoma, trichoepithe- nodular tumours {296,1883}. most frequently on the trunk.
lioma or fibroepitheliomas as these have BCC recurrences are more common in
scattered CK20 positive Merkel cells lesions on the nose and nasolabial fold, Histopathology
compared to basal cell carcinoma where but this may be in part due to the difficul- The histopathology consists of superfi-
they are rare or absent {13,2104}. ty in achieving adequate margins in cial lobules of basaloid cells which proj-
these sites {638,651}. Tumours recurring ect from the epidermis or from the sides
Prognosis and predictive factors after radiotherapy are usually aggressive of follicles or eccrine ducts into the der-
Basal cell carcinomas are locally inva- and infiltrative {2209}. Lesions which mis and are surrounded by loose myxoid
sive tumours and metastases occur in metastasize are usually large, ulcerated, stroma. The lobules are usually confined
Fig. 1.3 Nodular BCC. Cribriform nodular basal cell carcinoma. Fig. 1.4 Nodular BCC with monster giant cells.
to the papillary dermis. Some examples associated with telangiectasia but may Micronodular basal cell
of superficial basal cell carcinoma become ulcerated or cystic. Endophytic carcinoma
appear multifocal on vertical sections but nodules may present as flat indurated
may be connected by a stroma when lesions. Haemorrhagic lesions may ICD-O code 8090/3
reconstructed by three-dimensional resemble haemangiomas or melanoma
techniques using digital image analysis. when pigmented. Nodular basal cell car- Clinical features
There are, however, examples of multi- cinomas make up 60-80% of tumours Micronodular basal cell carcinoma pres-
focal superficial basal cell carcinoma and occur most frequently on the head. ents as elevated or flat infiltrative
where the lobules are separated by large tumours. The most common site is the
distances and represent discrete Histopathology back.
tumours that are truly multifocal and may Histopathology shows large lobules of
measure only a few millimetres in diame- basaloid cells (“germinative cells”) with Histopathology
ter. Mixed patterns with a nodular, peripheral palisading nuclei that project This variant has small nodules that per-
micronodular or infiltrative component into the reticular dermis or deeper. The meate the dermis {1010}. Individual nod-
may be seen in some tumours. lobules may have associated mucinous ules may appear to be separated by nor-
degeneration with cysts or have an ade- mal collagen. The tumour nodules may
noid (cribriform) pattern. Some nodules approximate the size of follicular bulbs
Nodular basal cell carcinoma may have an organoid appearance with and form subtle extensions into deep tis-
smaller basaloid lobules that are con- sue. In contrast to nodular basal cell car-
ICD-O code 8097/3 nected by loose fibromucinous stroma. cinoma the surgical margins of micron-
Clinical features The periphery of such nodules should be odular basal cell carcinoma may be
Nodular (solid) basal cell carcinomas scanned to ensure that an outlying underestimated. Perineural extension
often appear as elevated pearly nodules micronodular pattern has not developed. may be seen.
A B
Fig. 1.6 Nodular cystic BCC A There are well circumscribed cystic nodules of atypical basaloid cells pushing into the deep dermis in a nodular pattern. B High
power view of nodulocystic basal cell carcinoma showing cribriform cystic spaces filled with stromal mucin.
16 Keratinocytic tumours
Fig. 1.7 Fibroepithelial basal cell carcinoma (fibroepithelioma of Pinkus). Fig. 1.8 BCC with adnexal differentiation; basaloid
follicular hamartoma.
Infiltrating basal cell highlighting subtle groups of tumour most often found on the back and are
carcinoma cells (that may consist of 1-2 ker- rarely multiple {1834}. Prior radiotherapy
atinocytes on cross section), in assess- may predispose to these tumours.
Definition ing clearance of the tumour and in con-
This variant of BCC is composed of thin firming perineural involvement. Histopathology
strands, cords and columns of basaloid The histopathology is characterised by
cells that infiltrate between the collagen Differential diagnosis an arborising network of cords of basa-
bundles of the dermis and may extend Due to the cord-like arrangement of this loid cells that extend downwards from
into deeper tissues. variant there is a morphological overlap the epidermis and create a fenestrating
with the tumour pattern seen in micro- pattern. There are strands of basaloid
ICD-O code 8092/3 cystic adnexal carcinoma (sclerosing cells that surround fibrovascular stroma.
sweat duct carcinoma), desmoplastic Ductules may be present in some of the
Clinical features squamous cell carcinoma and desmo- cords which may represent extension of
The infiltrative basal cell carcinoma pres- plastic trichoepithelioma. the tumour down pre-existing eccrine
ents as a pale, indurated poorly-defined ducts {2263}. The cords also are associ-
plaque. These tumours are usually found ated with small follicle-like bulbs which
on the upper trunk or face. Paraesthesia Fibroepithelial basal cell project into the surrounding connective
or loss of sensation may develop rarely carcinoma tissue.
as a manifestation of perineural exten-
sion, particularly in lesions on the face. Definition Histogenesis
This variant is important in that the mar- This variant of BCC is characterised by a Fibroepitheliomas, like BCCs, may be
gins at the time of surgery may be fre- unique clinicopathological presentation best classified as a form of appendageal
quently underestimated. and an indolent behaviour. tumour. These tumours have mutations of
the PTCH1 gene. In some fibroepithe-
Histopathology ICD-O code 8093/3 liomas transition to classical basal cell
Infiltrative patterns of basal cell carcino- carcinomas may be seen, and this con-
ma appear as strands, cords and Synonyms version may reflect a further mutation. A
columns of basaloid cells with scant Fibroepithelioma of Pinkus, Pinkus variant of fibroepithelioma with extra-
cytoplasm. Peripheral palisading and tumour mammary Paget’s cells has been
retraction spaces are usually not seen. described in the perianal area {2461}.
There is no fibrosis/sclerosis as seen in Clinical features
the sclerosing/morphoeic variant. The These tumours usually appear as an ele-
infiltrative pattern is particularly associat- vated flesh coloured or erythematous
ed with perineural invasion. Low molecu- nodule that may resemble a seborrhoeic
lar-weight keratin markers are useful in keratosis or acrochordon. The lesions are
Histogenesis
The cytokeratin profile of basal cell carci-
noma is essentially identical to that of tri-
choblastomas (immature trichoepithe-
lioma) and developing fetal hair follicles
linking all basal cell carcinomas to the
pilosebaceous pathway of differentiation
{2086}. It has been proposed that basal
cell carcinoma be renamed trichoblastic
A carcinoma {1623}.
Basosquamous carcinoma
Definition
B C Basosquamous carcinoma is a term
Fig. 1.9 Basal cell carcinoma, nodular type, with follicular differentiation. A The overall view shows a used to describe basal cell carcinomas
resemblance to typical nodular basal cell carcinoma, with the addition of a cellular fibrous stroma. B There that are associated with squamous differ-
is follicular bulbar differentiation in parts of the tumour, with formation of hair bulb accompanied by mes- entiation {285,2102}.
enchymal bodies. Focal dystrophic calcification. C 1603 High power view showing groups of atypical basa-
loid cells with peripheral palisading with trichohyaline granules and abrupt trichilemmal keratinization.
ICD-O code 8094/3
Histopathology Synonyms
Basal cell carcinoma with This variant is characterized by the pres- Metatypical carcinoma, basosquamous
adnexal differentiation ence of adnexal differentiation including cell carcinoma
basaloid buds, ductal, sebaceous and
Definition trichilemmal elements. Follicular differen- Clinical features
This variant is characterized histological- tiation may be prominent in more superfi- This variant has no distinguishing clinical
ly by adnexal differentiation in a BCC. cial BCCs. Eccrine or apocrine differenti- features.
ation has also been observed in some
ICD-O code 8098/3 basal cell carcinomas {997,2022}. It is Histopathology
important to distinguish such tumours The tumour cells have more abundant
from sweat gland carcinomas which cytoplasm with more marked keratiniza-
Clinical features have an increased risk for metastases. tion than typical basal cell carcinomas.
This variant has no distinguishing clinical Some forms of adnexal basal cell carci- The nuclei have vesicular chromatin with
features. nomas show overlap and may be better pleomorphism and palisading may be
focally lost. Some examples of this vari-
ant may merge with sebaceous carcino-
ma as lipid vacuoles or ducts may be
focally apparent. This tumour may also
have central fibrosis and a radiating
peripheral rim of infiltrative cells extend-
ing into the deep dermis or subcutis.
18 Keratinocytic tumours
Keratotic basal cell carcinoma
Definition
This variant is characterized by the pres-
ence of prominent keratin formation (horn
cysts) in the centre of tumour islands.
Clinical features
This variant characteristically appears
pearly and may be studded with small
keratin cysts (milia).
Histopathology
These tumours share the overall archi-
A B
tectural features of a nodular BCC.
Keratinization may be laminated and
infundibular in type or hyaline and
trichilemmal in type or consist of kera-
tinised shadow cells representing pilo-
matricomal differentiation {66}. Dys-
trophic calcification is frequently present.
Trichilemmal keratin may be associated
with accentuated apoptosis in surround-
ing tumour cells and the presence of
pale keratinocytes.
Differential diagnosis
This variant is distinguished from
basosquamous carcinoma by the pres- C D
ence of numerous, superficial small ker- Fig. 1.11 Basal cell carcinoma (BCC). A Adenoid BCC. B Morpheiform BCC. C BCC with rosettes. D BCC
atin cysts. Basosquamous carcinoma is with sebaceous differentiation.
usually larger and less well circum-
scribed.
embedded in a dense fibrous stroma variants including the nodular, micron-
{1932}. Some authors use the term mor- odular, multifocal superficial and keratot-
Other variants phoeic for any BCC with a fibrous stro- ic types. Melanocytes are scattered
ma, while others restrict it to those BCC’s through the tumour nests, while
Other variants account for less than 10% with keloidal collagen bundles in the stro- melanophages are present in the stroma
of all basal cell carcinomas. Many of ma {1923}. Enhanced procollagen gene {1495}. This variant can be misdiag-
them do not have distinctive clinical fea- expression has been found in this variant nosed clinically as malignant melanoma.
tures. {1657}. Furthermore, smooth muscle α-
actin is often present in the stroma. This Miscellaneous
Cystic variant usually presents as an indurated, Other rare variants, subject to isolated
One or more cystic spaces, of variable pale plaque with a slightly shiny surface case reports, include the clear-cell {165},
size, are present near the centre of the and indistinct margins. "signet-ring"-cell {1269,2503}, granular-
tumour nests. There is sometimes in- cell {1659} and giant ("monster")-cell
creased mucin between the cells border- Infundibulocystic {680} types. Adamantanoid {1403}, neu-
ing the central space {2112}. Often confused with the keratotic type, roendocrine {817} and schwannoid
this variant is composed of small {2032} variants have also been
Adenoid infundibular-like structures with a central described.
There are thin strands of basaloid cells in keratinous plug and a peripheral compo-
a reticulate pattern. Stromal mucin is nent of basaloid cells {1218}. The nests
often present. The adenoid type may are arranged in an anastomosing pat-
occur in association with the nodular tern. Multiple lesions are sometimes
(solid) type. present {1178}.
Definition ing skin usually shows changes of actinic are immunocompromised (including
Squamous cell carcinoma is a malignant damage. those infected with the human immunod-
neoplasm of epidermal (and mucous eficiency virus {1704}, are usually more
membrane) keratinocytes in which the Histopathology aggressive. Tumours with deep invasion,
component cells show variable squa- Squamous cell carcinoma consists of poor differentiation, perineural invasion
mous differentation. nests, sheets and strands of squamous and acantholytic features are more likely
epithelial cells which arise from the epi- to recur or metastasize. Narrow surgical
ICD-O code 8070/3 dermis and extend into the dermis for a margins are another risk factor for recur-
variable distance. The cells have abun- rence {2389}.
Epidemiology dant eosinophilic cytoplasm and a large, The clinical setting in which the SCC aris-
Most cases arise on the sun-exposed often vesicular, nucleus. There are promi- es also influences the risk of metastasis.
skin of elderly people. They can occur on nent intercellular bridges. There is vari- Tumours arising in sun-damaged skin
all cutaneous surfaces and mucous able central keratinization and horn pearl have the lowest risk, in the order of 0.5%
membranes, and in younger patients, formation, depending on the differentia- or less, while for those arising in skin not
especially those with a fair complexion tion of the tumour. exposed to the sun, the risk is 2-3%. The
who tan poorly. Its incidence in an The degree of anaplasia in the tumour risk is further increased for tumours aris-
Australian study was 166 cases per nests is used to grade the tumours. A ing in Bowen disease {1203}, on the lip,
100,000 of the population, the highest in rather subjective assessment is usually vulvar, perineal and penile skin and in a
the world {828}. It is relatively uncommon made using the categories of ‘well,’ Marjolin ulcer, radiation scar or thermal
in Black people. ‘moderately’ and ‘poorly’ differentiated. burn. Tumour thickness is a prognostic
Most squamous cell carcinomas arise in variable, just as it is for melanoma. SCCs
Etiology solar keratoses and evidence of this less than 2 mm in thickness rarely metas-
Ultraviolet-B radiation is the most impor- lesion is usually present at the periphery tasize, while those between 2 and 5 mm
tant etiological factor. Less important fac- of the invasive tumour. thick are of intermediate risk (about 5%).
tors include radiation therapy, previous Squamous cell carcinomas occasionally Tumours greater than 5 mm in thickness
burns, arsenic, coal tar {1759}; industrial infiltrate along nerve sheaths, the adven- have a risk of metastasis of about 20%
carcinogens, immunosuppresion, HPV titia of blood vessels, lymphatics, fascial {1254}. Tumours greater than 2 cm in
infection, and inflammatory lesions and planes and embryological fusion plates diameter are more likely to recur and
ulcers of long standing (see Intro- {218}. The presence of perineural lym- metastasize than smaller lesions {1985}.
duction). Organ transplant recipients are phocytes is a clue to the likely presence
particularly prone to develop these of perineural invasion in deeper sections
tumours. Most of the fatal cases have {2289}.
been reported from Australia, suggesting There may be a mild to moderate chronic
that sunlight, which also has a profound inflammatory cell infiltrate at the periph-
effect on the cutaneous immune system ery of the tumours. This infiltrate some-
plays a role in the formation of these times includes eosinophils {1455}.
aggressive tumours {1974}. HPV infec- Rare histological variants of SCC include
tion is commonly found in these immuno- clear-cell {1344}, signet-ring {1557}, pig-
supressed patients {264}. mented {451}, basaloid {573}, inflamma-
tory, infiltrative {1395}, desmoplastic
Localization {1546} and rhabdoid {1534} types.
Most SCCs arise in areas of direct expo- The cells in SCC are positive for epithe-
sure to the sun, such as the forehead, lial membrane antigen and cytokeratin.
face, ears, scalp, neck and dorsum of The keratins are of higher molecular
the hands. The vermilion part of the lower weight than those found in basal cell car-
lip is another common site. cinoma {1672}.
20 Keratinocytic tumours
Acantholytic squamous cell Clinical features neous epithelial markers that include
carcinoma ASCC presents similarly to conventional high molecular weight keratins such as
SCC, as a slowly growing scaly and AE-2/3. Involucrin, vimentin and EMA
Definition occasionally ulcerated papule/plaque on immunostains may also be positive
Acantholytic squamous cell carcinoma the sun-exposed skin. {1808,2011}. Low-molecular weight ker-
(ASCC) is a histologic variant of cuta- atins such as AE-1, CAM 5.2 are typical-
neous squamous cell carcinoma (SCC) Histopathology ly negative. Various intercellular peptides
that is histologically defined by loosening Invasive lesions typically show a thick- have been invoked in the pathogenesis
of the intercellular bridges resulting in ened, and/or ulcerated epithelium. of acantholysis including the intercellular
acantholysis. These tumours may pres- Scanning magnification reveals a flat- adhesion molecule syndecan, E-cad-
ent as intraepidermal (in-situ) or invasive tened thinned, normal or hyperplastic herin and the anhidrotic ectodermal dys-
SCC. epidermis with or without asymmetric plasia gene product {183,1635}. It has
and infiltrating dermal tumour islands. At also been recently shown that decreased
ICD-O code 8075/3 intermediate power, prominent TP53 and PCNA expression correlated
suprabasilar or intratumoural acantholy- with a decrement in desmosomes seen
Synonyms sis is seen. Zones of acantholysis are ultrastructurally {1889}.
Adenoid squamous cell carcinoma, capable of producing large intra-epider-
pseudoglandular squamous cell carcino- mal cavities. Acantholytic areas may Differential diagnosis
ma extend down adjacent follicular struc- The changes described above constitute
tures involving the follicular epithelium an important histologic means of sepa-
Epidemiology and rarely, circumscribe the follicle simu- rating this entity from acantholytic disor-
The acantholytic variant accounts for 2- lating a glandular arrangement. ders. The differential also includes true
4% of all cutaneous SCC {1149,1687, Acantholytic foci may also produce a adenosquamous cell carcinoma of the
1819,2549}. The age range is wide but it pseudovascular pattern mimicking skin that exhibits squamous and glandu-
usually affects aged individuals with a angiosarcoma (pseudovascular SCC) lar differentiation on ultrastructural exam-
male predominance. {139,1675,1688}. At high power typical ination and histochemical staining {2482}.
features of squamous malignancy are
Etiology identified including dyskeratosis, ker- Prognosis and predictive factors
As in conventional SCC, ultraviolet light atinocytic atypia, consisting of an The behaviour of ASCC like other SCCs
constitutes the most important etiologic increased nuclear-to-cytoplasmic ratio is depth-dependent and may be more
risk factor. and nuclear hyperchromasia, altered aggressive than conventional SCC {461,
maturation within the epithelium, and 1097,1149,1687,1819,1985}. In-situ le-
Localization increased typical and atypical mitotic fig- sions are capable of recurrence and in
The tumour involves predominantly the ures. up to 10% of cases, may show micro-
skin of the head and neck region, partic- invasion. The overall rate of metastases
ularly on and around the ears {1149, Immunoprofile with lesions greater than 2.0 cm of inva-
1687,1819,2549}. The lesional cells in ASCC stain for cuta- sion ranges from 5-19%.
A B
Fig. 1.13 A Acantholytic SCC, Intermediate-power photomicrograph depicting acantholysis extending down adjacent follicle epithelium. B Squamous cell carcino-
ma (acantholytic)
Spindle-cell squamous cell cell carcinoma. Sometimes there is a his- CAM5.2 or MNF116. Some tumours may
carcinoma tory of rapid growth. coexpress cytokeratin and vimentin, sug-
gesting metaplastic change to a neo-
Definition Histopathology plasm with mesenchymal characteristics
This is an uncommon variant of squa- It may be composed entirely of spindle {1116}.
mous cell carcinoma that exhibits a cells, or have a variable component of
prominent spindle cell morphology. more conventional squamous cell carci- Prognosis and predictive factors
noma. The spindle cells have a large Spindle-cell squamous cell carcinoma is
ICD-O code 8074/3 vesicular nucleus and scanty a poorly differentiated variant of squa-
eosinophilic cytoplasm, often with indis- mous cell carcinoma that may be associ-
Etiology tinct cell borders. There is variable pleo- ated with an aggressive clinical course
Lesions usually arise in sun-damaged or morphism, usually with many mitoses. {2180}. These tumours account for slight-
irradiated skin. A case has been report- ly over one-third of cutaneous squamous
ed in association with lichen sclerosus of Differential diagnosis cell carcinomas which metastasize
the vulva {2057}. The incidence of this It may be difficult to separate from other {1985}. Metastases usually occur to the
variant may be higher in immuosup- cutaneous spindle cell neoplasms regional lymph nodes in the first
pressed patients. including spindle cell melanoma, atypi- instance.
cal fibroxanthoma and, less often,
Clinical features leiomyosarcoma. Some cases can only
Spindle-cell squamous cell carcinoma be confirmed ultrastructurally, as all ker- Verrucous squamous cell
presents as a plaque or nodule on the atin markers are negative {2180}. CK5/6 carcinoma
skin. It may be clinically indistinguishable is positive in two-thirds of all cases, a
from the more usual type of squamous higher figure than obtained with AE1/3, Definition
Verrucous squamous cell carcinoma is a
rare variant of well-differentiated squa-
mous cell carcinoma with low malignant
potential.
Synonyms
Oral florid papillomatosis, Ackerman’s
tumour {32,348}, epithelioma cunicula-
tum {41,2096,2108}, giant condyloma
acuminatum, Buschke-Löwenstein tu-
mour {359,1347,1947,2124,2570}, papil-
lomatosis cutis carcinoides {218,870,
2108}.
Epidemiology
Fig. 1.15 Verrucous squamous cell carcinoma Fig. 1.16 Verrucous squamous cell carcinoma Verrucous carcinoma comprises 2-12%
22 Keratinocytic tumours
of all oral carcinomas, and is found pre-
dominantly in men (age peak in 5th
decade, range 34-85) {348}. Verrucous
carcinoma of the extremities (epithelioma
cuniculatum) most often affects men in
the 6th decade {2108}. The incidence of
the genital type (Buschke-Löwenstein
tumour) varies between 5- and 24% of all
penile cancers; the tumour tends to
occur in men younger than 50 years
(range 18-86) {218}.
Etiology
Leading theories of the pathogenesis
include chronic irritation, inflammation
and impaired immune response {2096,
2108}. Important factors for the develop-
ment of oral verrucous carcinomas are
poor oral hygiene with ill-fitting dentures
or decaying teeth, chewing of tobacco or
betel nuts, and use of snuff. In genital
lesions poor hygiene and phimosis play
a major role. Other theories include HPV A B
infection (mostly HPV 6, 11) {898} and Fig. 1.17 Verrucous squamous cell carcinoma A, B Note the well-differentiated proliferative process and
chemical carcinogens {2096,2108}. the bulbous nature of the squamous downgrowths.
Localization
Common sites include buccal and retro- epithelium shows an asymmetric exo- Prognosis and predictive factors
molar mucosa, gingiva, floor of mouth, and endophytic growth pattern with If the tumour is completely excised,
tongue and hard palate. They also arise pushing rather than destructive or infiltra- prognosis is excellent; after inadequate
on the soles, rarely the palms and distal tive margins. Usually, there is deep pen- excision, the recurrence rate is high and
fingers, and on amputation stumps. etration below the level of the surround- the survival decreases. In long-standing
Genital lesions occur primarily on the ing epidermis / mucosa. Tumour cells cases or after irradiation and / or
glans and prepuce of the penis {778, exhibit only minimal atypia and very low chemotherapy the biologic character of
2108,2570}. It is uncommon in the vagina mitotic activity. The presence of neu- the disease may change into a metasta-
and the perianal region {1347,1947, trophils is an important diagnostic clue; sizing squamous cell carcinoma {1216}.
2124}. Rare cases have been described they may form small intraepidermal
on the scalp, face, back and extremities, abscesses. Draining sinuses containing
sometimes associated with long-stand- inflammatory cells and keratin debris Pseudovascular squamous
ing ulcerations or scars, especially in the may also be present. No foci of the usual cell carcinoma
pretibial area (papillomatosis cutis carci- squamous cell carcinoma should be
noides) {218,870,2096,2108}. found {1833}. Definition
Pseudovascular SCC is an aggressive
Clinical features Differential diagnosis variant of SCC with marked acantholysis
These lesions show cauliflower-like The separation from benign reactive resulting in angiosarcoma-like areas
appearance with exophytic and endo- processes and SCC of the more usual {139,1688}.
phytic growth, and a papillomatous sur- type can be difficult. The presence of
face. They are pale in colour and some- blunted projections of squamous epithe- ICD-O code 8075/3
times have draining sinuses. Some are lium in the mid and/or deep dermis is
tender and painful, particularly on the suspicious for verrucous carcinoma. The Synonyms
sole of the foot. There is slow but relent- squamous downgrowths are bulbous. Pseudoangiosarcomatous SCC,
less growth over the course of a long Small collections of neutrophils may pseudoangiomatous SCC
time {2570}. extend into the tips. Clinicopathological
correlation and adequate sampling are Epidemiology
Histopathology often helpful. The tumour is exceedingly rare.
In all cases a well-differentiated prolifera-
tive epithelial process is visible, the Precursor lesions Clinical features
malignant nature of which may easily be Oral lesions may develop in areas of pre- It usually presents as a circumscribed
overlooked, particularly if the biopsy is vious leukoplakia, lichen planus, lupus white-grey ulcer or a nodular tan-red/pink
small and superficial. The squamous erythematosus or candidiasis {218}. tumour, most often located on sun-
A B
Fig. 1.19 Adenosquamous carcinoma. A Overt squamous differentiation in parts of the tumour. B Sheets of atypical dyskeratotic squamous cells from the squa-
mous area of the tumour.
24 Keratinocytic tumours
A B C
Fig. 1.20 Adenosquamous carcinoma. A Well formed glandular structures containing mucinous secretion in the glandular area of the tumour. B PAS stain.
Intracytoplasmic targetoid PAS positive and diastase sensitive globules in the glandular areas of the tumour. C CEA immunohistochemical stain. Positive luminal
staining in glandular structures.
Definition and the average age at first biopsy is 55 {2567,2572}. Human papillomavirus
Bowen disease (BD) is a form of squa- years. Both exposed and non-exposed (HPV) genomes have been demonstrat-
mous cell carcinoma in situ. It is a distinct skin sites are equally affected. The dis- ed by in situ hybridization in the nuclei of
clinicopathologic entity of the skin and ease uncommonly affects black skin, in keratinocytes in the stratum malpighii
mucocutaneous junction. which it is found more commonly on non- and stratum corneum of the BD lesions.
sun-exposed areas. HPV types 16 and 18 have been linked to
ICD-O code 8081/2 lesions of genital BD and non-condylo-
Etiology matous genital warts, i.e., bowenoid
Synonyms The exact underlying cause of BD papulosis {1098}. HPV is less commonly
Squamous cell carcinoma in situ remains unclear, although multiple fac- associated with nongenital BD. HPV
(SCCIS), intraepidermal carcinoma, tors are likely to be responsible for it. types 15 and 16 have been identified in
bowenoid dysplasia, bowenoid squa- Many lesions arise without an apparent some cases of BD of the distal extremi-
mous carcinoma in situ (BSCIS), vulvar cause. However, it is known that chronic ties. Evidence of other papillomavirus
intraepithelial neoplasia (VIN III). sun damage disrupts normal keratinocyt- types, including HPV31, 54, 58, 61, 62
The terms bowenoid dysplasia and ic maturation, causes mutation of the and 73, have also been identified in
BSCIS are customarily applied to cuta- tumour suppressor gene protein (TP53) some cases of BD. Aberrations in local
neous and mucocutaneous lesions of the {375,1075}, and results in the develop- and systemic immunity, trauma, chronic
male and female external genitalia. BD is ment of keratinocytic atypia as seen in irritation, mutagenic factors, and tobacco
no longer used in gynaecological pathol- lesions of BD. The predilection for exposure are other possible etiologies of
ogy. It has been replaced by the concept anatomic sites affected by BD on sun- BD.
of vulvar intraepithelial neoplasia (VIN). exposed glabrous skin and lesions being
The degree of epithelial atypia seen in reported more commonly in patients with Localization
BD corresponds to VIN, grade III (VIN III) a history of PUVA or UVB therapy {1410}, Based upon a large series of 1001 biop-
{362,1580}. attest to the critical role of causal rela- sy-proven BD in Australia, most lesions
tionship between UV damage and BD. occurred on a sun-exposed glabrous
Epidemiology Ingestion of inorganic arsenic may play a area {1315}. About one-third (33%) of the
Bowen disease occurs predominantly in role, as lesions of arsenical keratosis (As- lesions occured in the head and neck
fair-complexioned Caucasian men, but K) may display identical histopathologic areas, especially the face. Men had pre-
both sexes are affected. One in five features to BD. A large number of cases dominance of lesions on the scalp and
patients (20%) is a woman. The disease of As-K with associated invasive carcino- ears, whereas women had a predomi-
commonly affects patients in the 6-8th ma have been reported in a rural popula- nant involvement of the legs and cheeks.
decades of life. However, the average tion using well water containing a high BD rarely affects the nail bed and peri-
age at onset of the disease is 48 years, concentration of inorganic arsenic ungual area {2070}.
Clinical features
The classic appearance of cutaneous
BD is a single or multiple erythematous,
rounded to irregular, lenticular, scaly, ker-
atotic, fissured, crusty, nodular, eroded,
pigmented patches or plaques. The
plaques are devoid of hair, and usually
appear sharply demarcated from the sur-
rounding unaffected skin. Areas of nor-
mal-appearing skin may occur within the
boundaries of larger lesions of BD. The
plaques vary from 1-5 cm in overall
dimensions. In intertriginous areas, BD
may appear as moist patches without
scale. In anogenital locations, the lesions
A B appear polypoid or verrucoid, frequently
Fig. 1.21 A Bowen disease. Sharply circumscribed, bright red plaque of erythroplasia of Queyrat (EPQ). pigmented. Erythroplasia of Queyrat
B Bowen disease. Erythematous, scaly, fissuring plaques of BD on lower leg of a middle-aged woman. (EPQ) presents as an asymptomatic,
26 Keratinocytic tumours
A B
C D
Fig. 1.22 Bowen disease (BD). A Low-power photomicrograph of BD. Note hyperkeratosis, full-thickness of epidermal atypia, extensive pilar epithelial involvement,
and a lichenoid upper dermal mixed chronic inflammatory infiltrate. B Atypical keratinocytes encircle an acrosyringium. C Atypical squamous cells extend along
acrosyringia. D Prominent vacuolated atypical cells, focally mimicking koilocytotic change and pagetoid appearance seen in BD.
bright red, velvety to shiny, sharply cir- glans penis. Such lesions have a greater These changes are confined by an intact
cumscribed plaque. The mucocuta- potential for developing into invasive car- dermoepidermal basement membrane.
neous junction of the glans penis, coro- cinoma than does BD involving glabrous Lesions of BD from hair-bearing areas
nal sulcus, or undersurface of the fore- skin {875}. Although evidence for the invariably demonstrate involvement of
skin is involved, and lesions are usually association of BD and internal malignan- the pilar acrotrichium, infundibulum, and
found in older, uncircumcised men. cies is reported in earlier studies, more sebaceous gland. In some lesions,
There are two clinical variants of BD: recent population-based cohort studies prominent vacuolated atypical cells
those involving glabrous skin, and those do not confirm the link {484}. focally mimic koilocytotic viral cytopathic
of the anogenital area. On the glabrous change and exhibit a pagetoid appear-
skin, BD manifests as asymptomatic, Histopathology ance. The acrosyringium is occasionally
slowly enlarging, scaly patches or The typical low-power microscopic fea- involved. An inflammatory infiltrate of
plaques. The average duration of the tures of BD are hyperkeratosis, paraker- lymphocytes, macrophages, and plasma
lesion is 6.4 years. Plaques of BD atosis, hypo- or hypergranulosis, plaque- cells is seen in the upper dermis.
enlarge slowly, and expand centrifugally, like acanthosis with increased cellularity, Capillary ectasia is commonly noted.
sometimes for decades. Anogenital BD and a chronic inflammatory infiltrate in Prominent solar elastosis is also present
involves the mucocutaneous junction the upper corium. The epidermis exhibits in lesions on sun-exposed skin. An inva-
and adjacent mucosa. If untreated, 5-8% loss of normal polarity and progression of sive carcinoma arising in BD shows vari-
of patients may develop invasive carci- normal surface keratinocytic maturation. able histologic differentiation, with squa-
noma. The invasive carcinomas are larg- A “windblown” appearance of crowding mous, basosquamous, pilar, sebaceous
er (up to 15 cm), rapidly growing tumours of atypical keratinocytes, with hyperchro- {1120}, pilosebaceous, poorly-differenti-
that occur in pre-existing scaly plaques matism, pale-staining to vacuolated ated, and occasionally ductal features
{1203}. cells, occasional multinucleated cells, {1203,2016}. The atypical vacuolated
The clinical entity of erythroplasia of individual cell keratinization (dyskerato- keratinocytes are negative for cytoplas-
Queyrat (EPQ) is regarded as BD of the sis), and abnormal mitoses are noted. mic mucin; some, however, contain
Bowen disease 27
glycogen. Melanin pigment may be pres-
ent in the atypical cells, and in the pig-
mented genital lesions, melanophages
are numerous. The abnormal keratinizing
cells are intensely reactive with glucose-
6-phosphate dehydrogenase. Ultrastruc-
tural changes of BD include decrease in
tonofilament-desmosomal attachments,
aggregated tonofilaments and nuclear
substance, and absence of keratohya- A B
line granules {1204}.
Differential diagnosis
Bowenoid solar keratosis differs from BD
by its clinically smaller size, exclusive
location on sun-exposed skin, and pres-
ence of superficial keratinocytic matura-
tion. Bowenoid papulosis is distin-
guished from BD by its clinical appear-
ance of multiple papular to coalescing
lesions on the anogenital areas, and the C D
typical microscopic salt and pepper dis- Fig. 1.23 Bowen disease. A Full thickness squamous cell atypia. B There is full thickness squamous cell
tribution of atypical keratinocytes and atypia with apparent sparing of the basal keratinocytes and hyperpigmentation of the basal keratinocytes.
mitoses in the affected cutaneous and C Full thickness squamous cell atypia with scattered bizzare keratinocytes. D Full thickness squamous cell
mucocutaneous lesions, as well as fre- atypia with marked nuclear pleomorphism.
quent HPV positive koilocytotic cells
{1790}. The pagetoid variant of BD is
sometimes difficult to distinguish from Genetics Bowenoid papulosis
extramammary Paget disease. In the lat- The atypical keratinocytes of BD contain
ter, mucicarmine, Cam 5.2 and CEA pos- large numbers of aneuploid cells {241}. Definition
itive tumour cells are present in the epi- Increased expression and mutation of Bowenoid papulosis is a clinicopatholog-
dermis, individually or in small nests, TP53 observed in lesions of BD suggest ical entity characterised by the presence
forming glandular structures at the der- that loss of normal TP53 tumour suppres- on the genitalia of solitary or multiple ver-
moepidermal junction. These features sor activity may be an important mecha- ruca-like papules or plaques with histol-
are absent in BD. The vacuolated cells in nism of oncogenesis in BD {375,1075, ogy resembling full thickness epidermal
BD contain glycogen and not mucin. In 1946}. Allelic deletion of one or more 9q dysplasia as seen in Bowen disease.
malignant melanoma in situ, the basilar chromosome markers has been detected
keratinocytes are replaced by neoplastic in occasional lesions of BD. However, no Synonyms
melanocytes. The presence of intercellu- deletion of 9p markers was seen {1866}. Multicentric pigmented Bowen disease,
lar bridges and prominent dyskeratotic There have been no clonal chromosomal multifocal indolent pigmented penile
keratinocytes are features favouring the abnormalities by cytogenetic analysis of papules
diagnosis of BD. Melanoma cells do not cell cultures from BD {1003}.
contain cytokeratins of 54 and 66 kilodal- Epidemiology
tons (kd); the reverse applies with the Prognosis and predictive factors Bowenoid papulosis occurs mainly in
cells in BD. Surgical excision with complete removal young individuals and although uncom-
may cure BD. The origin of BD from pilar mon the incidence is increasing. There is
Histogenesis outer root sheath cells at the sebaceous a male predominance.
It has been suggested that BD most like- gland level explains in part the high
ly originates from germinal cells of the recurrence rate, following treatment with Etiology
pilar outer root sheath and the pluripo- superficial curettage and desiccation, The etiopathogenesis of this condition
tential epidermal cells of the acrotrichi- topical fluorouracil, and X-ray. Invasive almost certainly favours linkage to
um. This concept is substantiated by the adnexal carcinoma may develop in human papillomavirus infection particu-
findings of various types of histologic dif- untreated plaques of BD of prolonged larly oncogenic types 16, 18, 33,35 and
ferentiation in carcinoma arising in BD duration following expansile growth. The 39. DNA sequences have been identified
{1120,1203,2016}. Using immunohisto- metastatic rate in these uncommon by various workers {908,1737,2113}.
chemical localization of keratins and tumours was 18% and fatality was Consequently in females there is a high-
involucrin, the atypical cells of BD exhib- observed in 10% of cases in a large case er incidence of abnormal cervical/vagi-
it a diversity of differentiation {1093}. series {1203}. nal smears both in affected patients and
in partners of men with penile lesions.
Whilst controversies regarding the bio-
28 Keratinocytic tumours
logical potential of bowenoid papulosis (VIN) III or penile intraepithelial neoplasia mutation of TP53 observed in lesions
exist, with the possibility of invasive (PIN) III by some pathologists {570}. suggest that loss of normal TP53 tumour
malignancy, in most cases the clinical There is loss of architecture. The base- suppressor activity is likely to be an
course is benign and some lesions ment membrane is intact. Mitoses are important mechanism of oncogenesis in
regress. frequent, sometimes with abnormal bowenoid papulosis. To date, there have
forms often in metaphase. Dyskeratotic been no clonal chromosomal abnormali-
Localization cells are also seen. Typical koilocytes are ties by cytogenetic analysis of cell cul-
Bowenoid papulosis was first described uncommon {908}. The stratum corneum tures from bowenoid papulosis.
as a condition affecting the groin {1438}. and granular cell layer often contain
It was later defined {1305,2447} as an small inclusion - like bodies which are Prognosis and predictive factors
entity involving the genitalia or perigeni- deeply basophilic, rounded and sur- Bowenoid papulosis appears in many
tal areas. Isolated cases of extragenital rounded by a halo. cases to remain benign {1790} and spon-
bowenoid papulosis have been taneous regression has occasionally
described {902,1147}. Differential diagnosis occurred; however, close follow up is
The basophilic bodies, together with the essential.
Clinical features numerous metaphase mitoses, are the
The lesions are usually asymptomatic features which suggest a diagnosis of
with variable clinical presentation: multi- bowenoid papulosis rather than Bowen
ple generally small, round fleshy disease itself.
papules, isolated or confluent (2.0-20
mm), with a smooth papillomatous sur- Histogenesis
face, sometimes with desquamation A study based on histomorphology and
resembling lichenoid or psoriasiform der- DNA ploidy analysis has suggested that
matoses. The colour of lesions can vary bowenoid papulosis is a form of low-
from pink to reddish-purple to brown / grade squamous cell carcinoma in situ
black. {269}. Electron microscopy has shown
structures resembling viral particles
Histopathology {1274,1790} within the granular layer.
The histological features demonstrate
epidermal atypia ranging from partial to Somatic genetics
full thickness atypia similar to in situ Many of the atypical keratinocytes of
squamous cell carcinoma i.e. Bowen dis- bowenoid papulosis not unlike Bowen
ease. On the genitalia changes may be disease, contain large numbers of aneu-
termed vulvar intraepithelial neoplasia ploid cells. Increased expression and
Bowen disease 29
Actinic keratosis C. James
R.I. Crawford
M. Martinka
R. Marks
A B
Fig. 1.25 Actinic keratosis. A There is focal parakeratosis, acanthosis and basal squamous atypia overlying a dense lichenoid inflammatory infiltrate. B Actinic ker-
atosis. There are elongated rete ridges with squamous cell atypia and focal acantholysis.
30 Keratinocytic tumours
A B
C D
Fig.1.26 Actinic keratosis. A Atrophic variant with atypical basal keratinocytes and focal parakeratosis. B Medium power magnification shows keratinocyte atyp-
ia in the stratum malpighii with a loss of polarity, nuclear enlargement, hyperchromasia, dyskeratosis, increased mitotic activity and parakeratosis. C Downward
prolongations and buds of atypical squamous cells does not indicate true stromal invasion. Note severe dermal solar elastosis and telangiectasia. D Acantholytic
variant with suprabasal acantholysis, squamous atypia, dyskeratosis and superficial follicular involvement.
been proposed, however, invasive SCC The hypertrophic variant shows acantho- Keratinocyte atypia aids distinction from
commonly arises from KIN I or II. sis, papillomatosis and conspicuous acantholytic dermatoses. Downward
Lesions in which impaired maturation hyperkeratosis with alternating paraker- extensions of the basal epidermis can
and atypia appear to involve the full epi- atosis {244}. Elongation of rete ridges, induce pseudoducts, and acantholysis
dermal thickness have been labelled dilated vessels and vertically oriented may spread along appendages.
“bowenoid actinic keratoses” (BAK) collagen bundles in the papillary dermis The pigmented variant shows increased
{1128}. Multinucleate keratinocytes and suggest superimposed lichenification. melanization of atypical keratinocytes
a verrucous architecture, can be seen in The atrophic AK variant is easily misdi- and dermal macrophages {1128}.
AKs in the setting of immunosuppression agnosed if the basal keratinocytic atypia The lichenoid variant has keratinocyte
{294,1856}. in a parakeratotic epidermis devoid of apoptosis and vacuolation, exocytotic
The abnormal keratinization often rete ridges is missed. Budding of the lymphocytes and a band-like superficial
involves the epidermis between spared basal epidermis and extension of atypia dermal lymphocytic infiltrate including
acrotrichia and acrosyringia, which in into adnexae are common. colloid bodies {2318}. The epidermis in
contrast retain columns of normal kera- The bowenoid variant is difficult to differ- early lesions is acanthotic, but more
tinization. Some lesions show spread into entiate from Bowen disease. Whilst some advanced regressing lesions are atroph-
the infundibular and isthmic segments of claim they are identical, others empha- ic with pigment incontinence.
follicles or less commonly along eccrine size the lack of full thickness atypia, less Keratinocyte atypia exceeding that
ducts {1835}. Dermal changes include defined edge, follicular sparing and expected in a reactive process differenti-
solar elastosis, an infiltrate of lympho- acrosyringeal involvement in BAK ates this lesion from benign lichenoid
cytes and plasma cells and increased {1128,2476}. keratosis.
vascularity. Inflammation is most frequent The acantholytic variant reveals clefting, The confident identification of early SCC
in lesions of the head and neck, particu- usually suprabasal, with varying acan- in an AK can be difficult {1158}.
larly the lips. tholysis and dyskeratosis {1409}. Detachment of individual irregular aggre-
Actinic keratosis 31
gates of keratinocytes from the epider- sion rate of the former {1350}. AK {791}. Metastases from invasive car-
mis, keratin pearl formation and exten- 69% of AK were aneuploid in one image cinomas arising in AK are infrequent if
sion of atypical squamous cells into the analysis DNA-cytometry study {241}. the lip is excluded, occurring in 0.5-3%
reticular dermis are helpful {1158,2476} Recurrent chromosomal changes are of such carcinomas {1459,1630}.
numerical (+7,+20) and structural,
Immunoprofile involving the distal long arm of chromo-
Keratin and involucrin distribution is sim- some 4,1p31,3p13 and the centromeric Arsenical keratosis
ilar to normal epidermis {1093} whilst region of chromosome 3 {1143}.
CD95 (Fas) is lost in two thirds of AK Definition
{741} and retinoid receptors are reduced Prognosis and predictive factors Arsenical keratosis is a precancerous
{2554}. Expression of E-cadherin/catenin Untreated AK have been reported to lesion occurring in patients exposed
and TP53 increases in the progression to develop into invasive SCC in 8-20% of (therapeutic, environmental or occupa-
invasive SCC {1770,2170}. patients {838}. AK’s are also risk markers tional) to arsenic {2109}. This is a clinico-
for basal cell carcinoma and melanoma pathological diagnosis. Arsenic is con-
Genetics {2023}. Individual AK’s can however be centrated in a variety of tissues, includ-
There is a 2-fold risk of AK in an stable for many years, and may regress ing skin, hair, and nails {49,421,2007,
Australian Caucasian population carry- after sun protection. One estimate has 2109}.
ing the glutathione-S-transferase null suggested a rate of malignant transfor-
genotype {386}, further increased by fair mation less than 0.1% yearly {1516, Epidemiology
skin and an inability to tan. 1517}. Older patients with multiple Lesions may occur after a latent period of
Around 50% of AK’s show TP53 muta- lesions followed over 10 years demon- 2 years, but usually take 20-30 years to
tions {1696,2602} and over-expression of strate a lifetime risk of progression manifest {2568}. A study of 262 exposed
cyclin D1 {2235} whilst independent acti- between 6-10% {641} whilst 14% of individuals revealed characteristic ker-
vation of HRAS is identified in 16% patients with >10 AK’s develop invasive atoses of the palms and soles in over
{2235,2307}. SCC within 5 years {1639}. Sixty percent 40% {49}. Other skin lesions include
The majority of TP53 mutations involve of invasive SCC’s have been proposed to melanosis, Bowen disease, squamous
single cytosine to thymine substitution develop from AK’s and, more recently, cell and basal cell carcinoma {421,2007,
{1396,1696,2307}. Progression of AK into contiguous AK has been identified in 2109}. Visceral cancers, particularly
invasive SCC may involve deletion of the 82.4-97% of SCC {1085,1517,1627}. involving the lung, and genitourinary
9p21 region of the p16 (CDKN2A) Clinically hypertrophic lesions reveal tract can also occur {49,421,2007,2109}.
tumour suppressor gene {1653}. invasive SCC in 36% {2290}. There is a high arsenic content in some
Loss of heterozygosity (LOH) at four or Some classify AK as a type of SCC drinking waters and naturopathic medi-
more loci has been demonstrated in {791,994,1442} rather than a precursor. It cines {1823,2007,2109}.
>50% of AK’s in a UK Caucasian popula- cannot however be proven that AK
tion {1913} and in just under 20% of inescapably progresses to invasive SCC. Clinical features
lesions in a Japanese group {1350}. PCR The hypothesis that AK requires further Arsenical keratoses begin as yellowish
microsatellite analysis has exposed loss genetic aberrations before the expres- verrucous papules, 4-10 mm in diameter.
on 17p(64%), 13q(52%), 17q(46%), sion of clinical malignancy, is plausible These typically occur on thenar emi-
9p(39%), 3p(31%) and 9q(22%) {1914}. {1810}. nences, lateral borders of palms, base or
The higher rate of LOH in AK than inva- Immune responses and adjacent normal lateral surfaces of fingers, soles, heels
sive SCC could reflect the low progres- keratinocytes modulate the behaviour of and toes {49}. A combination of mela-
A B
Fig. 1.27 Arsenical keratosis. A Arsenical keratosis with vacuolation of the keratinocytes. B Arsenical keratosis showing acanthotic epidermis, some vacuolation
of the keratinocytes and dysplasia.
32 Keratinocytic tumours
A B
Fig. 1.28 Arsenical keratosis. A .Arsenical keratosis with full thickness dysplasia, resembling Bowen disease. B Hyperkeratotic type.
nosis and multiple keratoses in non-sun- PUVA keratosis high doses of UVA to epidermal ker-
exposed areas in adults is highly sug- atinocytes. PUVA is used in the treatment
gestive of chronic arsenic exposure Definition of patients with psoriasis and other disor-
{2007}. PUVA keratosis is a form of keratosis that ders.
arises in response to PUVA therapy. Patients treated with long-term PUVA
Histopathology therapy are at increased risk for develop-
A spectrum of histological appearances Epidemiology ment of actinic keratoses and squamous
exists {49,421,2007,2109}. Lesions may There are no detailed studies on the true cell carcinoma.
show compact hyperkeratosis, acantho- frequency of actinic keratoses attributa-
sis, papillomatosis, hypertrophic actinic ble solely to PUVA, but estimates have Clinical features
keratosis-like lesions and a pattern varied from 2-5% {11,1057}. There are PUVA keratoses resemble actinic ker-
resembling seborrhoeic keratosis {2007, long term epidemiological data indicat- atoses. They occur on PUVA-treated
2109,2568}. Vacuolated cells in the ing increased risk of squamous cell car- skin.
Malpighian layer suggest arsenical ker- cinoma in patients on high dose PUVA,
atosis, but this is not a reliable criterion. recorded as 300 treatments or more Histopathology
Arsenical keratoses may spare adnexae, {2265}. More recently, phototherapy PUVA keratoses are said to have less
similar to solar-related keratoses {2109}. using a narrow band of ultra-violet radia- keratinocytic atypia than sunlight-
Bowenoid arsenical keratoses may dis- tion in the UVB range has been used with induced actinic keratoses {2417}.
play vacuolated, dyskeratotic cells with increasing frequency, substituting for
abnormal mitoses and multinucleated PUVA therapy in a substantial proportion
giant cells {1823}. Arsenical-induced of patients {2264}. There are no long-
pigmentation comprises melanosis and term data published as yet on the risk of
dermal arsenic deposition {49}. actinic keratoses and squamous cell car-
cinoma in patients receiving narrow band
Histogenesis UVB phototherapy.
The exact nature of arsenical carcino-
genesis is unclear. Etiology
Arsenic and its metabolites are shown to PUVA is a photochemotherapy using
cause chromosomal abnormalities and either an oral or topical psoralen product
gene amplification {421,1823,2109}. in association with long-wave ultraviolet
Human papillomavirus may be a co-fac- radiation (UVA) {374}. This treatment is
tor in the pathogenesis {820}. locally immunosuppressive, and delivers
Actinic keratosis 33
Verrucas J.N. Breuer-McHam
M. Tommasino
C.A. Harwood
D. Weedon
M. Martinka
C. Gross
34 Keratinocytic tumours
the enzymes required for transcription or filamentous network by viral E4 proteins. Localization
replication of viral DNA and therefore is Host immune response {2246,2608}: Warts can occur on any skin or mucosal
entirely dependent on subverting cellular Persistent papillomavirus infections are surface. Certain HPV subtypes cause
proteins for these functions. In particular, common, indicating that HPVs have specific kinds of warts and show special
in HPV types 16 and 18, proteins E6 and evolved mechanisms to evade immune affinity for particular body locations.
E7 promote continued cell cycling of surveillance. There is no viraemic phase, Subtypes causing common warts are
suprabasal epidermal cells by abroga- low levels of viral proteins are expressed found on the hands, fingers, and palms.
tion of the functions of TP53 and pRb in the basal cell layer, and extensive viri- Periungual subtypes are often seen in
respectively. HPV genomes are thereby on production only occurs in the more nail biters. Verruca plantaris is seen on
amplified to high levels during vegetative immunologically privileged terminally dif- the sole of the feet. Condylomata acumi-
viral replication for assembly into infec- ferentiated layers. However, a successful nata lesions (genital HPV infection)
tious virions after encapsulation by L1 immune response is eventually generat- appear on the vulva, cervix, perineum,
and L2 proteins in the granular layer and ed in most cases, since two thirds of anus, or penis. Scrotal condylomata are
above. Virus assembly does not lyse ker- cutaneous warts regress spontaneously very rare and only seen in 1% of HIV pos-
atinocytes, but rather the infectious virus within 2 years and multifocal lesions itive males.
is shed with desquamating cornified often regress concomitantly. Cell mediat-
cells, and viral release is facilitated by ed immune responses appear to be pri-
disruption of the keratinocyte intracellular marily responsible.
Table 1.02
Correlation between cytopathological changes of verrucas and causal HPV types
Verruca vulgaris
2 Prominent Eccentric nucleus; condensed heterogeneous
keratohyaline granules (granular)
Palmo-plantar
1 (Myrmecia) Prominent, endophytic Vacuolated cells with large, eosinophilic keratohyaline
granules forming ring-like and sickle-like figures. Basophilic
nuclear inclusions (spinous, granular)
60 (Ridged wart) Acanthosis and mild Eosinophilic, homogeneous and solitary inclusions
papillomatosis; endophytic
65 (Pigmented plantar wart) Prominent; endophytic Eosinophilic, homogeneous and solitary inclusions
Verruca Plana 3 Subtle; no parakeratosis Central, pyknotic, strongly basophilic ‘bird’s eyes’ nuclei
and basket-weave like (upper spinous and granular)
appearance of stratum corneum
Epidermodysplasia 5 Nests of large, clear cells; Basophilic cytoplasm containing keratohyaline granules of
verruciformis stratum corneum loose with various shapes and sizes; clear nucleoplasm (upper
basket-weave like appearance spinous and granular)
Condyloma acuminata 6,11 Marked acanthosis, some Less prominent vacuolisation of granular cells
papillomatosis and hyperkeratosis
Verrucas 35
Clinical features and correlation with clinical infections are more common than HPV-4 and HPV-7. In children, HPV-6
viral genotyping visible warts {1282}. Genital warts are and/or HPV-11 are rarely found. Other
Cutaneous and mucosal HPV types form generally caused by low-risk mucosal HPV types have rarely been implicated,
two distinct groups that infect skin or HPV types rather than the high-risk types usually in immunosuppressed individuals
mucosa, although viral tropism is not associated with anogenital neoplasia {106}.
absolute {605}. Clinical manifestations {605}. Bowenoid papulosis (section
depend on the HPV type involved, the 1.5.01) may clinically resemble genital Localization
anatomical location and the immune sta- warts, but histologically resembles squa- Common warts may be solitary or multi-
tus of the host {1282}. mous cell carcinoma in situ and contains ple, and they are usually found on
Cutaneous infections: In general, classifi- high-risk HPV types. Giant condyloma exposed parts, particularly the fingers
cation of warts is based on morphology acuminata (Buschke-Lowenstein tumour) and on the dorsum of the hands.
and anatomic localization and cutaneous may also resemble genital warts but is an
warts have traditionally been classified anogenital verrucous carcinoma har- Clinical features
as verruca vulgaris or common warts, bouring low -risk HPV types {2476}. Oral They are hard, rough-surfaced papules
palmoplantar warts, including superficial warts are also associated with HPV types that range in diameter from about
and deep types, verruca plana or plane 6 and 11 and focal epithelial hyperplasia 0.2:1.5-2.0 cm. New warts may some-
warts and epidermodysplasia verruci- (Heck’s disease) resembling gingival, times form at sites of trauma (Koebner
formis (EV). Recent studies suggest that buccal and labial flat warts or condylo- phenomenon).
histological and clinical characteristics of mata usually harbours HPV 13 or 32
warts are mainly determined by viral {2476}. Histopathology
genotype, indicating that HPV typing Common warts show marked hyperker-
may allow a more accurate classification. atosis and acanthosis. There are out-
However, the use of highly sensitive PCR Verruca vulgaris growths of epidermis presenting as slen-
techniques for HPV detection and geno- der spires in filiform warts or blunter dig-
typing has highlighted the presence of a Definition itate processes in other variants.
greater diversity of HPV types than was Verruca vulgaris is a benign, squamous Columns of parakeratosis overlie the
previously appreciated {975}. These indi- papillomatous lesion caused by infection papillomatous projections. There may be
viduals often harbour multiple HPV types, with the human papilloma virus (HPV). haemorrhage into these columns.
particularly epidermodysplasia-verruci- Hypergranulosis is present where the
formis (EV)-HPV types. These HPVs were Synonym cells contain coarse clumps of kerato-
previously thought to occur only in the Common wart. hyaline granules. Koilocytes (large vac-
context of the rare genodermatosis EV, uolated cells with small pyknotic nuclei)
characterised by infection with unusual, Epidemiology are present in the upper malpighian layer
widespread, cutaneous warts and asso- Verruca vulgaris occurs predominantly in and the granular layer. Small amounts of
ciated with increased risk of non- children and adolescents, although keratohyalin may be present in the cyto-
melanoma skin cancers harbouring EV- adults are also frequently infected. They plasm of these cells. There is often some
HPV types on ultraviolet radiation have been found in up to 20% of school inward turning of the elongated rete
exposed sites {1492}. There is also students {1262}. Clinically detectable ridges at the edges of the lesion.
mounting evidence that EV-HPV types verrucae develop from a few weeks to 18 Tricholemmal differentiation and squa-
play a cofactor role with UVR in NMSCs months after inoculation {1691}. mous eddies may be seen in old warts.
arising in immunosuppressed individuals Dilated vessels are often found in the
{974}. Etiology core of the papillomatous projections. A
Mucosal infections: Over 25 HPV types Common warts are preferentially associ- variable lymphocytic infiltrate is some-
are recognized to infect anogenital and ated with HPV-2, but they may also be times seen, and this may be lichenoid in
aerodigestive mucosa {605}, and sub- caused by other types such as HPV-1, presumptive regressing lesions.
Fig. 1.29 Verruca vulgaris showing the Koebner Fig. 1.30 Verruca vulgaris. There is hyperkeratosis,
phenomenon. Note the linear arrangement of the papillomatosis and interning of the elongated rete
lesions as a consequence of scratching. ridges.
36 Keratinocytic tumours
A B
Fig. 1.31 Verruca plantaris. A, B Plantar wart. Note papillomatosis, acanthosis, hyperkeratosis, viral cytopathic changes.
Fig. 1.32 Verruca plantaris on the volar surface of Fig. 1.33 Plantar wart (myrmecia type). Nuclei are Fig. 1.35 Multiple flat warts on the chin of a young
the toe. Clinically, the lesion was painful. retained in the stratum corneum as basophillic female.
round bodies surrounded by a clear halo.
Verrucas 37
Fig. 1.36 Flat wart in a patient with epidermodys- Fig. 1.37 Flat wart. There are superficial vacuolated keratinocytes with perinuclear clearing.
plasia.
Deep plantar wart (myrmecia) - HPV1, suppression are possible predisposing cytosis, vacuolated keratinocytes with
HPV63 {505,2390}. factors {778,909,2262}. perinuclear clearing around centrally
Common and mosaic wart - HPV2, HPV4 located nuclei (so-called “birds-eye
{1055} Localization cells”) and hypergranulosis.
Endophytic common wart - HPV4 {1055} Most lesions are located on the back of Flat wart-like lesions can be encountered
Ridged and flat warts (associated with or the hands and fingers, distal forearm, in patients with epidermodysplasia verru-
without cyst, respectively) - HPV60 {505, lower leg and face. ciformis. These lesions may show typical
1055,1214,2390} blue-grey cytoplasm {907,909,1491}.
Large plantar wart - HPV66 {1556} Clinical features Regression of plane warts is accompa-
Flat warts generally are smaller than nied by superficial lymphocytic infiltrate
common warts and typically develop as in the dermis with exocytosis and single
Verruca plana small round to oval epidermal papules epidermal cell apoptosis {2476}.
measuring 1-4 mm in diameter. Lesions
Definition are mostly skin-coloured with a smooth Prognosis and predictive factors
Verruca plana are benign, HPV-induced, and flat surface, but may be hyperpig- Flat warts commonly persist for several
slightly elevated, flat-topped, smooth mented. The number ranges from one to years. Due to immunologic rejection in
papules. several hundred and the distribution is some long-standing cases, lesions have
asymmetric, sometimes linear (Koebner disappeared almost from one day to the
Synonyms phenomenon). next showing some local inflammation
Flat wart, verruca plana juvenilis. without leaving a scar. There are no
Histopathology reports regarding recurrences in such
Epidemiology Histology reveals a loose hyperkeratosis cases. In other cases warts lose evi-
Verruca plana are relatively common. with basket-weave-pattern but little or no dence of viral cytopathic change and
Children, adolescents and young adults papillomatosis as in verruca vulgaris. persist as localized verrucous epidermal
are most frequently affected. There is plate-like epidermal hyperplasia hyperplasia {909}.
of about twice the thickness of the sur-
Etiology rounding normal epidermis with com-
HPV types 3 and 10 are most commonly pressed papillae but dilatation and tortu-
associated with verruca plana. Minor osity of capillaries in the papillary dermis.
trauma, atopic dermatitis and immuno- Superficial epidermal layers show koilo-
38 Keratinocytic tumours
Acanthomas D. Weedon
E. Haneke
R.M. Williamson
G.F. Kao
M. Martinka R.E. Wilentz
G.W. Elgart M. Morgan
R.J. Mortimore S. Chimenti
C. Gross L.L. Yu
Epidemiology
Warty dyskeratoma occurs mostly in mid-
dle aged to elderly adults {1166}.
Etiology
There are no known etiological factors. A
recent study showed no evidence of HPV
in 13 cases using PCR {1166}.
Localization
The head and neck region is most com-
monly involved {873,1166,2306,2321}.
Cases arising in oral {869} and laryngeal
{1185} mucosa and in a subungual {147}
location have been reported. It has been
suggested that lesions arising in sites
devoid of hair follicles maybe a separate
entity {1166}.
Fig. 1.38 Epidermolytic acanthoma. This lesion shows hypergranulosis and marked cytoplasmic vacuoliza- Clinical features
tion with clumps of eosinophilic material, sparing the basal layer. Most lesions are solitary flesh coloured to
Acanthomas 39
brown papules, nodules or cysts with an blance to that seen in several vesiculob- Lentigo simplex
umbilicated or pore-like centre or central ullous disorders {320,1566,1885,2476}.
keratin plug {873,1166}. Most are 1- Definition
10mm in size {873}. Occasionally the Epidemiology Lentigo simplex is characterized by a
lesions are multiple {121,2306}. In the 31 cases reported by Brownstein clinically flat epidermis with microscopic
{320}, the patients ranged in age from acanthosis and highly localized well-cir-
Histopathology 32-87 years. The median age was 60 cumscribed pigment on sun exposed
Warty dyskeratoma is a well-demarcated years; the male to female ratio was 2:1. skin.
endophytic lesion characterized by
prominent acantholytic dyskeratosis. Etiology Synonyms
This results in suprabasal clefting with Although it is known that immunosup- Solar lentigo, actinic lentigo, “ink spot”
formation of villi which protrude into a pression increases the incidence of cuta- lentigo and lichen planus like keratosis.
lacuna. There is typically abundant ker- neous neoplasms, the role of impaired
atin present within the centre of the pro- immune surveillance resulting in acan- Epidemiology
liferation forming a plug {829,873,1166, tholytic acanthoma is speculative {1885}. Lentigines are common pigmented
2306}. Keratin pearls are commonly seen lesions most frequently seen on the sun-
as are small cysts lined by infundibular Localization exposed skin of light skinned individuals.
type epithelium {1166}. Mitotic figures Truncal skin, i.e., back, chest, or flank, is
are commonly identified and may most commonly involved, followed by Localization
exceed 5 per HPF {1166}. extremities, neck, groin, axilla, ear, scro- These lesions occur essentially only on
Three architectural variants have been tum and shoulder. skin or mucosa and spare the palms and
described namely cup-shaped, cystic soles. There is relative sparing of sun-
and nodular and combinations of these Clinical features protected areas, but some lesions may
may occur {1166}. There may be an epi- Acantholytic acanthoma is a solitary, ker- occur in these sites.
dermal collarette present and the sur- atotic, asymptomatic to occasionally pru-
rounding epidermis may show papillo- ritic papule or nodule. Multiple lesions Clinical features
matosis, hypergranulosis and hyperpla- have been recorded in a renal transplant Lentigines are well-circumscribed mainly
sia {1166}. A connection to folliculoseba- patient {1885}. flat (macular) localized collections of pig-
ceous structures is commonly demon- ment. The lesions are common and are
strable {873,1166}. Macroscopy ubiquitous in light skinned individuals.
The stroma often shows a characteristic The scaly, flesh-coloured, hyperkeratotic Most are somewhat randomly distributed
appearance with dense collagen or growths range in size from 0.5-1.2 cm. on sun-exposed skin. The presence of
fibroblasts and focal intrastromal clefts. many lesions may raise the consideration
There may be an associated mixed Histopathology of a syndrome, particularly when there is
inflammatory cell infiltrate {873,1166, The tumour shows a well-defined area of extensive involvement of the lips. Peutz-
2321}. papillomatous epidermal hyperplasia. Jeghers syndrome is the presence of
There is hyperkeratosis with prominent numerous lentigines associated with mul-
Differential diagnosis acantholysis involving multiple levels of tiple hamartomatous gastrointestinal
Comedonal Darier disease shows identi- the epidermis. Suprabasal or subcorneal polyps {893}.
cal histological features and is differenti- clefts with some dyskeratotic cells (corps
ated on clinical grounds {623}. ronds and grains) and occasional villi are Macroscopy
Familial dyskeratotic comedones is a noted. The upper dermis contains a vari- Individual lesions may be smooth-
rare condition which tends to spare the able perivascular lymphohistiocytic and edged, but many have an irregular out-
scalp and face and shows less marked occasional eosinophilic infiltrate. line. Most appear entirely uniform in
acantholysis and dyskeratosis than warty colour and range from light tan to brown
dyskeratoma {941}. Differential diagnosis to black. While lesions may approach 1
Acantholytic acanthoma must be distin- cm in greatest dimension, nearly all clini-
Histogenesis guished from other acantholytic disor- cal lesions are 1-5 mm.
It has been recently suggested that this ders and from various acanthomas. In the large cell acanthoma variant, the
lesion is a follicular adnexal neoplasm Pemphigus, Grover disease, and Hailey- tumours are macroscopically very deeply
{1166}. Hailey disease are disorders with more pigmented and may simulate malignant
extensive clinical papulovesicular erup- melanoma in situ.
tions. Lichen planus like keratoses have a high-
Acantholytic acanthoma Epidermolytic acanthoma shows epider- ly variable appearance and may show
molytic hyperkeratosis, and no acanthol- pink, orange, or rust coloured hues. Most
Definition ysis is present. Clear cell acanthoma are minimally raised from the skin sur-
Acantholytic acanthoma is a rare benign contains numerous pale cells, with abun- face and have a paving stone outline that
epidermal tumour. The lesion displays a dant intracytoplasmic glycogen, which is is frequently polygonal rather than round-
striking characteristic microscopic fea- absent in acantholytic acanthoma. ed {677}.
ture of acantholysis that bears resem-
40 Keratinocytic tumours
Histopathology
All lentigines demonstrate a sharply cir-
cumscribed focus of epidermal hyper-
plasia. The tumours are strikingly
melanized, and many retain residual
melanin in the overlying stratum
corneum. This pigment occasionally sim-
ulates parakeratotic nuclei seen in der-
matitis, a feature referred to as “pigment-
ed parakeratosis”. Fig. 1.39 Pigmetned seborrhoeic keratosis. There are elongated interlocking retes consisting of a prolifera-
While clinically macular, the typical lesion tion of bland and pigmented basaloid and squamous cells with formation of pseudo horn cysts
of lentigo simplex demonstrates a specif-
ic form of epidermal hyperplasia charac-
terized by elongate rete ridges with
somewhat club shaped or bulbous ends.
This appearance is characteristic of
other settings of epidermal hyperme-
lanization, such as in melanocytic nevi.
However, it is so typical of lentigines that
in every circumstance where found, this
form of epidermal hyperplasia is referred
to as lentiginous epidermal hyperplasia.
In most circumstances where it is seen,
the underlying papillary dermis demon-
strates a variable amount of eosinophilic
collagen deposition (or fibrosis). This
may imply that the epidermal prolifera- Fig. 1.40 Pigmented reticulated seborrhoeic keratosis. There are slender elongated interlocking rete ridges
tion requires a scar like response in the with hyperpigmentation and no squamous cell atypia, accompanied by focal pseudo horn cyst.
underlying dermis. However, inflamma-
tion is an inconstant feature in these
lesions {277,1634}. but may relate to the marked accumula- Seborrhoeic keratosis
Because of the histologic similarity to the tion of melanin pigment {277,1033,1959}.
epidermis of melanocytic nevi, lentigines A final variant is the lichen planus like Definition
are defined partially by what is absent in keratosis. While some authors maintain Seborrhoeic keratoses are benign hyper-
the tumours: namely nevomelanocytic that a variety of lesions may develop into plastic tumours of epidermis which are
nests. The presence of even rare nests is these lichenoid proliferations, most con- more common in older individuals.
sufficient to separate the diagnosis as cur that a large proportion begin as
lentiginous junctional nevus (or “jenti- lentigines. Several lines of evidence Synonyms
go”). point to this origin and have been Seborrhoeic wart, senile wart, stucco
Thus, to make a diagnosis of lentigo the reviewed. Histologically, these lesions keratosis, melanoacanthoma.
requisite features are: localized lentigi- often suggest a solitary lesion of lichen
nous epidermal hyperplasia, marked epi- planus as they were initially described. Epidemiology
dermal hypermelanosis, and the lack of Most demonstrate hypergranulosis and a Seborrhoeic keratoses are the most com-
nevomelanocytic nests. In fact, despite band like superficial infiltrate but unlike mon of the cutaneous neoplasms and
the remarkable melanization of the routine lichen planus they may show occur in the majority of elderly Caucasian
tumour, increased numbers of melano- overlying parakeratosis or an inflamma- patients. These lesions are by no means
cytes are not found in lentigines. tory infiltrate which contains a mixture of limited to Caucasians, but are present in
Two clinical variants are known: large cell inflammatory cell types with some neu- numerous older individuals of any race.
acanthoma and lichen planus like kerato- trophils or eosinophils. Careful evaluation The lesions are unusual in children and
sis. In large cell acanthoma, the pres- of most lesions demonstrates some even young adults are rarely affected.
ence of a localized proliferation of larger- residual lentigo simplex and pigment Identical histological features are seen in
than-normal keratinocytes with marked within dermal melanophages {1373}. certain epidermal naevi.
melanization is seen. These lesions are There is no appreciable sex predilection.
strikingly dark and are often clinically Differential diagnosis In part due to the very widespread inci-
highly suspicious for malignant mela- The separation between seborrhoeic ker- dence of the lesion, most cases are spo-
noma. atosis and lentigo is somewhat arbitrary, radic although several syndromes are
The other characteristic histologic fea- but most authors describe the epidermis associated with seborrhoeic keratosis.
ture of this variant is the larger than nor- as flat in lentigo simplex while the skin Recent studies support the long held
mal appearance of the keratinocytes. surface is clearly raised in seborrhoeic belief that seborrhoeic keratosis is a
The reason for this feature is unknown, keratosis. clonal process in the skin {1679}.
Acanthomas 41
A B
Fig. 1.41 Pigmented seborrhoeic keratosis. A and B There are elongated interlocking retes consisting of a proliferation of bland and pigmented basaloid and squa-
mous cells with formation of pseudo horn cysts
Clinical features trointestinal origin, but lymphomas and collections or nests of keratinocytes with-
Seborrhoeic keratoses are slightly leukaemias have also been reported. It in the thickened epidermis. These foci of
raised, tan to brown or black papules. should be emphasized that some enlarged keratinocytes arranged in cir-
Sun exposed skin is especially affected, authors dispute the syndrome entirely cular collections are suggestive of the
but lesions may be present on any site of and favour a coincidental association epidermal collections seen in some
the skin except for palms or soles. They due to the high frequency of seborrhoeic cases of in situ squamous carcinoma,
often have a “stuck on” appearance and keratoses in the elderly patients {955, but lack the cytological atypia inherent in
may be easily removed. Irritated lesions 2110}. malignant neoplasms.
often demonstrate a crust and prominent
hyperkeratosis which diminishes the visi- Histopathology Irritated seborrhoeic keratosis
bility of the epidermal pigment. Thus, Seborrhoeic keratoses are well-defined There is a heavy lichenoid inflammatory
many of these irritated seborrhoeic ker- proliferations of epidermal keratinocytes cell infiltrate in the upper dermis.
atoses are pink to red and quite scaly. which may be endophytic, exophytic or Apoptotic keratinocytes are usually quite
Many of these lesions appear more flat. There are seven major types of seb- numerous. Features of the hyperkeratotic
smooth-surfaced and are mistaken for orrhoeic keratosis: type (see below) may also be present.
basal cell carcinoma clinically. Sometimes there is a heavy inflammatory
While most seborrhoeic keratoses are Acanthotic (common) seborrhoeic cell infiltrate, including neutrophils, which
uniform in colour, speckled examples are keratosis may not have lichenoid features.
common. Pigmented seborrhoeic ker- The acanthotic type is composed of Squamous eddies are often present in
atoses may be mistaken clinically for broad columns or sheets of basaloid or the epidermis.
malignant melanoma. There is some cor- squamoid cells with intervening horn
relation between the many described cysts. There may be varying degrees of Hyperkeratotic seborrhoeic keratosis
histological variants of seborrhoeic ker- hyperkeratosis, papillomatosis and acan- This variant shows varying degrees of
atosis and the clinical appearance of the thosis. hyperkeratosis, papillomatosis and acan-
tumour. thosis. Some cases show inflammatory
Keratoses are generally very well circum- Reticulated seborrhoeic keratosis features similar to the irritated variant.
scribed clinically. Usual lesions are oval This common variant is often sampled
in configuration, but linear or unusually histologically because clinical examples Flat seborrhoeic keratosis
shaped lesions are common. are frequently deeply pigmented. They There is mild hyperkeratosis, often mild
Dermatosis papulosa nigra appears to form a net like or retiform pattern of acan- basal pigmentation (‘dirty feet’) and only
be a form of multiple seborrhoeic ker- thosis. minimal acanthosis. There are no horn
atoses of the face seen primarily in cysts. The cells contrast with those of the
patients of African descent. This condi- Pigmented seborrhoeic keratosis adjacent normal epidermis by being
tion is not known to be associated with Pimented seborrhoeic keratoses are in more compact.
any type of internal malady {658}. every way similar to usual seborrhoeic
keratoses, but in addition demonstrate Immunoprofile
Leser-Trélat syndrome pronounced epidermal melanin pigment. All studies confirm the presence of ker-
This syndrome is the rapid onset of mul- atins throughout the tumour. Some stud-
tiple pruritic seborrhoeic keratoses asso- Clonal seborrhoeic keratosis ies have also demonstrated the pres-
ciated with malignancy. The tumours Clonal seborrhoeic keratosis is an unusu- ence of carcinoembryonic antigen (CEA)
associated have primarily been of gas- al variant, which demonstrates whorled {314,319,665}.
42 Keratinocytic tumours
ally all layers of the lesion. The ker-
atinocytes are rich in melanin granules.
Definition
Clear cell acanthoma (CCA), is a benign
epidermal neoplasm characterized by
the presence of glycogen-rich clear/pale
cells.
Synonyms
Degos acanthoma, pale cell acanthoma.
Localization
It is usually located on the lower extremi-
ties of middle-aged or elderly individuals.
Other sites are the upper extremities,
head and neck, trunk, buttocks and gen-
ital area.
Clinical features
It usually occurs as a solitary, slowly
growing, dome-shaped papule, nodule
or plaque. The lesion has sharp margins,
Fig. 1.42 Melanoacanthoma. There are elongated interlocking rete ridges consisting of a proliferation of
bland basaloid and squamous cells with formation of pseudo horn cysts, intimately mixed with numerous sometimes with a keratotic scale, and a
melanocytes throughout the lesion. red or pink colour, giving the tumour a
vascular appearance. Clinical variants
include multiple, pigmented, giant, atyp-
Differential diagnosis melanocytes. It is considered to be a ical, cystic and polypoid CCA {345}.
Dowling Degos disease has lesions variant of seborrhoeic keratosis. The clinical differential diagnosis may
indistinguishable from seborrhoeic ker- Melanoacanthoma of the oral mucosa is include pyogenic granuloma, irritated
atosis except for their small size and the an unrelated disorder. seborrhoeic keratosis, squamous and
presence of a reticulated network of basal cell carcinoma, melanocytic nae-
adjacent lesions. Synonyms vus and nodular amelanotic melanoma.
The hyperkeratotic form may resemble a Melanoacanthosis, deeply pigmented
verruca vulgaris. Seborrhoeic keratoses seborrhoeic keratosis. Histopathology
lack parakeratotic columns overlying the There is a circumscribed, sharply demar-
digitate hyperkeratosis and there is no Epidemiology cated epidermal proliferation with psori-
haemorrhage, dialated capillaries, koilo- Most patients are adults beyond 40 years asiform elongation of plump and inter-
cytosis or inward turning of the acanthot- of age. Sex predominance is not known. connected rete ridges. The keratinocytes
ic downgrowths. There are no reliable frequency data. differ from those of the adjacent normal
epidermis by their pale/clear cytoplasm
Precursor lesions Localization containing a large amount of glycogen,
Some believe that the solar lentigo (lenti- Most melanoacanthomas are located on best demonstrated with a periodic acid-
go senilis) is a precursor lesion of reticu- the trunk. Schiff reaction. The keratinocytes of the
lated seborrhoeic keratosis. Others basal layer and the intraepidermal por-
regard it as an early form of this lesion. Clinical features tion of the adnexae are not involved.
Clinically, the lesion resembles a darkly Parakeratosis, infiltration of neutrophils,
Prognosis and predictive factors pigmented seborrhoeic keratosis. There which may form microabscess in the
In a small number of cases Bowen dis- are no characteristic symptoms. It may stratum corneum, and the absence of the
ease coexists with seborrhoeic keratosis. resemble a melanoma with der- granular layer are additional characteris-
matoscopy. tic findings. Dilated capillaries and a
scattered inflammatory infiltrate can be
Melanoacanthoma Histopathology observed in the papillary dermis. The
Melanoacanthoma has the same archi- presence of melanophages in the papil-
Definition tecture as common seborrhoeic ker- lary dermis and an increased number of
Melanoacanthoma of the skin is a benign atoses. However, they stand out by their melanocytes provide clues to the diag-
mixed proliferation of keratinocytes and abundant dendritic melanocytes in virtu- nosis of a pigmented CCA.
Acanthomas 43
Histogenesis
The histogenesis of CCA is not yet com-
pletely clear. Initially considered a
tumour of sweat gland or hair follicle ori-
gin, these sites were later excluded
because of the different cytokeratin
expression compared to CCA {1743}.
Some investigators hypothesized that
CCA is a benign epidermal tumour of
unknown etiology, probably caused by a
specific disturbance of keratinocyte dif-
ferentiation. The expression of involucrin
and epithelial membrane antigen further
suggest that CCA is derived from surface
epithelium. However, since CCA shows A
histopathologic findings and cytokeratin
expression similar to those observed in
psoriasis, others believe that it might rep-
resent an inflammatory disease rather
than a neoplastic process {742}.
Definition
Large cell acanthoma, a benign lesion, is B C
now considered to be a stage in the evo- Fig. 1.43 Clear cell acanthoma. A There are well circumscribed interlocking columns of pale to clear ker-
lution of a solar lentigo to a reticulated atinocytes with absent granular layer and no squamous cell atypia. B Note sharp demarcation between
seborrhoeic keratosis {1576,1959}. It normal epidermis (right) and tumour (left). C High power view of tumour cells showing pale cytoplasm due
was thought to represent a particular to glycogen accumulation.
type of actinic keratosis {1875,2095},
Bowen disease {2038}, or a distinct enti-
ty {69,1871,2039}. {2165}. Hypopigmentation is also seen keratoses show parakeratosis and
{69}. Dermatoscopy may rule out greater nuclear pleomorphism.
Epidemiology melanoma.
Most patients are middle-aged to elderly
persons. Sanchez Yus et al (1988) esti- Histopathology Keratoacanthoma
mated that approximately 1-2.5 LCAs are Large cell acanthoma is a sharply delim-
diagnosed per 1000 skin biopsies ited lesion standing out by its unique Definition
whereas Scholl (1982) saw only 4 cases large keratinocytes that have about dou- Keratoacanthoma is a squamoprolifera-
among > 1000 actinic keratoses and > ble the size both of their cytoplasm and tive tumour, mainly of hair-bearing skin.
3200 seborrhoeic keratoses. nuclei compared to normal ker- Although it has distinctive clinical and
atinocytes. Often, considerable numbers histological features, some regard it as a
Etiology of melanocytes are present. Three vari- variant of squamous cell carcinoma
Chronic sun exposure is the probable ants have been described: a basic pat- {190,1701}.
cause of LCA. tern with mild to moderate acanthosis, a
verrucous pattern with papillomatosis ICD-O code 8071/1
Localization and hyperkeratosis, and a flat-hyperker-
Most lesions tend to occur on the trunk atotic pattern {2039}. The granular layer Synonym
and extremities. is thick, there is usually orthohyperker- Well-differentiated squamous cell carci-
atosis and the rete ridges may be slight- noma (keratoacanthoma type).
Clinical features ly bulbous.
The lesion resembles a solar lentigo, flat The growth fraction is low {86,1576} Epidemiology
seborrhoeic keratosis or stucco kerato- although there is a considerable propor- Most cases develop in older persons,
sis. Most cases are lightly pigmented flat tion of both aneuploid and hyperdiploid particularly in the sixth and seventh
plaques or patches, usually less than 10 cells {86}. decades. There is a male preponder-
mm in diameter. Hyperkeratosis or even ance. Keratoacanthomas are more fre-
verrucous appearance has been Differential diagnosis quent in subtropical areas.
described. In Black patients, LCA may Flat seborrhoeic keratoses differ by the
present as darkly pigmented lesions smaller size of the constituent cells. Solar
44 Keratinocytic tumours
A B
Fig. 1.44 Large cell acanthoma. A There is abrupt transition between normal epidermis (left) and large cell acanthoma (right). There is hyperkeratosis, hypergran-
ulosis and markedly enlarged keratinocytes. B The tumour cells have enlarged nuclei without hyperchromasia and a low nuclear to cytoplasmic ratio.
Acanthomas 45
A B
Fig. 1.46 A A low power view of keratoacanthoma demonstrating a central crateriform lesion filled with a keratotic plug and flanked by epidermal buttresses and
consisting of tongues and lobules of squamous cells pushing into the deep dermis. B Regressed keratoacanthoma. The crateriform architecture remains but the
tumour cells are replaced by flattened epidermal keratinocytes, accompanied by dermal fibrous scarring, a lichenoid inflammatory infiltrate and focal foreign body
giant cell reaction to keratin in the dermis.
A B
Fig. 1.47 Keratoacanthoma. A The tumour cells have abundant pale eosinophilic cytoplasm and pleomorphic nuclei, accompanied by a dermal lymphocytic and
eosinophilic infiltrate. B Focal neutrophilic aggregates in tumour nests are characteristic of keratoacanthoma.
growth and a favourable outcome have The differential diagnosis from squamous Genetics
been recorded {842}. cell carcinoma may be difficult or impos- A genetic defect has been reported in
Regressing keratoacanthomas are shal- sible in superficial shave and punch patients with the Ferguson Smith type of
lower lesions with a large keratin plug biopsies. Features favouring keratoacan- “multiple self-healing epitheliomas” (ker-
and buttressing at the margins. There is thoma include the flask-like configuration atoacanthomas). The Muir Torre syn-
progressive dermal fibrosis and disap- with a central keratin plug, the pattern of drome, in which sebaceous tumours
pearance of tumour nests in the dermis. keratinization, the large central squa- develop in association with visceral
Foreign body giant cells may be present mous cells, the lack of anaplasia and a tumours, usually gastrointestinal can-
around residual keratin fragments. sharp outline between tumour nests and cers, and often with keratoacanthomas,
(PCNA / MIB-1 labelled proliferating cells the stroma {555,2477}. epidermal cysts and colonic polyps, is
are found in the periphery of the squa- inherited as an autosomal dominant trait.
mous nests in keratoacanthoma, in con- Histogenesis Mutations have been found in some
trast to a more diffuse pattern in squa- The great majority of keratoacanthomas cases in one of the DNA mismatch repair
mous cell carcinoma. Expression of TP53 develop on hair-bearing skin {474} and genes MLH1 and MSH2.
is found in both tumours. Subungual ker- are presumed to be derived from follicu- Prognosis and predictive factors
atoacanthomas have characteristic lar keratinocytes, perhaps with a pro- Most lesions regress spontaneously over
dyskeratotic cells, some showing dys- grammed life span. Those rare tumours several months {260}. This regression
trophic calcification, towards the centre that arise on glabrous skin and mucous may, in part, be immunologically mediat-
of the tumour nests. This variant has membranes presumably derive from ed {1782}. Even lesions with perineural
fewer neutrophils and eosinophils. epithelial keratinocytes. and intravenous invasion have a
46 Keratinocytic tumours
favourable outcome. Keratoacanthomas Epidemiology hyperkeratosis, frequently with parakera-
can recur in up to 8% of cases. This is LPLK is a relatively common lesion. Most totic foci. Actinic elastosis is often pres-
more likely with lesions on the fingers, patients are middle-aged to elderly. ent {785}. Features of solar lentigo, large
hands, lips and ears. Trauma may be There is a female predominance. cell acanthoma or early seborrhoeic ker-
responsible for recurrent lesions in some atosis may be present at the margins.
cases. Rare cases that have developed Etiology The inflammatory infiltrate often extends
metastasis have been reported {1038}. The cause of the lesion is not exactly around the superficial vascular plexus.
Possible explanations include misdiag- known. However, chronic sunlight expo-
nosis of the original lesion, the develop- sure appears to be an important factor. Differential diagnosis
ment of a supervening squamous cell Localization Lichenoid solar keratosis shows atypia of
carcinoma not recognized in the original Most LPLKs are located on the upper epidermal keratinocytes. In lichen
material, genuine ‘rogue’ variants or trunk and upper extremities. planus, the inflammatory cells do not
transformation of the initial lesion into a usually extend around the superficial
squamous cell carcinoma in immunosup- Clinical features vascular plexus. Furthermore paraker-
pressed patients {2476}. Clinically, LPLK presents as a flat, irregu- atosis, plasma cells and/or eosinophils
larly hyperkeratotic plaque with often may be present in LPLK. Similar changes
irregular borders. It may be irregularly may be seen in lichenoid drug eruptions.
Lichen planus-like keratosis pigmented or pale in colour. The lesion Clinical information may be required to
resembles a basal cell carcinoma, separate these entities.
Definition Bowen disease, actinic keratosis or flat
Lichen planus-like keratosis (LPLK) is a seborrhoeic keratosis. Itching and some
benign lesion of the skin that represents pain may occur {1373}. Dermatoscopy
the attempted immunologic regression of can rule out melanocytic lesions.
a solar lentigo, seborrhoeic keratosis,
large cell acanthoma or other epidermal Histopathology
proliferative lesion {1569,2150}. LPLK is characterized by a lichenoid
lymphocytic infiltrate leading to basal
Synonyms vacuolar change and numerous apoptot-
Benign lichenoid keratosis. ic cells. There is hypergranulosis and
Acanthomas 47
CHAPTER 2
Melanocytic Tumours
__________
1
Morphology code of the International Classification of Diseases for Oncology (ICD-O) {786} and the Systematized Nomenclature of Medicine (http://snomed.org).
Behaviour is coded /0 for benign tumours, /3 for malignant tumours, /2 for non-invasive tumours, and /1 for borderline or uncertain behaviour.
50 Melanocytic tumours
TNM classification of malignant melanoma
TNM classification 1,2 pT – Primary tumour (pathological classification)
pTX Primary tumour cannot be assessed*
T – Primary tumour pT0 No evidence of primary tumour
The extent of the tumour is classified after excision, see pT. pTis Melanoma in situ (Clark level I) (atypical melanocytic hyperplasia,
severe melanocytic dysplacia, not an invasive malignant lesion)
N – Regional lymph nodes
NX Regional lymph nodes cannot be assessed pT1: Tumour 1mm or less in thickness
N0 No regional lymph node metastasis pT1a: Clark level II or III, without ulceration
N1: Metastasis in one regional lymph node pT1b: Clark level IV or V, or with ulceration
N1a: only microscopic metastasis (clinically occult) pT2: Tumour more than 1mm but not more than 2mm in thickness
N1b: macroscopic metastasis (clinically apparent) pT2a: without ulceration
N2: Metastasis in two or three regional lymph nodes or intralymphatic pT2b: with ulceration
regional metastasis pT3: Tumour more than 2mm but not more than 4mm in thickness
N2a: only microscopic nodal metastasis pT3a: without ulceration
N2b: macroscopic nodal metastasis pT3b: with ulceration
N2c: satellite or in-transit metastasis without regional nodal pT4: Tumour more than 4mm in thickness
metastasis pT4a: without ulceration
N3: Metastasis in four or more regional lymph nodes, or matted pT4b: with ulceration
metastatic regional lymph nodes, or satellite or in-transit metasta
sis with metastasis in regional lymph node(s) Note: *pTX includes shave biopsies and regressed melanomas.
Note: Satellites are tumour nests or nodules (macro- or microscopic) within 2cm of Stage grouping3
the primary tumour. In-transit metastasis involves skin or subcutaneous tissue more Stage 0 pTis N0 M0
than 2 cm from the primary tumour but not beyond the regional lymph nodes. Stage I pT1 N0 M0
Stage IA pT1a N0 M0
M – Distant metastasis Stage IB pT1b N0 M0
MX Distant metastasis cannot be assessed pT2a N0 M0
M0 No distant metastasis Stage IIA pT2b N0 M0
M1 Distant metastasis pT3a N0 M0
M1a: Skin, subcutaneous tissue or lymph node(s) beyond the Stage IIB pT3b N0 M0
regional lymph nodes pT4a N0 M0
M1b: Lung Stage IIC pT4b N0 M0
M1c: Other sites, or any site with elevated serum lactic dehydro Stage III Any pT N1, N2, N3 M0
genase (LDH) Stage IIIA pT1a-4a N1a, 2a M0
Stage IIIB pT1a-4a N1b, 2b, 2c M0
pT1b-4b N1a, 2a, 2c M0
Stage IIIC pT1b-4b N1b, 2b M0
Any pT N3 M0
Stage IV Any T Any N M1
__________
1
UICC (2002). TNM classification of malignant tumours. Sixth edition. Wiley, New York
2
AJCC (2002). Cancer staging manual. Sixth edition. Springer, New York
A help desk for specific questions about the TNM classification is available at http://www.uicc.org (activities, TNM)
3
Clinical staging includes complete excision of the primary melanoma [pT] with clinical/radiological assessment for regional and distant metastases.
Pathologic staging includes complete excision of the primary melanoma [pT] and pathologic assessment of the regional lymph nodes [pN] after partial or
complete lymphadenectomy. Stage 0 or stage IA patients do not require pathological evaluation of their lymph nodes.
Incidence and mortality ing. Survival has improved substantially, melanoma is observed with relatively low
mainly in countries with high incidence mortality rates, due to the fact that
Approximately 79,000 males and 81,000 rates. This is mainly due to early detec- melanomas are diagnosed in early
females were diagnosed with melanoma tion of melanomas as a result of an stages {609}.
world-wide in 2002, of which about 80% increasing awareness of the disease,
occurred in the predominantly white pop- probably partly owing to the success of Migrant studies
ulations of Northern America, Australia, primary and secondary prevention cam- Groups of migrants from regions of low
New Zealand and Europe. On a global paigns. melanoma incidence to high incidence
scale, malignant melanoma was the 16th regions acquire higher rates of
and 15th most commonly diagnosed Geographical differences melanoma than in their home country, but
cancer in males and females respective- The levels of both melanoma incidence lower than those in the host country, in
ly and occurred most frequently in and mortality vary considerably world- both sexes {96,689}. Incidence and mor-
Australia and New Zealand (4th most wide. Rates are high in populations tality rates of native Australians and New
common males, 3rd in females), North- where Caucasians predominate, and Zealanders, who are largely of British ori-
America (6th in males, 5th in correspondingly low in countries where gin, are estimated to be roughly twice
females),and Europe (16th in males, 8th inhabitants are of mainly Asian or African those of recent British immigrants to
in females) {724}. origin. these countries {96,1255}. Likewise,
In 2002, around 22,000 males and native Israelis experience a twofold
19,000 females died of the disease Melanoma in Caucasians increased risk of incidence compared to
worldwide {724}. Melanoma is one of the As the most important environmental risk immigrants to Israel from Europe, a risk
most important cancers when consid- factor in Caucasians is exposure to ultra- that remains at least three decades fol-
ered as a cause of loss of life as it is com- violet radiation, incidence within white lowing immigration {2260}. The risk of
monly diagnosed in relatively young peo- populations generally increases with immigrants has been shown to approach
ple {54,310,350,1761}, and can be fatal if increasing proximity to the equator. The that of the native populations in both
untreated. It has been calculated that, in highest rates are observed in Australia, Australia and Israel with increasing dura-
the United States, a person dying of where many inhabitants are of Northern tion of residence in the host country {96,
melanoma would die, on average, some European descent and live in a climate 533,689,1255,2260}.
17 years before the age of 65, whereas in with substantially more sunshine than the Amongst Northern European migrants to
Denmark, the mean figure is put at 14-15 norm in Northern Europe. Australia, the incidence rates of
years, and in Belgium 6-8 years {54, In Western Europe, a diverging pattern is melanoma have been observed to
310,1761}. observed: incidence rates are higher in increase with duration of residence, but
Melanoma had a poor prognosis in the Northern Europe (more distant from the decrease with later age of arrival, sug-
1950’s and 1960’s, but from the mid equator) than in the South, reflecting a gesting that exposure at young ages is
1970s, mortality rates have been stabilis- combination of lighter skin type and high- important in determining risk {1255}. The
ing in many high-risk populations, er wealth in the North of Europe. In lowest risk in immigrants to Australia has
although incidence rates are still increas- wealthy populations, a high incidence of been found to be for Southern European
and Eastern Asian migrants, reflecting
the protective effect of a higher degree of
skin pigmentation {1255}. Differences in
skin colour are also assumed to be the
reason underlying the higher incidence
of melanoma in white immigrants to
Hawaii from the United States mainland
{1031}.
Melanoma in non-Caucasians
U.S. Whites have rates 15 times higher
than U.S. Blacks, and a similar contrast
in risk is observed in the White and Black
populations of South Africa and
Fig. 2.1 Age-specific incidence of cancer. All data are based on data from Europe 1990-1997. Zimbabwe {1780}. Melanoma is also rel-
Source: European Network of Cancer Registries. EUROCIM 4.0, Lyon 2001. atively uncommon among Asians {1295,
52 Melanocytic tumours
In the United States, Australia and
Northern Europe, where incidence rates
were very high during the 1980s, the
rates have been rising less sharply or
levelling off since the mid-1990’s, espe-
cially in younger age groups {516,609,
1137,1353,1472,2144,2244,2245}. In
contrast, in Southern and Eastern Europe
and in Latin America, rates are increas-
ing {7,609,1353,1579,2144}. Incidence
rates in Asia have been rather stable
{1142,1295}. There is insufficient data at
present to report on time trends in
melanoma incidence among African
populations. Over the last decades,
increases in incidence have mainly been
observed for thin melanomas, whereas
the rate of thick melanomas seems to be
relatively stable {618,1433}. This
increase in the number of thin mela-
nomas is mainly observed in countries
with high incidence rates, where increas-
es in rates are mainly seen in the super-
ficial spreading melanomas {414,
560,1052,1137,1472,1501}. In countries
with lower incidence rates, increases are
generally more evenly spread across
thickness categories.
Fig. 2.2 Age-standardized incidence rates for malignant melanoma of skin, per 100 000 population and year, Although trends in incidence rates of
adjusted to the world standard population. From D.M. Parkin et al. {1779}. melanoma vary greatly, mortality rates
show less variation. Mortality rates have
been levelling off in many populations
1746} and Middle- and South-American considered beautiful to have a light skin. with high melanoma incidence rates,
populations {891}, probably due to a bet- The avoidance of sun-exposure and such as Australia, the United States, and
ter protection afforded by a larger even more extreme measures, such as North-western Europe {516,609,827,
amount of pigment in the skin and possi- bleaching of the skin, have been report- 1353,1411,1412}. In some countries, a
bly different (‘wiser’) sun-exposure pat- ed {952,2081}. levelling off of incidence rates is now also
terns. Melanomas appear more often on observed, starting in younger age
the non-pigmented areas of the skin in Time trends groups {609}.
non-Caucasians {940}, are often of the Since the 1970’s there have been reports
acral lentiginous melanoma type and of alarming increases in melanoma, ini- Stabilisation of melanoma incidence
appear on the palms of hands, soles of tially in terms of mortality {1393} and then rates
the feet and under the nails {200,554}. A in incidence {1481}. These reports Age-period-cohort analyses indicate that
common problem in these populations is observed a doubling in rates every one in Western populations (USA, Australia,
that pigmented lesions in the skin are or two decades (mean annual incre- New Zealand, Sweden, the Netherlands,
often more difficult to notice, and are ments of between 3% and 7%) per Germany) the increasing mortality rates
therefore often detected at relatively late annum in populations of European origin have started to level off, starting in
stages, which, at least in part, explain the for both genders {1761}. The incidence cohorts born in the 1930s and 1940s
high case-fatality rates {200,554}. In rates increased markedly for intermittent- {534,827,1050,1136,1692,1983,2244,
many African and Asian societies it is ly exposed body sites (trunk, legs, etc.) 2352}. In Southern Europe, generally
whereas increases in the face and neck those with lower incidence rates (e.g.
were moderate. In males, the largest Italy and Spain) there has been no sign,
Table 2.01 increases were found on the trunk, and in as yet, of a downwards trend {1480,
Age-standardized incidence rates per 100 000 per-
females on the legs and arms {332,459, 1849,2144}.
son / year in the SEER registry (USA) {1781A}.
1007,1472,1482,1699,2120,2245,2350}. A recent plateau in melanoma mortality
Population Males Females In an analysis of the SEER data, it was rates (in some cases followed by inci-
found that melanomas of all stages dence rates) is reported in high-inci-
Blacks 1.00 0.5 increased from 1988-1997, but that local- dence countries, such as Australia, USA,
Whites 15.4 11.6 ized and in situ lesions increased the Sweden, Norway and Germany {609,
most {1137}. 1353,1761,2120,2245}. Only the mortali-
54 Melanocytic tumours
the popularity of sunbathing and tanning. increase the risk of melanoma develop- being frequently observed in young
Given an induction time of some 20-40 ment by increasing sunbathing-time. Of patients, and on body sites that are inter-
years between exposure and melanoma fifteen case-control studies examined by mittently exposed to sunlight.
occurrence, these factors are in accor- an expert panel, only 3 showed a signifi-
dance with the continuing increases - cantly reduced risk of melanoma, with Nodular melanoma
mainly on the trunk in men and on the relative risks between 0.2 and 0.6, the It usually presents as a rapidly growing
legs in women {331,332,619,620,682, others observing no significant effect (4 pigmented nodule (amelanotic nodular
772,2409}. studies) or an increased risk (8 studies, melanomas are rarely observed), which
RR between 1.7 and 3.5) {2400A}. The bleeds or ulcerates. This is the most
Ozone layer increasing use of sunscreens may there- aggressive type of melanoma. It often
Another explanation for the increases is fore have contributed to the increases in presents on body sites that are intermit-
the depletion of the ozone layer, which melanoma incidence. tently exposed to sunlight.
protects the earth’s surface against UVR
by filtering out a large part of the UVR Vaccination Acral lentiginous melanoma
from the sunlight before it reaches the Vaccination during childhood against These lesions are pigmented, arising on
earth’s surface. Chemical substances tuberculosis with the Bacille Calmette- the palm of the hand, sole of the foot or
released in the earth’s atmosphere are Guérin (BCG) vaccine or against small- under the nails. They often present late
slowly breaking down the ozone layer pox with the vaccinia vaccine, or having and represent the most common type of
{2199}, increasing the amount of UVR experienced one or more infectious dis- melanoma in heavily pigmented people.
that reaches the earth’s surface and like- eases may decrease the risk of develop-
ly increasing the risk of skin cancer. ing melanomas (odds ratios between Age distribution
Estimates indicate that skin cancer inci- 0.29 and 0.44) {1303,1330,1331,1821, Malignant melanoma (hence referred to
dence rates could increase dramatically 1822}. Part of the increases in melanoma as melanoma) is a tumour affecting pre-
by the end of this century compared to incidence could be due to the abolish- dominantly adults and elderly patients,
the situation around 2000 {1240}. ment of this type of vaccination in with a peak of incidence around the sixth
Europe. decade of life. In recent years, however,
Socio-economic status it has been increasingly recognized in
Melanoma is more common among peo- middle-aged and young adults, and can
ple with a higher socio-economic status, Clinical features be observed in children and adolescents
probably due to a higher excessive inter- as well. Thus, no age group is spared,
mittent exposure to UVR (outdoor sports, Sites of involvement and a high level of suspicion should be
winter sports, sunbathing, getting a tan) Most commonly affected site per unit sur- exerted in examination of any dubious
in this group. Increasing wealth over the face area of skin in both sexes is the face pigmented lesion regardless of the age
past 6 decades in large parts of the and male ear head and neck {772,890}, of the patient.
Western (i.e. predominantly Caucasian) with back and shoulders in men and the
populations may indirectly have contribu- lower limbs in females also having high Origin
ted to the increases in incidence rates of rates per unit area. The clinical features of melanoma are
melanoma and other skin cancers. variable and depend on type and stage
Major subtypes of evolution of the tumour, and on loca-
Most classification schemes of mela- tion of it. Melanoma may occur de novo,
Melanoma prevention noma categorize them clinically into four that is, without a precursor lesion, or may
major types, but such classification has develop within a pre-existing benign
Sunscreens little prognostic value and diagnostic rel- melanocytic naevus {1168,1750}. It has
An international group of experts con- evance, thus being of very limited useful- been estimated that 20-30% of
vening at the International Agency for ness in clinical practice. melanomas arise within a pre-existing
Research on Cancer investigated the melanocytic naevus, but this figure in
preventive effects of sunscreen use on Lentigo maligna melanoma. truth may be higher, as in many
the development of skin cancer: They This type of melanoma develops when instances it is very difficult to distinguish
concluded that the use of protective an invasive tumour arises in a lentigo histopathologically residual complexes
cream could indeed prevent erythema maligna. It is most common in the head of a benign naevus from those of the
and squamous cell carcinoma after non- and neck region and in elderly people, melanoma. All types of melanocytic
intentional sun-exposure (i.e., exposure and has a relatively favourable progno- naevi can give rise to a melanoma, but
to the sun without the objective of getting sis. some are more frequently involved, such
exposed, for example, work-related as congenital melanocytic naevi.
exposure). Its protective effect for basal Superficial spreading melanoma. Melanoma has only rarely been
cell carcinoma and melanoma, however, This type of melanoma grows laterally observed in association with Spitz naevi
is not yet determined, as it is difficult to before vertical invasion develops. {1380}, but this may be due also to the
study due to a long latency period. Increasingly, this is the most common difficulty in discerning histopathological-
Paradoxically, there is inconsistent evi- type of melanoma in Caucasians, and ly melanocytes of a melanoma from the
dence that the use of sunscreens may has a relatively favourable prognosis atypical melanocytes frequently found in
D E F
Fig. 2.4 Clinical presentation of melanomas. A Malignant melanoma arising in a congenital naevus. B Stereotypical cutaneous melanoma characterized by asym-
metry, uneven pigmentation, and irregular margins. C "Small" melanoma (< 3 mm) characterized by a relatively symmetrical, evenly pigmented small papule.
D Melanoma in situ. Note flat pigmented lesion with different hues of brown and slightly irregular margins. E Early "invasive" melanoma characterized by marked
asymmetry and variegations in colour. F A nodule of melanoma arising within an in situ component. Note the irregular pigmentation and asymmetry of the flat part
of the lesion.
Spitz naevi. Melanoma arising within a pathologically {282}. In addition, when lar growth from the outset without hori-
pre-existing blue naevus is commonly assessed with the ABCD rule many zontal spread, usually within a few
referred to as malignant blue naevus, an benign melanocytic naevi have atypical months (so-called nodular melanoma).
imprecise term that should be avoided. features, thus decreasing specificity of Finally, exceptional cases of dermal
Melanoma may arise at the site of pre- this diagnostic criteria, too. melanomas without any intraepidermal
existing scars (e.g., burn scar) {1758}. component have been recorded {2305}.
Recurrence at the site of a scar from pre- Pigmentation and growth
vious biopsy or narrow excision is a sign Most (practically all) de novo melanomas Regression
of incomplete excision of the primary are pigmented lesions that begin as a flat Partial regression of part of the lesion
tumour. Recurrence at the site of a com- macule, representing the neoplastic takes place commonly during the entire
plete excision (with negative margins growth of malignant melanocytes con- process of growth of melanoma, resulting
verified histologically) represents locally fined to the epidermis (melanoma in situ) in the presence of whitish-grey areas that
metastatic disease rather than persist- . Lesions in this stage are characterized accentuate the asymmetry and uneven
ence {1000}. by a relatively homogenous brown pig- pigmentation of the lesion. In rare cases,
mentation with slightly irregular borders. complete regression can be observed,
ABCD rule Over time (in most instances probably leading to the disappearance of all neo-
The most useful criteria for clinical diag- several years) lesions spread horizontal- plastic melanocytes. Usually, these
nosis of melanoma are asymmetry and ly showing more irregular contours and lesions show uneven pigmentation with
uneven pigmentation of the lesion, and variegations of the pigmentation, and whitish, grey and black areas correspon-
have been integrated in the acronym revealing histopathologically involvement ding to the presence of variable fibrosis
“ABCD” (Asymmetry, irregular Border, of the superficial (papillary) dermis. and infiltrates of melanophages in the
uneven Colour, Diameter > 6 mm) {1552}. When the papillary dermis is filled by dermis. With time, the pigmentation may
Although the “ABCD” mnemonic is con- neoplastic melanocytes the lesions disappear almost completely. Although
sidered the standard approach for the appear as irregular, unevenly pigmented regression is an immune-mediated phe-
clinical diagnosis of melanoma, it has plaques. In later stages the neoplasms nomenon corresponding to the elimina-
severe limitations when applied to early exhibit vertical growth resulting in the for- tion of malignant melanocytes by cyto-
lesions of it, that may have a relatively mation of papules or nodules, usually toxic lymphocytes, complete regression
homogenous pigmentation, sharp mar- confined to one area of the lesion. The of a melanoma can be associated with
gins, and small diameter. Melanomas papules and nodules represent areas metastatic spread, thus being a bad
less than 5 mm in diameter have been where the tumour grows vertically rather than a good prognostic sign. The
referred to as “small melanomas” in the through the dermis, eventually involving prognostic role (if any) of partial or focal
literature, and may be the source of diag- the subcutaneous tissues. In a minority of regression has not yet been elucidated,
nostic pitfalls both clinically and histo- cases, melanoma exhibits a rapid nodu- but it seems negligible {764}.
56 Melanocytic tumours
A B C
D E F
Fig. 2.5 Clinical presentation of melanomas. A Nodular melanoma. Large, darkly pigmented tumour practically devoid of a flat component. B Melanoma with promi-
nent regression resulting in almost complete disappearance of large part of the lesion. C Complete regression of melanoma. The grey pigmentation is due to the
presence of heavy infiltrates of melanophages within a fibrotic papillary dermis. The patient had regional lymph node metastases at presentation. D Ulcerated nodu-
lar melanoma resembling a granuloma pyogenicum. Note focally small areas of slight pigmentation at the margins. E So-called "lentigo maligna" (melanoma in situ
on sun-damaged skin) arising on the nose. F Acral melanoma. Note the marked irregularity of the margins, confering a "multifocal" appearance to the lesion.
Melanoma is more frequent in particular uneven pigmentation {670,1963}. atoses or common warts (verrucous
settings (so-called “markers”) including Differentiation of early lesions of mucosal melanoma) {101}. These cases may be
a familial history of melanoma, a previous melanoma from so-called melanosis (a misinterpreted clinically as pigmented
melanoma in the same patient, presence benign condition characterized by seborrhoeic keratoses or other verrucous
of many melanocytic naevi, presence of prominent hyperpigmentation of the tumours.
giant congenital naevi, skin type 1 or 2, mucosa without or with only slight
as well as in rare conditions such as increase of melanocytes at the dermo- Dermatoscopy
xeroderma pigmentosum among others epidermal junction) may be very difficult Besides clinical examination, der-
{53,901,1196,1202,2231,2481}. Patients or even impossible clinically as well as matoscopy (dermoscopy, skin surface
presenting with one or more of these fea- histopathologically. microscopy, epiluminescence micros-
tures should be monitored closely, and copy) has been increasingly regarded as
suspicious lesions should be biopsied. It Subungual melanomas a valuable aid in diagnosis of early
is important to remember that multiple In early stages these are sometimes melanoma clinically. Dermatoscopic
primary melanomas may be observed characterized by the presence of a well instruments enlarge the lesion 6-100-
rarely in some patients {1196}. demarcated, pigmented longitudinal fold, thus allowing detection of structures
streak (longitudinal melanonychia) {263}. and signs not visible to the naked eye. In
Clinical variants The so-called Hutchinson sign (periun- addition, connection of the dermato-
Amelanotic melanoma gual spread of the pigmentation on the scopic devices to a computer allows one
Although melanoma is a tumour charac- proximal or lateral nail fold) may be to take standardized digital pictures that
terized by variable degrees of pigmenta- absent in early lesions, thus representing can be compared over time, thus being
tion, in rare instances the pigment may a pitfall in the clinical diagnosis. much more sensitive for detection of min-
be missing altogether (so-called amelan- imal structural changes of the examined
otic melanoma). Amelanotic melanomas Ulceration lesion {719}. Finally, computer-assisted
are more frequent on the face, where Rapidly growing, ulcerated melanomas diagnostic systems based on dermato-
they often display the histopathologic may be misdiagnosed clinically as gran- scopic images are available as aids for
features of desmoplasia (desmoplastic uloma pyogenicum. Pigmentation in the evaluation of suspicious pigmented
melanoma), but can be observed also on these cases may be scant and confined lesions {91}.
other parts of the body {77,2285}. only to small areas of the tumour. Several dermatoscopic diagnostic
approaches have been proposed, all of
Mucosal melanoma Verrucous phenotype them relying on the examination of dis-
Melanomas arising within a mucosa (oral In rare cases, melanoma may present tinct patterns and structures. Of particu-
mucosa, genital mucosa) are often multi- with a verrucous surface similar to what lar value in the diagnosis of melanoma
focal, and are characterized by dark, can be observed in seborrhoeic ker- are the presence of an irregular pigment
58 Melanocytic tumours
clue to the diagnosis of melanoma.
Confluent single melanocytes replace
the basal layer in a manner such that, at
least focally, keratinocytes do not seem
to intervene between them. Confluence
of nests of melanocytes is a more sub-
jective determination.
especially variability in the widths of den- Contour amount of cytoplasm is less at the base
drites at the same level of the epidermis Dysplastic naevi have a flat base at the of a benign melanocytic neoplasm than
(anisodendrocytosis) are useful clues to interface between the papillary and retic- in its upper nests. If the cytoplasm of the
melanoma in these settings. ular dermis, Spitz naevi have flat or upper cells of a naevus is pigmented, its
The extreme cytologic atypia typically wedge shaped bases, superficial blue lower cells tend to be less pigmented or
seen in thick melanomas in the dermis naevi are wedge shaped, congenital and achromic. The sizes of aggregations of
and in metastases of melanoma, with congenital-like naevi have an uneven melanocytes also should be smaller
very large, irregularly shaped and bright- base, with melanocytes clustered around toward the bottom of a benign neoplasm
ly eosinophilic nucleoli is not usually to adnexa and sometimes around vessels, of melanocytes.
be found in the intraepidermal compo- and deep (often cellular) blue naevi have The scientific basis of maturation rests on
nent of a melanoma. a lobulated base, with blunt masses of changes in metabolism (less tyrosinase
cells that protrude into the subcutis . activity and more acetylcholinesterase
Architectural criteria in the dermis Melanomas that involve the dermis typi- activity) and telomeric exhaustion
The presence of the intraepidermal cally have uneven, sometimes jagged {865,1620}.
changes of melanoma is of course a clue bases. Maturation occurs to a limited extent in
that the dermal component of a some melanomas, but in most there are
melanocytic neoplasm might represent Maturation cells at the base of the lesion nearly as
melanoma as well. Again, architectural Maturation of melanocytes is in some large as those at the top, and dispersion
criteria are more important than cytolog- ways a misnomer- a mature melanocyte from large nests to small ones and single
ic ones, although the balance is more is dendritic, and synthesizes pigment cells is often absent {1989}. Pigmentation
even than in assessing the intraepider- within an epithelium. The process com- near the base of a melanocytic neoplasm
mal portion of a melanoma. monly referred to as maturation is really can also be a clue to melanoma, but it
senescence; it reflects a loss of metabol- commonly occurs in blue naevus.
Symmetry ic activity, reproductive capacity and in
The most important aspect of symmetry some cases a tendency to become fat- Mitotic activity
of the dermal component of a melanocyt- just as mammalian senescence does. Mitoses in the dermal portion of a lesion
ic neoplasm pertains to its outline, or sil- Maturation of melanocytes occurs in do not mandate a diagnosis of
houette. most naevi, with the exception of blue melanoma. As a rule, the mitotic figures
Other forms of symmetry pertain to what naevi (including deep penetrating naevi). in benign naevi are found in melanocytes
lies within the silhouette- the composition The best-known form of maturation is the within the papillary or superficial reticular
of the neoplasm. The sizes and shapes progressive diminution in the size of the dermis. If the lesion in question only
of nests, the pigmentation and cytologic nuclei of melanocytes at increasing extends to this depth, the number of
features of the melanocytes and infil- depth within a lesion. Nucleoli also dimin- mitoses becomes important, as does the
trates of lymphocytes and melano- ish in size, and if they are eosinophilic in question of whether the mitoses are in
phages ideally are the same on both the upper part of a lesion they tend to clusters (reflecting “hot spots”) or are
sides of the lesion, at the same level of become basophilic at its base. Nuclear atypical. Atypical (asymmetric, tripolar or
the dermis. A disproportionately large maturation in melanocytic lesions can be ring) mitotic figures can occur in Spitz
nest of cells with cytologic features that quantified by morphometric studies naevi, but are rare in other forms of nae-
contrast with those on the other side of {211,1398}. vus. Ki67 / MIB-1 marks cells that are
the lesion may be a clue to melanoma. In addition to nuclear maturation, the actively cycling, and the number of such
60 Melanocytic tumours
cells should diminish toward the bottom melanomas may migrate into the papil-
of a benign melanocytic neoplasm. The lary dermis. In the dermis, these cells
finding of a low proliferation rate is no may either undergo apoptosis and dis-
guarantee of benignancy. A high rate in a appear {1070}, or may survive without
lesion thought to be benign should trig- proliferating. In the latter case, the lesion-
ger reassessment. al cells may persist in the dermis, but
they do not expand to form a tumorigenic
Cytologic features of melanoma in the nodule.
dermis
The cells of a melanoma may be large or Vertical growth phase (tumorigenic)
small melanocytes, round or spindled, In the next phase of progression, a tumor
Fig. 2.9 Lymphoscintigraphy in a patient with a
amelanotic or deeply pigmented. nodule appears either within the confines melanoma on the central upper back.
Large spindled melanocytes comprise of a pre-existing plaque, or, sometimes, Top: summed 10-min dynamic images in posterior
the dermal component in some de novo in a lesion which is then termed and anterior projections after injection of tech-
melanomas. They often are not reliably “nodular melanoma” {675} cells. netium-99m antimony sulphide colloid intradermal-
demarcated from each other by clefts, as The key biological feature of vertical ly at melanoma site. Dominant lymphatic channels
is the case in Spitz naevi. They can form growth phase is the ability of the lesional pass laterally to both axillae and upwards to inter-
elongated, sometimes sinuous fascicles, cells to survive and proliferate in the der- val nodes on back. Delayed scans 2 h later show a
especially in melanomas with neuroid dif- mis. This ability may be manifested by single sentinel node in each axilla and three inter-
val nodes (also sentinel nodes in this patient) on
ferentiation and in desmoplastic melano- growth to form a true “tumour” or
upper back. From J.F. Thompson et al. {2348A},
mas. The spindled melanocytes of swelling, or by the presence of mitotic
with kind permission of The Lancet.
desmoplastic melanoma can also be activity. Tumorigenic vertical growth is
found singly between thickened collagen easily recognized when there is a bulky
bundles. They tend to be hyperchromat- nodule present. In thin lesions, such as 2088}. The reason why “dormant” metas-
ic, and have irregular nuclear mem- AJCC stage I melanomas, either of two tases begin to grow after such a long
branes and small nucleoli. criteria suffices for the diagnosis of verti- time is yet unknown.
Melanocytes with abundant pale cyto- cal growth phase, namely the presence In most patients with metastatic disease,
plasm and dusty melanin (large, pale of either “tumorigenicity” or “mitogenici- the regional lymph nodes are affected
melanocytes) are typically present in the ty”. The term "mitogenic" refers to the first, but distant metastases may be
dermis in some dysplastic naevi, naevi at presence of any mitotic figures in lesion- observed in patients who do not have
special sites (scalp, breast and genitalia) al cells in the dermis. The term “tumori- obvious lymph node involvement.
and in deep penetrating naevi. They are genic” is here defined as the presence of Besides lymph nodes, the most common
a common cytologic type in melanoma, a cluster of cells in the dermis larger than site of metastatic spread is the skin.
especially in the superficial spreading the largest intraepidermal cluster. Visceral metastases are more frequently
and nodular patterns. located in the lungs, liver, central nerv-
Small round melanocytes with scant ous system, and bones, but any organ
cytoplasm, resembling those of the Metastatic spread may be affected.
mature portion of a naevus can predomi- In 1992, sentinel node (SN) biopsy was
nate in naevoid melanomas Most distant metastases from melanoma proposed as a minimally invasive proce-
become evident clinically or are detect- dure that provided accurate assessment
Radial and vertical growth ed during follow-up visits within a few of regional node status in melanoma
Radial growth phase years from excision of the primary patients {1655}, allowing full regional
Most melanomas evolve through an initial tumour. However, it is important to node dissection to be avoided in the
stage of tumor progression, as a flat or remember that late metastases (> 10 80% of patients who had negative SNs.
plaque - like lesion which expands along years, sometimes even over 25 years The SN concept is simple: lymph drain-
the radii of an imperfect circle. Because after excision of the primary tumour) are ing from a tumour site passes first to a
of this clinical analogy, this phase has not uncommon in this neoplasm {566, so-called sentinel node before onward
been termed the “radial growth phase”
{494}.
Table 2.02
The radial growth phase may be in situ Melanoma antigens
(confined to the epidermis), or in situ and
invasive, but in the latter case the cells Type of antigen Antigen
do not have capacity for proliferation in
the dermis {674,832}. Proliferation in the Differentiation antigens Tyrosinase, gp100, Melan-A/MART-1, TRP-1,
TRP-2, MC1R, AIM-1
epidermis may give rise to a pattern of
Gangliosides GM3, GD3, GD2, GM2, 0-acteyl GD3
single cells, or of clusters or nests of
Mutated proteins CDK4, ß-catenin, CDC27, MUM-2,
atypical neoplastic melanocytes. Like the triosephosphate isomerase
cells of junctional nevi, which may Products of unusual DNA transcrips TRP-2, N-acteylglucosaminyl transferase
migrate into the dermis to form com- Cancer / testis antigens (CTAs) MAGE, BAGE, GAGE, RAGE, NY-ESO-1
pound nevi, the cells of in situ
62 Melanocytic tumours
also ectopic melanin synthesis in cells of markers for the other diagnostic options
other lineages. Differentiation markers are negative. Given the low specificity of
show a broad expression in many benign S-100 for melanocytic differentiation the
melanocytic lesions and (most) primary diagnosis has to be substantiated. For
melanomas. However, in melanoma this purpose MART-1 (syn. Melan-A) is a
metastases expression decreases which powerful marker both having a high sen-
is accompanied by heterogeneity. sitivity and specificity. Its sensitivity is
higher than gp100 (recognized by
Progression markers HMB45) in cutaneous melanoma and
These markers are preferentially metastasis, although in non-cutaneous
expressed in one or few stages in melanoma it may be the reverse.
melanocytic tumour progression. Based
on their tissue distribution, early, interme- Immunotherapy
diate and late progression markers are Vaccination trials have been started
discerned. Progression markers include using gp100 and tyrosinase presented
molecules that are involved in key by dendritic cells, and MAGE3. Patients
A B processes in the pathogenesis of metas- are selected on the basis of an appropri-
Fig. 2.11 Immunoreactivity for A gp100 and B tasis, i.e. proliferation, migration and ate HLA haplotype and extent of antigen
MART-1 of metastatic melanoma cells. Note the
matrix degradation. They may be derived expressed {611}. Expression of gp100
extranodal tumour embolus in A (arrow).
from the neoplastic cells and/or the stro- and tyrosinase is estimated on immuno-
mal cells, and serve as targets for vari- histochemically stained melanoma
Immunoprofile ous clinical interventions. slides; for MAGE3 RT-PCR is used.
64 Melanocytic tumours
lar invasion when present appears to be tumour thickness and ulceration. A list of
associated with a worse prognosis prognostic markers is presented in Table
{1213}. 2.5. It should be noted here that the clin-
ical relevance of these markers is
Radial growth phase regression increasing as the primary melanomas
Several studies have demonstrated currently diagnosed are relatively thin
worse prognosis when radial growth (1.0-1.5 mm) and rarely show ulceration.
phase regression is present {491}. It is expected that a set of prognostic
Possibly in these cases, a small area of markers may help to select melanoma
tumourigenic vertical growth phase was patients for adjuvant therapy. Such a set
present before the regression obliterated may be designed on the basis of the out-
it. come of ongoing expression array stud-
ies.
Microscopic satellites 2. Microstaging. The presence of
Like clinical satellites, microscopic satel- melanoma deposits in various stages of
lites are indicative of a lesion with com- the disease is assessed by the demon-
petence for metastasis and are associat- stration of differentiation markers.
ed with a worse prognosis {962}. However, they may decrease during
tumour progression and do not reveal the
Patient gender and lesional cell location aggressiveness of the tumour cells.
In most series, even when other prog- Nevertheless, the extension of the pri-
nostic factors are controlled, female mary tumour that includes thickness
patients have better survivals, and the measurement and identification of
survival is better for patients whose microsallelites, can be facilitated by S-
lesions are on the limbs compared to the 100 or MART-1 immunohistochemistry.
trunk or extremities {491}. This also is applicable for the detection
of melanoma cells in sentinel nodes.
Immunoprofiling for the assessment Immunohistochemistry on serial sections
of prognosis is preferred to molecular staging of sen-
Two strategies are followed: tinel nodes as it has a similar sensitivity,
1. Identification of markers suggestive of a higher specificity and it preserves mor-
aggressive subpopulations in primary phology.
melanoma {1990}. For this purpose late
progression markers are used. Only a
limited number of progression markers
have prognostic implication independent
of the conventional dominant factors, i.e.
Table 2.05
Prognostic markers in malignant melanoma
Ki67 ↑ _
PCNA ↑ _
Cyclin A ↑ _
p16 ↓ _
αvβ3 ↑ _
ICAM-1 ↑ _
CD44 ↑ +
MMP-2 ↑ _
t-PA ↑ +
gp100 ↓ _
Mitf ↑ +
c-kit ↓ _
c-myc ↑ _
p53 ↑ +
Osteonectin ↑ _
1
-: Unfavourable: +: favourable
A B
Fig. 2.13 Superficial spreading melanoma. A Low power magnification of the papular component. B Pagetoid spread of single melanocytes as is typically found in
many examples.
66 Melanocytic tumours
A B
Fig. 2.14 Superficial spreading melanoma. A Single cells and small nests are irregualrly arranged along the junction. Toward the centre a large melanocyte is pres-
ent in mid-spinous layer. A Langerhans cell is in nearly the same position toward the edge but is much smaller. B The invasive portion of the melanoma, showing
nuclear pleomorphism. At the base there is a lymphocytic infiltrate.
other and may merge. There is often a of the lesion. In both forms there is fibro- somal aberrations in SSM are losses of
lack of maturation, manifested by a fail- sis of the papillary dermis, vascular pro- chromosomes 9, 10, 6q, 8p and gains of
ure of nests, cells, nuclei or nucleoli to liferation and ectasia, and variably dense chromosomes 1q, 6p, 7, 8q and 20 {173}
become smaller towards the base of the infiltrates of lymphocytes and melano- Melanomas with increased copies of
lesion. Pigment is often irregularly distrib- phages. The epidermis may show loss of chromosome 7 that show mutations of B-
uted. Mitoses, sometimes atypical, are rete ridges. The type of regression raf selectively increase the copy number
often seen whereas necrotic melano- described above affects the radial of the mutated allele suggesting that the
cytes are rarely identified. A lymphocytic growth phase. Occasionally, a vertical mutation precedes the chromosomal
infiltrate may be present at the base of growth phase may undergo regression, aberration {1493} The minimal deleted
the neoplasm or may infiltrate among its and sometimes the regressed portion region on chromosome 9 includes the
cells (so called tumour infiltrating lym- may be replaced by a large mass of CDKN2A locus on 9p21 as can be seen
phocytes or TILS). Melanoma may melanophages, representing a phenom- by high-resolution comparative genomic
undergo regression, which clinically and enon called “tumoural melanosis”. hybridization (CGH) {876}
grossly most often involves a portion of
the lesion, or occasionally its entirety. Immunoprofile Prognosis and predictive factors
Histologically this regression may be There are no specific differences in the The prognosis of SSM does not differ sig-
complete or partial within a given area. immunophenotype of SSM and other nificantly from other forms of melanoma
Complete regression of a portion of a forms of melanoma. (see Introduction).
melanoma (“segmental regression”) is
manifested by absence of melanocytes Somatic genetics
in the affected area. In partial regression, SSM has a high incidence of mutations in
there is a strikingly diminished number of the BRAF oncogene on chromosome
melanocytes compared to the remainder 7q34 {1493}. The most common chromo-
A B
Fig. 2.15 Nodular melanoma. A On scanning magnification the tumour has a polypoid configuration with slight asymmetry. Cohesive nodules of tumour cells fill the
dermis. B Superficial portion of the tumour. Epithelioid melanoma cells are present as single units and in nests that vary in size and shape along the dermoepider-
mal junction and above it. Similar nests are present in the upper dermis along with numerous melanophages and lymphocytic infiltrates. Some of the epithelioid
melanoma cells contain fine melanin granules.
68 Melanocytic tumours
A B
Fig. 2.16 A Nodular melanoma with asymmetrical distribution of lesional cells, lymphoctic infiltrates and melanophages. B The tumour is composed of melanocytes
with large, pleomorphic, vesicular nuclei, some in mitosis.
High nuclear-to-cytoplasmic ratios are found in other tumours. Other frequent Prognosis and predictive factors
often noted. The tumour cells fail to findings are nuclear pseudoinclusions, In the T (tumour) category, tumour thick-
“mature” with progressive descent into prominent nucleoli and cytoplasmic inter- ness increased mitotic rate and ulcera-
the dermis. The cytoplasm of the epithe- mediate filaments corresponding mor- tion are the most powerful predictors of
lioid cells often has eosinophilic granular phologically to vimentin filaments. In a survival, and the level of invasion has a
qualities. It may contain melanin gran- minority of melanomas poorly developed significant impact only within the sub-
ules that vary in size, or appear fine and intercellular junctions may be present group of thin (≤1 mm) melanomas {131}.
“dusty”. There is absence of melanin in {1016}. Other adverse prognostic factors include
the amelanotic tumours. The surrounding increased tumour vascularity, vascular
stroma may demonstrate variable Precursor lesions and histogenesis invasion, microscopic satellites, male
mononuclear cell infiltrates, fibroplasia, It is more common for NM to begin de gender, increased age, and anatomic
telangiectasia, and melanophages novo than to arise in a pre-existing nae- location on the head, neck and trunk
{154,163}. vus {163}. One hypothesis holds that NM {122,1528,2597}. In the N (nodes) cate-
represents a final common pathway of gory the following three independent fac-
Immunoprofile very rapid tumour progression from a tors have been identified: the number of
S-100 protein, HMB-45, Melan A (MART- brief intraepidermal proliferative phase of metastatic nodes, whether nodal metas-
1), MAGE-1, NKI/C-3, tyrosinase, SSM, lentigo maligna, or acral lentigi- tases were clinically occult or clinically
melanoma cell adhesion molecule (Mel- nous MM {154,163}. apparent, and the presence or absence
CAM) MUC18 and microphthalmia tran- of primary tumour ulceration. In the M
scription factor (MITF), are expressed by Somatic genetics (metastases) category, nonvisceral
most melanomas {732,1500,1855}. Comparative genomic hybridization and metastases are associated with a better
Melanoma cells also express bcl-2 pro- mutation analyses have revealed marked survival compared with visceral metas-
tein, neuron specific enolase and differences between melanomas tases {131}.
vimentin {626,1861,2131}. Antigens depending on the anatomic site and sun-
which may demonstrate higher rates of exposure patterns {173,1493}. These
expression in melanoma cells than in studies did not find unique genetic fea-
naevus cells include Ki-67 (MIB-1), prolif- tures in nodular melanomas that justify
erating nuclear antigen (PCNA), p53, regarding them as a unique type, sup-
cyclin D1, and p21 WAF1(9). The loss of porting the ‘common pathway hypothesis
expression of CDKN2A (cyclin depen- {154,163}.
dant kinase inhibitor), and the increased
expression of ß3 integrin, have been Genetic susceptibility
associated with vertical growth phase The proportion of melanomas that have a
and more invasive forms of melanomas familial basis ranges from 6% to 14%.
{1029,1500,1904,2277,2278,2406}. Approximately 20% of all individuals with
a family history of melanoma have muta-
Electron microscopy tions in CDKN2A which maps to chromo-
The demonstration of stage II some 9p21. In a very few families CDK4
melanosomes is the hallmark of mapping to chromosome 12q14 has
melanoma diagnosis. They are rarely been found to be mutated {1851}.
Nodular melanoma 69
Lentigo maligna P. Heenan
A. Spatz
R. Cerio
B.C. Bastian
Definition described it as “senile freckle” in 1892 of melanoma in situ on the head and
Lentigo maligna (LM) is a form of {1090} and subsequently as “lentigo- neck and that patients with LM are less
melanoma in situ that occurs on the sun melanosis” {1089}. Dubreuilh {652} likely than patients with melanomas of
exposed skin of elderly people, mainly described these lesions as “mélanose the trunk to have more than 60 naevi
on the face but also, less often, at circonscrite précancereuse” which sub- whereas they had a stronger association
extrafacial sites including the neck, sequently came into common use as with the number of solar keratoses
upper back and forearm. It is character- melanosis circumscripta precancerosa {2508}.
ized histologically by linear and nested until the classification of Clark {492} in
proliferation of atypical melanocytes 1967 introduced the category of Pathogenesis
along the dermo-epidermal junction and melanoma commencing in lentigo According to some authorities, the term
down the walls of hair follicles and sweat maligna (Hutchinson’s melanotic freckle). LM encompasses a phase regarded as a
ducts. The melanocytic lesion is associ- That classification was widely but not uni- melanoma precursor in which there is
ated with severe actinic damage, mani- versally accepted; the World Health proliferation of melanocytes in severely
fested by epidermal atrophy and solar Organisation (WHO) classification of sun damaged skin in intermittent pattern
elastosis. When dermal invasion by atyp- 1974 classified superficial spreading without the confluent growth, pagetoid
ical melanocytes occurs in association melanoma and melanoma arising in spread and nesting of atypical melano-
with (LM), the term lentigo maligna Hutchinson melanotic freckle (lentigo cytes that, according to this concept,
melanoma (LMM) is used. maligna melanoma) in one category represent malignant melanoma in-situ of
{2337}. The World Health Organization LM type, whereas the lesions with less
ICD-O code 8742/2 (WHO) classification of 1996 separated severe, intermittent junctional prolifera-
melanoma in-situ into superficial spread- tion are termed atypical melanocytic
Synonyms and historical annotation ing or pagetoid type and lentigo maligna hyperplasia {759} or, preferably, atypical
LM has also been known as Hutchinson melanoma, whilst acknowledging that lentiginous melanocytic proliferation.
melanotic freckle, after Hutchinson first there may be no essential biological dif-
ference between some or perhaps all Localization
categories of melanoma {999}. Head and neck are by far the most com-
mon sites in both sexes. Extrafacial LMM
Etiology differs in its site distribution between
The strong association between LM and women and men {549}. A study in
its occurrence in the severely sun dam- Scotland showed that extrafacial LMM in
aged skin of elderly people has been men occurred mainly on the trunk where-
widely accepted as evidence that LM as in women 80% occurred on the limbs,
and LMM represent a distinctive form of mainly the lower leg. The mean age of
melanoma, resembling etiologically the patients with extrafacial LMM was signif-
non-melanocytic skin cancers, and sug- icantly lower than that of patients with
gesting that LM arises in response to head and neck LM, suggesting that the
accumulated sun exposure, in contrast association between LMM and sunlight
with the more common forms of may not be related only to the cumulative
melanoma that appear to be related to effects of solar exposure.
intermittent sun exposure {1048}. It has
also been suggested, however, that dif- Clinical features
ferences in body site distribution LM may be recognized as a small lesion,
between the commonly accepted differ- usually as a mottled light brown macule
ent types of melanoma, through their with irregular margins on the face of a fair
interaction with amount and pattern of skinned elderly patient with evidence of
sun exposure, can explain virtually all the severe solar skin damage, only a few mil-
observed pathological and epidemiolog- limetres in diameter, but usually greater
ical differences between LM and the than 10 mm. The classical lesions are
more common types of melanoma that broad, flat zones of varied pigmentation
Fig. 2.17 Lentigo maligna. Broad, flat, variably pig- occur in widespread anatomical distribu- with an irregular border. With increasing
mented lesion with a very irregular, ill-defined bor- tion {16,996}. Recent studies have found size of the lesion, variation in pigment
der on the cheek of a 78-year-old patient. that LM remains the main histologic type and irregularity of the border also
70 Melanocytic tumours
become more pronounced, nodules may
develop within the lesion and the borders
may become difficult or impossible to
define where zones of pallor or mottled
pigmentation merge imperceptibly with
the surrounding skin.
Histopathology
LM is characterized by a predominantly
junctional proliferation of atypical
melanocytes, frequently extending down
the walls of hair follicles and sweat ducts,
in association with epidermal atrophy
and severe solar elastosis. Although the
junctional proliferation may form conflu-
ent linear pattern in some areas, else-
where the atypical melanocytes may be
distributed as single units separated by
basal cells. Irregular junctional nests of A
atypical melanocytes are frequently
present, as are multinucleate giant cells
including those of starburst type {512}.
Marked pleomorphism is a feature of the
atypical melanocytes which show cyto-
plasmic retraction artefact and nuclei of
stellate, ovoid and crescentic forms,
some of them pressed against the cell
wall, with a variable chromatin pattern
and clear or variably pigmented cyto-
plasm. Pagetoid foci of atypical epithe-
lioid melanocytes present an appear-
ance indistinguishable from melanoma in
situ of so-called superficial spreading
type.
A lymphocytic infiltrate and focal fibro-
plasia are frequently present in the papil- B
lary dermis underlying LM, with severe Fig. 2.18 Lentigo maligna. A Atypical melanocytes, mainly epithelioid cells with clear cytoplasm, are
solar elastosis and telangiectasia. arranged in confluent pattern along the dermo-epidermal junction and extending down the wall of a central
hair follicle. A few single atypical melanocytes are also present above the basal layer. The epidermis is
Regression, shown by fibrosis, hypervas-
atrophic overlying severe elastosis. B Severe nuclear pleomorphism and scattered multinucleate giant
cularity, melanophages and a patchy
cells are present in the junctional proliferation and down the walls of adnexal structures including a sweat
lymphocytic infiltrate, is a common fea- duct.
ture and should prompt a careful search
for invasion by atypical melanocytes. The
presence of regression at a lateral mar- degree of pigmentation varies, including The degree of pigmentation in LM may
gin of excision should be emphasized in cells with abundant clear cytoplasm vary markedly between different exam-
the report as an indication for re-exci- adjacent to cells in which the morpholog- ples of the tumour and within one tumour.
sion, even when the margins appear ic detail may be obscured by coarse Zones of amelanosis at the periphery of
clear of atypical melanocytes. melanin granules. the lesion may lead to failure by the
In LMM, dermal invasion occurs in asso- The invasive component in LMM may be pathologist to detect atypical cells at the
ciation with LM. The invasive component desmoplastic and/or neurotropic with margin of excision, thus leading to per-
may consist of atypical melanocytic spin- very subtle, diffuse invasion that predis- sistent growth and “local recurrence” of
dle cells more frequently than is seen in poses to incomplete excision and true the tumour.
the other common forms of cutaneous local recurrence. Dermal invasion may
melanoma, but epithelioid, small naevoid also originate from atypical melanocytes Differential diagnosis
and tumour giant cells may also be pres- in the walls of hair follicles and sweat In cases of extensive amelanosis (ame-
ent in varied proportions. The cells of ducts, thus creating a problem in meas- lanotic LM) {60}, the distinction between
these various types may occur in cohe- urement of tumour thickness because it in-situ squamous cell carcinoma or extra-
sive groups, strands or as single cells in is inappropriate to measure tumour thick- mammary Paget disease may be difficult
a diffuse pattern, often associated with ness from the granular layer of the epi- in routine sections, necessitating the use
lymphocytes and melanophages. The dermis in this instance. of special stains to demonstrate epithe-
Lentigo maligna 71
Somatic genetics
A recent study has shown an association
between DNA repair-deficiency and a
high level of TP53 mutations in
melanomas of xeroderma pigmentosum
patients {2231}. The LMM found in xero-
derma pigmentosum patients of the XP
complementation group, group XP-C,
were associated with an accumulation of
unrepaired DNA lesions. Lentigo maligna
melanomas have been found to rarely
show mutations in BRAF {1493}.
Comparative genomic hybridization
shows more common losses involving
chromosome 13 and less common loss-
es of chromosome 10, when compared
to other melanoma types {173}.
72 Melanocytic tumours
Acral-lentiginous melanoma Y. Tokura
B.C. Bastian
L. Duncan
Definition gal-mucosal melanoma (P-S-M mela- an anatomic nomenclature, its use is dif-
Acral lentiginous melanoma (ALM) is a noma) {2129}, or unclassified plantar ferent among articles. We define it as a
distinct variant of cutaneous melanoma, melanoma {100}. Although often consid- melanoma located on the non-hair bear-
which occurs on the palms, soles, and ered to be interchangeable, ALM and ing skin of the palms and soles or under
subungual sites, and has a characteristic acral melanoma embody distinct con- the nails because of presentation of the
histologic picture. Following the three cepts that must be distinguished from genetic data. Although P-S-M melanoma
other major clinicopathological subtypes each other. ALM is a histologic designa- was described on the basis of clinical
of melanoma, i.e. superficial spreading tion that shows similarities to lentigo and histologic similarities between the
melanoma, lentigo maligna melanoma, maligna melanoma, while acral tumours on these sites, the acral
and nodular melanoma, ALM was pro- melanoma is an anatomic designation melanomas and mucosal ones are rec-
posed as the fourth subtype by Reed in that refers to melanoma located on the ommended to be treated separately,
1976 {1905}. In this article, we also use acral sites. Acral melanoma, thus, because of their different clinical behav-
the term acral melanoma and define it as encompasses both ALM and such sub- iours {494}.
a melanoma located on the non-hair types as superficial spreading
bearing skin of the palms and soles or melanoma and nodular melanoma that Epidemiology
under the nails. The reason for this usage may develop in acral locations. Racial differences are quite pronounced
is described below. Occasionally, the terms acral melanoma in the incidence and predilection sites of
and acral lentiginous melanoma are melanomas. This is particularly true for
ICD-O code 8744/3 used interchangeably, since the majority acral melanoma wherein acral melanoma
of cases of acral melanoma are ALM comprises 2% and 80% of cutaneous
Synonyms {1071,1592,1905} and the histological melanomas in Caucasian and dark-
Historically, this type of melanoma has distinction between ALM and superficial skinned patients respectively. In a
been designated as ALM {1905}, acral spreading melanoma is not always pos- German study approximately 7% of
melanoma {494}, palmar-plantar-subun- sible {2220}. Even if acral melanoma is patients with cutaneous melanoma had
A B D
Fig. 2.20 Acral-lentiginous melanoma (ALM). A ALM on the heel, showing varying shades of tan to brown pigmentation. B ALM on the lateral aspect of the foot,
showing irregularly bordered pigmentation with a slightly ulcerated lesion. C ALM on the sole, showing an irregularly pigmented macule with notched borders.
D ALM on the second toe, showing subungual pigmented lesion extending to adjacent skin.
Acral-lentiginous melanoma 73
A B
Fig. 2.21 Acral-lentiginous melanoma. A ALM, showing marked acanthosis, elongation of the rete ridges, broadened horny layer, and large, atypical melanocytes
with large, often bizarre nuclei and nucleoli, and cytoplasm filled with melanin granules. B ALM, showing lentiginous proliferation of atypical melanocytes at the
border of the tumour.
tumours located on acral sites {1337}. effected twice as often as women {1220, occurrence on the thumbs and great
Whereas 77% of cutaneous melanoma in 1268,1428,2130}. On the other hand in toes may suggest a role for trauma in the
Japanese patients occurs on acral sites western countries, there is less of a male etiology of subungual melanoma {2130}.
{2130}. In African and African- predominance in patients with ALM Since sun exposure obviously plays little
Americans, the highest incidence of {1337,2220}. role in palmoplantar sites, the causative
cutaneous melanoma has been reported role of ultraviolet light is presumed to be
on relatively non-pigmented areas, such Localization negligible in ALM.
as the soles, nail plates, and mucous The term acral has been used differently
membranes {1417}. Thus, ALM is the throughout the literature. Most publica- Clinical features
most common type of melanoma in dark- tions use acral for the non-hair bearing, Acral melanomas in the early stages
skinned peoples and Asians {1268, i.e. glabrous skin of the palms and soles, appear as a pigmented macule similar to
2129}. Nevertheless the absolute inci- and the nail bed, whereas others also lentigo maligna. Acral melanomas com-
dence of acral melanoma in dark- include the dorsal aspect of the hands monly exhibit clinical evidence of a
skinned African and light-skinned and feet under this term. In a German biphasic growth pattern, with a more
Caucasian populations in North America study, using the latter definition, acral rapid evolution from an entirely flat clini-
is similar, suggesting that the observed melanoma occurred on the feet in 87% cal lesion to a lesion containing an ele-
racial difference may relate to a cases (plantar sites, 57%; subungual, vated focus than is observed in the other
decreased incidence of non-acral 5%; and dorsum, 9%) and on the hands types of melanoma. The radial growth
melanoma in African American popula- in 23% (palm, 1%; subungal, 14%; and phase of ALM is characterized by a mac-
tions {2268}. Compared with the escalat- dorsum, 9%) {1337}. Thus, the plantar ular pigmented lesion with highly irregu-
ing incidence that typifies other sites were greatly more often affected lar, notched borders and varying shades
melanoma subtypes, the incidence of than the palmar sites {1337,2130,2201, of pigmentation. Within a background
ALM has remained static {661}. 2220,2296}. In contrast to ALM, superfi- pigmented macule, acral melanomas
Overall, ALM occurs in an older patient cial spreading melanoma occurs more often develop a clinically apparent verti-
population than does superficial spread- commonly on the sun-exposed dorsal cal growth phase. This is manifest as an
ing or nodular melanoma, and, in popu- aspects of the hands and feet, whereas elevated papule or nodule, sometimes
lations where ALM is common, this nodular melanoma occurs on all acral with a verrucous surface, and corre-
tumour more often afflicts men than sites with relatively equal frequency sponds to the histological vertical growth
women. Overall, the age distribution of {1337}. In addition to the sole, nail plate phase of malignant melanocytes.
ALM is similar to that of lentigo maligna is an especially frequent site with a fre- Ulceration is more often seen in ALM
melanoma, peaking in the seventh quency of 16-19% in ALM {1337,2130}. than in other types of melanoma.
decade of life, whereas superficial In contrast to the palmar/plantar Subungual melanomas often begin as
spreading melanoma and nodular melanomas, subungual melanomas brown to black discolouration of the nail
melanoma peak in the sixth decade occur more often on the hands than on that frequently become bands or streaks
{1337}. The mean age of ALM ranges the feet {745,1221,2130,2315}. In the of pigmentation. Thickening, splitting, or
from 55 to 68 years in European coun- Japanese series, the number of subun- destruction of the nail plate may occur.
tries {767,1337,2123}. In Japanese gual melanomas on the fingers is 62-72% The irregular macular hyperpigmenta-
patients, there is a peak in the sixth and on the toes 28-38%, with an 82% tion, coloured tan to dark brown, is also
decade in both males and females. In incidence on the thumbs and great toes recognized around the nail plate {2130}.
Japan, Korea, and Taiwan, men are {1221,2130}. The high percentage of In one study, 17% of the patients noticed
74 Melanocytic tumours
the pre-existence of some pigmented cases, 95%) is a more sensitive marker fications in acral melanoma preferentially
skin lesions, and 21% related a history of than either HMB-45 (80%) or MART-1 involving chromosome 11q13. In addi-
trauma {2130}. Pigmented streaks are (70%) {1268}. However, S-100 protein- tion, the studies revealed that all
not uncommon in patients with deeply negative ALM has been reported {83}. melanomas showed these features, inde-
pigmented skin, nevertheless, a history The intesitity of HMB-45 but not of S-100 pendent of their histological growth pat-
of a new or recently changing pigmented protein is correlated well with the melanin tern, as long as they were located on
lesion should prompt the consideration content. HMB-45-negative cases are all glabrous, i.e. non-hair bearing skin of the
of a biopsy for histological evaluation of amelanotic, but amelanotic cases are not palms and soles or subungual sites
the lesion. In this case, reflection of the all negative for HMB-45 {1268}. The (Bastian et al, to be published). In addi-
proximal nail fold to enable biopsy of the melanoma cells also express vimentin tion, melanomas involving these anatom-
nail bed may be necessary for definitive {1268}. Focal staining for CAM5.2 or ic sites also had a significantly lower
diagnosis. epithelial membrane protein may occa- mutation rate of the BRAF oncogene
Unfortunately, clinical misdiagnosis is not sionally be found {1268}. (6/39, 15%) than melanomas on the trunk
uncommon in patients with ALM {409, (23/43, 53%) {1493}. The molecular
767,1327,1592,2222}. Therefore, aware- Somatic genetics genetic analyses therefore suggest
ness of atypical presentations of ALM Comparative genomic hybridization melanomas of the palms of soles and
that may contribute to misdiagnosis or (CGH) of melanomas on acral non-hair subungual sites represent a genetically
diagnostic delay assumes particular bearing skin showed distinct differences distinct form of melanoma, independent
importance. ALM lesions are frequently to melanomas on non-acral skin {171}. A of their histological growth pattern.
treated or followed for considerable time study of 15 acral melanomas and 15
under the clinical diagnosis of wart, cal- superficial spreading melanomas from Prognosis and predictive factors
lus, fungal disorder, subungual non-acral sites showed that all (100%) In general, the prognosis of invasive
haematoma, keratoacanthoma, nonheal- acral cases had gene amplifications, acral melanoma is poor. This can party
ing ulcer, foreign body, naevus, ingrown whereas amplifications were found in two be explained by the above described
toenail, etc {2222}. of the superficial spreading melanomas diagnostic delay and increased tumour
(13%). The most common amplified thickness at the time of diagnosis.
Histopathology region is chromosome 11q13 which However, there are some studies sug-
The histology of ALM is characteristic but occurred in 50% of these types of gesting that acral melanomas may
not distinct. In the radial growth phase, melanoma. A recent study has shown undergo a more aggressive course inde-
the lesions are characterized by marked that cyclin D1 is one of several candidate pendent of tumours thickness {151,308,
acanthosis, expanded cornified layer, genes in this region. This conclusion was 661,1337}. In a study from Germany, 63
elongation of the rete ridges, and lentigi- based on the observation that amplifica- out of 64 patients (98.5%) with melanoma
nous proliferation of atypical melano- tion of the cyclin D1 gene was always of the sole subsequently developed
cytes along the basal epidermis at the accompanied with overexpression of the metastases {775}; a corresponding fig-
border of the tumour {1337,1767}. The cyclin D1 protein, and that inhibition of ure from Japan in 1983 was 35% {2130}.
intraepidermal component of acral cyclin D1 expression in vitro and in The same hospital recorded that the 5-
melanoma includes large, atypical xenograft models led to apoptosis or year survival rate of subungal melanoma
melanocytes with large, often bizarre tumour shrinkage {2072}. increased from 53% in 1969-82 to 83% in
nuclei and nucleoli, and cytoplasm filled FISH studies on primary lesions of acral 1983-93 {1221}, presumably because of
with melanin granules {2130}. These melanoma showed that the amplifica- early awareness of lesions and develop-
melanocytes in the basal layer often tions arise early in acral melanoma and ment of treatment {2012}. However, oth-
exhibit long, elaborate dendritic process- can already be detected at the in situ ers have reported that ALM is not a sig-
es {2130}. stage {171}. The in situ portion of acral nificant prognostic indicator {661,2201},
Atypical melanocytes can extend along melanoma may extend beyond what is and adjustment for histologic and clinical
the sweat ducts into the deep dermis. recognizable histopathologically. FISH stage renders the prognostic importance
In the vertical growth phase, tumour nod- detected gene amplifications were iden- of anatomic location insignificant {151,
ules often contain predominantly spindle- tified in single basal melanocytes imme- 308}. These conflicting results can in part
shaped cells and are associated with a diately adjacent to the in situ component be explained by the different definitions
desmoplastic reaction {2130}. The junc- of acral melanoma; they were equidis- used for acral melanomas in the studies.
tional component of thicker tumours tantly spaced and looked histopathologi- Future studies using refined criteria
often shows nesting of tumour cells and cally inconspicuous {171}. Based on the including genetic information are neces-
upward migration to the cornified layer observation that these “field cells” were sary to assess the prognosis of this
{1337}. found at the histopathologically unin- melanoma type.
volved excision margins of an acral
Immunoprofile melanoma that recurred multiple times
As in the other types of melanomas, the authors propose that field cells may
immunohistochemical stainings for S-100 be a form of minimal residual melanoma
protein, HMB-45, and MART-1 (also that leads to persistence if not removed.
known as Melan-A) are of great diagnos- More recent studies using array CGH
tic value in ALM. S-100 protein (positive have confirmed the frequent gene ampli-
Acral-lentiginous melanoma 75
Desmoplastic melanoma and S.W. McCarthy
K.A. Crotty
desmoplastic neurotropic melanoma R.A. Scolyer
Definition rineural or intraneural and often extends junctional component, preceding the
Desmoplastic melanoma (DM) is a spin- beyond the desmoplastic component. development of a bulky dermal and sub-
dle cell melanoma in which the malignant DM may also present as a recurrence or cutaneous tumour. The latter was com-
cells are separated by collagen fibres or occasionally as a metastasis from other posed of atypical melanocytes and spin-
fibrous stroma. It displays variable cyto- types of melanoma. dle cells often with elongated nuclei and
logical atypia, cellularity and stromal a dense collagenous ground substance.
fibrosis and more often than not has an ICD-O code 8745/3 Many others subsequently highlighted
accompanying junctional component. the frequent neurotropism of DMs.
Neurotropism is a common associated Historical annotations
feature (in at least 30% of cases) and DM was first described by Conley et al. Epidemiology
when it occurs such tumours are termed in 1971 {526} as a clinically inconspicu- Desmoplastic melanomas represent
desmoplastic neurotropic melanomas ous superficial melanocytic lesion, main- between 1-4% of melanomas. In a large
(DNM). The neurotropism may be pe- ly on the head and neck, with an atypical series from the Sydney Melanoma Unit
A B
C D
Fig. 2.22 Desmoplastic neurotropic melanoma. A Male, 73 yrs, cheek. A few atypical enlarged melanocytes are present in the junctional zone. The fibrohistiocytic
pattern is accompanied by scattered lymphocytes, some in clusters. Mitoses are hard to find. B Female, 24 yrs, lip. There are "neural transforming" areas with thick
neuroid bundles in the upper dermis. Note occasional atypical junctional melanocytes, a few subepidermal spindle cells and scattered lymphocytes. C Male, 73 yrs,
cheek. Malignant spindle cells with elongated nuclei appear to be within and between collagen bundles. D Female, 24 yrs, lip. "Neural transforming" areas with
neuroid bundle (top of picture) containing atypical elongated spindle nuclei. Intraneural and perineural involvement of a small nerve is also present. There is a
prominent infiltrate of lymphocytes.
76 Melanocytic tumours
A B
Fig. 2.23 Desmoplastic melanoma. A Male, 57 yrs, upper lip. Abnormal junctional melanocytes, spindling dermal melanocytes and a patchy lymphocytic infiltrate.
B Female, 76 yrs, forearm. Abnormal junctional melanocytes and dermal spindle cells with patchy lymphocytes.
(SMU) the median age at diagnosis was (LM)/Hutchinson melanotic freckle (HMF) usually non-pigmented, are found in and
61.5 years (range 24-91) {1867,1868}. or superficial spreading melanoma. between mature collagen bundles. The
As in other histogenetic types of Unusual presentations include a young latter may be thickened and/or associat-
melanoma, males are more often affect- age {439,1077}, an erythematous nodule ed with a mild to marked stromal fibrosis.
ed (M:F = 1.75:1) {358A,1867,1868}. {1326} and alopecia {563}. The distribution of spindle cells is usually
haphazard but occasionally they form
Etiology Macroscopy parallel bundles or storiform areas. The
The etiology is unknown, but the majority Ulceration is uncommon although it was spindle cells often extend into the sub-
occurs in sun-exposed skin. Some have found in 17% of the SMU cases {1868}. cutis diffusely or in fibrous bands and
occurred in irradiated areas {1125}. may involve deep fascia, especially peri-
Tumour spread and staging cranium. The overlying epidermis may
Localization The tumours usually infiltrate deeply into be thinned or thickened. Charac-
DM may be found in many sites but most the reticular dermis but local spread may teristically there are accompanying small
commonly involves the head and neck involve subcutaneous tissue, deep fas- islands of lymphocytes and plasma cells
region (37%), including ear, nose and lip cia including periosteum and pericrani- within and/or at the edge of the tumour.
{1077}. Males predominate except on the um, bone and salivary gland. Neuro- The cytological atypia of the spindle cells
lower limbs. The vulva is a rare site for tropic foci may be found well beyond the usually varies from mild to moderate.
DM {1664}. main tumour. In the SMU series, neu- However, even in cases with mild atypia,
rotropism was found only in tumours there are usually a few larger or more
Clinical features exceeding 1.5 mm in thickness and Clark elongated hyperchromatic nuclei. The
Most present as a painless indurated level 4 or 5 {1867,1868}. Initial metas- cytoplasm of the spindle cells is often
plaque but some begin as a small papule tases from DM may involve regional poorly defined. In examples where the
or nodule {2501}. Almost half lack pig- lymph nodes or distant sites. spindle cells are small, well scattered
mentation {1867}. Pale lesions are often and associated with solar elastosis, the
mistaken for basal cell carcinoma, der- Histopathology lymphoid islands may be the main clue to
matofibroma or a scar. Pigment is usual- In DM the spindle-shaped melanocytes, the diagnosis. Paucicellular variants are
ly due to an associated lentigo maligna which often resemble fibroblasts and are easily missed on punch and shave biop-
A B C
Fig. 2.24 Desmoplastic melanoma. A The spindle cells stain poorly with S100 unlike the Langerhans cells and interdigitating cells. B Variable S-100 positive nuclear
and cytoplasmic staining. C Crowded abnormal spindle cells and atypical mitoses.
Somatic genetics
A B Chromosomal aberrations and gene
mutations have been found in sporadic
Fig. 2.25 Desmoplastic melanoma. A Firm, skin-coloured plaque. B Male, 68 yrs, scalp. This punch biopsy
was initially diagnosed as a scar. Only an occasional spindle cell was S-100 positive and no abnormal junc- and familial melanoma {799}. Allelic loss
tional melanocytes were found. A larger desmoplastic melanoma was removed from the same site 6 months at the neurofibromatosis type 1 (NF1)
later. Clues to the diagnosis are the small foci of lymphocytes and permeation of the band of dermal elas- gene locus is frequent in DM {931}. Basic
tosis by spindle cells. fibroblast growth factor (bFGF) and other
fibrocytokines are often present in the
sies. Junctional change is sometimes factor (MTF) is not a sensitive or specific nuclei of DMs {1335}. Loss of heterozy-
minimal or absent {1125}. Occasionally marker {356,885,1294}. Type IV collagen gosity of matrix interacting protein 1
there is an associated banal naevus. and laminin are frequently expressed in (MXI1) is frequent {1893}. No BRAF
Vascular invasion is rare. Even rarer DM {1857}. Vimentin is usually positive mutations were found in 12 desmoplastic
cases show heterotopic bone and carti- although positive staining does not usu- melanomas {596}, consistent with the
lage {1644}. ally assist in diagnosis. finding that melanomas on chronically
The median Breslow thickness in the sun-exposed skin only rarely have BRAF
SMU series was 2.5 mm (0.2-18 mm) Differential diagnosis mutations {358B,596,1493}.
{1867,1868}. The thickness and extent of The differential diagnosis includes
invasion is usually best determined in S- desmoplastic naevus {958}, which like Prognosis and predictive factors
100 stains. The mitotic rate is variable but DM may have perineural extension but Recurrences are common especially
is often low. Abnormal mitoses are com- lacks asymmetry, mitotic activity, marked after incomplete excision {526}, marginal
mon in the more cellular tumours. nuclear atypia and lymphoid infiltrates. excision <10 mm or if neurotropism is
The neurotropism is characterized by the Well established desmoplastic Spitz present {1867,1868}. The conflicting
presence of one or more foci in which the naevi may have many HMB45 negative results regarding the risk of regional
spindle cells extend in a circumferential spindle cells but these naevi are usually node field metastases and prognosis of
fashion around nerves in the dermis or symmetrical with epidermal thickening, DM patients may be due to a hetero-
deeper and/or thickened nerves contain- include at least a few plump cells and geneity of tumours classified as DM and
ing abnormal cells within their nerve have rare or absent mitoses. Sclerosing failure to account for tumour thickness
sheath. Spindle cells may also form cellular blue naevi, which are most fre- {2115A}. Regional nodal metastases
structures resembling nerves (“neural quent on the scalp, also lack mitoses appear to very uncommon in paucicellu-
transforming”). Neurotropism may be and are more or less diffusely HMB45 lar DMs with prominent fibrosis and are
present in melanomas without desmopla- positive. Immature scars, especially in associated with longer survival {358A,
sia. re-excision specimens, may focally 932A, 985A}. Otherwise, disease free
Melanomas of any histogenetic type may resemble DM as they may have some S- survival rates are similar to other
have desmoplastic areas. The proportion 100 positive spindle cells {476,1951}, melanomas of comparable thickness
of desmoplasia in a melanoma neces- foci of lymphocytes and mitoses. {126}. Neurotropism, HMB45 positivity,
sary for the diagnosis of DM has been ill Other differential diagnoses include der- high mitotic rate, male gender, thickness,
defined in several studies, but proposals matofibroma/fibrous histiocytoma, fibro- ulceration and site all appear to affect
for diagnostic criteria have been made sarcoma, “malignant fibrous histiocy- survival which overall is 79% at 5 years
{358A,985A,1546A}. toma”, malignant peripheral nerve {1868}. Of patients with a recurrence,
Metastases in lymph nodes may be sheath tumour and leiomyosarcoma. 78.2% experienced it within 2 years.
epithelioid cells, or spindle cells with or These tumours can usually be separated Wide local excision is the treatment of
without desmoplasia. by morphology and appropriate immuno- choice {99A}. Radiation therapy has
histochemistry. been effective in some cases {71,1125}.
Immunoprofile
The spindle cells are positive with S-100 Histogenesis
although only a few nuclei are positive in It is most likely that the desmoplastic
some otherwise typical cases. HMB45 is cells are derived from melanocytes that
usually negative except for any foci of have undergone adaptive fibroplasia.
epithelioid cells {2476}. NSE, NKI/C-3 Some authors have suggested that the
and smooth muscle actin {1929} may be desmoplasia occurs because of a fibrob-
positive. Melan A (MART-1) is usually lastic stromal response and neurofi-
negative. Microphthalmia transcription brosarcomatous differentiation of the
78 Melanocytic tumours
Melanoma arising from blue naevus L. Requena
J. A. Carlson
A B
Fig. 2.26 Melanoma arising from blue naevus. Fig. 2.27 Melanoma arising from blue naevus. A Scanning magnification showing a blue naevus with a nod-
Note the presence of satellitosis (Courtesy of Dr. H. ule of malignant melanoma in deeper areas. B In deeper areas the nodule of malignant melanoma was
Kerl). composed of sheets of cells destroying pre-existing structures of the dermis.
Additional associations of unknown influ- naevi of Ota and Ito, and ocular Although the malignant component may
ence include subacute cutaneous lupus melanocytoses attest to this latter possi- involve the superficial dermis and ulcer-
erythematosus, leukoderma, Becker’s bility of under-reporting {542,660,1783, ate the epidermis, more often it appears
naevus and prostate adenocarcinoma in 2332,2414}. as a deep-seated expansile asymmetric
one patient {1629}, papillary thyroid car- At scanning magnification, two nodule involving the reticular dermis and
cinoma {94}, acute lymphocytic histopathologic patterns are evident. subcutaneous fat. Usually, there is an
leukaemia {2119}, psoriasis {238}, and One is represented by the benign com- abrupt transition from the benign blue
oral contraceptives {1404}. Phototherapy ponent of the blue naevus, which may naevus component to the nodule of
has been associated with cellular blue range from very focal to comprising the melanoma. The nodule or nodules of
naevus development {810}. main bulk of the neoplasm. Often this melanoma show both architectural and
benign component is represented by a cytological features of malignancy. The
Histopathology cellular blue naevus and less frequently melanomatous component consists of
By definition, a melanoma that develops the lesion contains a common blue nae- sheets of cells that involve diffusely the
in a pre-existing blue naevus is a dermal vus. Most cases, however, show a com- deep dermis destroying the pre-existing
melanoma without the features of bination of the so-called cellular and structures with pushing margins and
melanoma in situ involving the dermo- common blue naevi, making this distinc- sharp demarcation between the neo-
epidermal junction or adnexal epitheli- tion useless. The areas of cellular blue plasm and adjacent dermis or subcuta-
um. In fact, 82% of all reported cases naevus consist of solid aggregations of neous tissue. Neoplastic melanocytes
described an adjacent common and/or closely arranged monomorphous ovoid appear as large spindled to epithelioid
cellular blue naevus. The absence of an cells with abundant pale cytoplasm con- cells with abundant cytoplasm and pleo-
identifiable benign naevus component in taining little or no melanin and round morphic and hyperchromatic nuclei, with
some reports may be the result of vesicular nuclei with inconspicuous prominent nucleoli and frequent mitotic
replacement of it by the melanoma or nucleoli. In contrast, the areas of com- figures. Usually they contain little or no
incomplete sampling of the benign ele- mon blue naevus are made up of elon- melanin. Without the associated benign
ment. Although these cases could repre- gated spindled bipolar melanocytes, component, these dermal nodules would
sent de novo melanomas, a subtle, with long branching dendritic processes be histopathologically indistinguishable
hypocellular dermal melanocytosis as most of them filled with abundant gran- from typical nodular or metastatic
seen in naevi of Ota and Ito, and ules of melanin. Melanophages and scle- melanoma. Necrosis of individual cells
Mongolian spots may not have been rotic bundles of collagen are also fre- as well as necrosis en masse may be
observed. Reports of orbital, facial and quently observed between the fascicles also seen in the melanoma component,
shoulder melanomas associated with of dendritic melanocytes. although this finding seems to be less
80 Melanocytic tumours
frequent than in melanomas arising de Animal type melanoma (epithelioid Immunoprofile
novo (“malignant blue naevus”) {973}. A melanocytoma) is a rare variant of pri- Immunohistochemical studies in lesions
perivascular inflammatory infiltrate, most- mary cutaneous melanoma that may also of melanoma associated with blue nae-
ly composed of lymphocytes, which is mimic melanoma associated with blue vus have demonstrated a strongly posi-
usually lacking in blue naevus, is often naevus {567,1917}. Sheets and nodules tive reaction of the neoplastic cells, both
seen around the melanoma arising in of heavily pigmented epithelioid melano- of the benign and malignant compo-
blue naevus. cytes that tend to aggregate along hair nents, for vimentin, S-100 protein, HMB-
Melanoma arising in the setting of blue follicles and involve the entire thickness 45 and NKI/C-3 {280,1708,1996}.
naevus should be differentiated from the of the dermis with extension into the sub- However, the number of silver positive
so-called atypical cellular blue naevus cutaneous tissue histopathologically nucleolar organizer regions (AgNOR
{118,2371}. These lesions show clinico- characterize animal-type melanoma. score) {813,1826} and growth fraction as
pathologic features intermediate Epithelioid melanocytes in deeper areas measured by proliferating cell nuclear
between typical cellular blue naevus and show abundant, heavily pigmented cyto- antigen (PCNA) and Ki-67 (MIB-1) are
malignant melanoma associated with plasm and pleomorphic nuclei with significantly lower in the benign compo-
blue naevus. The lesions show architec- prominent eosinophilic nucleoli and nent of blue naevus than in the nodule of
tural atypia, characterized by asymmetry mitotic figures. Histopathologic features melanoma {1708,1826}.
and infiltrative margins, as well as cyto- of melanoma in situ at the dermo-epider-
logic atypia, which consist of hypercellu- mal junction are few or absent, and neo- Electron microscopy
larity, nuclear pleomorphism, hyperchro- plastic cells do not show evidence of Although some authors have interpreted
masia, mitotic figures and necrosis. maturation from superficial to deeper the neoplastic cells of melanoma associ-
However, follow-up data of patients with dermal areas. The overall architectural ated with blue naevus as being related
atypical cellular blue naevus demonstrat- and cytologic features of animal-type with Schwann cells {1588}, electron
ed that no patient experienced either a melanoma closely resemble those of microscopic studies have demonstrated
local recurrence or lymph node or viscer- melanoma associated with blue naevus, the presence of melanosomes in the
al metastasis. but animal-type melanoma lacks the cells, as well as the lack of cytoplasmic
Melanoma associated with blue naevus benign component of blue naevus or his- enclosures of unmyelinated axons, which
should be also distinguished from large tory of a pre-existing melanocytosis. rule out the possibility of Schwann cell
plaque-type or giant cellular blue naevus differentiation. Although the melano-
with subcutaneous cellular nodules {358, Metastatic spread somes in many cells of the malignant
1059}. Large pigmented plaques of Melanoma associated with blue naevus component are devoid of melanin {1014},
childhood onset that show slow enlarge- is an aggressive tumour with frequent incubation with dopa demonstrates that
ment during adolescence and subse- metastatic disease to regional lymph they are strongly dopa-positive {1625},
quent nodule formation clinically charac- nodes (31% of reported cases) and dis- thus confirming their melanocytic nature.
terize this rare plaque variant of cellular tant sites (42%). Sites of metastasis, in
blue naevus. Histopathologically, they decreasing order of frequency, include Somatic genetics
exhibit multifocal dermal and subcuta- liver (36%), lung (22%), brain (16%), skin Results of DNA flow cytometry studies in
neous proliferations of fusiform and den- (13%), bone (9%), and in less than 6% of melanoma associated with a blue naevus
dritic pigmented melanocytes, with high- reported cases, spleen, heart, kidney, are variable revealing diploid cell popu-
ly cellular nodules located in deeper pancreas, adrenal, thyroid and parotid lations in 4 cases {1574,1826} and aneu-
areas of the plaque. The follow-up of glands, ovary, and gastrointestinal tract. ploid populations in 2 cases {1826}. A
patients with large plaque-type blue nae- Melanuria and generalized melanosis molecular analysis failed to demonstrate
vus with subcutaneous cellular nodules have also been described in its terminal loss of heterozygosity on microdissected
indicates that these lesions behave in a stage {2185}. Metastases can appear as samples in one case of melanoma asso-
benign fashion. late as 20 years after diagnosis {813}, but ciated with blue naevus, using a panel of
Metastatic melanoma mimicking blue the median and mean time of discovery eight genes (MTS1, MXI1, CMM1, p53,
naevus can also be confused with is 1.75 and 3.6 years after diagnosis. NF1, L-myc, hOGG1, and MCC), many of
melanoma associated with a blue naevus Metastasis to lymph nodes should be dif- which are commonly associated with
{354,2517}. These blue-naevus like ferentiated from the presence of blue conventional melanomas {94}. These
metastases occurred in the same naevus cells in the capsule of the node findings suggest that melanoma associ-
anatomic region as the primary tumour or {181,392,405,1357,1358}. This well- ated with blue naevus may represent a
near the skin scar of a dissected lymph known pseudo-metastasizing phenome- distinct entity with a different molecular
node metastasis and were histopatholog- non seems to be the result of migration pathway to tumourigenesis than that of
ically characterized by atypical epithe- arrest during embryogenesis and is conventional melanomas. However, in a
lioid melanocytes, mitotic figures, and an characterized by monomorphous comparative genomic hybridization
associated inflammatory cell infiltrate at melanocytes of blue naevus involving study comparing common blue naevi,
the periphery of the lesions. In contrast only the capsule and the marginal sinus- cellular blue naevi, and atypical cellular
with melanoma arising in a pre-existing es of the lymph node. In authentic metas- blue naevi with melanoma associated
blue naevus, metastatic melanoma to the tases, nests of atypical melanocytes with a blue naevus, melanomas associat-
skin simulating blue naevus lacks the replace most of the parenchyma of the ed with blue naevus showed chromoso-
benign blue naevus component. node, effacing its architecture. mal abnormalities similar to that of con-
82 Melanocytic tumours
Melanoma arising in giant congenital H. Kerl
C. Clemente
I Sanchez-Carpintero
M.C. Mihm
naevi P.E. North B.C. Bastian
A B
Fig. 2.31 Melanoma arising from large congenital naevus. A The melanoma is clearly separate from the naevus cells that are on the left. B A protuberant nodule
shows the small dark naevus cells to the left and at the base of the melanoma that is composed of nests with dyscohesion.
nodules. They exhibit fully transformed response may be observed as well as Somatic genetics
malignant characteristics with very irreg- focal mucinosis. In our experience, the Comparative genomic hybridization
ular chromatin patterns and prominent vertical growth phase dermal nodules shows that melanomas arising in con-
nucleoli. There is variable pigmentation. may exhibit prominent areas of different genital naevi show similar chromosomal
Both single cell and zonal necrosis may cell types with different degrees of pig- aberrations as melanoma arising inde-
be observed. The melanoma cells as mentation {568,703,1197,1928}. pendently {175}. By contrast, the prolifer-
they abut or infiltrate as cords into the Histologically, the presence of a residual ative nodules arising in early life do not
adjacent naevus show no evidence of dermal naevic component with congeni- show chromosomal aberration support-
maturation but maintain their fully malig- tal features may be quite difficult to find, ing the view that they are benign {175}.
nant characteristics. Mitoses are com- particularly, if present in the wall of a ves-
mon and atypical forms are usually pres- sel.The differential diagnosis includes
ent. A lymphocytic host response is often the proliferative nodules that also arise in
noted. Occasionally, a desmoplastic host large congenital naevi.
Definition doubled in patients aged 15 to 19 years (15%), and upper limbs (15%).
Melanomas developing in individuals over the past decade but has remained
prior to the onset of puberty are child- unchanged in younger individuals Clinical features
hood melanomas and thereafter they are {204A,1037A}. Less than 80 well docu- Melanomas in individuals under the age
designated as melanomas in adoles- mented cases of melanoma in children of 20, particularly in adolescents, show
cents with the age limitation of 18 to 20 younger than 10 years have been fairly similar clinical features as com-
years. Childhood melanomas can be fur- recorded in the literature over a period of pared to melanomas in adults
ther subcategorized as 1) congenital 30 years. As in adults, childhood mela- {123A,1916A}. However melanomas in
melanoma (onset in utero to birth), 2) nomas have a predilection for Cauca- prepubertal individuals are so rare that
infantile melanoma (birth to one-year of sians. Individuals with congenital naevi they are usually unsuspected. Features
age), and 3) childhood melanoma (one especially large varieties, atypical naevi, suggesting melanoma in a pigmented
year to onset of puberty). family history of melanoma, xeroderma lesion such as a congenital naevus are
pigmentosum, and immunosuppression rapid increase in size, bleeding, devel-
Epidemiology are at increased risk for childhood opment of a palpable nodule (e.g., in a
The incidence of melanoma is excep- melanoma. giant congenital naevus), colour change
tionally rare in prepubertal individuals of a nodular lesion, surface changes
(estimated incidence approximately Localization such as ulceration, and loss of clearly
0.4% among all melanomas) {269A, Melanomas developing in patients up to defined margins. Recognition of
1487A} and uncommon under the age of 16 years of age most commonly involve melanoma appearing de novo requires a
20 years (incidence approximately 2%) the trunk (50%), followed by the lower high index of clinical suspicion, espe-
{123A}. The incidence of melanoma has extremities (20%), head and neck cially for amelanotic lesions. Utilizing the
84 Melanocytic tumours
conventional ABCDE criteria (Asymme-
try, ill-defined Borders, irregular Colour,
and large Diameter, Elevation) the clini-
cal detection of melanoma in adults, all
such suspicious lesions in children
should be evaluated for biopsy and
histopathological examination. Melano-
ma in children also may be associated
with pain or pruritus {155,417A,530A,
1037A,1619A,1859A,1930A,1990A, A B
2003A,2089,2232}.
Fig. 2.33 Small-cell melanoma from the scalp of a prepubertal individual. A The lesion resembles a con-
ventional melanocytic naevus at scanning magnification. B High magnification shows a highly cellular
Histopathology dermal component without maturation. There is a monomorphous population of small round melanocytes
The same histopathological criteria with scant cytoplasms resembling the neoplastic cells in lymphoma or neuroendocrine carcinoma. The
should be utilized for diagnosis as have nuclei are pleomorphic.
been developed for adult melanomas
{155,159A,417A,1990A,2232}. However,
clinical information must be strongly con- patients with XP are histologically often Differential diagnosis
sidered, particularly age, since cuta- similar to solar melanomas except that Childhood melanomas must be distin-
neous melanoma is almost nonexistent the actinic damage characteristic of guished from congenital and other naevi
under the age of two years and especial- adult tumors is absent {159A,2232}. exhibiting pagetoid melanocytosis,
ly in the neonatal period. lentiginous melanocytic proliferation,
The important stimulants of melanoma Small-cell melanomas atypical nodular melanocytic prolifera-
must be excluded: 1) atypical nodular Small-cell melanomas are comprised of tion, and from Spitz naevi. Conventional
proliferations developing in congenital monomorphous small cells, reminiscent criteria such as age, clinical presenta-
naevi in infants and young children and of small round cell malignancies such as tion, size, asymmetry, circumscription,
2) Spitz naevi. lymphoma, or a melanocytic naevus degree of cellular density, maturation,
Great attention should be given to avoid- {155,159A,2232}. These cells are often degree of cytological atypia, and mitotic
ing over diagnosis melanoma and at the arranged in sheets or in organoid config- rate should facilitate this discrimination in
same time to the under recognition of urations. The melanocytes contain most cases.
atypical and borderline lesions that basophilic round nuclei and condensed Pagetoid melanocytosis and lentiginous
require adequate surgery and follow-up chromatin. The high cellular density, lack melanocytic proliferation and are fea-
for disease recrudescence. Lesions not of maturation, and often prominent mitot- tures commonly observed in naevi devel-
clearly meeting sufficient criteria for ic rate are features suggesting melano- oping in children, particularly in glabrous
melanoma should be designated as bio- ma. In children, small cell melanomas skin. These changes must not be overin-
logically indeterminate. Features appear- may appear de novo or may develop in a terpreted unless architectural disorder is
ing to be most useful for the distinction of congenital naevus. Such melanomas prominent and cytological abnormalities
melanomas from naevi are large size with small-cell phenotypes have often are present throughout the breadth of the
(i.e., >7 mm), ulceration, high mitotic rate been localized to the scalp, shown strik- lesion.
(>4 mitoses/mm2), mitoses in the lower ing Breslow thicknesses, and fatal out- Virtually all atypical nodular melanocytic
third of the lesion, asymmetry, poorly come in most patients {159A}. proliferations developing in congenital
demarcated lateral borders, lack of mat- naevi are biologically benign. Exami-
uration, finely-divided melanin, and Melanomas simulating Spitz naevus nation of these atypical tumors with refer-
marked nuclear pleomorphism {155, On occasion melanomas in both children ence to karyotype, expression of cell-sur-
159A,2232}. Melanomas in children can and adults may exhibit features strongly face antigens, growth in soft agar, chro-
be (somewhat artificially) categorized suggesting a Spitz naevus. These fea- mosomal aberrations, and other parame-
into three principal groups {155, tures include both architectural and cyto- ters has shown that they have the prop-
159A,2232}. logical attributes such as epidermal erties of an immature proliferative but
hyperplasia, wedge-shaped configura- benign tumor {71A,175,1496A}.
Conventional melanomas tion, epidermal clefting about intraepi- Various authors have proposed criteria
About 40 to 50% of melanomas in chil- dermal nests, large epithelioid cells and for distinguishing Spitz naevi from
dren are similar histologically to those in spindle cells arranged in fascicles, etc. melanomas. Criteria favoring melanoma
adults {159A,2232}. The intraepidermal {155,159A,2232}. include asymmetry, ulceration, deep
components of such melanomas conse- extension (particularly subcutaneous
quently may be pagetoid, lentiginous, or In addition to conventional melanomas fat), large size (>1 cm), prominent cellu-
nested. Melanomas of glabrous skin are and typical Spitz naevi, there is also an lar density, lack of maturation, deep
exceedingly rare in childhood {159A, intermediate group of Spitz-like lesions mitoses (i.e., more than 3 mitoses in the
2232}. Solar (so-called lentigo maligna) that demonstrate not only some features lower third), high mitotic rate (i.e., >4 to
melanomas do not occur in childhood. of Spitz naevi but also varying degrees of 6/mm2), abnormal mitoses, and marked
However, melanomas diagnosed in atypicality. nuclear atypia.
Melanoma of childhood 85
Naevoid melanoma N.S. McNutt
S. Kossard
.
A B C
Fig. 2.34 Naevoid melanoma. A Naevoid melanoma, papular lesion. (A) At low magnification, note the lack of maturation and the lack of good naevus nest forma-
tion in the dermis. B Naevoid melanoma, papular lesion. (B) At intermediate magnification, many of the cells are hyperchromatic and atypical. C Naevoid
melanoma, papular lesion. Perivascular infiltration is at the base of the lesion.
86 Melanocytic tumours
A B C
D E F
Fig. 2.35 Naevoid melanoma. A Verrucous type. Note the crowding of the cells in the dermal papillae. B Naevoid melanoma, verrucous type. Note the atypical
mitosis in the dermis. C Naevoid melanoma, verrucous type. There is vascular invasion at the base of the lesion. D Naevoid melanoma with spindle and epithelioid
cells. The diffuse dermal pattern with scattered atypical cells, without dermal maturation, shares some features with early desmoplastic melanomas. E Naevoid
melanoma with spindle and epithelioid cells. Note the nuclear atypia. F Naevoid melanoma with spindle and epithelioid cells. Note the lack of maturation of cells
in the base of the lesion.
figures can be found in the dermis in tion. A103 antibody, which binds to the showed an average number of 5.83
most lesions and often multiple mitoses antigen Melan-A, reacts with the (SD+/- 1.69) AgNORs per nucleus. This
are noted. However, small lesions may melanocytic cells throughout the lesion provided some separation from benign
have very few mitoses. Naevoid {265}. small dermal naevus cells, which had an
melanomas can occupy a portion of a The reactivity of the tumour cells with the average of 2.71 (SD+/- 0.50) AgNORs
pre-existing intradermal or compound antibody MIB-1 to detect the protein Ki- per nucleus. The comparison mean num-
naevus. The melanomas have a relative- 67 in cycling cells is positive in both the ber in 10 superficial spreading
ly uniform population of small cells with upper and lower portions of the tumour. melanomas was 8.49 (SD+/- 1.58)
hyperchromatic angulated nuclei or a In some lesions, the reactivity is slight but AgNORs per nucleus {1316}.
population of medium-sized to large greater in the deep portion than in the
melanoma cells with more open nuclear superficial portion of the lesion. Under Histogenesis
chromatin and pale cytoplasm. controlled conditions, antibodies to Naevoid melanomas may arise from the
Inflammatory reaction usually is slight detect proliferating cell nuclear antigen dermal component of small compound or
and may be absent. The lesions often are (PCNA) have been used to grade intradermal naevi or from the junctional
dome-shaped, polypoid, or verrucous in melanomas {1160,1934}. In specimens component of melanocytes in normal
profile {261,568,1562,1563,2092,2543, with varied fixation conditions, PCNA has skin, or a pre-existing small naevus or
2596}. not been found to be reliable because it lentigo. It is possible that some naevoid
is sensitive to underfixation and to over- melanomas represent early nodular
Immunoprofile and other special stains fixation in formalin {1563}. Silver staining melanomas lacking an evident junctional
HMB-45 reactivity is variable and may be of nucleolar organizing regions component.
negative or positive {265,1562,1563}. (AgNORs) in 10 small cell melanomas
When positive, aberrant patterns of reac- Prognosis and predictive factors
tivity are common. HMB-45 reactivity Table 2.07 Histological criteria for metastatic Predictive features of naevoid melanoma
may be uniform throughout the dermal spread of naevoid melanoma. prognosis are tumour thickness, mitotic
portion of the lesion even though there is rate, and large cell type. From 3,500
Metastases Mean Mean
no junctional component. This reactivity melanomas, Schmoeckel et al. {2092}
thickness mitotic index
pattern can also be found in blue naevi, selected naevoid melanomas with at
some Spitz naevi, and in so-called deep Without least 5 years of follow-up unless there
penetrating naevi, and combined naevi (n=18) 2.24 mm 0.99/mm2 was earlier metastasis. Thirty-three
{1563,2198}. HMB-45 antibody reacts cases were selected: 18 were disease
with the premelanosomal glycoprotein, With free for at least 5 years. Fifteen had
gp100, and indicates an immature status (n=15) 1.82 mm 2.96/mm2 developed metastases. Eight had died of
of the cell with regard to melanin produc- disseminated melanoma. The “most
Naevoid melanoma 87
important criterion was tumour thick-
ness” (but mitoses also seem important
{1160}):
McNutt et al. {1562} studied 16 naevoid
melanomas and observed that 2 died of
melanoma (both large cell type), and one
was alive with metastases (10 years,
small cell type). Thirteen had wide exci-
sions with no evidence of residual dis-
ease or were lost to follow-up. A B
Zembowicz et al. {2596} selected 20
cases of naevoid melanomas from their
files. Three had died and 6 had metas-
tases. There was a three-year follow-up
on 8 cases, with a mean follow-up period
of 2 years. They conclude: “Naevoid
melanoma, as currently defined in the lit-
erature and in the present study, seems
to have a prognosis similar to that of clas-
sical melanoma.”
Wong et al. {2543} studied 7 cases of C D
naevoid melanoma (two dome-shaped Fig. 2.37 Naevoid melanoma. A The melanocytes are arranged as a sheet rather than as discrete nests.
and five verrucous types) and found B The aggregates of melanocytes do not disperse very much at the base of the lesion, where there is a
local recurrences in 3 and regional dense lymphocytic infiltrate. C Naevoid melanoma and its recurrence. Atypical spindle and epithelioid cells
metastasis in one patient after 2 years, are at the base of the lesion. D Mitotic figure among small and monotonous melanocytes.
with a follow-up of 5 months to 5 years.
Lohmann et al. {1444} studied 10 were thought to deviate from the normal While some of them are naevoid
patients with diagnostically controversial cells by only a single enzyme defect, and melanomas, many have the architectural
lesions who underwent sentinel node greatly resembled normal hepatocytes. patterns of ordinary superficial spread-
biopsy. The differential diagnosis was Initially the minimal-deviation melanomas ing melanomas, lentigo maligna
between Spitz naevus and melanoma. In were characterized as having small cells, melanomas, and acral-lentiginous
5 of the 10 patients, there were sentinel without much cytologic atypia, but they melanomas. In contrast, naevoid
node deposits of tumour in the parenchy- all had the architectural patterns of other melanomas closely resemble a benign
ma. All patients were alive and free of melanomas. As this concept evolved, compound or intradermal naevus in
disease on follow-up of 10 to 54 months. minimal deviation melanomas were divid- architecture. They are all included in the
ed into the following types: blue naevus original concept of minimal deviation
type, Spitz naevus type, halo naevus melanoma. Confusion in terminology
Variants and differential type, borderline melanoma, as well as arises between small cell melanoma and
diagnosis the ordinary minimal deviation what we define as naevoid melanoma.
melanomas. This created considerable This confusion is due to the use of the
Minimal deviation melanoma confusion, particularly since the name terms “small naevoid cell type” in small
In the writings of Dr Richard Reed et al. “minimal deviation” implies a better prog- cell melanomas, just on the basis of cell
{1911}, this category was analogous to nosis, which has not been a consistent size and without restrictions on the archi-
the minimal deviation hepatomas of finding {2255}. Naevoid melanoma as tecture of the lesion. As defined above, a
experimental liver carcinogenesis, which defined here was mixed into the various diagnosis of naevoid melanoma requires
types of minimal deviation melanoma both architectural and cytological mimic-
and was not recognized as a separate ry of a naevus.
category {1911}. The concept of minimal Recently a subtype of small-cell naevoid
deviation melanoma has become so melanoma has been described that
vague that the recommendation has develops predominantly in elderly indi-
been made to stop use of that term. viduals with sun-damaged skin {1313}.
However, there are attempts to clarify the This variant has an atypical lentiginous
definition of minimal deviation melanoma junctional melanocytic proliferation with a
as distinct from naevoid melanoma nested pattern that may be mistaken for
{568}. a junctional naevus. This variant has a
male predominance and the melanomas
Small cell melanoma occur predominantly on the trunk. The
Fig. 2.36 Naevoid melanoma. The lesion has a ver- Melanomas composed of small cells epidemiology suggests that these junc-
rucous profile, easily mistaken for papillomatous have been studied separately by tional lesions may be precursors of lenti-
naevus. Kossard and Wilkinson in 1997 {1317}. go maligna or superficial spreading
88 Melanocytic tumours
melanoma in situ. This type of lesion short-term follow-up. The cases with only they lack an epidermal component and
needs further studies as to whether it a single nodal metastasis have been are composed of small epithelioid cells.
represents a melanoma sui generis or a called metastasizing Spitz naevi. Some
lesion with a high propensity to develop of these lesions fit the restricted definition Early nodular melanoma
further mutations leading to melanoma. It of naevoid melanomas if they do not It is most likely that some naevoid
does not fit into the current restricted def- have a significant junctional component. melanomas are an early stage in the evo-
inition of naevoid melanoma since it has Anecdotal reports indicate that some lution of nodular melanomas.
a prominent junctional component and cases classified as metastasizing Spitz
does not involve the dermis in the early naevus by one institution go to another Desmoplastic/neurotropic melanoma
stages. institution years later with widespread Although some of these lesions could fit
metastases leading to death. The criteria into the definition of naevoid melanoma,
Deep penetrating naevus to distinguish between Spitzoid it is conventional to separate them as a
This type of naevus has a plexiform melanoma, melanoma arising in a Spitz distinct entity. Desmoplastic melanomas
growth pattern in the dermis, and despite naevus, Spitzoid variant of naevoid generally have spindle-shaped cells and
its name “deep penetrating” most of the melanoma, and metastasizing Spitz nae- naevoid melanomas, as defined here,
lesions are restricted to the upper and vus are controversial and require further generally have more epithelioid cells.
middle reticular dermis, giving rise to the investigation. Examination of sentinel Both tumours can present as predomi-
concept of the “superficial form of deep lymph nodes in controversial cases of nantly dermal lesions. Desmoplastic
penetrating naevus” {2127}. The naevus Spitzoid tumours has found a significant melanomas can resemble desmoplastic
cells form cords in the dermis composed number of nodal implants of tumour naevi, especially hypopigmented blue
of large spindled and epithelioid cells {1444}. naevi. Desmoplastic and neurotropic
resembling a combination of the cells in melanomas are best separated from
a blue naevus with cells in a Spitz nae- Proliferative nodules in a congenital naevoid melanomas since they can be
vus. Mitotic figures are very rare and are naevus recognized as a distinct group of
not atypical. They do not have much of Benign proliferative nodules may arise in tumours that has been characterized suf-
an epidermal component unless the the dermis in congenital naevi in some ficiently for diagnosis.
deep penetrating naevus component is very young patients and may be multiple.
part of a combined naevus. They must Distinction from naevoid melanoma may Metastatic melanoma
be distinguished from naevoid be difficult since mitotic figures are pres- The histologic features of naevoid
melanoma, large cell type, which has ent in the dermal nodules of naevus melanoma can be exactly reproduced in
mitoses in the dermis. However, some cells. Features of benign proliferative satellite metastatic papules and nodules
lesions given a diagnosis of deep pene- nodules that have been emphasized are of melanoma in the skin. The lack of an
trating naevus (with mitoses) have multiplicity of nodules of similar sizes and intraepidermal component, confluent
metastasized and may represent exam- appearances, and a gradual blending of growth patterns, sharp circumscription,
ples of naevoid melanomas. the cells of the nodule with the surround- symmetry, and dermal mitotic figures can
ing background congenital naevus cells all be found in metastatic melanoma. A
Spitzoid melanoma at the periphery of the nodules. Sharp diagnosis of naevoid melanoma should
This designation is used primarily for demarcation of the proliferative nodules be made with great caution in an individ-
melanomas that mimic a Spitz naevus. is more common in naevoid melanomas ual with a known history of melanoma.
The presence of a significant junctional arising in the dermal component of a Misdiagnosis of primary naevoid
component and prominent pagetoid congenital naevus {568}. melanoma as metastatic melanoma can
upward migration of large atypical lead to the clinical impression of a
melanocytes distinguish this tumour from Melanoma arising in the dermal metastatic melanoma for which a primary
a naevoid melanoma. If the Spitzoid component of a large or “giant” lesion is never found. On the other hand,
melanoma is almost entirely intradermal, congenital naevus individuals given a diagnosis of naevoid
it is a variant that would fit into the defini- In studies of melanomas arising in giant melanoma, who subsequently rapidly
tion of naevoid melanoma, large cell congenital naevi, many arose from the develop extensive metastases, may
type. dermal component {254,1912,1928}. A actually represent patients with a
significant proportion of such metastatic lesion that resembled a pri-
Metastasizing Spitz naevus melanomas are composed of small, mary naevoid melanoma. Multiplicity of
A small number of lesions given the initial hyperchromatic atypical cells and were lesions resembling naevoid melanomas
diagnosis of Spitz naevi have led to interpreted to be similar to melanoblasts, simultaneously in the same patient points
metastases and even the death of leading to diagnosis of melanoblastoma. toward metastatic disease. However mul-
patients. Some cases have had only a These lesions were highly malignant. tiple naevoid melanomas have been
single lymph node metastasis removed They are a variant that fits the current reported in an immunodeficient patient
without further evidence of disease on definition of naevoid melanoma since {1804}.
Naevoid melanoma 89
Persistent melanoma and local P.J. Heenan
J.C. Maize
metastasis of melanoma M.G. Cook
P.E. LeBoit
Table 2.08
Histological features of persistent melanoma and local metastases of melanoma.
Epidermal component Usually present, with or without a dermal component A. Absent in most cases.
. B. Epidermotropism uncommonly. The dermal component
usually extends beyond a zone of epidermotropism when
present. Sometimes the epidermotropic component is more
extensive, simulating primary melanoma {998}.
Dermal growth pattern The full range of patterns associated with A. Single or multiple symmetrical dermal and/or
primary melanoma. subcutaneous nodules.
B. Diffuse small groups and strands of neoplastic
melanocytes (this pattern occurs in the smallest and
presumably earliest metastases).
Cell type The full range of cell types seen in primary melanoma, Usually monomorphic atypical melanocytic population of
frequently including a mixture of cell types. epithelioid, spindle or small (naevoid) cells.
Epidermal collarette Uncommon Usually present, when nodules of metastatic melanoma are in
the superficial dermis.
Fibrosis Frequently present in zones of regression and in Little or no reactive fibrosis in the stroma of the tumour.
desmoplasia.
Scarring Present in the dermis and often also in the subcutis. Present when the metastasis occurs at the primary
excision site.
NOTE: 1. In cases of persistent melanoma, histological review of the primary excision confirms the presence of in-situ or invasive melanoma (or both) at a margin of excision.
2. The microscopic features of metastatic melanoma involving the scar of the primary excision are the same as those of metastatic melanoma at a site distant from the
scar, with the additional feature of the scar at the site of the completely excised primary melanoma {2573}.
90 Melanocytic tumours
variably pigmented patch adjacent to or
surrounding the scar of the primary exci-
sion site. In some cases there may also
be nodule formation when there is per-
sistent dermal invasion, especially of
desmoplastic melanoma.
Macroscopy
The lesion frequently is a variably pig-
mented, often pale macule with poorly
defined borders. In many cases of per-
sistent desmoplastic melanoma there is
no abnormal pigmentation in the epider-
mis overlying a firm nodule.
Histopathology
In the uncommon event of incomplete
excision of both the epidermal and inva-
sive components of one of the common
forms of cutaneous melanoma, the histo-
logic appearances are those of the origi-
nal tumour, frequently with pagetoid infil-
tration of the epidermis overlying inva-
sive atypical epithelioid melanocytes,
usually with little or no pigmentation,
forming an expansile growth pattern
adjacent to a zone of scarring. More
commonly, the persistent lesion consists
of in-situ melanoma with or without focal
dermal invasion. Persistence of incom-
pletely excised desmoplastic melanoma
may present only sparse, subtle infiltra-
tion of a sclerotic nodule in the dermis
and/or subcutis, containing atypical
spindle cells with hyperchromatic, vari-
ably pleomorphic nuclei and sometimes
only sparse mitoses, distributed singly
and in strands between the collagen
bundles. As in the primary tumour, a
patchy lymphocytic infiltrate may provide
a clue to perineural invasion. Desmo-
plastic melanoma may very closely simu- Fig. 2.39 Persistent melanoma. A Melanoma in-situ at the lateral margin of the excision of a primary
late a surgical scar in the primary lesion melanoma. B "Local recurrence", at the excision site two years later, showing invasive melanoma, exten-
and can be very poorly circumscribed sive adjacent melanoma in-situ and dermal scarring.
{1194}. However it can be distinguished
by its infiltrative pattern beyond the zone
usually expected to be involved with scarring following surgery. The features excision of melanoma may be due to the
of persistent desmoplastic/neurotropic coincidental growth of an entirely new
melanoma may be seen proximal or dis- and distinct tumour such as dermatofi-
tal to the scar at the primary excision site, broma or pigmented basal cell carcino-
along the line of nerves. ma. The most important differential diag-
In assessing locally recurrent melanoma nosis, however, lies between true persist-
it should always be remembered that ence of incompletely excised primary
melanoma metastases may be epider- melanoma and the other form of “local
motropic and simulate primary recurrence” due to metastatic mela-
melanoma {998}. noma. Metastatic melanoma in or adja-
Fig. 2.38 Local melanoma metastasis. So-called cent to the primary excision scar usually
"local recurrence" of melanoma in the scar at the Differential diagnosis presents as a rapidly growing papule or
excision site of a primary melanoma completely Rarely, pigmentation of the epidermis or nodule without pigmentation of the over-
excised with a margin of 25mm. growth of a nodule at the site of previous lying dermis, sometimes associated with
Persistent melanoma 91
multiple similar, rapidly growing lesions
separate from the primary excision site.
Histologically, metastases involving the
scar present exactly the same features
as cutaneous metastases at a distance
from the scar {2573}
Histogenesis
Persistent melanoma occurs because a
primary melanoma was incompletely A B
excised. The histogenesis, therefore, is
essentially that of the original melanoma.
Somatic genetics
The genetic factors are those that apply
to the original melanoma.
92 Melanocytic tumours
Congenital melanocytic naevus H. Kerl
D. Massi
P.E. LeBoit
B.C. Bastian
A B C
Fig. 2.41 Congenital melanocytic naevus, superficial type. A Papule with brown to black colors and a mamillated surface. B Band-like infiltrate of melanocytes in
the upper dermis. Adnexocentric arragement and "splaying" of melanocytes between bundles of collagen in the upper and mid-portion of the reticular dermis.
C Monomorphous melanocytes around and focally within an arrector pili muscle.
congenital naevi; dermal variant of mini- entire dermis and often extending into seven out of nine cases showed chromo-
mal deviation melanoma in a giant con- the septa of the subcutaneous fat can be somal aberrations {175}. Six of the seven
genital naevus {1907}, dermal melano- observed. cases with aberrations (86%) showed
cytic tumour of uncertain potential in a The “proliferative“ nodule, which is usual- numerical aberrations of whole chromo-
giant congenital naevus. ly found in the upper and mid dermis somes exclusively. This pattern differs
consists of roundish epithelioid or spin- significantly from the findings in
Clinical features dled melanocytes. The cells are large melanomas arising in congenital naevi or
There is usually a dark brown to black and appear to blend with the surround- melanoma in general in which the major-
plaque or nodule above a giant congen- ing smaller melanocytes (naevus cells). ity (96%) have aberrations involving only
ital melanocytic naevus. The lesions may Atypical nuclei and mitotic figures can be partial chromosomes {173}. Loss of chro-
become lighter and show regression observed. mosome 7 was seen in three of the nine
after years. Occasionally a palpable proliferative nodules. Loss of chromo-
mass can be found deeply in the skin. Differential diagnosis some 7 was not observed in 132
These nodular proliferations in congenital Proliferative nodules in congenital melanomas that were not associated with
melanocytic naevi behave in a benign melanocytic naevi can be misinterpreted giant congenital naevi {173}. However,
fashion. as a melanoma that developed in the one melanoma arising in a congenital
intradermal component of a congenital naevus in an eight-year-old boy showed
Histopathology naevus (see Melanoma arising in giant a similar loss of chromosome 7.
The background congenital melanocytic congenital naevi) {1009}.
naevus reveals the characteristic fea-
tures of a congenital melanocytic naevus Somatic genetics
of the deep type. A dense diffuse infil- In a study of proliferative nodules using
trate of small melanocytes involving the comparative genomic hybridization
94 Melanocytic tumours
Blue naevi E. Calonje
K. Blessing
E. Glusac
G. Strutton
Common blue naevus Clinical features lesions often display prominent sclerotic
The most common presentation consists stroma making the diagnosis difficult.
Definition of a single asymptomatic, relatively well- Lesions with very poor pigmentation are
Common blue naevus (BN) is a benign, circumscribed, dome-shaped blue or rarely encountered {234,402}. Tumour
usually intradermal melanocytic lesion blue-black papule less than 1 cm in cells are bland and spindle-shaped or
characterized by pigmented dendritic diameter. The characteristic blue colour dendritic and usually contain abundant
spindle-shaped melanocytes and, more is produced by the Tyndall effect. cytoplasmic coarse melanin pigment.
rarely, epithelioid melanocytes. The Tumours may rarely present as a plaque Nuclei are small, and an inconspicuous
melanocytes are usually separated by {1025,2494}. Eruptive lesions have rarely basophilic nucleolus is sometimes pres-
thickened collagen bundles. been documented. Exceptional clinical ent. Numerous melanophages are a rela-
presentations include a speckled variant tively constant feature in the vicinity of
ICD-O code 8780/0 {1044}, hypopigmented lesions {278}, an tumour cells. Extension of tumour cells
example with satellite lesions {1195} and into nerves and, less frequently, blood
Epidemiology a case with widespread lesions. vessel walls, may be found. Mitotic fig-
BN is relatively frequent, has predilection Localized hypertrichosis has been ures are exceptional. Rarely, a blue nae-
for females and presents mainly in young described in a single case {57}. vus may coexist with a trichoepithelioma
adults between the second and fourth {48}.
decades. Although most tumours are Histopathology In some instances, metastatic melanoma
acquired, congenital examples have BN and cellular blue naevus show a wide may mimic common blue naevus {354}.
been documented {1872}. Familial cases histological spectrum, frequently over- Blue naevus may co-exists with other
may be seen and usually present with lapping with other melanocytic lesions types of naevus (see combined naevus).
multiple lesions {258,1292}. including deep penetrating naevus and
pigmented Spitz naevus {1637}. Immunoprofile
Localization BN is typically located in the reticular Tumour cells are usually diffusely positive
The anatomical distribution is wide but dermis and only exceptionally extends for melanocytic markers including S-100,
most lesions occur on the distal upper into the papillary dermis or subcutis. The HMB45, melan A and microphthalmia
limbs (particularly the dorsum of the epidermis appears unremarkable, transcription factor (MITF-1). Unlike the
hand), followed by the lower limbs, except in the rare so-called compound case in most other benign melanocytic
scalp, face and buttocks. Lesions have blue naevus, in which dendritic junction- naevi and in melanomas, HMB45 strong-
also been documented in the vagina al melanocytes are identified {733, ly stains the entire lesion in blue naevi.
{1002,2356}, cervix {2393}, prostate 1190}. Low power examination reveals a
{1414}, oral cavity (mainly the hard generally symmetric but often ill-defined Somatic genetics
palate) {327,328} and the capsule of tumour of variable cellularity. Concen- Mutations in the BRAF gene appear to be
lymph nodes without a primary cuta- tration around adnexa without adnexal rare in BN. Chromosomal aberrations are
neous lesion {695,858,1497}. destruction is typical. Poorly cellular uncommon {1490}.
A B C
Fig. 2.44 Common blue naevus. A Typical clinical appearance of a common blue naevus. B A more cellular example with hyalinization of dermal collagen.
C Melanocytes often extend into the perineurium of dermal nerves.
Blue naevi 95
A B C
Fig. 2.45 A Mongolian spot. Typical prominent macular blue/grey discolouration on lower back and buttocks. B Naevus of Ota with involvement of the periorbital
skin and conjunctiva. The blue cast is typical. C Naevus of Ota. Bipolar, deeply pigmented melanocytes in the reticular dermis.
Prognosis and predictive factors appear unremarkable. Low power exam- the nasal and oral mucosa, optic tract
BN is benign, and malignant transforma- ination reveals a mild increase in cellular- and the leptomeninges are involved.
tion is exceptional {883} (see chapter ity in the deep reticular dermis, consist- Lesions identical to naevus of Ito or nae-
Melanoma arising from blue naevus). ing of few variably pigmented dendritic vus of Ota may present rarely in other
Simple excision is curative and local melanocytes, which are usually, oriented anatomical sites. A limited form resem-
recurrence is very rare {973}. parallel to the epidermis. Melanophages bling naevus of Ota presenting in the
are occasionally seen. zygomatic area is called naevus of Sun.
Mongolian spot
Clinical features
Definition Naevus of Ito and Lesions are usually large, macular, ill
Mongolian spot (MS) is a form of dermal Naevus of Ota defined and have a blue or blue-grey
melanocytosis presenting on the lower colour. A speckled appearance is seen
back and characterized by scattered Definition rarely. There is no tendency for sponta-
pigmented dendritic melanocytes in the Naevus of Ito (NI) and naevus of Ota neous regression. Bilateral involvement
reticular dermis. (NO) are dermal melanocytoses with has been documented rarely {1026}. Co-
identical histological features, which dif- existence between NI and NO is a rare
Epidemiology fer in their characteristic clinical presen- occurrence {615,1026}. Glaucoma is a
MS presents at birth and has marked tation. NI typically presents in the shoul- rare complication of NO {1434}.
predilection for Black and Oriental der region, following the distribution of
patients with the same sex incidence the lateral brachial and posterior supra- Histopathology
{1260,1261}. The incidence in Caucasian clavicular nerves. NO involves the skin The histology of NI and NO is indistin-
children is approximately 9.5% {543}. and mucosal surfaces (including the guishable. The epidermis appears unre-
conjunctiva), following the distribution of markable but may show increased
Localization the ophthalmic and maxillary branches of melanin in basal cells and a mild
Most lesions occur on the lower posterior the trigeminal nerve. increase in the number of basal melano-
trunk with predilection for the sacro- cytes. In the superficial and mid-dermis
gluteal region. Lesions identical to MS Synonyms there are scattered dendritic or spindle-
and naevus of Ito or naevus of Ota may Naevus Ota: Oculodermal melanocyto- shaped, often bipolar deeply pigmented
present rarely in other anatomical sites. sis, Naevus fuscoceruleus ophthalmo- melanocytes. Melanophages are rare.
maxillaris.
Clinical features Prognosis and predictive factors
MS is characterized by a macular area of Epidemiology Malignant transformation is exceptional
blue-green or blue-grey discolouration Both NI and NO are relatively rare, affect and more common in NO {1783,2194,
varying in size from a few to 10 or more mainly patients of Oriental or African ori- 2345,2414}. In the latter setting it may
cm. Lesions fade gradually, usually dis- gin and have some predilection for occur in the skin, eye or meninges.
appearing completely when patients females {1027,1307,1626,2243}. Presen-
reach adolescence. tation is mainly at birth (up to 50%) or
Association with cleft lip {1096} and the during childhood and adolescence. Cellular blue naevus
mucopolysaccharidoses, including Hur- Adult onset is very rare {447}.
ler and Hunter syndromes) {880, 2063} Definition
has been documented. Lesions with the Localization Cellular blue naevus (CBN) is an
clinical and histological features of MS NI typically involves the supraclavicular, acquired dermal/subcutaneous pigment-
may rarely present at other body sites. deltoid and less commonly, the scapular ed tumour with prominent cellularity and
area. NO usually involves the sclera, an expansile growth pattern.
Histopathology conjunctiva, and skin around the eye and
The epidermis and superficial dermis zygomatic and temporal areas. Rarely ICD-O code 8790/0
96 Melanocytic tumours
Epidemiology cellular areas may alternate with sclerot-
CBN tends to present between the sec- ic or hypocellular areas. In most cases
ond and fourth decades of life with there are focal areas representing or sim-
female predilection, and it is more com- ulating a common blue naevus. High
mon in Caucasians. Congenital cases power examination reveals bundles of
are exceptional {1095}. oval or spindle-shaped cells with pale
cytoplasm, alternating with bundles of
Localization deeply pigmented spindle-shaped cells.
The anatomical distribution is wide, but In addition, dendritic melanocytes and/or
CBN have predilection for the buttocks round, somewhat epithelioid melano-
and sacral region (50% of cases), fol- cytes may be seen. Cytoplasmic melanin
Fig. 2.46 Cellular blue naevi on the upper back.
lowed by the scalp, face, distal limbs and is coarse and granular, and nuclei are
other sites on the trunk {1957,2336}. regular and vesicular, with a single small
Lesions may also rarely occur on the usually present with multiple lesions inconspicuous basophilic nucleolus.
eyes, cervix, vagina, breast and sper- {396,399}. Sporadic lesions are usually Maturation with depth is not a feature. A
matic cord {266,1957,2336}. Aggregates solitary and may occur in genital skin frequent finding however, is the focal
of tumour cells have been reported in the {1117,1646,1736}. presence of elongated slender melano-
capsules of regional lymph nodes drain- cytes resembling Schwann cells, indica-
ing an area where an otherwise typical Macroscopy tive of neurotization as seen in ordinary
benign cellular blue naevus is present The cut surface of a CBN characteristi- naevi. Some tumours exhibit a focal alve-
{287,1957,2261,2336}. This phenome- cally shows a dark brown to black, well- olar growth pattern {1597} and desmo-
non is regarded as a benign occurrence defined dermal and subcutaneous plasia is occasionally prominent {1599}.
rather than an ominous finding. tumour. In some cases there are areas of Degenerative changes including haem-
haemorrhage and cystic degeneration. orrhage, cystic change and fibrosis, are
Clinical features seen in some cases. Focal mild or promi-
Tumours are usually large, varying from 1 Histopathology nent myxoid oedematous change may
to several centimetres, and the colour Low-power examination reveals a fairly also be a feature {1598}, and balloon cell
varies from light blue-brown to dark blue. characteristic picture with a dumbbell- change has been documented {1806}.
Lesions are asymptomatic and grow very shaped multinodular tumour occupying Occasional cases display a number of
slowly, presenting as a non-ulcerated the reticular dermis and often extending unusual features including mitotic figures
firm nodule {1957,2336}. Exceptional into subcutaneous tissue. A junctional (1/10 HPFs), focal necrosis, and/or
cases present as a large plaque {358}. component is not usually found. Areas of nuclear pleomorphism or hyperchroma-
Rare tumours arising in the scalp have pigmentation alternate with poorly pig- tism. Such cases show some overlap
been described with invasion of the mented areas and, in a minority of cases, with the malignant variant of CBN and
underlying bone {1596} and even the pigment is very scanty {2595}. Cellular have been described as atypical CBN
brain {854}. areas tend to be more prominent towards {118,2371}.
The epithelioid variant of blue naevus is the centre of the tumour, and the cellular- The epithelioid blue naevus is composed
very rare and has mainly been described ity may be most marked where the neo- of large round epithelioid and short spin-
in patients with Carney complex who plasm protrudes into the subcutis. The dle-shaped deeply pigmented melano-
A B C
Fig. 2.47 Cellular blue naevus. A Typical low-power appearance with a dumb-bell architecture. B Bundles of bland spindle-shaped melanocytes alternating with
focally pigmented cells. Scattered melanophages are also seen. C Typical small vesicular nuclei with a small basophilic nucleolus.
Blue naevi 97
A B A
C D B
Fig. 2.48 Hypopigmented cellular blue naevus. A In some cases, melanin is almost completely absent. Fig. 2.49 Cellular blue naevus. A This lesion has a
B Myxoid change may be prominent in some cases. C One of the melanocytes is much larger than the oth- central focus of cystic change. B The edge of the
ers. Some refer to such cases as ‘atypical cellular blue naevus’. D Large melanocytes are present, some cystic area.
are multinucleated.
cytes. Some examples of this variant of Deep penetrating naevus mented dermal and, very rarely, superfi-
BN probably represent combined naevi cial subcutaneous tumour. The base of
{903}. Definition the lesion parallels the epidermis. The
Deep penetrating naevus (DPN) is a dis- junctional component, which is usually
Immunoprofile tinctive deeply pigmented lesion show- present and may be subtle, consists of
Tumour cells in CBN are positive for S- ing overlapping features with blue nae- small round nests of ordinary naevus
100, melan-A and HMB45. In tumours vus and Spitz naevus. cells. In fact, in most cases, a superficial
with prominent desmoplasia, and in dermal component, representing an ordi-
those with neurotization, staining for Synonym nary naevus, may be found and therefore
melan-A and HMB45 tends to be patchy. Some cases have been described under these lesions may be regarded as com-
CD34 has been reported to be positive in the heading of plexiform spindle cell bined naevi {1953}. Much less common-
tumour cells in a group of congenital naevus {164}. ly, focal changes mimicking a Spitz nae-
CBN {2204}. vus or a blue naevus are found {1953,
Epidemiology 2127}. Tumour cells are arranged in
Genetics DPN is an acquired lesion presenting nests or bundles and have a short spin-
Similar to other naevi, cellular blue naevi mainly between the second and third dle-shaped or, less commonly, round
do not show chromosomal aberrations decades of life with no sex predilection morphology. The cytoplasm contains
when analysed by CGH. In a small series {1953,2127}.
of atypical cellular blue naevi, three out
of eight cases showed single chromoso- Localization
mal losses with chromosome 3p being DPN has a wide anatomical distribution
affected in two of these cases {1490}. with predilection for the face, upper trunk
and proximal limbs {164,537,1575,1953,
Prognosis and predictive factors 2127}.
Although limited case series have char-
acterized these lesions as benign, some Clinical features
cases with atypical features have result- The tumour presents as a solitary, well-
ed in recurrences or death from systemic circumscribed blue or dark brown/black
metastasis. They may therefore be dome-shaped papule or nodule usually
regarded as having uncertain malignant less than 1 cm in diameter.
potential and treated with complete exci-
sion if possible and perhaps long term Histopathology
follow-up. Malignant transformation in Low power examination typically reveals Fig. 2.50 Deep penetrating naevus with a typical
CBN is very rare {64,883}. a compound wedge-shaped deeply pig- wedge-shaped architecture.
98 Melanocytic tumours
abundant melanin and nuclei are vesicu-
lar with frequent intranuclear inclusions
and a single small basophilic nucleolus.
Hyperchromatism and variation in
nuclear size may be seen, but as a rule
mitotic activity is low or absent (usually
not more than 1 per section). The
melanocytes follow the path of adnexal
structures and blood vessels and there is
frequent perineural extension. Maturation
is not seen. Some tumours have the cyto-
morphology of DPN but are superficial
and lack the deep penetrating compo-
nent. Similar changes are seen in a com-
mon form of combined naevus.
A B
Prognosis and predictive factors
Local recurrence is exceptional, and only
a single case has been reported spread-
ing to a regional lymph node {874}.
C D
Fig. 2.51 Deep penetrating naevus. A A wedge shape and nests of cells around adnexal structures are char-
acteristic findings. B The large pale cells in a deep penetrating naevus are arranged as discrete nests.
C A thin rim of sustentacular cells is present around the edges of many nests. D Toward the base of the
lesion nests of pale large cells are present near adnexal structures.
Blue naevi 99
Combined naevus R.L. Barnhill
Definition cases, the head and neck in 23.6%, Table 2.09 The naevus components potentially
A combined naevus or “melanocytic nae- upper extremities in 22.0%, lower occurring in combined naevus
vus with phenotypic heterogeneity” is a extremities in 9.9%, and perineum and
melanocytic naevus either congenital or buttocks in 4.4% {2116}. Naevi with a sig- Common acquired naevi
– junctional
acquired, containing two or more distinct nificant blue naevus component com-
– compound
melanocytic naevus components. monly involve the face, back, and shoul-
– dermal
der {757}. Naevi with prominent compo- Congenital naevi
Synonyms and historical annotation nents of Spitz naevus often occur on the – junctional
Melanocytic naevus with phenotypic het- head and neck (face) or extremities as – compound
erogeneity; inverted type A naevus; nae- do conventional Spitz naevi {1961}. – dermal
vus with focal dermal epithelioid compo- Dysplastic naevi (naevi with architectural dis-
nent, and naevi with dermal nodules. Clinical features order and cytological atypia)
The term combined naevus was used ini- The gross morphological features of – junctional
tially to describe the combination of a combined naevi are probably related to – compound
Blue naevi
conventional naevus and blue naevus the types of and predominant cellular
– ordinary or common
{61,653,702,1402,2331}. However, the populations present, e.g., focal dermal
– hypercellular
spectrum of combined naevus has been pigmented components, blue naevus, – cellular
subsequently extended to include com- Spitz naevus, etc. Most of these naevi – plaque
ponents of any type of naevus (Table measure less than 5 to 6 mm in greatest – epithelioid
2.09){135,156,520,1610}. There may be diameter {156,757,1864,2116}, are rea- Spitz naevi
poor concordance in the interpretation of sonably symmetrical, are well-circum- – junctional
some cases, because of overlapping scribed papular or dome-shaped – compound
features and the difficulty of defining the lesions, and exhibit dark brown, blue to – dermal
morphological limits of blue naevi, Spitz black colouration. Thus many such naevi – desmoplastic
Deep penetrating naevi
naevi, deep penetrating naevi, plexiform are often diagnosed clinically as blue
Plexiform pigmented spindle cell naevi
pigmented spindle cell naevi, and naevi naevi or melanoma because of the pre-
Naevi with dermal epithelioid cell components
with dermal epithelioid cell components. dominant dark colour. Some of these (clonal naevus)
naevi may also demonstrate a small well- – inverted type A naevus
Epidemiology circumscribed blue or blue-black focus, – naevus with dermal nodules
There are no population-based data e.g., often 1–3 mm in diameter, within an Other
available as to the prevalence of com- otherwise ordinary flesh-coloured, tan, or
bined naevi. However they appear to brown naevus (melanocytic naevi with
constitute less than 1% of melanocytic focal dermal pigmented components) nents are intimately admixed in 82% of
naevi sampled for histopathological {135,156,520,757,2116}. Some naevi cases whereas they are adjacent in the
examination {2116}. These naevi occur in may show irregular borders and pigment remainder. The most common pattern of
all age groups (3 to 83 years in a recent patterns also raising concern for combined naevus is that of a common
study) with a mean age of 30 years melanoma. acquired or congential naevus in combi-
{2116}. A slight predominance of women Naevi with prominent Spitz components nation with discreet foci of pigmented
has been consistently reported in sever- are often diagnosed as an unusual nae- epithelioid and/or spindle cells (which
al studies {757,1864,1961,2116}. vus, Spitz naevus, dermatofibroma, or probably includes inverted type A nae-
The developmental biology of combined possibly melanoma. vus and melanocytic naevus with dermal
naevi has not been delineated. Their epithelioid cell components, dermal nod-
genesis may be related to more than one Histopathology ules, or a component of “deep penetrat-
pathway of melanocytic differentiation Combined naevi may potentially encom- ing” or plexiform pigmented spindle cell
occurring in a single naevus. It cannot be pass the entire phenotypic repertoire of naevus) {158,164,537,2126}. The latter
excluded that there is focal neoplastic melanocytic naevi. By definition two or cells are often enlarged, contain abun-
progression in some proportion of these more distinct naevus components are dant granular melanin, and are disposed
lesions. present. Any combination of naevus in nests or fascicles in the superficial,
components and percentage of the nae- superficial and deep, or deep portions of
Localization vus components may occur. However or beneath the ordinary naevus, some-
Scolyer et al. found a predilection for the 99% of combined naevi have only two times or commonly in plexiform arrange-
trunk (chest, back, abdomen) in 35.2% of components {2116}. The two compo- ments. The sizes of the nests or fascicles
C D
Fig 2.52 Combined naevus. A Combined naevus (melanocytic naevus with phenotypic heterogeneity). The lesion is well-defined with central dark brown papule and
lighter brown annulus (Courtesy of Harold Rabinovitz, M.D.). B There is a conventional compound naevus with small fairly discrete aggregates of heavily pigment-
ed cells in the dermis. C This field shows small nests of pigmented polygonal melanocytes and melanophages admixed with the background conventional naevus.
D The pigmented polygonal melanocytes have abundant cytoplasms and contain nuclei that resemble those in the surrounding small naevus cells. The polygonal
cells show transition to the surrounding conventional cells.
may vary from being minuscule to large melanocytes, melanophages, and vari- combination of cell types is possible
lobular or digitate aggregates. The nuclei able fibrosis. Less commonly, the spindle {156,2116}. Thus, one may encounter
are usually comparable in size to the sur- cells typical of cellular blue naevus may naevi containing various admixtures of
rounding conventional naevus cells, or also be present with or without dendritic ordinary naevus cells, dendritic
may be slightly enlarged round, oval, or cells. The component of blue naevus melanocytes, Spitz naevus cells, and
elongate and uniform. On occasion the may extend deeply into the reticular der- perhaps other transitional cell types.
nuclei may show variable often slight to mis as nests or fascicles, often in a plex- Atypical features may also be observed
moderate atypia. Melanophages are also iform configuration. Despite the two or such as disordered patterns of melano-
frequently associated with these pig- more components, such naevi are usual- cytes and cytological atypia of both the
mented foci. This pattern of combined ly symmetric, well-circumscribed, order- intraepidermal and dermal components.
naevus is also probably morphologically ly, and display little or no cellular atypia.
identical to that of deep-penetrating nae- Spitz naevi uncommonly are observed in Somatic genetics
vus and plexiform pigmented spindle cell association with ordinary naevus ele- The conventional naevus component will
naevus {158,164,537,2126}. ments {1961}. The topographic relation- demonstrate frequent BRAF mutations in
Another common pattern is that of an ships of these two components include contrast to their absence in blue or Spitz
ordinary naevus and blue naevus. The the Spitz naevus component being adja- naevus components.
ordinary naevus component may be cent to, beneath, or admixed with the
compound or dermal, often overlies or is common naevus elements. Such naevi Differential diagnosis
adjacent to the blue naevus component, also may have a desmoplastic stroma as The differential diagnosis of combined
and commonly has a congenital pattern. in desmoplastic Spitz naevi. naevus is dependent on the particular
The blue naevus elements most often After the above relatively well-recognized cellular populations present. The histo-
consist of heavily-pigmented dendritic forms of combined naevus, almost any logical feature often of most concern is
Melanotic macules ineum, the introitus, vagina and cervix. Reticulated melanotic macule
They may be difficult to distinguish from These lesions appear on sun-exposed
Definition melanoma {1400}. areas of the trunk or shoulders as a dark-
Melanotic macules are pigmented brown or black reticulated macule with
lesions that occur on skin, mucous mem- Penile melanotic macule irregular borders.
branes, and in nail units {2035}. The This lesion usually presents in adult life Although the lesion has been named
lesions are characterized by hyperpig- as a pigmented patch, uniform or varie- “reticulated black solar lentigo” {277}, it
mentation of the epidermal/epithelial gated in colour with irregular borders, on is different from the conventional solar
basal layer accompanied by a slight the glans penis or on the penile shaft. lentigo {1171}.
increase in number of melanocytes. Multiple macules can be observed.
There are several syndromes, which are PUVA-lentigines
associated with multiple melanotic mac- Labial melanotic macule PUVA-lentigines are pigmented macules,
ules/lentigines (Peutz-Jeghers, NAME, The lesion occurs in about 3% of per- which develop as a direct response to
LAMB, LEOPARD, Carney complex (See sons, mostly in women on the vermilion the effects of long-term therapy with
Chapter 7). border of the lower lip. The lesions can PUVA (psoralens + UVA).
be also present on the oral mucosa and
Synonyms on the tongue. A single or multiple (oral Histopathology
Genital: Genital melanosis/lentiginosis; melanosis), brownish-black or black Similar histopathologic changes can be
Vulvar melanotic macule; penile melanot- macules with irregular sharply demarcat- demonstrated in all types of melanotic
ic macule; penile lentigo. ed borders can be observed {925}. macules. There is usually no perceptible
Labial/oral: Labial/oral melanosis; labial or a slight increase in the number of
melanotic macule; labial lentigo. Variants melanocytes, which are situated at the
Volar: Volar melanosis. Volar melanotic macule dermo-epidermal junction in solitary
Nail apparatus: Melanosis of the nail bed Clinically a brown, tan, or grey macule units. The melanocytes exhibit small and
and matrix; ungual melanosis. (less than 5 mm in diameter) is located monomorphous nuclei and delicate den-
Skin: Reticulated black solar lentigo; “ink on palms and soles usually in Black drites. Using Fontana-Masson silver
spot” lentigo. patients. stain, the dendrites are better visible.
Atypia is not observed. The basal layer
Clinical features Ungual melanotic macule reveals prominent hyperpigmentation.
Melanotic macule of vulvar and other Pigmented bands (not thicker than 3 Occasionally hyperplasia of the epider-
female genital sites mm) are observed in the fingernails of mis can be seen. Melanophages and a
The condition occurs usually on the vulva young individuals (longitudinal melano- mild inflammatory infiltrate are often
as a flat asymmetric macule with a dia- nychia). The lesions are common in dark- present in the superficial dermis.
meter from less than 1–5 cm. Multiple skinned races and in the Japanese pop- Reticulated melanotic macules show
lesions are present in >50% of the cases. ulation. In Laugier-Hunziker syndrome, marked hyperpigmentation of the epider-
The tan-brown to blue-black macules longitudinal melanonychia is accompa- mis especially at the tips of the rete
mostly involve the labia minora. But they nied with labial/oral melanotic macules. ridges whereas the suprapapillary plates
can also occur on the labia majora, per- are spared and nearly devoid of melanin.
A slightly increased number of finely
dendritic melanocytes can be observed
in the lower layers of the epidermis. In
contrast, solar lentigo represents an
evolving seborrhoeic keratosis revealing
small buds or nubbins of hyperpigment-
ed keratinocytes.
PUVA-lentigines are characterized by an
increased number of melanocytes, which
are concentrated mostly in pigmented
rete ridges as solitary units. Some
A B melanocytes may show atypical nuclei.
Fig. 2.53 Melanotic macule on the lip. A Brown-black macule with irregular margins on the lower lip.
B Pigmentation of the epithelial basal layer and melanophages in the papillary dermis.
Synonyms
Lentigo simplex, naevus incipiens.
B Clinical features
Small flat roundish uniform brown or
black sharply circumscribed macules
usually less than 6 mm in diameter, which
are most frequently found on the trunk
and extremities of children and adults,
are observed.
Histopathology
Simple lentigo consists of an increased
number of melanocytes disposed as soli-
tary units in the basal layer of variably
A C elongated and hyperpigmented rete
Fig. 2.54 Simple lentigo - Lentiginous melanocytic naevus. A Small uniform brown macules; (stars) simple ridges. The melanocytes have small
lentigo. (arrows) lentiginous melanocytic naevus. B Simple lentigo. Increase in the number of melanocytes round to oval and monomorphous nuclei.
in single units along the basal layer - especially around elongated hyperpigmented rete ridges. Distinct They are positioned equidistant from one
nests are absent. C Lentiginous melanocytic naevus. Features of lentigo simplex can be recognized. The another and are seen more pronounced
aggregation of melanocytes in tiny nests indicates the transformation of this lentigo simplex into a lentigi- at the tips of the rete ridges. Pigment is
nous melanocytic naevus.
abundant and found throughout the epi-
dermis including the stratum corneum.
Differential diagnosis tional sampling, over time if indicated. If Melanophages are usually present in the
Early stages of melanoma in situ must be the problem cannot be resolved com- papillary dermis. Giant melanosomes
differentiated from melanotic macules. plete excision may be appropriate. can be present.
Melanoma in situ (genital / labial areas) When one or more small nests of
can manifest as a sparsely cellular prolif- melanocytes (i.e. three or more melano-
eration of melanocytes. Sometimes in a Simple lentigo – lentiginous cytes per congregation) in such a lesion
partial biopsy the only clues are nuclear melanocytic naevus is observed, it is then called lentiginous
hyperchromasia or irregularly shaped naevus (evolving junctional naevus).
dendrites. In more fully developed Definition The histology of naevus spilus (congeni-
cases, melanocytes are more regularly Simple lentigo and lentiginous tal speckled lentiginous naevus) is indis-
distributed, can become confluent and melanocytic naevus are pigmented mac- tinguishable from simple lentigo-lentigi-
may also be situated above the junction. ules representing the early stages in the nous melanocytic junctional naevus.
Lesions with more than a slight increase development of a melanocytic naevus. In
in melanocytes, even without atypia simple lentigo, melanocytes are Prognosis and predictive factors
should be carefully evaluated, with addi- increased in number along the basal Melanotic macules have been incorrectly
interpreted as premalignant lesions and
possible precursors of melanoma
{1757A,2394A}. Current evidence sup-
ports the notion that melanotic macules,
irrespective of their location, should be
considered benign in their clinical
behaviour, since they tend to remain sta-
ble and unchanged when followed over a
long period of time.
Simple lentigo and lentiginous melanocy-
tic naevus are wholly benign melanocytic
A B proliferations which have no potential for
Fig. 2.55 Lentiginous junctional melanocytic naevus. A There are elongated rete ridges with increased malignant transformation.
numbers of single melanocytes at their sides and bases, with some tiny junctional nests. B In this exam-
ple, there are lymphocytic infiltrates and fibroplasia of the papillary dermis.
Definition quently, the “B-K Mole Syndrome” was aggregated pigmented lesions (common
Solitary or multiple naevi, variable in renamed to ‘Dysplastic Naevus Syn- acquired naevi and dysplastic naevi)
colour, border, and size, with preferential drome’, with further sub-classification confined to the left upper quadrant of his
location on the upper trunk and extremi- into sporadic or familial types. body. Within this quadrant, two malignant
ties. Dysplastic naevi (DN) occur as spo- In 1992, a U.S. National Institutes of melanomas at different stages of pro-
radic lesions and in a familial setting. Health Consensus Conference recom- gression developed from dysplastic
They may progress to malignant mended “naevus with architectural disor- naevi {2266}. Hidden areas such as the
melanoma. der” in order to avoid the negative con- scalp and genitalia need thorough evalu-
notation associated with the word “dys- ation as dysplastic naevi may be seen in
ICD-O code 8727/0 plasia” {1}. However, this term has failed these areas {731,2029}. In Greene’s orig-
to gain wide acceptance {2153}. inal description, it was noted that unlike
Synonyms In a recent survey by the American ordinary moles, dysplastic naevi are
Atypical naevus {896} has been pro- Academy of Dermatology, 98% of often found on the scalp, buttocks and
posed as a synonym for clinically dys- respondents recognized the dysplastic female breast {897}. Lesions on the
plastic naevus. Other past designations naevus as a distinct entity {2373}. scalp, genitalia and upper back should
include naevus with architectural disor- be considered for excision due to the dif-
der {1}, and melanocytic naevus with Epidemiology ficulty with patient self-examination of
architectural disorder and cytologic atyp- The estimated total number of individuals these locations {749}, although careful
ia {1,2158}. The concept of Clark naevus affected by the familial form is approxi- follow-up is a reasonable alternative.
includes a large number of junctional mately 32 000 in the United States
and superficial compound naevi of which {1320}. Clinical features
the dysplastic naevus is a subset. Sporadic, histologically dysplastic naevi Patients may have one, several or up to
are seen in up to 50% of White adults, hundreds of lesions. In one study,
Historical annotation depending on how the lesion is defined. patients who had DN outside the familial
Originally, Wallace H. Clark and cowork- {535,571,1828}. The estimated preva- melanoma setting had an average of 10
ers described patients with multiple atyp- lences of dysplasia in a population per person {157}. The clinical features
ical naevi for which they proposed the based series of naevi ranged from 7-32% originally ascribed to DN included ill-
term “B-K mole syndrome”, using the first {1829}. The prevalence of clinically defined or irregular border, irregularly
initial of the surname of two probands defined dysplastic naevi also varies distributed pigmentation, background
{496}. The authors photographically doc- according to the criteria used, ranging erythema, and size greater than 5 mm
umented two lesions that progressed from 5–20%. {496,2029}. Lesions often differ from one
over time to malignant melanoma. another in the same individual and in
Therefore, the authors considered the “B- Etiology addition, they are often different between
K mole” a precursor of melanoma. Soon Ultraviolet radiation has been implicated individuals {778}. Some lesions may
thereafter, in 1980, Elder et al found in the genesis of dysplastic naevi and have a central papular component with a
lesions similar to those in “B-K mole” melanoma. Noz et al found higher in vitro macular flare that blends into surround-
patients with non-familial cutaneous sensitivity to DNA damage by ultraviolet ing tissue resulting in an ill-defined, fuzzy
malignant melanoma {673}. Subse- B radiation in melanocytic naevus cells periphery. The surface texture has been
compared to foreskin melanocytes described as “pebbly” {2476}. Other
{1732}. One recent study found an lesions are macular or plaque-like with-
increased relative risk for melanoma in a out a central papule or nodule. Irregula-
dysplastic naevus group with poor in rities in pigment range from tan to dark
vitro DNA repair capacity {1360}. brown to black. There are often areas of
pink and some lesions are amelanotic.
Localization Characteristically, lesions first appear
Dysplastic naevi can occur anywhere on around the time of puberty and if they are
the body but are most commonly found not apparent by age 20, it is unlikely that
on the trunk {496}. In females, there may an individual has the familial melanoma/
be a considerable number on the legs dysplastic naevi trait {897}.
{5559}. A “quadrant” form of dysplastic
Fig. 2.56 Dysplastic naevus. A solitary leasion on naevus distribution has been reported Diagnostic criteria
the abdomen. Note the variegated appearance. where a 59-year-old man had numerous The Dutch Working Group produced five
as in no case are the atypical cytologic Growth fraction / MIB-1 index Electron microscopy
features as frankly atypical as seen in Some authors assert that the presence of The melanosomes in epidermal
fully developed melanoma. the proliferation marker Ki-67 in dysplas- melanocytes in dyslastic naevi are
tic naevi indicates that these lesions are abnormal, with incompletely developed
Immunoprofile precursors to melanoma {760}. The per- lamellae and uneven melanization
Mild to moderate staining of dysplastic centage of cells that expressed Ki-67 {2476}. Abnormal spherical and partially
naevi is observed using antibody to was an independent prognostic factor melanized melanosomes similar to those
HMB45 antigen. This antibody also often {1308}. Kanter et al found that percent- observed in superficial spreading
stains intradermal melanocytes within ages of MIB-1 immunoreactivity in the melanoma have been observed by elec-
melanomas but not as strongly in com- intradermal portion of the lesions was tron microscopy {672,1363}. Based on
mon melanocytic naevi {2214}. S-100 is a negligible for benign congenital and these transmission electron microscopy
protein found in the central nervous sys- acquired naevi, as well as in dysplastic findings, one group suggested that dys-
tem that is also present in melanocytes, naevi compared to melanomas which plastic naevi lie on a continuum between
including melanoma. S-100 protein is exhibited a markedly increased prolifera- naevi and superficial spreading
found at the dermo-epidermal junction tive activity, especially vertical phase melanoma. No correlation has been
and at all levels of the dermis in dysplas- melanomas {1201}. At the current time, it shown prospectively between ultrastruc-
tic naevi {1792}. However, S-100 staining is not recommended that proliferation tural findings and progression or
is non-specific as it is seen in common markers be used as a reliable method for predilection to the development of MM.
naevi, dysplastic naevi as well as malig- distinguishing between naevi and
nant melanoma. melanoma.
A B
Fig. 2.58 Dysplastic naevus. A The junctional component shows both architectural and cytological atypia. There is a mild, superficial perivascular lymphocytic infil-
trate. B Mild atypia of the junctional nests and dermal papillary fibroplasia.These is some melanin incontinence.
Variants ria for grading dysplastic naevi {1925}. In compared with pooled controls {377}.
Toussaint and Kamino observed 1993, Duncan et al advocated grading However, the criteria used to define
histopathologic changes of “dysplastic” dysplatic naevi into groups based on lesions as “dysplastic” naevi were sub-
naevi in other types of naevi. They also cytology. Dysplastic naevi with slight, jective from the outset so the validity of
noted that some dysplastic naevi demon- moderate and severe cytologic atypia such studies remains in question.
strated features of other varieties of were differentiated. However, concor- Park and Vortmeyer examined the fre-
naevi. 2,164 cases of compound dance between experienced der- quency of p16 and p53 deletion in nine
melanocytic naevi that fulfilled the matopathologists ranged from 35% to dysplastic naevi and 13 benign intrader-
histopathologic criteria for the diagnosis 58%. Because of lack of reproducibility, mal naevi with five microsatellite mark-
of compound dysplastic naevus were DeWit et al. did not recommend grading ers. Hemizygous deletion was detected
reviewed. 87.6% had the histopathologic atypia in dysplastic naevi {612}. An in seven of nine dysplastic naevi at one
characteristics of dysplastic naevus, analysis of 12 histologic parameters in or more loci for p16. No loss of heterozy-
8.3% showed a dermal component with 123 dysplastic naevi failed to identify gosity was detected in any of the benign
a congenital pattern, 3.1% demonstrated parameters useful in differentiating mild intradermal naevi {1775}.
epidermal and dermal characteristics of from moderate dysplasia {1854}. Despite
Spitz naevus, 0.3% had features of a these considerations, melanoma risk has Molecular genetic alterations
combined blue naevus, 0.6% had a halo been associated with the degree of atyp- Greene performed an extensive review of
phenomenon and 0.1% showed intrader- ia in dysplastic nevi {102}. the genetics of malignant melanoma and
mal naevus. The authors advocate dysplastic naevi in 1998. Many studies
describing dysplastic melanocytic naevi Somatic genetics demonstrate an autosomal dominant
by categorizing them into six groups: 1) Cytogenetics and CGH mode of inheritance and speculate
dysplastic naevus; 2) dysplastic naevus Jaspers et al performed cytogenetic pleiotropic manifestations of a proposed
with a congenital pattern; 3) dysplastic investigations on lymphocytes and melanoma gene on chromosome 1
Spitz naevus; 4) dysplastic combined fibroblasts from 25 individuals with dys- (1p36). CDKN2A, a tumour suppressor
blue naevus; 5) dysplastic halo naevus; plastic naevus syndrome and compared gene localized on chromosome 9, is also
and 6) dysplastic neuronaevus {2370}. the results with a a control population of reported to be a melanoma gene. The
clinically normal relatives and unrelated relationship of melanoma to mutation of
Differential diagnosis individuals. In five DNS patients, CDKN2A has been confirmed {895}.
The clinical differential diagnosis of dys- increased frequencies of cells with ran- Hussein evaluated skin tissue samples of
plastic naevi includes congenital dom chromosomal rearrangements melanoma, dysplastic naevi and benign
melanocytic naevi, pigmented basal cell including translocations and inversions melanocytic naevi for microsatellite insta-
carcinoma, Spitz naevus, common were observed. These abnormalities bility. Microsatellites are short single
acquired melanocytic naevi, melanoma were absent in the control population sequence motifs repetitively scattered
in situ, and superficial spreading malig- {1134}. throughout the human genome. The vari-
nant melanoma. The histologic differen- Caporaso analyzed the karyotypes of ation in microsatellite pattern length
tial diagnosis includes melanoma, recur- 163 family members from 13 melanoma- between tumourous and matching non-
rent naevus, halo naevus, congenital prone families to investigate whether tumourous tissues is referred to as
naevus, a growing naevus in a child and chromosomal instability contributes to microsatellite instability. Microsatellite
Spitz naevus. familial melanoma. Cutaneous malignant instability has been associated with other
melanoma and dysplastic naevi syn- familial and sporadic tumours. Hussein’s
Grading drome patients each had increased results demonstrated MSI at 1p and 9p
Some authors emphasize cytologic crite- structural and numerical abnormalities chromosomal regions in dysplastic naevi
In some anatomic sites, naevi may have difficult to clinically distinguish from have been found the most reliable fea-
atypical histological features. This chap- melanoma {289,1511,2013,2017,2018}. tures indicative of melanoma {493,707}.
ter discusses three clinicopathologic On epiluminesence microscopy (ELM)
entities: acral, genital and Meyerson dermatoscopy), the pigmentation of AN
naevi, but other site specific features is accentuated in dermal glyphic furrows Genital naevus
have been described, including naevi and occasionally around eccrine ostia,
occuring in flexures, umbilicus, ear and thereby creating reproducible patterns Definition
scalp. {45,1232,2014,2015}. In acral melano- Melanocytic naevi on the perineum and
mas the pigment is distributed along the genitalia, hereafter “genital naevi (GN)”,
dermatoglyphic ridges {45}. include different naevic types distin-
Acral naevus guished and united by unusual, variably
Etiology present junctional features.
Definition The origin of AN is hypothesized to
Acral naevi (AN) are benign melanocytic involve repeated trauma {701,2181, Synonyms
proliferations from the palms and soles. 2182}, foci of “unstable” melanocytes A subgroup of GN with "unusual histolog-
{1416} and racially-correlated variations ic features" {480,782} or "atypism" {1608}
Synonyms in melanosome aggregation {1612}. have been dubbed "atypical melanocytic
AN or “naevi on volar skin” include histo- naevus of the genital type (AMNGT)
logic subtypes termed “Melanocytic Histopathology {495}".
Acral Naevus with Intraepidermal Ascent Distinction of acral naevi from melanoma
of Cells (MANIAC)” {1545} and “atypical can be difficult because both may be Epidemiology
or acral lentiginous naevus” {501,1511}. asymmetric, poorly circumscribed and About 10% of men and women have pig-
have intraepidermal ascent of cells {292, mented genital lesions {574,784,1955},
Epidemiology 701,984,1545,2181,2182}. Suprabasal but many are lentigines {784,1955}.
Clinical studies which are unable to dis- melanocytes in AN are relatively more Histologically confirmed GN occur in 2%
tinguish lentigines from true naevi, record columnar, circumscript and less volumi- of women {267,480,1955}.
discrete pigmented volar lesions in less nous than in melanomas {1246}. AMNGT comprise a minority of all GN
than 1{1763} to 92% {1416} of subjects, Signoretti et-al. have shown that symme- {267,480,1955}. They typically present
with most studies suggesting a range of try, circumscription, the columnar organ- by the twenties {1608} and, in contrast to
3 – 41% of the population {63,519,574, ization of ascending melanocytes and vulvar melanoma, are seen exclusively in
1338,2223,2418}. In a histologically con- organization of the junctional component premenopausal women {1608,2015}.
firmed study, 3.9% of Caucasians had are all influenced by the histologic plane Dysplastic naevi may also occur on the
AN {1473}. Darker patients tend to have of section; to wit, naevi sectioned per- genitalia but they are usually observed in
a greater percentage {519,1763} and pendicular to dermal glyphics are more people with dysplastic naevi elsewhere
higher total of naevi on acral surfaces likely to have benign attributes {2017, on their bodies {267,1608}. Vulvar naevi
{63,519,1553,2418}, though this is not 2018}. Subsequently, severe melanocytic were said to have increased premalig-
always found {574,1416}. Pigmented atypia and a dense lymphocytic infiltrate nant potential {1763}, though recent data
acral lesions are generally more common
in the second and third decades
{63,1338,1415,2418}.
Localization
Plantar naevi are probably more common
than palmar naevi {63,574,1473,2418}.
AN may occur on both pressure-bearing
and pressure-spared surfaces {45,63,
1415}.
Clinical features A B
AN are usually less than 8 mm with a light Fig. 2.60 Acral naevus. A Epiluminesence microscopy of an acral naevus demonstrating linear hyperpig-
to dark brown striated macular compo- mentation within the furrows of dermal glyphics. B Intraepidermal melanocytes with short dendrites are
nent. Congenital AN can be particularly seen along and above the basal layer.
Meyerson naevus
Definition
Meyerson naevus is a benign naevus of
junctional, compound or intradermal type
surrounded by an eczematous halo
{2478}.
Immunoprofile
Lymphocytes in MN are predominately Fig. 2.63 Meyerson naevus. Spongiosis, parakeratosis and irregular acanthosis characterize the epidermis.
CD4 positive {729,1816}. ICAM-1 has
been reported to be increased on ker-
atinocytes and endothelium within MN
{717}.
naevus
A B
Fig. 2.64 Persistent (recurrent) melanocytic naevus. A Small irregular black macule. A scar surrounds the
lesion. B Persistent (recurrent) melanocytic naevus. Melanocytes are arranged as solitary units along the
dermo-epidermal junction and also above it. Atypical nuclei can be observed. Note involvement of the fol-
licle.
Fig. 2.65 Persistent (recurrent) melanocytic naevus. Trizonal arrangement: 1) Dermal melanocytic naevus.
2) Above the melanocytic naevus a scar revealing fibrosis. 3) Intraepidermal changes with nests of
melanocytes with irregular shapes and a tendency to confluence at the dermo-epidermal junction.
found from early childhood to young data has been presented to the effect show chromosomal aberrations, whereas
adulthood in which there are some fea- that systemic metastasis may not occur, 25% showed an isolated gain of chromo-
tures of Spitz naevus and others of or may be much less frequent than in some 11p {174}. Preliminary studies indi-
melanoma. Common denominators adults with conventional melanomas cate that the increased copy number of
include a vertical orientation, extension matched for thickness. Clearly, further chromosome 11p is due to the formation
into the subcutis with no diminution in studies are needed to determine if these of an isochromosome 11p {1494}. About
cellularity and a blunt, multinodular inter- lesions are fundamentally Spitz naevus, 70% of the Spitz naevi with increased
face, ulceration, a plasmacytic infiltrate melanoma, or neither. copies of chromosome 11p have muta-
and deep mitotic figures. Such cases tions in the HRAS gene which maps to
have been described as “malignant Spitz Somatic genetics this location {172}. HRAS mutations have
naevus” and also simply regarded as While most cells in most Spitz naevi been found only in a minority of cases (<
melanomas {2205}. In the initial study of seem to be diploid, there are a propor- 10%) with normal copy number of chro-
“malignant Spitz naevus” there were 3/32 tion of polyploid cells, at least in the mosome 11p. Preliminary studies indi-
lesions in which palpable lymph node upper part of lesions as judged by image cate that mutations in BRAF occur infre-
enlargement had occurred, and another analysis cytometry {1386}. True aneu- quently in Spitz naevi.
3 in which lymph node involvement was ploidy may be uncommon, as evaluated
detected on elective dissection. Very by flow cytometry {2439}. In an analysis
similar lesions have been described as using comparative genomic hybridiza-
melanomas in children {1632}. Follow up tion the majority of Spitz naevi did not
A B
Fig. 2.69 Spitz naevus, desmoplastic type. A Rete ridges are uniformly elongated but jagged above the upper part of the lesion. B Thin spindle cells are present
between collagen bundles.
Definition scription. Spindled, pigmented melano- melanophages is found within the papil-
Pigmented spindle cell naevus (Reed) is cytes arranged in vertical nests at the lary dermis. A subset of cases shows a
a benign melanocytic naevus showing dermo-epidermal junction predominate considerable overlap with Spitz naevi.
dark pigmentation clinically, and a prolif- {158,2005,2068}. A few, and in some Cases with some cytological atypia have
eration of spindled melanocytes histo- instances many, melanocytes may be been termed “atypical pigmented spin-
pathologically. seen above the dermal/epidermal junc- dle cell naevus - pigmented spindle cell
tion, as well as confluence of the nests. naevus with architectural and/or cytolog-
ICD-O code 8770/0 The proliferation of melanocytes may be ic atypia”, and may represent a source of
confined to the epidermis, or may extend problem in differential diagnosis from
Synonyms and annotation into the papillary dermis. Occasional malignant melanoma {158}. A variant
This melanocytic naevus has been mitoses may be found. Cytomor- described as “plexiform pigmented spin-
named eponymously after Richard Reed, phologically there is a uniform prolifera- dle cell naevus” probably represents a
who described it in 1975 {1909}. It has tion of elongated, fusiform melanocytes, pigmnented spindle cells naevus invol-
also been referred to as Reed naevus or usually without atypical features. The ving the reticular dermis {158}.
Reed tumour. While some authors regard nuclei are relatively small, with uniform,
it as a subtype of the Spitz naevus, pig- delicate chromatin. Epithelioid melano- Prognosis and predictive factors
mented spindle cell naevus (Reed) pres- cytes are admixed in a minority of cases. Pigmented spindle cell naevus (Reed) is
ents with peculiar clinical and Commonly, the epidermis is slightly a benign melanocytic proliferation with
histopathologic features, allowing a hyperplastic and shows marked hyper- no potential for distant metastases. Local
reproducible diagnosis and classification pigmentation of the basal keratinocytes. recurrences may be observed in tumours
to be made. Intraepidermal eosinophilic globules (so- that were incompletely excised.
called “Kamino bodies”) can be
Epidemiology observed in about half of the cases. An
Pigmented spindle cell naevus (Reed) is inflammatory infiltrate composed of lym-
a melanocytic tumour found in children, phocytes and histiocytes with many
adults, and, rarely, older patients, with a
peak in the third decade. There is a pre-
dominance for females.
Clinical features
The patients present with a darkly,
homogenously pigmented, flat or slightly
dome-shaped, sharply circumscribed
papule or plaque located usually on the
limbs, especially the thigh {158,2005,
2068}. Less common locations are the
trunk and the head and neck region. The A B
lesions are usually of recent onset and
smaller than 1 cm. Surface skin micro-
scopy (dermatoscopy, dermoscopy)
reveals typically a “starburst” pattern
(characterized by the presence of pig-
mented streaks disposed in a radial
arrangement at the edge of the lesion).
A clinical misdiagnosis of malignant
melanoma is not infrequent, due to the
dark pigmentation and recent onset of C D
the lesions. Fig. 2.70 Pigmented spindle cell naevus (Reed). A Small, flat, dark papule. B Dermoscopy shows the char-
acteristic "starburst" pattern. C Elongated nests at the dermoepidermal junction and in the papillary dermis;
Histopathology note pigmentation of the basal keratinocytes and melanocytes, and the presence of numerous
Histologically, the tumours are symmetri- melanophages in the papillary dermis. D Fusiform melanocytes predominate. Note the mitosis in the upper
cal and show a sharp lateral circum- left corner.
Definition halo around a compound naevus, fol- tend to become smaller (i.e., more
A halo naevus presents as a small cir- lowed by fading and disappearance of “mature”) from the top to the bottom of
cumscribed symmetrical, usually papular the naevus. The halo then gradually re- the lesion. The epidermis may be hyper-
pigmented lesion with the appearance of pigments over a year or two, returning to keratotic with follicular plugging {2469}.
a common benign compound naevus, the appearance of normal skin. During The feature that distinguishes a halo nae-
surrounded by a symmetrical area of this period, especially in teenagers, other vus from a banal naevus is the presence
depigmentation, representing the “halo” similar lesions may develop. of a striking dense lymphocytic infiltrate,
{2469}. The lesion is defined histological- Studies in patients with halo naevi have an appearance that may arouse a suspi-
ly by the presence of a brisk lymphocyt- demonstrated circulating antibodies that cion of melanoma in some cases. The
ic infiltrate among dermal naevus cells, are reactive with neoplastic melanocytes lymphocytes extend among the lesional
and by loss of pigment in the epidermis including melanoma cells, and the infil- naevus cells, tending to obscure their
adjacent to the naevus. Some naevi with trating cells have been shown to be underlying nested pattern in some
a lymphocytic response of the type seen mainly T lymphocytes {2090}. Antigen- cases. Melanin-laden histiocytes and
in halo naevi do not have an obvious clin- presenting cells and CD8+ T cells have mast cells can be present as well as lym-
ical or histologic depigmented halo been identified in the inflammatory infil- phocytes {2090}. Occasional halo naevi
{948}. trates of halo naevi, implicating cytotoxic contain a few giant cells or there may be
mechanisms in destruction of naevus a frankly granulomatous response. Over
ICD-O code 8723/0 cells {2581}. Affected individuals also the ensuing weeks or months, the dermal
show activated lymphocytes in their naevus cells disappear and then the his-
Synonyms peripheral blood {148} as well as T cell tologic differential diagnosis may include
Sutton naevus; leukoderma acquisitum clonal expansion {1670} and anti-naevic lichenoid inflammatory dermatoses. Over
centrifugum {2297}. IgM antibody production {2359}. These a period of a year or two, the inflammato-
findings are consistent with the idea that ry cells disappear and histologic exami-
Clinical features halo naevi represent immunologically - nation of the site of a completely resolved
Halo naevi often present during the sum- mediated rejection of a naevus. The halo halo naevus may disclose essentially
mer, perhaps because the halo contrasts develops outside the naevus proper, normal skin, with little or no evidence of
better with tanned skin. They are most suggesting that there may be a cross- scarring or residual pigment {2469}. In
common in teenagers and young adults. reaction with a “field” of melanocytes that most halo naevi, there is little or no read-
In these cases, they are sometimes asso- surrounded the naevus prior to the onset ily observable melanocytic abnormality
ciated with dysplastic naevi, and are of the intense inflammation in the dermal in the epidermis at the “shoulder” of the
sometimes multiple. Less often, a solitary component. lesion beyond the lateral border of the
halo lesion develops in an older adult, dermal component, even though it is in
and in this circumstance the possibility of Histopathology this region that the striking clinical halo is
melanoma should be ruled out histologi- An early halo naevus presents as a small located. However, DOPA stains for tyrosi-
cally, especially if the central pigmented circumscribed lesion, less then 4 mm in nase and immunohistochemical (e.g.
lesion is clinically atypical or if the halo is diameter as a rule, composed of naevus Melan-A) or argentaffin stains for
eccentric or asymmetrical in contour. cells located in the papillary dermis and melanocytes reveal greatly reduced
Serial follow-up of halo naevi demon- usually also in the epidermis. The lesion numbers of them in the area of the halo
strates a characteristic time sequence, is symmetrical, and is composed of cells compared to the surrounding skin
beginning with the appearance of the that are uniform from side to side and {2469}.
Fig. 2.71 Halo naevus. There are two small naevi Fig. 2.72 Halo naevus. There is an apparently well circumscribed lesion which at first glance may be mis-
surrounded by rims of depigmentation. taken for a lymphocytic infiltrate.
The lesional cells in most halo naevi are an absence of identifiable melanocytes. naevus cells, and there is little or no ten-
unremarkable dermal naevus cells of the In comparison with adjacent normal epi- dency to single-cell upward (“pagetoid”)
large pigmented (type A) or small non- dermis, pigment may be visibly reduced, intraepidermal spread of the junctional
pigmented (type B) cytology. Pigment is and this contrast can be enhanced with a cells.
located in naevus cells and in melano- melanin stain. In most lesions, there is no Some halo naevi may be difficult to dis-
phages superficially, and is usually intra-epidermal melanocytic proliferation tinguish from dysplastic naevi that have
coarse in texture. In some lesions, the adjacent to the dermal component, but in an unusually brisk lymphocytic infiltrate.
dermal cells have nuclei that are larger a few lesions an adjacent component of Indeed, not only do halo naevi appear to
than is usual in common naevi, and melanocytic dysplasia may be observed. be common in patients with dysplastic
sometimes there is hyperchromatism and If an in situ or microinvasive (“ radial naevi but also a halo response may be
a degree of pleomorphism, with or with- growth phase”) component diagnostic of seen, clinically and histologically, in dys-
out nucleoli, representing cytologic atyp- melanoma is present adjacent to a der- plastic naevi themselves. If the charac-
ia which is present in about 50% of halo mal lesion simulating halo naevus, the teristic patterns of dysplasia are seen at
naevi and is usually mild or at worst mod- entire lesion is most likely to represent the “shoulder” of the compound portion
erate in degree {1640}. This cytologic melanoma. of a lesion whose other features are con-
atypia may represent a form of “inflam- sistent with a halo naevus, the diagnosis
matory” or reactive atypia. Mitotic figures Differential diagnosis of dysplastic naevus with halo reaction
are completely absent in most lesions. The distinction from common acquired or can be made. Especially if there is a his-
However, a few lesions judged to be most other types of naevi is usually easy tory of other atypical naevi and/or a per-
benign halo naevi have shown one or two because of the dense lymphocytic infil- sonal or family history of melanoma, sur-
mitotic figures {1909}. Such a finding trate. The most important differential veillance may be warranted for such indi-
should provoke careful examination of diagnosis is with melanoma. Compared viduals.
the lesion to rule out melanoma, with to nodular melanoma or to the tumouri- When naevus cells are inconspicuous
deeper sections and embedding of any genic (vertical growth phase) component among a dense infiltrate of lymphocytes,
residual gross tissue. Findings sugges- of superficial spreading melanoma, a inflammatory dermatoses such as
tive of melanoma in a lesion simulating a halo naevus is usually smaller (the cen- lichenoid keratoses may be simulated
halo naevus include the presence of a tral naevus is usually less than 4 mm in {844}. In these circumstances, an S-100,
separate population of cells with an diameter, while most melanomas are Melan-A or HMB45 stain may reveal the
expansile pattern of growth, severe uni- larger than 6 mm, though these values hidden naevus cells. Care must be taken
form cytologic atypia, and/or the pres- are by no means absolute). However, we in interpretation, since histiocytes may
ence of frequent mitoses, ulceration or have rarely observed small melanomas weakly express S-100, whereas activat-
necrosis. The halo phenomenon may with naevoid characteristics but with dif- ed melanocytes and melanoma cells
occasionally involve other types of naevi, fuse cellular atypia combined with mitot- may express HMB45. Finally, there are
including dysplastic naevi {2370}, Spitz ic activity in which diffuse lymphoid infil- lesions that have an infiltrative lympho-
naevi {972} and congenital naevi {2359}, tration was a prominent pattern. When cytic response similar to that of a halo
as well as melanomas {2090}, and there- pigment is present in a halo naevus, it is naevus but there is no clinical halo.
fore careful inspection of the underlying usually in the form of coarsely divided These lesions may be signed out
lesional architecture and cytology in mul- granules as is the case in most benign descriptively as “compound (or dermal)
tiple sections may be required for defini- naevi, and if there is a junctional compo- naevi with halo reaction” {1909}.
tive classification. nent, its character is that of a naevus Conversely, some naevi with a clinical
The halo region at the periphery of the rather than a melanoma. Thus, there is halo may lack a lymphocytic infiltrate of
dermal component of the lesion may usually a discontinuous rather than con- the type seen in halo naevi {812}. These
contain a few lymphocytes at the dermal- tinuous proliferation of predominantly may be termed “non-inflammatory halo
epidermal interface, with a reduction or nested rather than predominantly single naevi”.
Appendageal Tumours
__________
1
Morphology code of the International Classification of Diseases for Oncology (ICD-O) {786} and the Systematized Nomenclature of Medicine (http://snomed.org).
Behaviour is coded /0 for benign tumours, /3 for malignant tumours, and /1 for borderline or uncertain behaviour.
__________
1
{894,2219}.
2
A help desk for specific questions about the TNM classification is available at www.uicc.org/index.php?id=508 .
Introduction
Introduction 123
extent, the differentiation of neoplasms syndrome). Trichilemmomas have muta-
probably reflects their distribution {1544}. tions in PTEN, the same gene as involved
in Cowden syndrome. Mutations in DNA
Genetics repair genes occur in the sebaceous
Approximately one third of sweat gland neoplasms of the Muir-Torre syndrome
carcinomas contain TP53 mutations and, to a lesser degree, in sporadic
{239A}. Otherwise, little is known about sebaceous neoplasms.
the genetics of most epithelial neo-
plasms, with the exception of those that Prognosis and predictive factors
occur in multiplicity as part of autosomal In general, adnexal carcinomas of low
dominant syndromes (see Chapter 7). cytologic grade have a good prognosis,
The mutations found in the germlines of especially if the lesion is relatively small
patients with syndromes and multiple and completely excised. Those of high
tumour suppressor genes tend to be the cytologic grade may metastasize widely.
same as occur as somatic mutations in For many adnexal carcinomas, there are
sporadic adnexal neoplasms. Some simply insufficient numbers of reported
trichoblastomas have mutations in the cases to develop much of an idea
PTCH gene, as found in naevoid basal regarding their prognosis.
cell carcinoma syndrome (Gorlin-Goltz
A B
Fig. 3.01 Tubular carcinoma on the retroauricular Fig. 3.02 Tubular carcinoma. A The neoplasm involves the full-thickness of the dermis and extends into sub-
left region. cutaneous tissue. The stroma is sparse and the epithelium predominates over the stroma. B Some neo-
plastic aggregations of this tubular carcinoma exhibit focally an adenoid cystic pattern.
Synonyms
Sclerosing sweat duct carcinoma {541},
eccrine epithelioma, syringomatous car-
cinoma.
Clinical features
The carcinoma occurs on the face of
adults, more commonly in women. It
affects commonly the face {469} and lip,
Fig. 3.03 Microcystic adnexal carcinoma. Scanning magnification of microcystic adnexal carcinoma illus-
uncommonly other locations, and grows trates the zonal effect with solid nests and cysts superficially with complex glands deep.
slowly over a period of months to years.
It is similar usually to a depressed scar
and rarely causes ulceration. cysts) to deep (epithelial cords and scle- ogy. Cytologically, the lesions are well
rosis). differentiated, lacking nuclear pleomor-
Histopathology Unusual examples contain sebocytic phism or mitotic figures. In fact, the find-
The classical pattern is that of small, zones {1862}, and others contain areas ing of nuclear pleomorphism should
superficial, solid to cystic structures that similar to follicular sheath, thus suggest- cause one to reconsider whether the
are similar to small infundibular cysts and ing differentiation toward the folliculo- diagnosis of microcystic adnexal carci-
ducts. In the middle depth, the lesion is sebaceous-apocrine unit. In other cases, noma is correct.
composed completely of small ducts, the lesions are exclusively ductal, caus-
often in very subtle patterns, frequently ing some authors to designate them as Immunoprofile
with involvement of nerves and perineur- “syringomatous carcinoma” or “scleros- There is cytoplasmic staining with
al spaces. In the deepest areas, “Indian” ing sweat duct carcinoma” and suggest- AE1/AE3, CK7, and bcl-2. EMA and Ber-
filing and sclerosis are common findings. ing that these examples could be EP4 stain in a membranous pattern
Thus, there is a sense that the lesion is derived from eccrine ducts. Some MACs around ductal cells near the lumen.
stratified from superficial (tubules and have solid poromatous or clear cell cytol- Alpha SMA and S100 protein stain the
A B C
D E F
Fig. 3.04 Microcystic adnexal carcinoma. A There are a few cysts and solid nests, but no nuclear pleomorphism. The pattern of the lesion helps to recognize it as
carcinoma. B Not only are there ducts; there are also strands and small nests of neoplastic cells. C This example of microcystic adnexal carcinoma again illus-
trates the zonation pattern, in this case with a few cysts superficially. Note the deep nests that are present in and around the sucutis; not every case will contain
compressed ducts exclusively in the deep zones. D This example is similar to some poromas. There are solid nests of monomorphous cells as wells as nests of
cells with clear cytoplasm. Some authors have designated these lesions "syringomatous" carcinoma. E Despite the striking structural patterns of these lesions,
most do not contain nuclear pleomorphism. F Peripheral nerve, completely encircled by the neoplasm. Note the ductal space.
Differential diagnosis
The principal differential diagnoses are
with superficial biopsies of columnar tri-
choblastoma (desmoplastic trichoepithe-
lioma) or morpheiform basal cell carcino-
ma (trichoblastic carcinoma), all of which
are CK7 negative. Syringoma is a possi-
ble consideration in some cases. Rare
examples of metastatic carcinoma to the
skin can also mimic it.
Genetics
There is a single report of a 6q deletion
{2538}. There is also a report of 2 micro- Fig. 3.05 Malignant mixed tumour. Lobulated biphasic tumour consisting of epithelial and mucinous-mes-
cystic adnexal carcinomas, one of which enchymal components. The former predominate at the periphery, while the latter predominate at the cen-
was diploid, and the other, aneuploid, ter.
when examined with DNA image cytom-
etry {2437}.
Prognosis
Treatment is surgical, with microscopic
control of margins if possible {9}.
Radiotherapy has proven successful
rarely, but some reported cases have
taken on an even more virulent biology
after such treatment.
A B
Malignant mixed tumour
Definition
Malignant mixed tumour (MMT) is an
exceedingly rare cutaneous adnexal car-
cinoma with a significant risk for aggres-
sive behaviour and a propensity for
metastasis. MMT is regarded as the
malignant counterpart of benign mixed
tumour {1919} albeit histological diagno- C D
sis is foremost based on the biphasic
nature of the neoplasm rather than an
admixture of benign mixed tumour rem-
nants with carcinomatous tissue {2515}.
Synonyms
Malignant apocrine mixed tumour.
Malignant chondroid syringoma. E F
Fig. 3.06 Malignant mixed tumour. A Hyperchromatic tumour cells with mitoses. B Note variations of cyto-
Epidemiology logical differentiation and pleomorphism. C Focal zone of tubule formation. D Highly pleomorphic tumour
MMT represents an exceedingly rare lobules with mitoses at the periphery of the tumour. E Note the pseudo-sarcomatous pattern with hyper-
cutaneous adnexal neoplasm which chromatic spindle cells and many mitoses. F Nests of plasmacytoid tumour cells amidst a myxoid stroma.
occurs in a wide age range (15 months Plasmacytoid epithelial differentiation is a hallmark of myoepithelial differentiation.
B
Fig. 3.07 Porocarcinoma. A Multinodular ulcerated Fig. 3.08 Porocarcinoma. There is a dermal component, partly in apposition with the epidermis, and a large
plaque. B Closely arranged polygonal cells with tumour nodule extending into the deep subcutaneous tissues. The lesion is remarkably well demarkated.
hyperchromasia.
by Pinkus and Mehregan in 1963 as epi- fibroma, basal cell carcinoma, squamous tiated from Paget disease by its relative-
dermotropic eccrine carcinoma {1837}. cell carcinoma, or pyogenic granuloma. ly sparse epidermal involvement and
Diagnosis is made by skin biopsy. greater dermal invasion, and the pres-
Epidemiology ence of glycogen rather than mucin in
Eccrine porocarcinoma is a rare tumour, Histopathology tumour cells {913}. In the absence of
predominantly observed in elderly Eccrine porocarcinoma forms intraepi- residual eccrine poroma, it is very diffi-
patients with an average age of 67 years dermal and dermal nests and cords of cult to differentiate eccrine porocarcino-
{1072}. Women and men are equally epithelial cells with pale cytoplasm. The ma from squamous cell carcinoma
affected. The incidence in one large tumour masses form clearly demarcated {1571}.
series was 18 per 450,000 cases and frequently rounded nests of polygo-
(0.004%) {1571}. nal cells with pleomorphic and irregular- Immunoprofile
ly-shaped nuclei, prominent nucleoli, and The tumour nodules stain with antibodies
Etiology numerous mitotic figures. There is sharp to pan-cytokeratin; tumour cells may
Eccrine porocarcinomas may arise de demarcation of the epithelial nests of stain paler than adjacent epidermal ker-
novo or as a malignant transformation in cells from the adjacent epidermal ker- atinocytes {499,1072}. Ductal structures
a pre-existing poroma, hidroacanthoma atinocytes {1837}. The overlying epider- within the tumour stain strongly positive
simplex, or in association with naevus mis may be acanthotic. Both single with CEA and EMA {1359,2216}.
sebaceous {1571,2216,2604}. 18 to 50% tumour cells and nests of cells may
of eccrine porocarcinomas are associat- involve the epidermis in a pagetoid fash- Genetics
ed with pre-existing eccrine poromas. ion {1359}. Keratinization is usually Mutation of the p53 gene with loss of its
absent. Intercellular bridging between suppressor function has been widely
Localization the tumour cells is inconspicuous. The noted with malignant transformation. P53
Forty-four to 50% of eccrine porocarcino- tumour cells may contain glycogen protein expression has been observed in
mas arise on the legs, buttocks, or feet {2000}. Connection to the intradermal both eccrine poromas and eccrine poro-
{2216}. The trunk accounts for 24% of the eccrine ducts may be observed. Deep carcinoma {43,2327}. P16 staining is uni-
lesions and the head 18% of the lesions dermal intralymphatic invasion may be formly negative {914}.
with less frequent lesions located on the observed in up to 15% of the lesions
upper extremities {1072}. {1952}. Prognosis and predictive factors
The differential diagnosis includes Approximately 20% of eccrine porocarci-
Clinical features eccrine poroma, hidroacanthoma sim- nomas recur after excision {2216}.
Eccrine porocarcinoma presents as a plex, and Paget disease {913}. Eccrine Regional lymph node metastasis occurs
verrucous nodulo-ulcerative plaque. poroma and hidroacanthoma simplex in 20% of patients, while 12% develop
Clinically the lesions may resemble an may show focal atypia, but the lesions distant metastases {2216}. Patients with
eccrine poroma, verruca vulgaris, sebor- are symmetrical and well circumscribed. metastatic disease have a high mortality
rhoeic keratosis, melanocytic naevus, Eccrine porocarcinoma may be differen- rate {170}. Increased number of mitoses,
Clinical features
Typically there is a history of a long-
standing lesion that suddenly became
enlarged, ulcerated, tender, or changed
its colour. The size of the tumour ranges
from 0.8-10 cm. The mean duration of a
pre-existent lesion is about 20 years
before the diagnosis is made {725}. The
patient may also have multiple long-
standing spiradenomas, which often
Fig. 3.10 Spiradenocarcinoma. Well-defined, coexist with cylindromas {89}. Fig. 3.11 Hidradenocarcinoma involving the left
encapsulated mass with areas of solid and cystic preauricular skin of an elderly male. Note the pres-
changes and haemorrhage. ence of a retroauricular lymphadenopathy.
Mucinous carcinoma ing, painless nodular neoplasm. The that may be vacuolated. Nuclei are small
tumour has a tan, grey, or reddish colour, with very little atypia. Mitoses are rare.
Definition a smooth surface, and a consistency The epithelial mucin is PAS-positive,
Primary cutaneous mucinous carcinoma ranging from soft to firm. Positive trans- hyaluronidase and sialinase labile, and
(MC) is a rare epithelial neoplasm occur- illumination may be a helpful diagnostic consists of non-sulphated acid
ring mostly, but not exclusively, in mid- tool. mucopolysaccharides with sialic acid.
dle-aged and older patients. Although
MC is characterized by destructive local Macroscopy Immunoprofile
growth and the potential of metastasizing Grossly, most MC are well-circum- Neoplastic cells express low molecular
to regional lymph nodes and even be- scribed, un-encapsulated tumours in the weight cytokeratins, CEA, EMA, GCDFP-
yond them, it generally follows an indo- dermis and the subcutaneous fat. 15, alpha-lactalbumin, salivary amylase,
lent course with frequent local recurren- Tumour diameters range between 1 and beta-2-microglobulin. S100 expression is
ces. Mucinous carcinoma metastatic to 8 centimetres, albeit larger variants have inconstant {199,404,664}. Nuclear
skin from another organ, particularly the been reported {1231}. On excision, the expression of oestrogen receptors may
breast and gastrointestinal tract, may be tumour appears fixed to the adjacent be strong, but the pattern of progesteron
histologically indistinguishable from MC. dermis and does not “shell out” {1919}. receptors is more variable {945}.
The cut surface of excised specimens is Cytokeratin 20 expression allows differ-
ICD-O code 8480/3 gelatinous. entiation of mucinous gastrointestinal
carcinoma metastatic to the skin from
Synonyms Histopathology primary cytokeratin 20-negative cuta-
Primary cutaneous mucinous carcinoma. MC presents as an un-encapsulated neous MC {664}.
Colloid, gelatinous and adenocystic car- asymmetric dermal tumour that may
cinoma. extend into the subcutis and even deep- Variants
er tissue planes {1919}. Tumour satellites MC very rarely presents with focal neu-
Epidemiology may occur at some distance from the roendocrine differentiation {1876}, or with
MC is very rare and occurs mostly main tumour. MC is characterized by a growth pattern imitating infiltrating car-
between the fifth and seventh decades of large pools of basophilic mucin, which cinoma of the breast {2557}.
life, with an age range between 8 and 84 are compartmentalized by delicate Epidermotropism of neoplastic cells is
years. MC is slightly more common in fibrous septa, thereby creating a honey- unusual.
men than in women {1919}. comb pattern. Within the lakes of mucin
are small “floating” islands and bizarre Electron microscopy
Localization clusters of neoplastic epithelial cells, There are less well-differentiated inner
Most MC arise on the head, favouring sometimes exhibiting a cribriform pale cells and mucin-containing periph-
scalp and face with preference of the arrangement. The epithelial component eral dark cells {990}.
eyelids {199,305,1212,2217,2319}. Rare is denser at the periphery of the tumour.
sites are axillae, trunk, lower extremities, Small glandular or tubular structures Differential diagnosis
perianal area and vulva {1919}. containing mucin or showing signs of Before a diagnosis of MC is established,
apocrine secretion occur only rarely. The a primary carcinoma in a breast or anoth-
Clinical features small neoplastic cells are cuboidal, er organ (salivary and lacrimal glands,
MC presents as a solitary, slowly grow- round, or oval with abundant cytoplasm gastrointestinal tract, nose and
Histogenesis cases originally classified histologically pattern of glands often fills the solid
Histogenesis of MC has not yet been elu- as adenoma developed metastases, areas of tumour, while papillary epithelial
cidated, but there is strong morphologi- demonstrating that histologic parameters projections are common within cystic
cal evidence that MC may be apocrine in do not accurately predict behaviour or spaces. The papillary projections are
nature {1919}. allow distinction between adenoma and associated with fibrovascular cores in
adenocarcinoma {655}. Therefore, the some areas, while in other areas papillae
Prognosis and predictive factors term aggressive digital papillary adeno- are formed by heaped up epithelium
In contrast to most other sweat gland ma has been abandoned in favour of without stromal support. The epithelium
carcinomas, MC is a low-grade malig- classification of all such lesions as digital is composed of low columnar or cuboidal
nant neoplasm with a tendency to persist papillary carcinoma. cells. Cytologic atypia is usually not
at the original site but with a low metasta- marked. Mitoses and necrosis are fre-
tic potential. 10% of the MC so far report- Epidemiology quent findings. Cysts contain either
ed metastasized to regional lymph Digital papillary carcinomas present necrotic debris or eosinophilic secretory
nodes, but only 3% metastasized in a almost exclusively on the fingers, toes, material. Some tumours are well-circum-
more widespread fashion {1830}. While palms, and soles. Hands are involved scribed, while others have an infiltrative
multiple recurrences, due to the exis- more frequently than feet. There is a male growth pattern.
tence of tumour satellites, are not unusu- predilection, and most affected individu-
al, death from MC is exceptional {1919}. als are adults in the fifth and sixth Differential diagnosis
decades of life. The differential diagnosis includes papil-
lary eccrine adenoma, which is usually
Digital papillary carcinoma Clinical features well-circumscribed, and composed of
Most cases present as a slowly growing dilated ducts with a distinct two cell layer
Definition deeply seated nodule on a digit. Lesions and delicate papillae. Malignant adnexal
Digital papillary carcinoma is regarded may be several centimetres in diameter. neoplasms such as malignant acrospiro-
as an uncommon malignant adnexal Pain is occasionally a presenting com- ma and malignant spiradenoma are also
neoplasm with potential for both recur- plaint, and may be related to tumour in the differential, but typically lack the
rence and metastasis. extension into underlying bone, joint, or pattern of papillary growth and/or back-
nerve. Rarely, metastasis is the first man- to-back glands that characterize digital
ICD-O code 8408/3 ifestation of disease. Unless underlying papillary carcinoma. In addition, malig-
bone has been invaded, routine nant spiradenoma usually retains its
Synonyms roentgenographic examination may be characteristic two cell population (small
Aggressive digital papillary adenoma, essentially unremarkable. basaloid cells and large pale peripheral
digital papillary adenocarcinoma cells) in at least some foci.
Historically, this group of lesions was Histopathology
divided histologically into aggressive Typically, tumours are composed of Histogenesis
digital papillary adenomas and digital multi-nodular epithelial aggregates with The occurrence of digital papillary carci-
adenocarcinomas {1205}. However, cystic spaces in the dermis. A cribriform noma on acral sites where eccrine
Definition
Primary cutaneous adenoid cystic carci- ly 9.8 years {1219}. The size of the due to nuclear hyperchromatism and
noma is a neoplasm of disputed histoge- tumour ranges from 0.5-8 cm, with an crowding. Nuclear palisading is absent.
nesis characterized by a cribriform pat- average size of 3.2 cm. Patients typically The tumour nests are surrounded by a
tern and frequent perineural involvement. present with slowly expanding, firm, skin prominent eosinophilic hyaline basement
coloured nodules. Tenderness, ulcera- membrane-like material which is periodic
ICD-O code 8200/3 tion and bleeding are variable and acid-Schiff-positive, and diastase-resist-
depend on the site of involvement. In the ant. The cystic spaces often contain
Epidemiology scalp region, alopecia may be an associ- abundant mucin {1812}. The mucin is
Over 40 cases have been reported in the ated finding. characteristically alcian blue (pH 2.5)
literature. Adenoid cystic carcinoma positive. The epithelium consists of fairly
(ACC) affects middle-aged and older Histopathology uniform cells with darkly staining nuclei,
individuals (mean age: 58.1) and has a Primary cutaneous ACC is usually poorly which sometimes contain conspicuous,
predilection for women {1219}. circumscribed and is composed of small, solitary nucleoli. Individual tumour
islands, cords and strands of basaloid cells have a scant amphophilic cyto-
Localization cells with a glandular, cystic, cribriform plasm and an increased nuclear-cyto-
This neoplasm is most common on the and tubular arrangement embedded in a plasmic ratio. Mitotic activity is usually
scalp (35%) and chest and abdomen loose fibrous and sometimes mucinous sparse with 1-2 division figures per high
(24%) {446,1219}. stroma. It typically occupies the mid and power field (x40) {2514}. Perineural
deep dermis and may extend into the extension, a characteristic feature of sali-
Clinical features subcutaneous fat {793}. The epithelial vary gland adenoid cystic carcinoma
Primary cutaneous adenoid cystic carci- cords have an infiltrative pattern and are may be seen, however, not with the fre-
noma has an indolent and progressive not connected to the overlying epider- quency seen in other organs.
course. The average duration of the mis. The tumour has a characteristic Before the diagnosis of a primary cuta-
tumour prior to diagnosis is approximate- basophilic appearance on low power neous ACC is made, the possibility of a
A B
Fig. 3.17 Apocrine carcinoma. A Well differentiated cutaneous apocrine carcinoma. Glandular structures with tubulopapillary growth pattern and apical decapita-
tion secretion. B Poorly differentiated cutaneous apocrine carcinoma. Micronodular and trabecular growth pattern with hardly any gland formation, hyaline stro-
ma. The cells have scanty amphophilic cytoplasm and contain vesicular nuclei with prominent nucleoli and occasional mitotic figures.
ease are detected only on histologic develop erythema of the nipple and are- Tumour spread and staging
examination of the nipple in a mastecto- ola. The lesion then progresses to scaly, MPD without invasive carcinoma on his-
my specimen, without a clinically appar- crusted thick plaques and ultimately to tologic examination is classified as carci-
ent lesion {1971}. areas of erosion and ulceration. Patches noma in situ (Tis). MPD with a contiguous
No accurate epidemiologic data is avail- and plaques are almost always unilateral or non-contiguous invasive component
able for EMP. It is a rare condition that and sharply circumscribed, and some- on histology is staged according to the
comprises less than 2% of primary neo- times pruritic or painful. In approximately invasive component using the guidelines
plasms of the vulva. EMP occurring in half of the cases a breast mass is palpa- for staging of breast carcinoma.
sites other than the vulva is even less ble. Nipple retraction and serosan- Primary EMP is staged either according
common. In genital EMP, women are guinous discharge may be features of to the FIGO (Fédération Internationale de
more commonly affected than men. Most advanced cases with a large underlying Gynécologie et d’Obstétrique) or the
patients are above the age of 60. carcinoma. Not all patients with MPD TNM system of the AJCC (American Joint
have clinical symptoms; 10-28% of Committee on Cancer) for vulvar
Etiology cases are detected only on histologic tumours. After a long period of in situ
MPD is almost always associated with an examination in a mastectomy specimen growth EMP can eventually invade the
underlying carcinoma of the breast, and {1971}. The differential diagnosis dermis and acquire metastatic potential.
the etiology is the same as for breast car- includes squamous cell carcinoma in situ Typically, invasive carcinoma associated
cinoma. The inciting factors for primary and eczema. Once a diagnosis of MPD is with EMP first spreads to locoregional
EMP are unknown. Secondary EMP is an established the patient needs to be eval- lymph nodes and ultimately may develop
expression of an underlying internal uated with imaging studies and other distant metastases. Secondary EMP is
malignancy and the etiology parallels procedures for breast carcinoma. If MPD staged according to the criteria for the
that of the underlying tumour. is associated with a palpable tumour associated internal malignancy.
mass, the underlying carcinoma will be
Localization invasive in more than 90% of cases. If no Histopathology
MPD involves the nipple and areola and tumour mass can be detected clinically, On histologic examination MPD and EMP
in advanced cases may extend to the less than 40% of women will have inva- are characterized by neoplastic cells
adjacent skin. sive carcinoma. with large nuclei, prominent nucleoli and
EMP involves apocrine gland bearing Patients with EMP most commonly pres- abundant pale to amphophilic cytoplasm
areas and is most common in the genital ent with pruritus or burning. The skin that are scattered throughout the entire
area, groin, perineum or perianal region. shows well-demarcated erythematous epidermal thickness. These cells occur
Axillae, eyelids and external auditory scaly patches and plaques, which may singly and in clusters and often are more
canals rarely may be involved. be ulcerated. Following a diagnosis of numerous in the basal layers of the epi-
EMP the patient needs to undergo thor- dermis. Acinus formation may be pres-
Clinical features ough examination to rule out an associat- ent. Paget cells can contain cytoplasmic
Patients who present with MPD initially ed internal malignancy. melanin pigment, a feature that should
Localization A B
Hidrocystomas have a predilection for
the face and neck, mainly the periorbital
area, but may also affect other parts of
the body such as the perineum.
Clinical features
Hidrocystomas present as dome-
shaped, cystic firm papules or nodules,
with a slightly blue colouration. In some
cases the content of the cyst is brown or C D
black.
Fig. 3.23 Hidrocystoma, papillary cystadenoma. A Example of the so-called "papillary apocrine gland cyst".
These lesions are characterized by the presence of papillary projections of epithelium into the lumen.
Etiology B The papillary projections contain a core of connective tissue and are lined by cuboidal epithelium. C This
The exact cause of hidrocystomas is not picture depicts a typical example of an apocrine hidrocystoma. The lesion is cystic and lined by a cuboidal
known. They have been reported to be epithelium. D At higher magnification the cyst is lined by a double layer of cuboidal cells with evidence of
exacerbated with high temperatures and decapitation and secretion.
Poroma
Definition
Poromas are benign adnexal neoplasms
with terminal ductal differentiation.
A
Although historically considered a neo-
plasm of eccrine differentiation, poromas
can show either eccrine or apocrine line-
age.
Synonyms
Eccrine poroma, hidroacanthoma sim-
plex, dermal duct tumour, syringoacan- B C
thoma Fig. 3.25 Poroma. A Broad tongues of uniform epithelium extend into the dermis from the undersurface of
the epidermis. B Pigmented poroma illustrating ductal structures and fibrovascular stroma. C Clear cell
Epidemiology change may be prominent in some poromas.
Poromas usually present as solitary
tumours on acral sites, although they can
be seen in virtually any cutaneous loca- rence in areas of chronic radiation der- of poroma within an acanthotic epidermis
tion. Most poromas arise in middle age matitis has been reported {1802}. with prominent surface keratinization.
with no sex predilection. Uncommonly, Occurrence of poroma within a naevus
multiple poromas are seen, either limited sebaceous has been documented Differential diagnosis
to palms and soles or in a widespread {1133}. Histologically the differential diagnosis
distribution, for which the term poromato- includes seborrheic keratosis, which typ-
sis has been applied. Histopathology ically shows keratinization with horn
Poromas are well-circumscribed tumours cysts, a more sharply demarcated lower
Clinical features composed of a proliferation of uniform border, and absence of ductal struc-
Poromas typically manifest as dome- basaloid, cuboidal cells punctuated by tures. Basal cell carcinoma may some-
shaped cutaneous papules, nodules or focal ducts and occasional cysts. The times be considered histologically, but
plaques, generally measuring less than 1 epithelial cells of poromas typically shows more obvious peripheral palisad-
cm in diameter. Some lesions are highly extend from the lower epidermis into the ing, nuclear variability, and little or no
vascular and may show a tendency to dermis in broad columns. The epithelium glycogen.
bleed, particularly on acral sites. of poromas is sharply demarcated from
Uncommonly, poromas are pigmented. adjacent keratinocytes. Nuclei are small Histogenesis
Rapid growth has been reported during and regular, and cytoplasm is modest in Poromas may show evidence of either
pregnancy {920}. Multiple poromas have amount. The cytoplasm often contains eccrine or apocrine differentiation {970}.
developed after electron beam therapy glycogen. Most poromas contain ductal Immunohistochemical studies reveal that
for mycosis fungoides {1348} and occur- structures lined by PAS positive diastase- poroma cells express a cytokeratin phe-
resistant cuticles. Small areas of necrosis notype similar to basal cells of the
as well as mitoses are seen in otherwise eccrine ducts in some cases {2466}. The
banal poromas, and are of no prognostic absence of myoepithelial cells also sug-
significance. Foci of sebaceous differen- gests differentiation toward the excretory
tiation may be observed. The stroma sur- (ductal) component of sweat glands.
rounding poromas is often richly vascu- Occurrence of poromas within follicu-
lar, and may contain granulation tissue. losebaceous lesions such as naevus
Architecturally, poromas show a spec- sebaceous, and presence of sebocytes
trum of change from predominately within poroma, implicates origin from
intraepidermal lesions (hidroacanthoma apocrine glands in some cases {662,
Fig. 3.26 Intraepidermal variant of poroma. There simplex) to primarily dermal-based neo- 970}.
are discrete nests of bland basaloid and cuboidal plasms (dermal duct tumour). Another
cells within the epidermis, associated with acrosy- rare variant has been termed syringoa- Genetics
ringium. canthoma, representing a clonal pattern Some cases of poromatosis have been
associated with hidrotic ectodermal dys- Localization eyelid hidrocystomas, whose genetic
plasia {2519}. Rare cases of poroma Most of syringofibroadenomas arise on aberration has been localized to chromo-
have occurred in the setting of naevoid acral areas {498,685,769,2248,2313, some 13q {1259}.
basal cell carcinoma syndrome {904}. 2344,2399}.
Studies of p53 protein have shown high Histopathology
expression in some poromas as well as Clinical features Syringofibroadenoma is characterized
in some porocarcinomas, but staining is The most common clinical presentation by multiple anastomosing cords and
not correlated with duration of tumours is solitary, often verrucous papules or strands of monomorphous cuboidal cells
{43}. Therefore, while p53 mutation may nodules {1529,2248,2313}. Unusual pre- {26,1529}. The epithelial cords extend
be involved in progression of some poro- sentations include large plaques, linear usually into the mid-dermis, and are
mas to porocarcinoma, other oncogenes lesions, and disseminated tumours embedded in a loose fibrovascular stro-
or factors are also likely play a role in {1259,2189,2248}. ma. Rarely, a clear cell variant has been
malignant transformation of poromas. observed {781,2415}.
Etiology
Prognosis Occasionally, syringofibroadenoma can Immunoprofile
Poromas are benign and simple excision be associated with other entities, both Light microscopy usually leads to a spe-
is curative. inflammatory and neoplastic, including cific diagnosis. The tumour cells are usu-
bullous pemphigoid {1720,1721}, lichen ally positive for both keratin 6 and 19 as
planus {780}, ulcers {1092,2399}, squa- well as filaggrin {1108,1304,1742,1745,
Syringofibroadenoma mous cell carcinoma {1399}, sebaceous 2314}.
naevus {1719}, and chronic lymphoede-
Definition ma {806}. Based on the latter association Prognosis and predictive factors
Syringofibroadenoma is a rare benign and the presence of fibrous stroma, Syringofibroadenoma is a benign condi-
eccrine tumour with anastomosing some authors consider syringofibroade- tion, and solitary lesions are cured by
strands and fibrovascular stroma, first noma as a hyperplasia rather than a neo- complete excision, while the treatment of
described by Mascaro {1529}. Multiple plasia {779,780,806,1092,1399,1719, multiple lesions is dependent on the size
lesions of syringofibroadenoma are 1720}. It may be associated with Schöpf- and location. Cases of syringofibroade-
referred to as eccrine syringofibroadeno- Schultz-Passarge syndrome {2189}, an noma with foci of atypical squamous
matosis {456,2189}. autosomal dominant syndrome with pal- cells have also been described {255,
moplantar keratoderma, hypodontia, and 1215}.
ICD-O code 8392/0
Synonyms
Eccrine syringofibroadenoma {663},
eccrine syringofibroadenomatous hyper-
plasia {1721}, eccrine syringofibroade-
nomatosis {456,2189}, acrosyringeal
adenomatosis {950}.
Epidemiology
Syringofibroadenoma is rare, with about
75 reported cases. It occurs primarily in
older adults. A B
Fig. 3.28 Hidradenoma. A There is a multinodular solid and cystic proliferation of monomourphous adnexal
keratinocytes. B Areas with cytoplasmic pallor are common (‘clear cell hidradenoma’).
and upper trunk, but they can also affect basaloid cells with hyperchromatic nuclei Histogenesis
other sites. located at the periphery, whereas pale The histochemical and immunohisto-
cells, which are larger with vesicular chemical studies have not clarified the
Clinical features nuclei and ample pale cytoplasm, tend to histogenesis of spiradenoma. The fre-
Usually, spiradenoma appears as a soli- be near the centre of the clusters. quent association of spiradenoma and
tary, well-circumscribed, firm nodule, Tubules lined by two rows of epithelial cylindroma, a likely apocrine neoplasm,
measuring usually less than 1 cm, but cells may be found within the tumour and the sporadic association of spirade-
giant variants {546} and multiple lesions nodules. A characteristic feature is the noma with neoplasms with follicular dif-
have also been described {1725}. presence of eosinophilic PAS positive ferentiation such as trichoepithelioma
Unusual cases show multiple spiradeno- globules throughout the entire neoplasm, {2500}, support an apocrine line of differ-
mas arranged in a zosteriform linear pat- sometimes surrounded by neoplastic entiation for spiradenoma on the basis of
tern {926,2162}. Spiradenoma appears cells in pseudorosette fashion. These the common embryologic origin for the
in adult life, although there are also globules are composed of basement three elements of the folliculo-seba-
reports of congenital cases {2091}, and membrane material. Sometimes the stro- ceous-apocrine unit. This is furthermore
in one patient spiradenoma developed ma shows striking oedema. supported by some examples of spirade-
within a naevus sebaceous of Jadassohn Spiradenoma in children may show a dif- noma that show decapitation secretion in
{2154}. Pain is one of the main clinical ferent histopathologic pattern. The neo- the cells lining the luminal border of the
characteristics of spiradenoma {926, plastic cells appear more immature, tubular structures. Therefore, the qualify-
2091,2154}. The mechanism of pain or making the distinction between clear and ing term of “eccrine” that almost invari-
tenderness in spiradenoma is not clear. dark neoplastic epithelial cells difficult, ably is applied to spiradenoma is inac-
and the neoplasm may be misinterpreted curate.
Histopathology as a mesenchymal neoplasm {1206}.
At low power magnification, spiradeno- Spiradenoma and cylindroma show sig- Prognosis and predictive factors
ma appears as a solid neoplasm com- nificant morphological overlap. In some Spiradenoma is a benign neoplasm.
posed of a single or few nodules of basa- patients with multiple lesions, some Because of the sharp demarcation of the
loid cells. These aggregations are round tumours show features of spiradenoma, tumour from the surrounding stroma,
with smooth borders and involve the full and others features of cylindroma. This excision is easily accomplished. Several
thickness of the dermis, sometimes supports the notion that spiradenoma examples of carcinomas arising in long-
extending into the subcutaneous fat. and cylindroma are closely related, prob- standing spiradenomas have been
Often, the intervening stroma is oedema- ably representing two morphologic described. In those instances, enlarge-
tous with ectatic vessels {546}. Dilated expressions of the same basic neoplas- ment of a nodule that had been stable for
vessels rimmed by sclerosis have been tic process {846,2280}. many years seems to be the sign of
interpreted as “ancient” changes due to malignant transformation {89,240,539,
long-standing lesions {2229}. Immunoprofile 699,884,2602}. It appears to be accom-
Another characteristic finding is the pres- The tumour cells express cytokeratins, panied by increased expression of p53
ence of abundant lymphocytes scattered and the tubular structures are CEA posi- protein {239}.
within the tumour nodules. At higher tive {1801,2465}. Inflammatory cells scat-
magnification, two distinct populations of tered within the neoplastic aggregations
neoplastic epithelial cells can be seen, have been identified as abundant T lym-
dark and pale. Dark cells are small, phocytes and Langerhans cells.
Histopathology
Histologically, endophytic invaginations
of epithelium extend from the epithelial
surface into the dermis. Typically squa-
A B mous epithelium is present at the surface
of the invaginations, and is contiguous
Fig. 3.32 Syringocystadenoma papilliferum. A Keratinizing squamous epithelium at the surface merges with
columnar epithelium in the deeper portions of the tumour. B Papillary projections are lined by pseudos-
with a double layer of cuboidal and
tratified columnar epithelium, and plasma cells are typically noted in the stroma. columnar epithelium in the deeper por-
tions of the lesion. Within the dermis,
broad villous projections protrude into
ing. The peripheral epithelial layer con- Histogenesis cystic spaces. Columnar epithelium is
sists of cuboidal to flattened cells Enzyme histochemistry {1361} and ultra- present toward the lumen of the spaces,
(myoepithelial) and the luminal layer of structural analysis {1361,2394} have and simple cuboidal epithelium can be
columnar cells that demonstrate decapi- demonstrated tubular apocrine adeno- seen at the periphery. Decapitation
tation secretion. In some tubules papil- mas to be of apocrine differentiation. secretion of luminal cells is a frequent
lary cellular extensions that are devoid of finding. Plasma cells are consistently
stroma project into the lumina. Addi- Prognosis numerous within the stroma, and are a
tionally, cellular debris and eosinophilic Tubular apocrine adenomas are benign highly reproducible finding in the stroma
granular material are identified within slow-growing neoplasms. Simple exci- of syringocystadenomas.
some lumina {1361}. The neoplasm lacks sion is curative. The differential diagnosis includes
cytologic atypia and mitotic activity. hidradenoma papilliferum, which differs
Overlying epidermal hyperplasia may be clinically by location in the perineal
present. In those neoplasms that occur in Syringocystadenoma region, and histologically by dermal nod-
conjunction with syringocystadenoma papilliferum ules showing a more complex papillary
papilliferum {76,489,2364}, the tubular growth pattern, and absence of plasma
adenoma component is typically present Definition cells in the stroma. The epithelial lining of
underlying the syringocystadenoma Syringocystadenoma papilliferum is a the two lesions shows histologic overlap,
component. The differential diagnosis benign adnexal neoplasm that occurs in however.
includes apocrine adenocarcinoma and association with an organoid naevus
papillary eccrine adenoma. In contrast to such as naevus sebaceous in at least Precursor lesions
apocrine adenocarcinoma tubular apoc- one-third of cases. Approximately one-third of cases arise in
rine adenomas lack cytologic atypia, are organoid naevi.
well circumscribed and possess a ICD-O code 8406/0
peripheral myoepithelial layer {1751}. Histogenesis
Tubular apocrine adenomas resemble Synonmys Syringocystadenomas show differentia-
papillary eccrine adenomas in many Syringoadenoma tion that is predominantly apocrine in
respects and previously these were pattern, but eccrine origin has been sug-
believed to be related neoplasms {489}. Epidemiology gested in some cases, as exemplified by
However on the basis of morphologic cri- Syringocystadenoma papilliferum occurs immunohistochemical labelling with
teria (papillary eccrine adenomas lack with equal frequency in both sexes. It is a eccrine marker IKH-4 {1109}. An intrigu-
decapitation secretion) and enzyme his- tumour of childhood or adolescence, ing finding is the presence of IgA and
tochemistry and ultrastructural analysis with many examples noted at birth. secretory component within the epithelial
demonstrating differences in differentia- These lesions tend to increase in size at cells in syringocystadenomas, and IgA
tion (apocrine versus eccrine) they are puberty, and sometimes multiply in num- and well as IgG within the plasma cells
now believed to represent distinct neo- ber as well as becoming more papillo- {2420}. This observation suggests that
plasms. In some instances both eccrine matous over time. plasma cells are attracted to tumour
and apocrine differentiation may be epithelium via a mechanism similar to
observed making a distinction between Clinical features that used by glands of the normal secre-
these neoplasms impossible {771}. The The majority of syringocystadenomas tory immune system.
terms tubulopapillary hidradenoma {705} affect the head and neck area, typically
and papillary tubular adenoma {2335} as one or more warty papules, some- Somatic genetics
have been suggested for cases with times in a linear array, or as a solitary Allelic deletions of the patched gene
apocrine and eccrine differentiation. grey or red plaque. Scalp and neck are 9q22 and loss of heterozygosity at 9p21
(p16) have been reported in syringocys- Histopathology tive {2257}. Neoplastic epithelial cells lin-
tadenoma papilliferum {281}. At scanning magnification, hidradenoma ing tubules and papillations also express
papilliferum consists of a cystic neo- strong immunoreactivity for androgen
Prognosis and predictive factors plasm composed of elongated tubules and oestrogen receptors {1739}.
Syringocystadenonas are benign and and large papillary structures with a
simple excision is curative. frond-like pattern. The papillae are com- Histogenesis
posed of a central axis of connective tis- Both the histopathologic and ultrastruc-
Hidradenoma papilliferum sue lined by two layers of epithelial cells. tural characteristics of hidradenoma
The basal layer is composed of pale- papilliferum support an apocrine line of
Definition staining cuboidal myoepithelial cells and differentiation, although some authors
Hidradenoma papilliferum is a benign the luminal layer is made up by columnar have postulated the possibility of origin
cystic and papillary neoplasm that cells with decapitation secretion. The from Wolffian ducts or accessory mam-
almost always develops in the vulval and cystic cavity and the lumina of the tubu- mary glands {576,1633}.
perianal regions of middle-aged women. lar structures contain apocrine secre-
tions in the form of eosinophilic homoge- Prognosis and predictive features
ICD-O code 8405/0 neous material. Hidradenoma papilliferum is a benign
The epithelial cells at the periphery are neoplasm cured by simple excision.
Epidemiology flattened, and decapitation secretion is Malignant transformation is a very
Most cases appear in women, although less evident, as a consequence of the uncommon event {588,1730,2274,2460}.
there are also reports in males {588, pressure exerted by the cyst contents. A case of adenosquamous carcinoma of
1441,1697,2421}. The neoplasm is rare The stroma surrounding the cystic cavity the vulva developing from a pre-existing
in Black patients. The age of presenta- is composed of compressed fibrous tis- hidradenoma papilliferum has also been
tion ranges from 20-90 years {2428, sue that is separated from the normal reported {142}.
2435}. adjacent dermis by clefts. These clefts
are responsible for the tendency of the Mixed tumour
Localization neoplasm to shell out easily after incision (chondroid syringoma)
The skin of the vulva and perianal of the epidermis.
regions are the most frequently involved In contrast with syringocystadenoma Definition
areas {588,1106,1441,1565,1568,1697, papilliferum, hidradenoma papilliferum is Cutaneous mixed tumours are benign
2324,2421}, although rare examples of not connected with follicular infundibula adnexal tumours of skin composed of
extra-genital or ectopic hidradenoma and there are not plasma cells in the axis epithelial and stromal elements with a
papilliferum have been reported on of connective tissue of the papillations. wide spectrum of patterns. These
postauricular skin {247}, eyelids {1106, Sometimes, neutrophils are scattered tumours are histologically analogous to
1697,2056,2421}, external auditory canal within the connective tissue framework. mixed tumours of the salivary gland, but
{1718}, face {1106,1697} scalp {845}, lack the tendency for local recurrence
axilla {1106,2421}, upper limb {2421}, Immunoprofile seen in the latter lesions.
back {727,1106} and thigh {2421}. Immunohistochemical studies demon-
strated that epithelial cells lining the ICD-O code 8940/0
Clinical features papillations express low-molecular
The lesion appears as a slow-growing weight cytokeratins. The luminal border Synonyms
cystic dermal nodule, usually asympto- of the cells lining tubular structures is Chondroid syringoma, mixed tumour of
matic, although it sometimes ulcerates also decorated by carcinoembryonic skin.
and bleeds. The neoplasm is a unilateral antigen, epithelial membrane antigen
skin-coloured nodule, papule or polypoid and gross cystic disease fluid protein-15. Epidemiology
exophytic lesion, most commonly locat- Immunostains for S-100 protein and Mixed tumours most often occur as soli-
ed on the labius majus. high-molecular-weight keratins are nega- tary slowly growing nodules on the head
and neck of adults, although other sites tumours contain hyaline cells character- entities such as myxoma. In other lesions
may be affected. There is a male ized by an ovoid shape, dense ground- with abundant epithelial elements, the
predilection. Most lesions are between 1- glass or hyaline-like cytoplasm, and an differential diagnosis includes benign
3 cm in diameter, although examples as eccentric nucleus {85}. The cells resem- adnexal tumours such as hidradenoma
large as 6 cm have been reported ble plasma cells, and have been called and syringoma, depending on the pat-
{1182}. plasmacytoid cells. In some cases, hya- tern of epithelial growth.
line cells are the predominant cell type,
Clinical features leading to the term hyaline-cell rich Histogenesis
Cutaneous mixed tumours present as chondroid syringoma {735}. The pres- It is generally accepted that there are
asymptomatic dermal nodules, with no ence of hyaline cells appears to be of no both apocrine and eccrine variants of
specific distinguishing clinical character- prognostic significance, although such mixed tumours. Ultrastructural studies
istics. cells may present a diagnostic challenge confirm that myoepithelial cells surround
to the unsuspecting pathologist {735}. the epithelial cells, and appear to pro-
Histopathology duce the stromal components of the
At low power, cutaneous mixed tumours Immunoprofile lesions {2423}. The stroma of mixed
are well-circumscribed lesions located in Immunohistochemical studies reveal tumours contains matrix components
the dermis and/or subcutis. A biphasic staining of the inner layer of epithelial such as types II and IV collagen,
growth pattern can be readily detected, cells with cytokeratin, CEA, and EMA, tenascin, fibronectin, and laminin {773}.
with epithelial elements embedded with- and staining of the outer cellular layer Ultrastructural and immunohistochemical
in a myxoid, chondroid, or fibrous stro- with S100 and vimentin {2559}. studies of hyaline cells in mixed tumours
ma. The epithelium often shows a pattern The stroma of mixed tumours usually suggest these cells derive from both the
of branching tubules, sometimes with comprises at least half of the lesion, and epithelial and stromal components of the
decapitation secretion suggesting apoc- may show variable patterns of differenti- lesions, possibly representing a regres-
rine differentiation. Solid cords and ation, including myxoid, fibroblastic, sive process {85}.
islands of epithelium as well as single fibrocartilagenous, chondroid, and even
cells may also be present. In some osteoid components. Combinations of Prognosis
cases, the epithelial elements are com- matrix components are the rule. Despite Cutaneous mixed tumours are benign
posed of small non-branching tubules the name chondroid syringoma, chon- lesions cured by simple excision.
that may contain eosinophilic cuticles. droid areas may be absent in the stroma.
Follicular differentiation occurs in some The stroma stains strongly for alcian blue
mixed tumours, in the form of follicular with hyaluronidase resistance.
germinative cells, shadow cells, or sebo-
cytes. Mixed tumours may exhibit clear Differential diagnosis
cell change within the epithelial cells. In In mixed tumours where stroma predom-
an estimated 40% of cases, mixed inates, the differential diagnosis includes
Pilomatrical carcinoma occurs mainly in middle aged and elder- aggregations of basaloid cells (matrical
ly individuals, may represent an interme- and supramatrical cells) {28,804,954,
Definition diate precursor lesion. 2064}. Foci of cornified material contain-
Pilomatrical carcinoma is the malignant ing shadow cells are characteristically
counterpart of pilomatricoma. Localization observed within the basaloid cell aggre-
Pilomatrical carcinomas mostly occur in gations. Some neoplasms show a vari-
ICD-O code 8110/3 the head and neck, upper extremities able desmoplastic stroma surrounding
and buttocks. Rare tumours have been the basaloid cell aggregations. Focal
Synonyms reported in the axilla and inguinal connections of basaloid cell aggrega-
Pilomatrix carcinoma, matrical carcino- regions. tions to the overlying epidermis and/or
ma, invasive pilomatrixoma, malignant ulceration are often noted. Basaloid cells
pilomatrixoma, matrix carcinoma. Clinical features exhibit hyperchromatic nuclei, with one
The clinical appearance of pilomatrical or more prominent nucleoli and ill-
Epidemiology carcinoma is generally not distinctive. defined cytoplasmic margins as well as
Pilomatrical carcinoma is an extremely Patients show solitary, occasionally variable numbers of occasionally atypi-
rare tumour. Most cases present in adults ulcerated or fungating nodules ranging cal mitotic figures (up to 10 mitoses per
with a broad age range {28,804,954, in size from 1-10 cm in diameter. Skin high-power field). Foci of geographical
2064}. The mean age at the time of diag- nodules are often of long duration rang- necrosis, calcification and ossification
nosis is about 48 years. The male to ing from several months to years before are observed. Mitotic activity is not a reli-
female ratio is 2:1. diagnosis, although occasional cases of able indicator of malignancy, because
recent onset and a history of rapid mitoses are common in pilomatricoma.
Etiology growth have been reported. Other parameters, such as an infiltrative
The majority of pilomatrical carcinomas growth pattern, as well as angiolymphat-
develop de novo, although malignant Histopathology ic, perineural, and bone invasion, are
transformation from a pre-existing pilo- The tumour is a large, asymmetrical, more reliable features {804,2064}.
matricoma has been reported {2064}. It poorly circumscribed dermal or dermal-
is conceivable that proliferating pilomatri- subcutaneous mass composed of sever- Immunoprofile
coma, a variant of pilomatricoma that al, irregularly shaped and variously sized Immunohistological studies have previ-
A B
Fig. 3.35 Pilomatrical carcinoma. A The neoplastic cells are present in apposition to the epidermis. B A large mass of shadow (ghost) cells is present. The clear
cells have more nuclear pleomorphism than in the pilomatricoma.
Proliferating tricholemmal
tumour
Definition
Proliferating tricholemmal tumour is a
solid-cystic neoplasm that shows tric-
holemmal differentiation similar to that of
the isthmus of the hair follicle.
Clinical features
The tumour is a solitary, multilobular,
large, exophytic mass, which may devel-
op within a naevus sebaceous {866,
1874}. Multiple lesions are very rare. The
size ranges from 2-10 cm in diameter,
although lesions up to 25 cm in diameter
have been described {407}. Alopecia
and ulceration can be found.
Macroscopy
The lesions often show a multilobular
appearance. The cystic structures often
contain compact keratin and calcified
material.
Histopathology
Proliferating tricholemmal tumour occurs
on a morphologic continuum. On one
end of the spectrum, it consists of a well-
circumscribed solid and cystic neoplasm
Fig. 3.38 Proliferating tricholemmal tumour. At scanning power the neoplasm appeares as a well-circum- which involves the dermis and some-
scribed cystic neoplasm involving deeper dermis and subcutaneous tissue of the scalp. times extends to the subcutaneous tis-
Trichoblastoma The differential diagnosis is non-specific differentiate these lesion from trichoblas-
for solitary lesions, but includes the toma, one seems to be that the carcino-
Definition “angiofibroma” of tuberous sclerosis mas infiltrate through skeletal muscle or
Trichoblastoma is a benign neoplasm dif- when multiple. other deep structures while there is a
ferentiated toward the trichoblast, i.e., conspicuous absence of the usual stro-
the folliculo-sebaceous-apocrine germ, Histopathology ma present in a classic nodular tri-
or follicular germ, for short. In many Trichoblastic epithelial components choblastoma. Rare examples with this
cases, advanced follicular differentiation associated with stereotyped stroma, pattern have metastasized {1960}.
can be present also {28,989,1083}. chiefly the follicular papilla, must be Retiform trichoblastomas are reticulated,
present to establish the diagnosis with with large fenestrations containing follic-
ICD-O code 8100/0 surety. There are five patterns; these can ular stroma.
be mixed in any given neoplasm. Cribriform trichoblastoma is the most
Synonyms Large and small nodular trichoblastomas common pattern when the neoplasms
Trichoepithelioma, trichoblastic fibroma, are usually circumscribed, sometimes are multiple, characteristic of Brook-
trichogenic trichoblastoma, lymphadeno- subcutaneous, and contain a uniform Fordyce disease. The trichoblasts are
ma (adamantinoid trichoblastoma), tri- distribution of solid trichoblasts with fol- usually fenestrated, but with small fenes-
chogerminoma, sclerosing epithelial licular papillae. In some cases, the follic- trations compared to the retiform pattern.
hamartoma, Brooke-Fordyce disease, ular “papillae” are not papillary in that Racemiform trichoblastoma contains
Brooke-Spiegler disease. they fail to invaginate into the epithelial epithelial nests that simulate “clusters of
components of the germ. The epithelial grapes”. This results in stromal compo-
Clinical features cells are deeply basophilic, uniform, and nents that connect with the surrounding
Trichoblastomas, as a rule, are solitary, overlap each other usually. Melanocytes stroma rather than being isolated from it
small papules that occur on any hair fol- can be prominent within the epithelial in fenestrations.
licle-bearing location (usually head and areas in some cases. Some cases have Columnar trichoblastoma (desmoplastic
neck), at any age, and can affect either nodules that are lymphocyte-rich, a pat- “trichoepithelioma”) occurs most com-
sex. They can also present as multiple tern termed originally lymphadenoma monly as a solitary depression on the
centrofacial papules or nodules, particu- {1561,2053}. face of a young woman. As a rule, these
larly in the diseases of Brooke-Fordyce It should be noted that, rarely, lesions neoplasms are confined to the superficial
and Brooke-Spiegler. The size of an indi- with a pattern similar to nodular tri- dermis. They contain stereotyped, thin
vidual neoplasm can vary from a few mil- choblastoma are really trichoblastic strands of epithelium compressed by
limetres to several centimetres, but most (basal cell) carcinomas that mimic tri- dense stroma. Small trichoblasts can be
are less than 1 cm in diameter. Most are choblastoma. While it is not completely seen in some cases, but are less com-
skin-coloured and ulcerated only rarely. understood what are all the factors that mon compared to conventional forms of
A B
Fig. 3.39 Trichoblastoma. A Large nodular trichoblastoma. Note the circumscription. Melanin pigmentation is present in this lesion. B Cribriform trichoblastoma. At
scanning magnification, there are small groupings of basophilic cells containing small fenestrations of stroma.
D E F
Fig. 3.40 Trichoblastoma. A This trichoblast has a typical follicular "papilla" that does not extend cleanly into an invaginated epithelial component of the follicular
germ. B Compared to the usual types of trichoblasts seen in nodular trichoblastoma, this trichoblastic carcinoma has diminished mesenchymal stroma, specifical-
ly diminished mesenchyme of the follicular papilla. C Trichoblast containing a superficial follicular papilla that protrudes into an invaginated follicular germ. This
is a fundamental finding in trichoblastomas of any pattern. D Retiform trichblastoma. This reticulated pattern is seen often in large, solitary lesions. E This sieve-
like pattern is commonly present in the small centrofacial lesions of Brooke-Fordyce disease and is the pattern known classically "trichoepitheliom". F Groupings
of follicular germinative cells that branch out, mimicking a "cluster of grapes". Absence of sieve-like areas seen in the cribrifom pattern.
trichoblastoma. The differential diagnosis but is negative for CEA and S100 {2511}. Prognosis and predictive factors
includes morpheiform basal cell carcino- CK 5, 8, 14 and 15 have been identified Because these are benign neoplasms,
ma, microcystic adnexal carcinoma, and, in some cases {2555}. It can be differen- no treatment is required, in most cases, if
rarely, metastatic carcinoma from breast. tiated from morpheiform basal cell carci- the diagnosis is established with certain-
Thus, superficial biopsies of such lesions noma and microcystic adnexal carcino- ty. Because some trichoblastomas may
should be investigated thoroughly, and ma, in most cases, by applying CK20, occur, rarely, in association with basal
additional biopsy or excision should be which marks neuroendocrine cells in cell (trichoblastic) carcinoma, and
requested for cases in which the diagno- desmoplastic trichoepithelioma, but not because of the difficulty in establishing
sis is uncertain. in basal cell carcinoma or microcystic the diagnosis in superficial biopsies, in
adnexal carcinoma {13}. Furthermore, some cases, additional biopsy or exci-
Immunoprofile CK7 is usually positive in breast carcino- sion should be considered if there is
Trichoblastomas, as a rule, cannot be dif- ma metastatic to skin and in microcystic uncertainty about the diagnosis.
ferentiated from basal cell (trichoblastic) adnexal carcinoma, but not in desmo-
carcinoma based solely on specific plastic trichoepithelioma. Stromelysin 3
expression of cytokeratins. The presence has also been identified in the stroma of Pilomatricoma
of presumed Merkel cells within a neo- morpheiform basal cell carcinoma, but
plasm, however, does seem to favour tri- not in the stoma of desmoplastic tri- Definition
choblastoma over basal cell carcinoma choepithelioma {2346}. Pilomatricoma is a relatively common
{1349}. Some trichoblastomas can con- benign cutaneous adnexal neoplasm
tain zones of ductal differentiation; when Somatic genetics with differentiation towards the matrix
this occurs, markers, such as CEA will Multiple trichoblastomas (Brooke- and inner sheath of a normal hair follicle
highlight those areas {2398} but they will Fordyce disease) are transmitted as an as well as hair cortex {28,1169}.
not aid in establishing the diagnosis. autosomal dominant trait linked to chro-
Uncommonly, excessive pigmentation is mosome 9p21 {6,951}. Solitary (spo- ICD-O code 8110/0
seen in nodular trichoblastoma, and radic) trichoblastomas have been linked,
these lesions contain markers for in some cases, to 9q22.3 {1538}, the Synonyms
melanocytes {1199}, but they are non- same locus for the naevoid basal cell Pilomatrixoma, calcifying epithelioma of
specific for the diagnosis, as basal cell carcinoma syndrome {4}. Familial multi- Malherbe, benign calcifying epithelioma
(trichoblastic) carcinoma can have simi- ple trichoblastomas and cylindromas
lar findings. (Brooke-Spiegler disease) have been Epidemiology
Desmoplastic trichoepithelioma contains linked to chromosome 16q12-q13 Pilomatricoma accounts for up to 0.2% of
AE14, EMA, and Leu-M1 (CD15) focally, {5,722}. all routine dermatopathologic specimens
Histopathology
There is usually a relatively well-circum-
scribed, deep dermal or dermal-subcu-
taneous, cystic neoplasm surrounded by
a variable connective tissue stroma {28,
1169}. A spectrum of histopathologic
features reflecting mainly different stages
of development is observed in individual
lesions. Early and well-developed pilo-
matricomas are characterized by small
to large-sized, cystic lesions lined focally
by aggregations of basaloid cells (matri-
cal and supramatrical cells) and few
Fig. 3.41 Pilomatricoma. There is a growth component of basolid cells with transition to pilar ‘shadow cells’. squamoid cells and filled centrally with
large masses of eosinophilic cornified
material (faulty hair matrix) containing
in certain centres. The tumour occurs in skin-coloured, but may show a bluish- shadow (ghost) cells as well as a few
all age groups {1169}. About 30-50% of purple to reddish hue or pigmentation. keratin filaments. A transition zone of
cases present in young individuals less Unusual presentations include rapidly retained nuclei from basaloid cells to
than 30 years of age. Previous studies growing or giant tumours (measuring up eosinophilic cornified material containing
have shown a female predominance. to 15 cm in diameter), lesions with over- shadow cells is focally observed.
lying striae or anetodermic changes, and Basaloid cells exhibit deeply basophilic
Localization multiple tumours. Multiple pilomatrico- oval or round nuclei and a variable num-
Pilomatricomas favour hair-bearing mas are quite rare. They are a marker for ber of mitotic figures. Inflamed or
areas, with the majority of cases arising myotonic dystrophy, and may rarely be regressing pilomatricomas are relatively
in the head and neck region as well as associated with a number of different large cystic tumours with prominent
upper extremities. conditions including Rubinstein-Taybi areas of shadow cells and foci of basa-
syndrome, Turner syndrome, Goldenhar loid and/or squamoid cells surrounded
Clinical features syndrome, sternal cleft defects, coagula- by a variable, often dense inflammatory
Patients present with solitary, asympto- tive defects, and sarcoidosis. Piloma- infiltrate with histiocytic giant cells, and
matic, slowly growing, cystic or firm nod- tricoma-like features are an occasional occasionally siderophages and/or mela-
ules measuring 0.5-3 cm in diameter finding in cutaneous cysts removed from nophages. Areas of granulation tissue
{28,1169,1170}. Lesions are commonly patients with Gardner syndrome. may be present. Occasional lesions dis-
A B
Fig. 3.42 Tricholemmoma. A Exo-endophytic tumour with wart-like silhouette and focal desmoplastic stroma. B Peripheral epithelia are arranged in a palisade.
Small central follicular microcyst.
Epidemiology
TF represents a rare hamartoma mostly
occurring during adulthood (with a wide
range of ages between 11 and 77 years
{28}) without sex predilection {887}.
Localization
TF favours the head and neck region,
B foremost the face. Most lesions are situ-
ated around the nose {887}.
Clinical features
TF presents as a solitary asymptomatic
dome-shaped lesion with a smooth sur-
face and a widely dilated central ostium
from which a small tuft of delicate white
hairs emerges. Lesions are small, rang-
ing between 0.5 and 1.0 cm in diameter
{28}.
A C Histopathology
Fig. 3.44 Trichofolliculoma. A Note reticulate pattern of vellus follicles in devolution. B Detail. Reticulate The main histological features of TF are
epithelial strands, sebaceous lobules and few vellus follicles. C Note sebaceous lobules and dense fibrot- reflected by its “Caput Medusae” pattern
ic stroma. Vellus follicles in different stages of devolution. {28}: embedded in a highly fibrocytic
stroma, large numbers of vellus follicles
with upper and lower segments like
and type IV collagen-positive basement Histogenesis those of normal follicles radiate from the
membrane. Central foci of epidermal / According to strict topographical anato- perimeter of a dilated infundibulum.
infundibular keratinization, occasional mical criteria, TL arises from the follicular TF is a symmetrical, well-circumscribed,
small and inconspicuous squamous infundibulum and differentiates toward vertically oriented lesion composed of
eddies, and keratinous microcysts in the outer [tricholemmal] root sheath {28}. three components: infundibulo-cystic,
larger lesions are occasional findings Its superficial folliculo-infundibular loca- follicular, and stromal {28}. The centre of
{28}. There are no mitoses. tion militates against the classification of the lesion is occupied by one or more
Desmoplastic tricholemmoma is a variant TL as a neoplasm of the lower portion of widely dilated infundibulo-cystic struc-
of TL characterized by a highly desmo- the hair follicle (i.e. the [outer] tricholem- tures that are continuous with the epider-
plastic stroma with broad zones of scle- mal sheath). mis and open to the surface of the skin
rosis and distinctive artifactual clefts. However, it is still a matter of debate through an ostium. The cystic lumina
Instead of “pushing” smooth lobular con- whether TL is of hamartomatous/neo- may be filled with innumerable corneo-
tours there may be a pseudoinvasive plastic {318,991,1906,1931} or of viral cytes and vellus hairs. From the epithelial
interface akin to pseudocarcinomatous origin {15,28,31}. The detection of HPV walls of the infundibular cystic spaces
epithelial hyperplasia, simulating carci- DNA in tricholemmomas by PCR {2688} smaller infundibula radiate, to which are
nomatous growth {1079,2333}. favours the latter view of TL as a resolv- attached vellus follicles in various num-
ing verruca vulgaris with tricholemmal bers. These vellus follicles are not asso-
Differential diagnosis differentiation {15,28, 31}. ciated with muscles of hair erection or
Warts, basal cell carcinomas, squamous with sebaceous ducts, albeit sebaceous
cell carcinomas, trichoblastomas, sebor- Prognosis and predictive factors cells arranged as solitary units or in lob-
rhoeic keratoses, and keratosis follicu- TL is an entirely benign cutaneous neo- ules may occur within the lining epitheli-
laris inversa may contain areas of tric- plasm. Multiple TLs are a hallmark of um of the central infundibulo-cystic
holemmal differentiation {31,1931}. The Cowden disease and should prompt a structure.
tumour of the follicular infundibulum search for internal malignancy. The morphology of the individual vellus
exhibits a plate-like pattern with inter- follicles may vary from normal to striking-
connecting horizontally oriented epithe- ly aberrant {28}. Normal vellus follicles
lial strands. Inverted follicular keratosis Trichofolliculoma may exhibit all stages of the follicular
consists of basaloid and squamous cycle {2106}. The whole lesion is embed-
epithelia, associated with large numbers Definition ded in a cellular connective tissue
of squamous eddies (i.e. concentric lay- Trichofolliculoma (TF) is a follicularly dif- sheath, which is separated from the adja-
ers of squamous cells in a whorled pat- ferentiated hamartoma generally appear- cent normal dermis by prominent shrink-
tern, sometimes keratinized). ing during adult life. age clefts. The highly fibrocytic stroma
Variants
TF is a complex lesion with protean fea-
tures {28}. Some of these are caused by A B
the evolutionary and devolutionary alter-
ation of the vellus hair follicles in their
regular biological cycles {2106}. In this
context, folliculo-sebaceous cystic
hamartoma {1275,2187} may be inter-
preted as a TF at its very late stage with
nearly complete regression of the tran-
sient follicular epithelium, but with con-
current growth and maturation of seba-
ceous elements {2105}. Sebaceous tri-
chofolliculoma {1846} exhibits distinct C D
sebaceous lobules at its outer circumfer-
ence, but lacks vellus follicles that radi-
ate from the epithelial lining of the dilated
infundibulum. The latter criterion militates
against the classification of sebaceous
trichofolliculoma as a true TF {28}. Hair
follicle naevus is regarded as a TF that
was histologically sampled at its periph-
ery {28}. There is a striking predomi-
nance of mature vellus follicles and the
E F
central infundibular lumen may be quite
Fig. 3.45 Pilar sheath acanthoma. A The characteristic infundibular and isthmic differentiation is stereo-
inconspicuous.
typed. Note the lack of a hair filament or inner root sheath. B The lobule contains red-pink corneocytes,
characteristic of the isthmus. C This pilar sheath acanthoma does not have the obvious widened ostium,
Prognosis and predictive factors but it does contain the lobules of isthmic epithelium. D The lobules have a nearly syncytial pattern. E This
TF represents an entirely benign cuta- lobule has clear-cell changes and syncytial, pink cell changes. Note the lack of inner sheath or hair fila-
neous hamartoma with no reports of ment. F The small, partly cornified cyst seen here contains no hair filament. Parts of the transient portion
tumour progression or aggressive clini- of the follicle are rarely seen in pilar sheath acanthoma.
cal course.
Epidemiology
Fibrofolliculomas/trichodiscomas are
rare appendageal tumours, occurring
equally in males and females, usually not
before the third decade of life.
Fig. 3.46 Histopathology of a typical tumour of the follicular infundibulum, with horizontal proliferation of pale
keratinocytes in the papillary dermis. Note the connection with the overlying epidermis.
Etiology
The etiology of the solitary lesions is
unknown. The BHD gene was mapped to
Prognosis and predictive factors of pale keratinocytes, which is localized 17p11.2 {1256}.
The neoplasm is benign; no treatment is in the papillary dermis and shows multi-
necessary. ple connections with the overlying epi- Localization
dermis or with the infundibulum. The The preferred sites of location are the
cells are paler and larger than normal face, neck and chest.
Tumour of the follicular keratinocytes and their cytoplasm stains
infundibulum with PAS. The tumour is sharply circum- Clinical features
scribed and limited by a dense network Fibrofolliculomas and trichodiscomas
Definition of elastic fibres easily demonstrated by cannot be distinguished clinically {248}.
Tumour of the follicular infundibulum (TFI) orcein staining. Desmoplastic and seba- The onset of the lesions is mostly in the
is a benign epithelial neoplasm of follicu- ceous variants have been described third to fourth decade of life. They are
lar origin. {557,1485}. skin coloured, smooth, dome-shaped
papules, measuring 2-4 mm in diameter
Synonym Histogenesis {248}. The lesions are asymptomatic.
Infundibular tumour. TFI derives from the normal follicular
infundibulum. The occurrence of multiple Histopathology
Epidemiology TFI suggests a possible genetic basis, There is a histomorphological continuum
TFI is an uncommon tumour occurring in which remains to be established. between fibrofolliculoma and trichodis-
adults, mainly after the age of 50. In two coma. However, most of these presented
studies, TFI accounted for less than 10 Prognosis and predictive factors cases were actually fibrofolliculomas
per 100,000 skin samples. They can be The prognosis is good, except in rare which were merely prepared histological-
observed on the face of patients with patients with multiple TFI who may devel- ly in an unusual sectioning technique,
Cowden syndrome or on the surface of op basal cell carcinomas. resulting in misinterpretation as perifollic-
naevus sebaceous. ular fibroma {2107}.
Immunoprofile
The epithelial and mesenchymal parts of
the lesions show the common reactivities
to cytokeratins and vimentin. The tumour
stroma is strongly reactive with antibod-
ies to CD34, reflecting its differentiation
towards the follicular mantle region.
Histogenesis
Histologic and immunohistologic data
suggest that fibrofolliculoma/trichodisco-
ma is derived from/differentiated to the
mantle region of the hair follicle {27,521}.
The mantle region is a specialized
epithelial-mesenchymal structure, locat-
ed at the lower end of the follicular
infundibulum {606} and is the source and
starting point for the development of the
Epidemiology
SC usually arises in adults, with an aver-
age patient age of 62 yrs. and a female
predominance, by a factor of roughly 2:1.
Tumours of the eyelids are preferentially
seen in Asian patients, and also may rep-
resent a complication of prior radiothera-
py {1067A}.
Clinical features
All SCs present as painless masses,
which can be multifocal. In the ocular
adnexae, they may be mistaken clinical-
ly for chalazions, blepharitis, cicatricial
pemphigoid, or conjunctivitis {642,839,
2542}. In extraocular sites, sebaceous
malignancies are commonly confused
with basal cell carcinomas and squa-
mous cell carcinomas.
Most extraocular SCs are encountered in A
the skin of the head and neck, followed
by the trunk, genitals, and extremities.
Rare cases may also be seen in the
mouth, salivary glands, lungs, and
breasts.
Macroscopy
SCs are nodules that typically enlarge
slowly but may occasionally grow rapid-
ly; some become ulcerated. A minority of B C
individuals with this tumour have the Fig. 3.47 Sebaceous carcinoma. A Sebaceous carcinoma, represented by a lobular proliferation of atypical
Muir-Torre syndrome {2227}. epithelioid cells in the dermis. Multivesicular cytoplasmic vesiculation is present. B Extensive in-situ
involvement of the surface epithelium is present in this example of sebaceous carcinoma. C “Bubbly” cyto-
plasmic vacuolization is apparent in sebaceous carcinoma.
A B
Fig. 3.48 Sebaceous adenoma. A Well circumscribed lobulated sebaceous tumour. Fully differentiated sebocytes predominate and epidermis is replaced by the
tumour. B High magnification of the periphery of the lobule.
Sebaceoma
Definition
Sebaceoma is a benign, adnexal neo-
plasm with sebaceous differentiation. It is
characterized by multiple, smooth-bor-
dered lobules and cystic spaces com-
posed primarily of immature sebaceous
cells admixed with randomly scattered
mature sebocytes.
Haematolymphoid Tumours
Lymphoma may involve the skin as the primary and only site of
involvement, or may spread to the skin as a secondary site of
disease. Some cutaneous lymphomas morphologically resem-
ble their counterparts in lymph node, but differ in terms of phe-
notype, genotype, and clinical behaviour, suggesting that they
represent an independent entity. Cutaneous follicular lym-
phoma demonstrates such fundamental differences from nodal
follicular lymphoma. Some lymphomas present only in the skin,
but never primarily in lymph nodes or other extranodal sites.
Mycosis fungoides is one such example. Finally, some cuta-
neous lymphomas exhibit a different clinical behaviour from
their nodal counterparts, despite apparent phenotypic and
genotypic similarities.
The members of the WHO Working Group, together with their
colleagues from EORTC, were able to formulate a classification
that respects the many unique features of skin lymphomas but
avoids a terminology restricted to primary cutaneous lym-
phomas. We are confident that this proposal will be used by
pathologists and dermatologists world-wide for years to come.
WHO / EORTC classification of cutaneous lymphomas1
Mature T-cell and NK-cell neoplasms
Mycosis fungoides 9700/3 Mature B-Cell neoplasms
Pagetoid reticulosis (localized disease) Cutaneous marginal zone B-cell lymphoma (MALT-type) 9699/3
Follicular, syringotropic, granulomatous variants Cutaneous follicle centre lymphoma 9690/3
Granulomatous slack skin Cutaneous diffuse large B-cell lymphoma 9680/3
Sezary syndrome 9701/3 Intravascular large B-cell lymphoma* 9680/3
CD30+ T-cell lymphoproliferative disorders of the skin Lymphomatoid granulomatosis* 9766/1
Lymphomatoid papulosis 9718/1 Chronic lymphocytic leukaemia* 9823/3
Primary cutaneous anaplastic large cell lymphoma 9718/3 Mantle cell lymphoma* 9673/3
Subcutaneous panniculitis-like T-cell lymphoma** 9708/3 Burkitt lymphoma* 9687/3
Primary cutaneous peripheral T-cell lymphoma
(PTL), unspecified 9709/3 Immature haematopoietic malignancies
Subtypes of PTL (provisional) Blastic NK-cell lymphoma *** / 9727/3
Primary cutaneous aggressive epidermotropic CD4+/CD56+ haematodermic neoplasm
CD8-positive cytotoxic T-cell lymphoma Precursor lymphoblastic leukaemia/lymphoma
Cutaneous gamma/delta-positive T-cell lymphoma T-lymphoblasic leukaemia* 9837/3
Primary cutaneous small/medium CD4+ T-lymphoblastic lymphoma* 9729/3
T-cell lymphoma B-lymphoblastic leukaemia* 9836/3
Extranodal NK/T-cell lymphoma, nasal type 9719/3 B-lymphoblastic lymphoma* 9728/3
Hydroa vacciniformia-like lymphoma (variant) Myeloid and monocytic leukaemias*
Adult T-cell leukaemia/lymphoma*
9827/3 Hodgkin lymphoma*
Angioimmunoblastic T-cell lymphoma* 9705/3
__________
1
Morphology code of the International Classification of Diseases for Oncology (ICD-O) {786} and the Systematized Nomenclature of Medicine (http://snomed.org).
Behaviour is coded /0 for benign tumours, /3 for malignant tumours, and /1 for borderline or uncertain behaviour.
* Extracutaneous lymphomas frequently involving the skin as a secondary site are printed in italics.
** Definition is restricted to lymphomas of alpha/ beta T-cell origin
***Recent evidence suggests an origin from a dendritic cell precursor. In recognition of uncertain histogenesis, the term CD4+/CD56+ haematodermic neoplasm” is preferred.
IIa T1 Limited lesions covering <10% of the N1 palpable peripheral lymph nodes M0 no involvement of
skin surface,or T2 generalized lesions pathology negative for CTCL visceral organs
covering 10% and more of the skin surface
__________
Modified, from Refs. {333,344,2537}.
The skin is the second most common site plasms {1121}, but we expand upon the Prelymphomatous (“abortive”) disorders
of extranodal lymphoma, following the unique features of many cutaneous lym- (PLD)
gastrointestinal tract {340}. Lymphoma phomas to emphasize their distinctive PLD show a chronic long-standing
may involve the skin as the primary and clinical and biological characteristics course, no spontaneous regression in
only site of involvement, or may spread to {336A,2522}. Additional clinical and mor- most cases, and no extracutaneous
the skin as a secondary site of disease. phological variants have been added, spread with involvement of visceral
Because the clinical implications of pri- where appropriate, in order to compre- organs. In some cases, clonality of the
mary and secondary cutaneous lym- hensively cover the many manifestations infiltrate can be demonstrated. However,
phoma are different, the dermatologist of cutaneous lymphoma. Atypical reac- in most cases the neoplastic cell clone
and pathologist should be familiar with tive lesions that may represent precur- never overcomes host control mecha-
both types of neoplasms. For this reason sors of cutaneous lymphoma are dis- nisms and cannot expand and therefore
it also is problematic to use a classifica- cussed where relevant {336A,2522}. does not convert into definite malignant
tion system restricted to primary cuta- lymphoma. Survival time is not affected.
neous lymphomas {2523}. It is important Cutaneous lymphoproliferative Definite malignant lymphoma of low-
for dermatologists, haematooncologists, disorders (CLD) grade malignancy (LLM). This category
and pathologists to use a unified system These include reactive lymphoid hyper- includes cutaneous lymphomas that
for the diagnosis and treatment of cuta- plasias (so called cutaneous “pseudo- show a slowly progressive course with
neous lymphoma {1858}. lymphomas”), prelymphomatous condi- systemic spread in later stages and have
Nevertheless, cutaneous lymphomas tions and definite malignant lymphoma of the potential for transformation into more
present some unique clinical aspects. low grade or of high grade malignancy. aggressive high-grade malignant lym-
There are some diseases that present According to their biologic behaviour, phomas. Survival time usually is greater
only in the skin, and are never primary in CLD can be subgrouped into prognostic than 5 years.
lymph nodes or other extranodal sites. categories which are not reflected in the
Mycosis fungoides is one such example. classifications, which however are of Definite malignant lymphoma of high-
Some cutaneous lymphomas morpholog- special interest for the patient and for the grade malignancy (LHM)
ically resemble their counterparts in treating physician. These diseases are characterized by a
lymph node, but differ in terms of pheno- When diagnosing a cutaneous lympho- more rapid course than the low-grade
type, genotype, and clinical behaviour, proliferative disorder, both the clinico- lymphomas and usually exhibit a bad
suggesting that they represent an inde- pathologic classification and the biologic prognosis with survival times less than 5
pendent entity. Cutaneous follicular lym- category should be considered. The years.
phoma demonstrates such fundamental advantage of such an approach is to pro-
differences from nodal follicular lym- vide the diagnosis according to the cur-
phoma. Finally, some cutaneous lym- rent WHO-classification of lymphomas,
phomas exhibit a different clinical behav- and in addition, to include essential infor-
iour from their nodal counterparts, mation about the biologic behaviour,
despite apparent phenotypic and geno- which may be significantly different than
typic similarities. These differences may that of the nodal counterpart. These data
be related to stage or tumour burden, or are crucial for the clinician involved in
more fundamental biological differences. counseling and treatment of the patient.
For example, some lymphomas com-
posed of large centrocytes and centrob- Reactive lymphoid hyperplasias (RLH)
lasts have an indolent clinical course (pseudolymphomas)
when presenting as a localized cuta- These are reactive benign lymphoprolif-
neous tumour, but a similar cytological erative processes, localized or dissemi-
process in lymph node would be consid- nated, which heal either spontaneously
ered aggressive, i.e. diffuse large B-cell after elimination of the causative factor
lymphoma. (e.g. drugs) or after treatment with non-
Dermatologists, haematooncologists, aggressive (no severe side effects to be
and pathologists must use a common expected after long term application)
language. In this spirit we utilize the modalities, and which do not recur after
WHO classification of lymphoid neo- removal of the causative agent.
Definition 1992 in the USA was 0.36/ 100’000 per- patches and present with palpable infil-
Mycosis fungoides (MF) is the prototype sons per year {2445}. tration of various degree (thin and thick
of cutaneous T-cell lymphomas (CTCL) Most frequently MF affects adults, usual- plaques). Tumours exhibit an exophytic
and can be defined as a peripheral, epi- ly in their 5th-6th decade, with a male to growth in most of the cases and tend to
dermotropic non-Hodgkin T-cell lym- female ratio of approximately 2:1 and a ulcerate. In advanced stages of the dis-
phoma of low grade malignancy initially preponderance of black (1.7) vs white ease there may be spread into the
presenting in the skin and showing step- populations. peripheral blood, involvement of lymph
wise clinical progression from patches to The increase of frequency paralleled by nodes, bone marrow and internal organs.
plaques and tumours, and distinct histo- a decrease of mortality rates between Besides physical examination, including
logical (except in early stages), pheno- 1979 and 1991 {2485} most probably is mapping of skin lesions and photodocu-
typic and genotypic features. due to changing criteria resulting in over- mentation, a skin biopsy for paraffin
diagnosing MF by including non-neo- embedding and for cryo-preservation
ICD-O code 9700/3 plastic conditions into this group. should be taken, preferentially at multiple
Data collected by the Surveillance, sites. Additional investigations include
Synonyms and historical annotation Epidemiology and End Results Program blood cell counts with PAS staining for
In 1806 Jean-Louis Alibert (1768-1837) (SEER) of the US National Cancer Insti- Sézary cells, chest x-ray and CT-scan of
{58} presented an extraordinary skin dis- tute indicate that the relative survival abdomen and of peripheral lymph
ease which he described in detail under changed little after 11 years, at which nodes. There is no need for taking a
the name of "Pian fungoides" in 1814 and point it was 66% {2485}. bone marrow biopsy in early patch and
as "Mycosis fungoides" in 1832 {58}. At plaque stages of MF without atypical
his time the etiology of the disease was Etiology cells in the peripheral blood. Biopsy of
completely unclear. It is worth noting that The etiology of MF is unknown. The role enlarged lymph nodes is mandatory.
Alibert in 1832 copied part of the text of environmental antigens, viruses or The current TNM-staging System for
from Bontius {283}. Ernest Bazin (1807- bacteria is controversial {2605}. CTCL takes into account body surface
1878) published three different stages involved less (T1) or more (T2) than 10%,
{184}: Localization quality of skin manifestation, i.e. patch-
Période érythemateuse (erythematous All parts of the skin may be involved with- es/plaques or tumours (T3) or erythroder-
stage: red colored patches) out any predilection site. ma (T4) in conjunction with presence or
Période lichénoide (the lichenoid stage: absence of lymph node (N0-N3) or vis-
itching and different plaques with small Clinical features ceral organ involvement (M0-M1) {334}.
papules). Clinically MF is characterised by a step-
Période fongoïdique, mycositique (fungal wise evolution with sequential appear- Tumour spread and staging
stage:mushroom-like tumours of different ance of patches, plaques and tumours. MF, like other cutaneous lymphomas, is a
size). Patches are circumscribed lesions with systemic disease with preferential hom-
discolouration and sometimes little scal- ing and proliferation of neoplastic lym-
Epidemiology ing, without palpable infiltration of the phocytes into the skin. Therefore skin
The incidence of MF from 1973 through skin. Plaques usually evolve out of lesions may spread all over the body sur-
A B C
Fig. 4.1 Mycosis fungoides. A Large patches involving hip and abdomen. B Plaque-stage MF affecting the left arm. C Medium-sized hyperconvoluted cerebriform
cells with prominent cytoplasmic halos in the epidermis, aligned within the basal layer.
A B C
Fig. 4.3 A Plaque-stage mycosis fungoides (MF). B Thick plaque with haemorrhage in MF. C Histopathology of plaque-stage MF. Intra-epidermal and dermal infil-
trate.
the presence of more than 25% blast zyme B). These cases have the same parakeratosis variegata) or without poik-
cells may be observed. clinical behaviour as the CD4 positive iloderma (parapsoriasis en plaques, pre-
cases. malignant type, parapsoriasis en
Immunoprofile grandes plaques simples), may after
The immunophenotypical prototype of Prelymphomatous precursor lesions several decades evolve into mycosis fun-
MF is CD2+, CD3+, CD4+, CD5+, The term “parapsoriasis” is confusing goides or CTCL in up to 10-50% of
CD45RO+,CD8, TCR-beta +, CD30-. and requires explanation. It encompass- cases. Few large (more than 5 cm in
During progression of the disease loss of es a number of different pathologic diameter) patches show pityriasiform
CD7, 2 and 5 can occur. Helpful in the states clinically manifested by chronic scaling with (poikilodermatous variant) or
diagnosis is the loss of CD7, CD2, CD5, recalcitrant erythematous scaling lesions without telangiectasia and netlike pig-
or CD4 in the epidermotropic cerebriform {311,312,1375}. mentation. There is no palpable infiltra-
cells. During progression of the disease Two groups of parapsoriasis can be dif- tion.
especially when transformation is pres- ferentiated {337}. The benign form ‘para- Histologically lesions in large plaque
ent CD4 positive epidermotropic cells psoriasis en plaques’ (Brocq disease), parapsoriasis (LPP) are different from MF
can have a cytotoxic phenotype (TIA-1, never evolve into malignant lymphoma. or other CTCL. Under patchy parakerato-
Granzyme B). In the transformed stage The large plaque forms (LPP) with poik- sis there is slight atrophy of the epider-
the blast cells can express CD30. iloderma (prereticulotic poikiloderma, mis, due to loss of rete ridges. The
Besides the CD4 prototype, a small num- parapsoriasis en grandes plaques poik- subepidermal zone is free of lympho-
ber of MF cases have a CD8 positive ilodermiques, poikiloderma vasculare cytes, which accumulate in a band-like
cytotoxic phenotype (TIA-1 and gran- atrophicans, parapsoriasis lichenoides, arrangement in the upper dermis, spar-
A B C
Fig. 4.5 Histopathology of transformed mycosis fungoides(MF). A Large-cell pleomorphic transformation. B Large cell anaplastic transformation. C Immunohisto-
chemistry reveals CD30 positive tumour-cells.
ing the papillary region. There is no sig- Somatic genetics Chromosomal abnormality possibly
nificant epidermotropism as usually seen There have been a few reports on famil- results in increased genetic instability as
in early stages of mycosis fungoides. The ial occurence of MF or CTCL {2160} and a basic prerequisite for the development
poikilodermatous variant of the diseases on a possible association of HLA-DR5 of CTCL. In G-banding studies, numeri-
in addition shows dilated blood vessels with MF {2004}. HLA class II susceptibil- cal aberrations of chromosomes 6, 13,
in the upper dermis. T-cell receptor ity alleles, i.e. HLA-DRB1*11, HLA- 15, and 17, marker chromosomes, and
gamma gene rearrangement, which is DQB1*03 and HLA-DRB1*1104 are structural aberrations of chromosomes 3,
clonal in about half of the patients with more prevalent among patients with MF 9, and 13 were increased in MF {1209}.
LPP, is without any prognostic signifi- and are likely to be important in the In contrast to nodal lymphomas, the
cance {2186}. There is no significant dif- pathogenesis of MF {1039,1118}. T-cell large cell transformation in cutaneous T-
ference between the observed and receptor beta and gamma chain genes cell lymphoma (CTCL) is not associated
expected survivals in patients with LPP. are clonally rearranged. In advanced with t(2;5)(p23;q35) chromosomal trans-
cases with extracutaneous involvement, location {613,1420}.
Histogenesis the same clone is usually detected in the Increased expression of C-myc, p62,
Mature skin homing T cells that express skin and in the extracutaneous lesions. In TP53 and proliferation markers (PCNA)
the cutaneous lymphocyte antigen (CLA) transformed cases the same clone is has been found in advanced stages of
enabel them to specifically home into the present in the pre-existing lesions and MF as compared to early stages of MF
skin. Functionally, the neoplastic cells in the high-grade lymphoma {207}. suggesting a relationship between levels
MF express TH2 phenotype, which In advanced stage, the rate of chromo- of these proteins and aggressiveness of
accounts for many systemic changes somal aberrations, especially of chromo- CTCL {1192}.
associated with MF due to the production somes 1, 6 and 11, increase with the
of a TH2-specific cytokine pattern (IL-4, activity of the disease and has prognos- Prognosis and predictive factors
IL-5, IL-10) leading to fever, oedema, tic significance in patients with MF. The majority of MF patients show an
eosinophilia, increase of IgE or IgA, and Aberrations of chromosomes 8 and 17 indolent clinical course over years or
impaired delayed type reactivity are especially associated with active or decades. The prognosis of the disease is
{656,2445}. progressive disease. defined by its stage. Patients with early
A B
Fig. 4.7 Mycosis fungoides (MF). A Bullous variant of MF. B Immunohistochemistry shows CD8 positive tumour-cells lining up in the basal layer.
A
Pagetoid reticulosis
A B C
Fig. 4.10 Syringotropic cutaneous T-cell lymphoma (CTCL). A Cutaneous patch with hair-loss. B Infiltration of a sweat gland. C EM showing the convoluted nucle-
us of a neoplastic cell between acinar cells.
Granulomatous MF
Granulomatous MF is characterized by
the histological presence of a granulo-
matous reaction {584}, sometimes featur-
ing a sarcoidal or granuloma annulare-
like pattern. Multinucleated giant cells
may be present {1387}.
The prognostic and clinical significance
Fig. 4.11 Pilotropic lymphoid infiltrate in follicular Fig. 4.12 Granulomatous MF. Granulomatous
mycosis fungoides (MF).
of a granulomatous reaction in MF
plaques with ulceration on the leg.
remains uncertain {454}.
Fig. 4.13 Granulomatous mycosis fungoides (MF) with sarcoidal infiltrate pattern.
Definition 5% of all cutaneous T-cell lymphomas sis associated with loss of normal circu-
Sézary syndrome (SS) is a rare variant of {2523}. It occurs almost exclusively in lating CD4 cells {2075}.
cutaneous T-cell lymphoma (CTCL), adults, characteristically presents over
characterized by erythroderma, blood the age of 60 and has a male predomi- Tumour spread and staging
involvement and a poor prognosis. nance {2523}. Haematological involvement was defined
Neoplastic lymphocytes are typically in the TNM classification of MF as more
mature T-helper cells with cerebriform Etiology than 5% atypical circulating lymphocytes
nuclei. Criteria for the diagnosis of SS SS is of unknown etiology. However, a (B1), but was not included as part of the
include the demonstration of a peripher- syndrome clinically indistinguishable Bunn-Lamberg staging system {1356}.
al blood T-cell clone by molecular or from SS is occasionally seen in HTLV-1 Sézary patients are all T4/B1 (erythroder-
cytogenetic methods; an expanded associated lymphoma/leukaemia. ma with blood involvement) but staging
CD4+ population resulting in a CD4:CD8 will vary from stage III if there is no lymph
ratio > 10, and immunophenotypic ab- Clinical features node involvement to IVB if there is bone
normalities such as absent expression of SS comprises a clinical triad of pruritus, marrow involvement. In practice, most
T-cell antigens (CD2, CD3. CD4 and/or erythroderma and lymphadenopathy. cases of SS are staged as IVA. In 1988,
CD5). Sézary syndrome (SS) is part of a The pruritus is commonly intractable and the definition of B1 was increased from 5
broader disease spectrum, erythroder- sufficiently severe to prevent the patient to 20%, by the NCI, but was still not
mic CTCL. The presence of a clonal T- sleeping or pursuing a normal life. included as part of the staging system
cell population in the peripheral blood Additional clinical features include alope- {2071}.
distinguishes SS from reactive disorders cia, ectropion, nail dystrophy, palmo- The problem is that erythrodermic CTCL
that exhibit erythroderma and circulating plantar keratoderma and leonine facies. represents a spectrum and that any
cells with cerebriform nuclei (pseudo-SS) Bacterial skin infection is common in attempt to distinguish SS from cases that
{777}. Sézary patients and may lead to a show a lesser degree of haematological
marked deterioration in their cutaneous involvement is necessarily arbritary. An
ICD-O code 9701 / 3 disease. An increased prevalence of alternative approach is to develop a
secondary malignancies, both cuta- staging system that incorporates both
Epidemiology neous and systemic, has been reported lymph node status and haematological
Sézary syndrome accounts for less than in SS and attributed to the immunopare- stage. A haematological staging system
Fig. 4.14 Erythroderma and scaling of the face in Fig. 4.15 Palmar hyperkeratosis and onychodystro- Fig. 4.16 Sézary syndrome. Note erythroderma,
Sézary syndrome. phy in Sézary syndrome. oedema of the skin, and swelling of lymph nodes.
Histopathology
Despite minor differences {1099}, the
range of histological changes in SS are
not dissimilar to those seen in patients
A B with mycosis fungoides {2135}.
Epidermotropism is a variable feature,
Fig. 4.17 Morphology of Sézary cells. A Blood film and B Ultrastructure showing a typical convoluted
nucleus. and the size of Sézary cells varies in the
skin as it does in blood. Only 2/3 of the
skin biopsies and 73% of patients had
diagnostic changes in the skin biopsies
Other causes of erythroderma need to
be differentiated from SS, particularly
drug induced erythroderma and chronic
actinic reticuloid, both of which may
show a high proportion of activated lym-
phocytes with cerebriform nuclei {2135}.
In cases with a non-specific histology,
the differential diagnosis would include
A B other causes of erythroderma such as
Fig. 4.18 Sézary syndrome. A Band-like infiltrate in the epidermis without epidermotropism. B Intraepi-
eczema or psoriasis.
dermal Pautrier micoabscesses.
Immunoprofile
A typical Sézary cell is a mature helper T
comprising five categories (H0-H4) was defined by 5% Sézary cells with a T cell cell with a memory phenotype. A classic
proposed by Russell-Jones and clone demonstrated by PCR, or a T cell immunoprofile is CD2, CD3, CD4, CD5,
Whittaker {1998}, and subsequent data clone demonstrated by Southern blot CD45RO positive and CD8 negative
showed an increase in disease-specific analysis only {2077}. The need for a {1368,2526}. The majority of Sézary cells
death rates for each category with the haematological staging system has also are also CLA positive {1827} and CD7
most significant change occurring at H2, been recognised by the International negative, and this latter feature has been
proposed as a method of distinguishing
Sézary cells from normal lymphocytes
{957}. However, further studies have
shown that the neoplastic cell population
is present in both the CD7 positive and
CD7 negative subset in the same patient
{657}. More recently, Bernengo et al have
demonstrated that CD4 positive Sézary
cells typically loose the CD26 marker
and that a diagnosis of SS or MF with
haematological involvement can be
made if the CD26 negative subset
exceeds 30% of the CD4 positive cells
{215}.
Complete loss of T cell antigens such as
CD2, CD3, CD4, or CD5 is present in
approximately 2/3 of patients with SS
{957}. An alternative approach would be
the identification of a tumour-specific
antigen {669}. Recently two differentia-
tion antigens P140 and SCS have been
reported in circulating Sézary cells and
P140 was also found in skin-infiltrating
A B cells of patients with SS {1715}.
Fig. 4.19 Sézary syndrome transforming into blast-stage. A Multiple nodules and tumours. B Large atypi-
cal cells in blastic transformation of Sézary syndrome.
Somatic genetics
Recurrent chromosomal translocations
have not been detected in Sézary syn-
drome, but complex clonal numerical
and structural chromosomal abnormali-
ties are common and associated with a
poor prognosis {1505,2343}. M-FISH
techniques have shown a high rate of
unbalanced translocations and associat-
ed deletions often involving chromo-
somes 1p, 10q, 14 and 15 {1505}. CGH
studies have identified a consistent pat-
tern of chromosomal gains/deletions (1p,
10q, 13q, 19, 17p losses and 4/4q, 17q
and 18 gains) which, with the exception
of 17q gains in Sézary syndrome, are
identical to mycosis fungoides suggest-
ing a similar pathogenesis {1210,1504}.
Allelic losses on 1p, 9p, 10q and 17p
have been confirmed by LOH studies
and a high rate of microsatellite instabili-
ty (MSI) has also been detected {2079,
2080}. These findings suggest that dys-
regulated genes at these chromosomal
loci are involved in the pathogenesis
{1554,2078}. There is a high rate of
genomic instability as indicated by the
presence of chromosomal instability
{1505}. Constitutive activation of Stat 3
and chromosomal amplification of JUNB,
a member of the AP-1 transcription factor
complex, have been identified in Sézary
syndrome {1089,1506}. A recent cDNA Fig. 4.20 Diagnostic pathways for the differential diagnosis of erythroderma. Algorithm for the evaluation
array study in Sézary syndrome has con- and diagnosis of erythroderma due to cutaneous T-cell lymphoma (E-CTCL) vs. 'reactive' causes of ery-
firmed the presence of JunB over- throderma. TCR, T-cell receptor. *A CD4/CD8 ratio > 10 or an absolute Sézary cell count of 1 109 L 1 have
expression and has also revealed over- been proposed as diagnostic criteria for Sézary syndrome (SS), but this algorithm requires additional
expression of other genes associated immunophenotypic or genotypic data. Even so, a Sézary cell count > 1 109 L 1 or a CD4/CD8 ratio > 10
with a TH2 phenotype such as Gata-3 increases the probability of neoplasia, and separates SS from E-CTCL with a lesser degree of blood involve-
and RhoB {1211}. These array findings ment. **Abnormal T-cell immunophenotype = an increased population of CD4+ cells that are CD26 (> 30%)
or p140+. CD7 is less reliable. Aberrant T-cell immunophenotype = loss of pan T-cell markers such as CD2,
appear to allow the identification of a
CD3 or CD5, and/or double-negative T cells (CD4 and CD8 ). In skin, the loss of CD7 from epidermal lym-
poor prognostic group {1211}. phocytes is CTCL specific.
From: R. Russell-Jones {1997}.
Prognosis and predictive factors
Sézary syndrome has a poor prognosis
with a median survival of 2 to 4 years
depending on the exact definition used
{777,1271,2044,2523}. Absolute Sézary
cell count and lymph node involvement
are independent prognostic factors. In
addition, large cell transformation and
the development of skin tumours on a
background of erythroderma are poor
prognostic signs.
Definition pathognomonic bulky pendulous skin stains demonstrate the loss of elastic
Granulomatous slack skin (GSS) is clini- folds develop as a result of progressive fibres at the sites of the infiltrates in all
cally characterized by the development destruction of elastic fibres. The lesions dermal layers. On occasion, involvement
of bulky skin lesions in the major skin then resemble cutis laxa. Occassionally of large vessels occurs. Ultrastructurally,
folds and histologically by a granuloma- ulceration occurs. Regional lymph- the lymphocytes show hyperchromatic
tous infiltrate composed of small lympho- adenopathy may be present. In contrast cerebriform nuclei similar to those seen
cytes and scattered multinucleated giant to granulomatous MF, GSS is in almost all in mycosis fungoides and Sézary syn-
cells containing nuclei arranged in a cases confined to intertriginous areas, drome {490}. Specific infiltration of
wreath-like fashion. and runs a more benign course than regional lymph nodes or internal organs
classic MF {1387}. exhibiting similar features as in the skin
Synonyms has been observed in rare cases.
Progressive atrophying chronic granulo- Histopathology
matous dermohypodermitis Early lesions of GSS display a bandlike Immunoprofile
infiltrate of small lymphocytes without The lymphoid tumour cells display a T
Epidemiology significant nuclear atypia {1379}. More helper phenotype with expression of
GSS is a rare form of primary cutaneous advanced lesions show a dense lympho- CD3, CD4 and CD45RO. There may be
T-cell lymphoma. GSS usually appears in cytic infiltrate throughout the entire der- loss of other T-cell markers like CD5 or
the third or fourth decade, but can also mis. Nuclear atypia of lymphocytes is CD7. In rare cases, the tumour cells
affect children {373}. GSS occurs almost less pronounced than in granulomatous express CD30.
exclusively in Whites. The male to female MF. The diagnostic hallmark is numerous
ratio is 2:1 to 3:1 {490}. multinucleated histiocytic giant cells, Genetics
which are scattered throughout the back- Clonal rearrangement of TCR genes can
Clinical features ground of the dense lymphocytic infil- be found in most cases and is a useful
GSS begins with slightly infiltrated, poik- trate. These giant cells contain 20-30 diagnostic tool in early stages of the dis-
ilodermatous sharply demarcated patch- nuclei located at the periphery of the ease {1382}. Trisomy 8 has been report-
es and plaques. Predilection sites are the cytoplasm. Elastophagocytosis and ed in two cases {136,2442}.
intertriginous areas, especially the axil- emperipolesis (phagocytosis of lymphoid
lary and inguinal folds. After years, cells by giant cells) are present. Elastic Histogenesis
The tumour cells represent skin-homing
T-helper cells.
Fig. 4.21 Granulomatous slack skin (GSS). Large Fig. 4.22 GSS showing characteristic multinucleat-
slightly infiltrated plaque in the groin. ed giant cells with emperipolesis of lymphocytes.
CD30-positive T-cell lymphoproliferative papulo-nodular skin lesions and atypical Clinical features
disorders (LPD) of the skin (CD30+LPD) lymphoid cells in a polymorphous inflam- LyP is characterized by grouped or dis-
represent a distinctive group of primary matory background {1466}. seminated asymptomatic papules and/or
cutaneous T-cell lymphoma. The spec- nodules, which regress spontaneously
trum of CD30+ LPD includes lymphoma- ICD-O code 9718/1 after a few weeks sometimes leaving
toid papulosis (LyP), primary cutaneous behind varioliform scars {1174}. Often
anaplastic lymphoma (C-ALCL) and bor- Epidemiology new lesions develop concurrently in the
derline cases which differ in their clinical LyP is a rare disease with an estimated same or another body region. Larger
and histological presentations {191, prevalence of 0.1 to 0.2 cases per 100 nodules up to 2 cm can develop and per-
1174,1225,1795,2520}. 000 and a male to female ratio of 1.5:1 sist for months {2524}. Clinicopathologic
A feature common to all is the expression {2456}. Mostly people in the third and variants of LyP include regional follicular
of CD30, a cytokine receptor belonging fifth decades are affected, but children and pustular forms {2076}.
to the tumour necrosis factor receptor can also be involved.
superfamily. Histopathology
The term ‘borderline lesions’ has been Localization The histological features of LyP are vari-
applied to lesions that show clinical pres- Although no definite predilection site has able and depend on the stage of the
entation of one entity (e.g. C-ALCL) but been identified, LyP lesions more often lesions and disease. Three histologic
histological features of another one (e.g. arise on the trunk, especially the but- subtypes (types A, B and C) have been
LyP). This discrepancy may result in diffi- tocks, and extremities. delineated {2524} which represent a
culties to assign such lesions to a distinct spectrum with overlapping features
entity. Clinical presentation plays a cru- Etiology {2148}. In fully developed LyP lesions,
cial role in such discordant cases. The cause of the disease is unknown. there is a wedge-shaped diffuse dermal
Endogenous retroviral elements have infiltrate which contains medium-sized to
been identified in LyP lesions {1242}. large pleomorphic or anaplastic lym-
Lymphomatoid papulosis (LyP) Interaction of CD30 and CD30L as well phoid cells with irregular nuclei, sparse
as TGF-beta and its receptor play an chromatin and mitotic activity. Some of
Definition important role in growth regulation, the large atypical lymphoid cells resem-
LyP is a chronic recurrent lymphoprolifer- including regression of tumoural lesions ble Reed-Sternberg cells. Ulceration
ative skin disease with self-regressing {1177,1648}. may be present. In type A lesions, scat-
Fig. 4.23 Lymphomatoid papulosis with papules and Fig. 4.24 Lymphomatoid papulosis. Wedge-shaped infiltrate with superficial ulceration and crust formation.
ulcerating nodules.
tered tumour cells are intermingled with in LyP are of T-cell origin with a CD3+, 20% of patients with LyP {191,1174}.
numerous inflammatory cells such as CD4+, CD8-. In 10% of the cases tumour Long-term follow-up is therefore recom-
neutrophils, eosinophils and histiocytes. cells express CD56+ {193}. Usually CD2 mended. These lymphomas are usually
Type C lesions show cohesive sheets of and CD5 are expressed, whereas often referred to as LyP-associated malignant
large atypical lymphoid cells with only a CD7 and sometimes CD3 are absent. In lymphomas. They can develop prior to,
few intermingled reactive inflammatory addition, expression of activation mark- concurrent with, or after the manifesta-
cells. The rare type B is characterized by ers such as HLA-DR and CD25 (inter- tion of LyP {1175} and result in a fatal out-
an epidermotropic infiltrate of small atyp- leukin 2-receptor) is found. Cytotoxic come in 2% of patients {191}. No risk fac-
ical lymphoid cells with cerebriform molecules such as TIA-1 and granzyme tors have been identified which definitely
nuclei and histologically resembles B are expressed in 70% of the cases indicate likely progression to associated
mycosis fungoides. Various histologic {1342}. CD56 is generally negative {968}. lymphomas in LyP patients. So far, only
types may be present in individual CD15, a marker for Reed-Sternberg cells fascin expression is found at a signifi-
patients at the same time. in Hodgkin lymphoma, is usually not cantly higher rate in LyP cases associat-
Due to an overlap of histologic features expressed in LyP. In contrast to the ed with systemic lymphomas {1243}.
between LyP and primary as well as sec- tumour cells expressing CD30 as in LyP
ondary cutaneous ALCL, final diagnosis type A and type C, the small atypical
depends on correlation of clinical pres- lymphocytes present in LyP type B are Primary cutaneous anaplastic
entation and histologic findings. usually negative for CD30. large-cell lymphoma
Immunohistochemistry Genetics Definition
A hallmark of the large atypical lymphoid Clonal rearrangement of T cell receptor Primary cutaneous anaplastic lymphoma
cells is their positivity for CD30 {1173, genes can be found in at least 40% of (C-ALCL) is a neoplasm composed of
1227}. The large atypical lymphoid cells LyP lesions. Cytogenetic studies have large atypical lymphocytes of either pleo-
demonstrated chromosomal deletions morphic, anaplastic or immunoblastic
and rearrangements of chromosomes 1, cytomorphology and expression of the
7, 9 and 10 {1813}. The t(2;5)(p23;q35) CD30 antigen by the majority, i.e. more
translocation is not detected in LyP than 75% of tumour cells. Primary cuta-
{613}. neous and primary nodal CD30+ ALCL
are distinct clinical entities that can have
Histogenesis similar morphologic features and some
LyP represents a proliferation of activat- overlap in immunophenotype, but differ
ed skin-homing T-cells with a unique in age of onset, genetic features, etiology
cytotoxic phenotype (TIA-1+). and prognosis {600,2259,2493}.
Genetics
A B Clonal rearrangement of T cell receptor
genes is detected by Southern blot and
PCR in most cases (over 90%) of C-ALCL
{1467}. The translocation t(2;5) (p23;q35)
resulting in expression of npm-alk protein
(p80), which is a characteristic feature of
systemic anaplastic large cell lym-
phomas, is rarely if ever found in C-ALCL
{228,613}. Systemic ALCL may present
with cutaneous disease, and the identifi-
cation of ALK-expression is helpful in this
C D distinction.
Fig. 4.27 CD30+ Primary cutaneous anaplastic large-cell lymphoma. A Large cells in a background of his-
tiocytes, plasma cells and small lymphocytes. B Large atypical cells in CD30+ anaplastic large-cell lym- Histogenesis
phoma. C Scattered tumour cells expressing CD30. D Expression of CD30 by almost all tumour cells. Activated skin-homing T-cell.
Definition neous nodules, usually in the absence of cytes are frequently present, particularly
Subcutaneous panniculitis-like T-cell lym- other sites of disease. The most common in areas of fat infiltration and destruction.
phoma (SPTCL) is a T-cell lymphoma sites of localization are the extremities The histiocytes are frequently vacuolat-
with preferential infiltration of subcuta- and trunk. ed, due to ingested lipid material.
neous tissue by atypical lymphoid cells Vascular invasion may be seen in some
of varying size, often with marked tumour Clinical features cases, and necrosis and karyorrhexis are
necrosis and karyorrhexis. Clinical symptoms are primarily related to common. However, the infiltrates usually
the subcutaneous nodules. The nodules are confined to the subcutaneous tissue,
ICD-O code 9708/3 range in size from 0.5 cm to several cm. with sparing of the dermis. This feature is
in diameter. Larger nodules may become helpful in the differential diagnosis from
Historical annotation necrotic, but ulceration of cutaneous other lymphomas involving skin and sub-
In the historical literature, most cases of lesions is rare. Systemic symptoms, most cutaneous tissue. The necrosis is prima-
SPTCL were probably diagnosed as his- commonly fever, are variable but usually rily apoptotic in nature, possibly related
tiocytic cytophagic panniculitis {562, present. Some patients may present with to the release of cytotoxic molecules
1527}. a haemophagocytic syndrome with pan- {1341,2133}. Cutaneous γδ T-cell lym-
cytopenias, fever, and hepatospleno- phomas can have a panniculitis-like
Epidemiology megaly {338,863,2480}. Lymphadeno- component, but commonly show both
Subcutaneous panniculitis-like T-cell lym- pathy is usually absent. dermal and epidermal involvement in
phoma is a rare form of lymphoma, rep- addition to subcutaneous disease {1060,
resenting less than 1% of all non- Histopathology 1341,2026,2366}. Plasma cells and reac-
Hodgkin lymphomas. It occurs in males The infiltrate extends diffusely through tive lymphoid follicles are generally
and females equally, and has a broad the subcutaneous tissue, usually without absent, in contrast to lupus profundus
age range. Cases have been reported in sparing of septae. The overlying dermis pannicultis, and other forms of lobular
children under the age of two years. Most and epidermis are typically uninvolved. panniculitis.
cases occur in adults {1060,1341,2026, The neoplastic cells range in size from In some cases of SPTCL the infiltrates in
2480}. small cells with round nuclei and incon- initial phases may appear deceptively
spicuous nucleoli to larger transformed benign, and the differential diagnosis
Etiology cells with hyperchromatic nuclei. The with benign panniculitis may be difficult
Unknown. In most patients the disease lymphoid cells have a moderate amount {338,863}.
presents sporadically. of pale-staining cytoplasm. A helpful
diagnostic feature is the rimming of the Immunoprofile
Localization neoplastic cells surrounding individual SPTCL is derived from αß cells, T-cells
Patients present with multiple subcuta- fat cells {1341}. Admixed reactive histio- with a cytotoxic profile.The cells are usu-
A B
Fig. 4.28 Subcutaneous panniculitis-like T-cell lymphoma (SPLTCL). A Erythematous plaques and nodules on the leg with ulceration. B Diffuse infiltration of sub-
cutaneous tissue simulating lobular panniculitis. Large atypical cells rimming around fat lobules.
ally CD8-positive, with expression of niculitis-like component is present. of T-cell receptor genes, and are nega-
cytotoxic molecules including granzyme tive for Epstein Barr sequences.
B, perforin, and T-cell intracellular anti- Histogenesis
gen (TIA-1) {1341,2026}. However, in Mature cytotoxic T-cell of the adaptive Prognosis and predictive factors
contrast to other cytotoxic TCLs related immune system. Dissemination to lymph nodes and other
to the innate immune system (enteropa- organs is uncommon and usually occurs
thy-type T-cell lymphoma, extranodal Precursor lesions late in the clinical course. The natural his-
NK/T-cell lymphoma), the cells are nega- Oligoclonal T-cell populations may be tory is often aggressive {694,863,917,
tive for granzyme M (metase) {694, found in some cases of lobular pan- 1300,2026}. A haemophagocytic syn-
1122,1325,2564}. The neoplastic cells nicultis, suggesting the potential for clon- drome is a frequent complication in αβ
are capable of producing a number of al evolution in rare cases {1484}. cases and usually precipitates a fulmi-
cytokines and chemokines, a feature that However, progression from cytophagic nant downhill clinical course. However, if
is related to development of systemic panniculitis without monoclonality to therapy for the underlying lymphoma is
symptoms and the haemopha-gocytic SPTCL rarely if ever occurs {1527}. instituted and is successful, the
syndrome {338,2340}. Cutaneous γδ T- haemophagocytic syndrome may remit.
cell lymphomas {119,338,1341,2026} are Somatic genetics
distinguished from SPTCL, even if a pan- The neoplastic cells show rearrangement
Etiology biopsy specimen {2366}. Epidermal infil- radiation {1665,2366}. In a recent series
The distribution of disease reflects the tration may occur as mild epidermotro- of 33 patients, 22 (66%) died within 5
localization of normal γδ T cells, which pism to marked pagetoid reticulosis-like years of diagnosis, and in the same
are believed to play a role in host mucos- infiltrates {221,1665,1879}. Subcuta- study TCRδ1 expression was an inde-
al and epithelial immune responses neous nodules may be pannicultis-like or pendent predictor of survival {2366}.
{268}. Impaired immune function associ- more solid in appearance and may show Among 33 patients with CGD-TCL, there
ated with chronic antigen stimulation rimming of fat cells, similar to SPTCL of was a trend for decreased survival for
may predispose to the development of alpha/beta origin {1533}. Dermal and patients who had subcutaneous fat
mucosal and CGD-TCLs {98,2539}. epidermal involvement often coexists involvement in comparison with patients
Epstein-Barr virus (EBV) is generally with subcutaneous disease, in contrast who had epidermotropic or dermal dis-
negative in CGD-TCLs, but may be posi- to SPTCL of αβ origin, which is mainly or ease only. Age, sex, and lymphadenopa-
tive in primary γδ TCL in mucosal sites exclusively subcutaneous in distribution thy did not have any discernible prog-
{98,1191,2366,2539}. {192,1060,2026}. nostic impact {2366}.
A B C
Fig. 4.34 Primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma. A The neoplastic infiltrate is markedly epidermotropic and pleomorphic
and is B positive for CD3 and C for CD8.
Epidemiology
These tumours account for 5 to 10% of all mentioned, cases of transformed MF Prognosis and predictive factors
primary cutaneous T cell or NK cell lym- may closely resemble peripheral T cell The prognosis is poor with 5-year sur-
phomas {195}. All ages may be affected, lymphoma unspecified and can only be vival rates of less than 20% {195,878}.
but the disease is most common in distinguished on clinical grounds. Cases with immunoblastic morphology
adults. may have an even more aggressive
Somatic genetics behaviour {197,2523}. Cases with soli-
Clinical features The TCR genes are clonally rearranged. tary/localized lesions seem to behave
Most lymphomas in this category present No consistent cytogenetic abnormalities just as aggressivelys as those with multi-
with rapidly growing tumours or nodules have yet been identified. ple lesions {195}.
that may be multiple or (more rarely) soli-
tary or localized {195,197,878,2523}. No
sites of predilection have been recorded.
Histopathology
Skin infiltrates are most often diffuse, but
nodular or band-like patterns can be
seen. Epidermotropism is mild or absent
in most cases. The tumour cells are
medium to large, usually with markedly
pleomorphic nuclei. Rare cases may
show a predominance of cells that are
more immunoblastic in appearance
{197,2523}. Small reactive lymphocytes,
eosinophils and plasma cells may be
present {195}, but the inflammatory
background is usually not as pro-
nounced as it can be in nodal malignan- A
cies.
Immunoprofile
The tumour cells express T-cell associat-
ed antigens (CD2, CD3, CD5), but usual-
ly lack CD7; most cases are CD4+, but
rare tumours may be CD8+ or positive
(or negative) for both CD4 and CD8
{195}. Cytotoxic antigens (TIA-1+,
granzyme B) are usually not expressed
{195}. Occasional tumour cells may be
CD30-positive.
Histogenesis
Skin homing T-cells.
B
Precursor lesion Fig. 4.36 Cutaneous small-medium pleomorphic T-cell lymphoma. A Small-medium lymphocytes with pleo-
There are no known precursor lesions. As morphic nuclei predominating. B Staining for CD3 confirms the T-cell lineage of the lymphocytes.
C D
Fig. 4.37 Primary cutaneous peripheral T-cell lymphoma, unspecified. A Grouped and B disseminated skin lesions. C The dermal neoplastic infiltrate is dense and
D consists of large, pleomorphic cells with irregular nuclei and numerous mitoses.
Definition integrated in the malignant T cell. HTLV-1 multiple papules tend to be distributed
Adult T cell leukaemia / lymphoma encodes the transcriptional activator Tax, over large areas of the body. Sub-
(ATLL) is a malignancy of mature CD4+ T which can transform T cells by increas- cutaneous tumours (4.8%), erythroderma
cells caused by the human T-cell ing the expression of a unique set of cel- (3.5%), and purpura (1.6%) are less fre-
leukaemia virus type I (HTLV-1). lular genes involved in T cell proliferation quent, and alopecia, folliculitis, erythema
{1589}. multiforme, and prurigo are rarely seen.
ICD-O code 9827/3 In addition to the four clinical types, the
Localization cutaneous type of ATLL has been pro-
Synonyms Based on organ involvement and severi- posed to indicate skin-limited lesions
Adult T-cell leukaemia (ATL) ty, ATLL is divided into four clinical cate- without lymph node involvement or
gories: acute, chronic, lymphoma, and leukaemic involvement {1144}. ATLL lim-
Epidemiology smoldering types {2171}. Cutaneous ited to the skin may be considered part
ATLL is endemic in some regions of the involvement is seen in up to 50% of of the smouldering type. Two patterns of
world, especially in southwest Japan, the patients. Lymph nodes, liver and spleen skin involvement are seen; i.e., tumoural
Caribbean islands, South America, and are frequently involved. and erythematopapular. The tumoural
parts of Central Africa {1848,2392}. subtype has been reported to have a
Clinical features worse prognosis than the erythe-
Etiology Patients with ATLL exhibit various cuta- matopapular one.
ATLL develops in 1% to 5% of individuals neous manifestations. The most frequent
infected with HTLV-1 after more than 2 manifestation is nodules/tumours Histopathology
decades of viral persistence. In most (33.9%), followed by red papules Individual skin lesions of ATLL exhibit
patients viral exposure occurs early in (22.6%), erythematous plaques (19.4%) varying degrees of tumour cell infiltration
life, and incidence figures are related to and macules (6.5%) {2142}. Nodules/ from the epidermis to subcutaneous tis-
the place of birth, not residence. tumours usually occur as solitary or sev- sue. Epidermotropism of the malignant T-
HTLV-1 proviral DNA is monoclonally eral lesions on limited sites, whereas cells is present in the majority of cases,
A B C
Fig. 4.38 Adult T-cell leukaemia/lymphoma (ATLL) A A large tumour on the right cheek. B Multiple erythematous plaques on the trunk. C Multiple papules on the
hand and forearm.
Immunohistochemistry
In general, the malignant T cells are pos-
itive for CD3, CD4, CD25, and CD45RO
but negative for CD7. CD8, CD19, and A
CD20 {2171}. CD30 expression may be
seen in larger transformed cells.
B
Fig. 4.39 Adult T-cell leukaemia/lymphoma (ATLL). A Erythematous macule, showing infiltration of atypical
lymphocytes in the upper dermis with Pautrier microabscess. B Tumour, massive infiltration of pleomorphic
lymphocytes in the dermis.
Definition
Extranodal NK/T-cell lymphoma, nasal-
type, is an EBV+, nearly always extrano-
dal lymphoma of small, medium or large
cells usually with an NK-cell, or more
rarely cytotoxic T-cell phenotype. The
skin is the second most common site of
involvement after the nasal cavity/
nasopharynx, and skin involvement may
be a primary or secondary manifestation A B
of the disease.
Synonyms
REAL: angiocentric T-cell lymphoma;
EORTC used to include in CTCL, large
cell, CD30- and CTCL, pleomorphic,
small/medium-sized
Epidemiology C D
Extranodal NK/T-cell lymphoma is a rare Fig. 4.41 Extranodal NK/T-cell lymphoma, nasal-type. A Angiocentricity and angiodestruction. B Involve-
disease occurring in adults, with a male ment of the subcutis. C Focal epidermotropism, present in approx. 30% of cases. D Cytologic detail show-
predominance. This lymphoma is more ing medium sized cells with irregular nuclear foldings.
prevalent in Asia, Central America and
South America.
Clinical features cells. The cells often exhibit irregular
Etiology Cutaneous involvement consists of nuclear foldings, moderately dense chro-
It is universally associated with EBV, and tumour nodules and plaques. Systemic matin, and pale cytoplasm.
genetic factors play a role in susceptibil- symptoms such as fever, malaise and
ity to the disease {443,1689}. weight loss are common. Some cases Immunoprofile
are accompanied by a haemophagocyt- The most common immunophenotype is:
Localization ic syndrome. The disease is closely relat- CD2+, CD56+, surface CD3-, cytoplas-
The majority of patients present with skin ed to aggressive NK-cell leukaemia, mic CD3ε+, CD43+ and cytotoxic gran-
lesions affecting more than one anatom- which also may have cutaneous manifes- ules + (TIA-1, granzyme B, perforin)
ic region, most commonly the trunk and tations, and is also EBV-associated. {1325}. Occasional cases are CD56-, but
extremities {443,1660}. then require EBV positivity or presence of
Histopathology cytotoxic granules for diagnosis;other-
A dense dermal infiltrate is often centred wise they should be classified as periph-
on the skin appendages and blood ves- eral T-cell lymphoma, unspecified. LMP-1
sels resulting in a column-like low power is inconsistently expressed, with EBER in
appearance {1689}. Prominent angio- situ hybridization preferred for diagnosis.
centricity and angiodestruction are often
accompanied by extensive necrosis Genetics
{443,1689}. Extension into the subcutis is The T-cell receptor is usually in germline
common. Approximately 30% of cases configuration.
show at least focal epidermotropism
{1689}. The mitotic rate is high and apop- Prognosis and predictive factors
totic bodies are numerous. NK/T-cell lym- Extranodal NK/T-cell lymphoma present-
Fig. 4.40 Extranodal NK/T-cell lymphoma, nasal- phoma has a broad cytologic spectrum ing in the skin is a highly aggressive
type. Clinical appearance with violaceous tumour ranging from small to large cells, with tumour with a median survival of less
nodules. most cases consisting of medium sized than 15 months {443,1660}. The most
Localization
The lesions occur predominantly in sun-
exposed areas, particularly the face and
limbs.
Clinical features
Patients present with facial and hand
oedema and a papulovesicular eruption
that affects sun-exposed and to a lesser
extent sun-protected areas. Individual
A lesions start with oedema and erythema
and then progress to vesicles, necrosis,
A
ulceration, crusts, and heal as varicelli-
form scars. Fever, wasting, hepato-
splenomegaly, lymphadenopathy and
hypersensitivity to insect bites are com-
mon. Some cases are accompanied by a
haemophagocytic syndrome. The dis-
ease may progress to lymph node and
visceral involvement.
B
Fig. 4.43 Hydroa vacciniforme-like cutaneous T-cell Histopathology B
lymphoma. A Infiltrate on the sun-exposed ear- The infiltrate consists of medium-sized Fig. 4.44 A Subcutaneous infiltrate of tumour cells
lobe. B Papules, vesicles and crusted erosions on atypical lymphoid cells set in an inflam- with prominent cytophagocytosis. B In situ hybridi-
face of young boy. matory background. The depth of the sation showing EBER+ tumour cells
Systemic peripheral T-cell lymphoma giant cells. The tumour cells in systemic
(PTL), unspecified, involves the skin in ALCL express a cytotoxic phenotype
approximately 20-30% of the cases {836, and are positive for CD30 and EMA. CD3
1453}. Skin lesions may be present at is negative in more than 75% of cases
diagnosis or can develop during disease {191, 1121}. CD5 and CD7 are often neg-
progression. Lesions are most often ative. CD2, CD4 and CD43 are more use-
tumours or nodules that may be solitary ful and are expressed in a significant pro-
or multiple. No sites of predilection have portion of cases. ALK expression and
been recorded. The histological and t(2;5) or variant translocations involving
phenotypic features are identical to the ALK and fusion partners other than NPM
systemic disease. The prognosis is very are present in the majority of cases {706,
poor {104,690,836,1453}. 809}. The natural history is aggressive
but long term complete remissions can
be obtained in most patients with ALK-
Systemic anaplastic large cell positive disease {191}.
lymphoma (ALCL)
Definition Epidemiology
Primary cutaneous marginal zone B-cell MZL most commonly affects adults aged
lymphoma (MZL) is an indolent lym- over 40 years. There is no clear gender
phoma composed of small B cells includ- preponderance {132,2141}.
ing marginal zone (centrocyte-like) or
monocytoid cells, lymphoplasmacytoid Etiology
cells and plasma cells. It is considered In Europe, Borrelia burgdorferi DNA has
part of the broad group of extranodal been identified in some cases of MZL
marginal zone B-cell lymphomas com- suggesting that it may play an etiological
monly involving mucosal sites (mucosa role. {433}. However, no association of
associated lymphoid tissue, MALT). Borrelia with CBCL has been found in the Fig. 4.48 Marginal-zone lymphoma. Firm nodules on
Primary cutaneous immunocytoma, pri- United States and Asia {2547}. the forehead.
mary cutaneous plasmacytoma and
cutaneous follicular lymphoid hyperpla- Localization
sia with monotypic plasma cells are con- MZL is predominantly localized on the uncommon. MZL with secondary spread
sidered variants of MZL. upper extremitites, and less often head to the skin is often multifocal {1418}.
and trunk.
ICD-O code 9699/3 Histopathology
Clinical features The infiltrate is characterized by residual
Synonyms In most cases, cutaneous MZL presents reactive lymphoid follicles surrounded by
EORTC (1997): Primary cutaneous with red to violaceous plaques or nod- pale staining cuffs of tumour cells.
immunocytoma / marginal zone B-cell ules with an erythematous border {2141}. Reactive germinal centres with distinct
lymphoma Ulceration and visceral dissemination are mantle zones are commonly found in
early lesions but may become colonized
by tumour cells as the disease progress-
es. The interfollicular infiltrate is com-
posed of small to medium-sized, centro-
cyte-like or monocytoid cells with slightly
irregular nuclei, moderately dispersed
chromatin, inconspicuous nucleoli and a
rim of pale cytoplasm {2234,2362}.
Variable numbers of lymphoplasmacy-
toid cells and plasma cells are typically
present at the periphery of the infiltrates
or in the subepidermal area. Intranuclear
PAS positive pseudoinclusions (Dutcher
bodies), are commonly found, particular-
ly in plasma cell rich forms of MZL.
Diffuse infiltrates almost completely con-
sisting of monocytoid cells, lympho-
epithelial lesions with infiltration of sweat
glands and the presence of very imma-
ture plasma cells should raise suspicion
of secondary cutaneous involvement.
Immunoprofile
The neoplastic cells express CD19+,
CD20+, CD22+, CD79a+, but are nega-
tive for CD5-, CD10-, bcl-6, CD23-. CD43
Fig. 4.46 Cutaneous marginal zone B-cell lym- Fig. 4.47 Cutaneous marginal zone B-cell lym- may be positive {132}. In contrast to FL,
phoma. Infiltrate extends through dermis to subcu- phoma. Neoplastic cells surround a residual germi- the tumour cells are bcl-2+, but negative
taneous tissue. nal centre. for bcl-6 and CD10 {603,1418}. Reactive
C D
Fig. 4.49 Plasmacytoid cells in cutaneous marginal zone B-cell lymphoma. A Monoclonal plasma cells are admixed with cells with monocytoid features. B In a sub-
sequent biopsy from the same patient, all of the cells have a plasmacytic morphology and express monoclonal Ig light chains. C Kappa. D Lambda.
germinal centres are bcl-6+ and bcl-2-. Histogenesis a minority of cases, similar to MZL of
Anti-CD21 staining often reveals regular Post germinal centre B-lymphocyte with other extranodal sites. Abnormalities of
and irregular networks of follicular den- plasmacytic differentiation and gene BCL10 are absent {906}.
dritic cells (FDC) in reactive follicles, but expression pattern {2273}.
not associated with tumour cells. The Prognosis
lymphoplasmacytoid cells and the plas- Somatic genetics MZL shows a protracted clinical course
ma cells show monotypic expression of IgH genes are clonally rearranged. The with a tendency for recurrences.
immunoglobulin light chains. There are most common translocation in gastric However, the prognosis is favourable
numerous admixed reactive T-cells. MZL, the t(11;18) involving the API2/MLT with 5-year-survival rates between 90
genes, has not been demonstrated in pri- and 100%. Transformation into diffuse
Precursor lesion mary cutaneous MZL {1418,2141,2279}. large B cell lymphoma occurs infrequent-
Cutaneous lymphoid hyperplasia due to However, the t(14;18)(q32;q21) involving ly {2141}.
Borrelia infection may mimic MZL and IGH and MALT1 was reported in approx-
has been postulated to represent a pre- imately one third of cases in a small
cursor lesion in some circumstances. series. Fas gene mutations are present in
Etiology
The etiology of primary cutaneous FCL is
unknown.
Localization
Most patients have local or regional dis-
ease. Trunk and head and neck regions
are by far the most frequent localizations
{429,744,2061,2523}. Presentation with
multifocal skin lesions is observed in a Fig. 4.51 Primary cutaneous follicle centre lymphoma. Neoplastic bcl6+ cells surround and infiltrate a reac-
small minority of patients. tive follicle with bcl6+ germinal center.
Histogenesis
Mature germinal centre derived B-lym-
phocyte {2273,2523}.
Somatic genetics
Clonally rearranged immunoglobulin
genes are present. Bcl-2 gene
rearrangement and t(14;18) chromoso-
mal translocation are absent in most
cases {209,430,467,1622,1820,2523}.
Inactivation of p15 and p16 tumour sup- B
pressor genes by promotor hypermethy- Fig. 4.52 Cutaneous follicle centre lymphoma, follicular growth pattern. A Small and large follicle centre
lation has been reported in about 10% cells. B Detail of large follicle centre cells
and 30% of PCFCL, respectively {468}.
Chromosomal imbalances have been
identified by comparative genomic directed forms of therapy, most common- cases. These secondary cutaneous
hybridization (CGH) analysis in a minori- ly radiation or surgical excision (small, forms are managed like a systemic lym-
ty of PCFCL, but a consistent pattern has isolated lesions), are generally effec- phoma. Whether cutaneous involvement
not been emerged {942,1503}. tive {194, 429, 1283, 1824, 1825, 1938, by FCL has an impact on prognosis is
2060, 2061, 2202, 2523}. presently unknown.
Prognosis and predictive factors
Primary cutaneous FCL have an excel-
lent prognosis (>95% 5-year survival). Secondary cutaneous follicular
Local recurrences, most often near the lymphoma (FL)
initial site of cutaneous presentation, may
develop but will not influence clinical out- Patients more often present with multiple
come. Cytologic grade or growth pattern lesions in non-contiguous skin sites
(follicular or diffuse) do not appear to {429,2060}. Unlike PCFCL, neoplastic
have an impact on prognosis in patients cells strongly express CD10 and Bcl2,
with primary cutaneous disease. Locally and show t(14:18) translocation in most
A B C
Fig. 4.53 Diffuse large B-cell lymphoma. A Dome-shaped nodules and tumours without ulceration on the trunk and in the face. B Soft tumour surrounded by an ery-
thematous infiltrate on the back. C Aggregation of non-ulcerated nodules and tumours confined to a limited area of the lower leg.
A B
Fig. 4.58 Intravascular large B-cell lymphoma. A Involvement of the cutis with livedoid palpable erythema. B Dilated dermal vessels filled with densely packed neo-
plastic lymphoid cells.
Definition Localization
Lymphomatoid granulomatosis (LYG) is Skin is the most common site of involve-
an angiocentric and angiodestructive ment outside the lung (25-50%), but
lymphoproliferative disease involving cutaneous involvement is rarely seen
extranodal sites, composed of Epstein without pulmonary disease. Extremities
Barr virus (EBV)-positive B-cells, and trunk are the most frequent localiza-
admixed with numerically predominant T- tions {185,393,1047,1124,1223,1560}.
cells. The skin is the most common
extrapulmonary site of involvement. Clinical features
Patients usually present with signs and
ICD-0 code 9766/1 symptoms related to the respiratory tract
{1124,1223,1426}. Skin lesions consist of
Synonyms multiple erythematous dermal papules
Angiocentric immunoproliferative lesion and/or subcutaneous nodules {185}.
{1432}, angiocentric lymphoma. Necrosis and ulceration are generally
associated with larger nodules. Indu-
Epidemiology rated plaques, lichen sclerosus et Fig. 4.62 Lymphomatoid granulomatosis. Histolo-
LYG is rare, usually presenting in adult atrophicus-like lesions, and alopecia are gical features include perivascular dermal infil-
life. It affects males more often than less commonly seen {185,1129}. Cuta- trate.
females (at least 2:1) {1223}. neous lesions rarely precede pulmonary
disease, and are seen either at diagnosis but a granulomatous reaction may be
Etiology (30%) or later in the course {185}. Other seen secondary to fat necrosis.
Patients with underlying congenital or sites of involvement include brain (26%),
acquired immunodeficiency are at kidney (32%), liver (29%) {1124}. Lymph Immunohistochemistry
increased risk for LYG {921,949}. nodes and spleen are spared. While EBV-positive B-cells are readily
Predisposing conditions include allo- found in the lung, they are generally rare
geneic organ transplantation, Wiskott- Histopathology in skin, with the predominant cell being a
Aldrich syndrome, human immunodefi- LYG is characterized by an angiocentric CD3+, CD4+ lymphocyte {185}.
ciency virus infection, and X-linked lym- and angiodestructive lymphohistiocytic
phoproliferative syndrome. infiltrate. Most cutaneous lesions show Histogenesis
In patients without evidence of underly- infiltration of subcutaneous fat, with or Mature B lymphocyte, transformed by
ing immunodeficiency, reduced immune without dermal involvement. Lympho- EBV.
function can usually be demonstrated cytic vasculitis is frequent, and fibrinoid
upon careful clinical or laboratory analy- necrosis may be present {2339}. Well- Somatic genetics
sis {2534}. formed granulomas are usually absent, The ability to detect clonal immunoglob-
A B
Fig. 4.60 Lymphomatoid granulomatosis. A The most common manifestations of LYG in the skin are papules Fig. 4.61 Cutaneous lymphomatoid granulomatosis.
which may grow into nodules. B Larger nodules may ulcerate superficially. From M.W. Beaty et al. {185}. Atypical EBV-positive large B-cells represent a
minority of infiltrating cells.
A B
Fig. 4.63 Mantle cell lymphoma. A Nodular perivascular and periappendageal infiltrates in all layers of the dermis. A subepidermal grenz-zone is present. B Tumour
cells show nuclear immunoreactivity for cyclin D1.
{654,1422}. Gene profiling has suggest- Clinical features gene rearrangements and a C-MYC
ed the presence of a small subset of BL usually presents as an extranodal translocation, most often with a
cases that lack cyclin D1 abnormalities mass often in the abdomen or, in endem- t(8;14)(q24;q32) {1483}. Many, if not all,
{1978}. Other primary and mostly sec- ic cases, in jaw or other facial bones. cases also have C-MYC mutations {230,
ondary abnormalities are also described Other patients have a leukaemic presen- 1483}.
{376,1045,2303}. tation. Cutaneous involvement in BL
appears to be extremely rare and at least Prognosis and predictive factors
Prognosis and predictive factors usually is associated with disease at BL is an aggressive but curable neo-
MCL has a median survival of 3-5 years other sites {123,141,349,700}. It has plasm with a 5 year overall survival of
with those having “non-nodal” disease rarely been described as occurring with 44% {3}.
doing better {376,1756,2301,2303}. ulceration from direct invasion from
Adverse prognostic indicators include a underlying bony lesions {349}, as distinct
high proliferative fraction, probably blas- cutaneous lesions at relapse {123} and in Chronic lymphocytic
toid morphology, secondary genotypic 12% of autopsied cases of American BL leukaemia / small lymphocytic
abnormalities and blood involvement (at (2 cases) {141}. lymphoma
least in patients with nodal disease).
Whether skin involvement in particular is Histopathology Definition
an independent prognostic indicator is Histologic sections show a diffuse prolif- Chronic lymphocytic leukaemia/small
uncertain. eration of medium sized transformed lymphocytic lymphoma (CLL/SLL) is a
lymphocytes with relatively round nuclei mature B-cell neoplasm composed of
with several nucleoli and a narrow rim of small, usually CD5+, CD23+, cyclin D1-
Burkitt lymphoma very amphophilic/basophilic cytoplasm. B-cells with relatively round nuclei having
There are many apoptotic bodies and tin- clumped chromatin {1662}. Especially in
Definition gible body macrophages creating a star- lymph nodes, there is often an associat-
Burkitt lymphoma is a mature B-cell neo- ry sky appearance. Skin involvement ed minor population of prolymphocytes
plasm composed of relatively uniform demonstrates a diffuse but sometimes and paraimmunoblasts that form prolifer-
medium sized transformed B-cells with a patchy dermal and subcutaneous infil- ation centres.
C-MYC translocation {630}. trate with a Grenz zone {123,700}.
ICD-O code
ICD-O code 9687/3 Immunohistochemistry Chronic lymphocytic leukaemia
Immunophenotypic studies demonstrate 9823/3
Epidemiology CD5-, CD10+,BCL-2-, CD20+ mature B- Small lymphocytic lymphoma
BL occurs in children in equatorial Africa cells with surface immunoglobulin 9670/3
(endemic), primarily in children and expression.
young adults elsewhere (sporadic) and Epidemiology
in immunodeficient patients. There is a Histogenesis CLL is the most common type of
male predominance. Germinal centre/post germinal centre B- leukaemia in the West and SLL are
cell reported to account for 6.7% of non-
Etiology Hodgkin lymphomas {3,1064}.
Endemic BL and a minority of sporadic Somatic genetics
BL are Epstein-Barr virus positive. All cases have clonal immunoglobulin
A B
Fig. 4.65 Hodgkin lymphoma. A Secondary involvement of the skin often occurs by direct extension, as in this large cutaneous nodule with ulceration. B cHL, skin.
Classical Reed Sternberg cells are present in a background of reactive lymphocytes.
Definition predilection for skin. At presentation finely clumped chromatin, and absent or
Blastic NK-cell lymphoma is a clinically there may be a single tumour, nodule or indistinct nucleoli resembling lym-
aggressive lymphoma, with a high inci- plaque {632,1817}. Lymph node, soft tis- phoblasts or myeloblasts {632,1121,
dence of cutaneous involvement and risk sue, peripheral blood or bone marrow 1817}. The cells have sparse cytoplasm.
of leukaemic dissemination. The blastic can be simultaneously involved. Central Mitotic figures are frequent. The overly-
appearance and CD56 expression initial- nervous system involvement can devel- ing epidermis is spared, with a distinct
ly suggested an NK-precursor origin op during the course of the disease. grenz zone. Inflammatory cells are
{632}. More recent studies suggest deri- absent. There is generally no necrosis or
vation from a dendritic cell precursor, as Clinical features angioinvasion.
reflected in the designation CD4+, Blastic NK-cell lymphoma frequently
CD56+ haematodermic neoplasm. involves the skin at presentation with a Immunoprofile
single tumour, or tumours and plaques. The tumour cells usually express CD4,
ICD-O code 9727/3 Additionally, lymph nodes, soft tissue, CD56, and CD43. Expression of CD7,
peripheral blood or bone marrow can be CD2 is variable, whereas surface and
Synonyms simultaneously involved. Most cases of cytoplasmic CD3 are negative {632,
CD4+, CD56+ agranular haematodermic blastic NK-cell lymphoma presenting in 1817,2391}. Cytotoxic molecules are
neoplasm, blastoid NK-cell lymphoma, the skin progress quickly to develop generally absent. In some cases TdT
monomorphic NK-cell lymphoma lymph node, bone marrow, and central and/or CD34 can be positive {313,1681,
nervous system involvement {450,739}. 2159}. CD68 can be weakly positive,
Epidemiology The clinical course is aggressive. There showing focal staining in the Golgi
Blastic NK-cell lymphoma is a rare lym- may be initial responses to multiagent region. Since lymphoblastic and
phoma. Currently, there are no reports chemotherapy, but a high risk of relapse. myeloblastic neoplasms can also be
showing any racial or ethnic predilection. Regimens for both aggressive lym- positive for CD56, stains for myeloperox-
Most patients are middle-aged or elderly phomas and acute myeloid or lymphoid idase, and CD3 should always be per-
{632,739,1817}. However, every age can leukaemias have been utilized. formed in order to exclude these entities
be affected. {2118,2299}. The cells express CD123
Histopathology and TCL1, both of which support a rela-
Localization The dermis contains a dense, monoto- tionship to dendritic cells {450,1012}.
Blastic NK-cell lymphoma has a nous infiltrate of medium-sized cells with Blastic malignancies of precursor NK-
Histogenesis
Based on the expression of CD56, an
NK-cell derivation was initially proposed.
However, the tumour was considered to
be of uncertain lineage in the WHO clas-
sification. Recently studies have sug-
gested a derivation from plasmacytoid
dendritic cells based on gene expres-
sion studies and cytokine production.
The cells express high levels of inter-
leukin-3 receptor alpha chain (IL-3R-
alpha).
Genetics
T-cell receptor genes are in germline
configuration. Tumour cells are negative
for EBV.
A
Definition cies are more common in skin than those Cytoplasmic CD3 appears before sur-
Precursor lymphoblastic leukaemia/ lym- of precursor T-cell origin {470,1431,1489, face CD3. CD7 is nearly always positive
phoma is a malignancy derived from pre- 2043}. {1843}. The phenotype reflects stages in
cursor cells of either T-cell or B-cell line- the maturation of a thymic T-cell.
age. There is overlap in the clinical pres- Clinical features
entation, and patients may present with Lymphoblastic lymphoma/leukaemia B-cell lymphoblastic leukaemia/ lym-
disease primarily in the bone marrow and may initially present in cutaneous or phoma. The tumour cells are positive for
peripheral blood (leukaemia) or in solid other extranodal sites as a single nodule TdT, CD43, and CD99 {1489,2043}. The
tissues (lymphoma). Because of similari- or tumour {1429,2041}. Frequent sites cells are usually positive for CD19 and
ties in stage of differentiation, and man- are the head and neck region, especially CD79a {326}. CD10 is expressed in most
ner of presentation, precursor T-cell and for patients with precursor B-cell disease cases. CD20, CD22, and CD24 are vari-
B-cell malignancies will be discussed {2043}. However, there is a high likeli- ably expressed. LCA may be negative.
together. hood of occult disease in the bone mar- The cells may contain cytoplasmic µ
row, and patients should be regarded as heavy chain, usually in the absence of
ICD-O code having systemic disease for therapeutic light chains.
Precursor T-lymphoblastic leukaemia purposes.
9837/3 Histogenesis
Precursor T-lymphoblastic lymphoma Morphology Precursor T- or B- lymphoblast.
9729/3 The dermis contains a monotonous infil-
Precursor B-lymphoblastic leukaemia trate composed of small to medium sized Somatic genetics
9836/3 cells with fine chromatin and scant cyto- Rearrangement of immunoglobulin heavy
Precursor B-lymphoblastic lymphoma plasm, characteristic of lymphoblasts. chain genes, and T-cell receptor genes
9728/3 Nuclear irregularities are variable, and usually correlates with B-cell or T-cell lin-
do not correlate with lineage. The epider- eage, respectively {544,1311}. However,
Synonyms mis is uninvolved, with a distinct Grenz lineage infidelity is common in precursor
Acute lymphoblastic leukaemia zone. The cells are interspersed among lymphoid malignancies. Light chain gene
Lymphoblastic lymphoma dermal collagen fibres, without a stromal rearrangement is a relatively late event in
or inflammatory response. B-cell differentiation.
Epidemiology The classification of lymphoblastic malig-
Lymphoblastic leukaemia/lymphoma is Immunoprofile nancies is closely related to a complex
rare. Approximately 3.5% to 7% of all T-cell lymphoblastic leukaemia/ lym- series of genetic abnormalities that cor-
malignant lymphomas of the skin are of phoma. The tumour cells are positive for relate with pathogenesis and clinical out-
the lymphoblastic type {339,2041}. Most terminal transferase (TdT), CD43, CD99 come {1121}.
cases are diagnosed in children and {1489,1949,2043}. They variably express
young adults. However, every age can CD1a, CD2, CD3, CD4, CD5, and CD8. Prognosis and predictive factors
be affected. Precursor B-cell malignan- CD10 may be positive in some cases. Precursor lymphoblastic leukaemia/ lym-
phoma is an aggressive disease.
However, cutaneous involvement is not a
poor prognostic factor, and response to
systemic multiagent chemotherapy may
be excellent {2043}.
A B
Fig. 4.70 Precursor B lymphoblastic leukaemia/lymphoma. A Soft non-ulcerated tumour on an erythema-
tous plaque without scaling. B Tumour cells expressing CD79a.
Definition papules, nodules and plaques. The most able {1172,1899 }. Staining for CD34 is
Myeloid leukaemia is a heterogenous common sites of involvement are the variable, and often negative in mono-
malignant disorder of myeloid precursor scalp, face, trunk, and extremities blastic leukaemias. The neoplastic cells
cells characterized by an increase in {2288}. Haemorrhagic lesions are com- are negative for CD3, CD20, CD30 and
blast forms in the peripheral blood and mon. Leukaemic gingival hyperplasia is S-100 protein. The presence of CD56
bone marrow. Specific skin involvement a striking feature of AMML and AMOL expression in specific skin infiltrates of
results from direct infiltration of the skin {649}. In the majority of cases, specific AML has been reported {1163,1258}.
by neoplastic cells. skin lesions develop in the setting of
established leukaemia. In rare instances, Histogenesis
Synonyms leukaemic skin infiltrates may precede Haematopoietic stem cells.
Extramedullary myeloid sarcoma, granu- peripheral blood and bone marrow
locytic sarcoma, chloroma. involvement {445,589,2368}. Somatic genetics
Genetic studies of specific cutaneous
Epidemiology Histopathology lesions in AML are scant and limited to
Acute myeloid leukaemia (AML) There is a moderate or dense, diffuse or isolated cases. An increased incidence
accounts for 10-15% of childhood nodular infiltrate in the dermis that of trisomy 8 in AML with skin infiltration
leukaemia but the incidence increases extends into the subcutaneous fat {329, has been reported {35}. Rarely, cases of
steadily with age. More than 50% of 1172}. The epidermis usually is spared. congenital AML may be present with skin
patients are older than 60 years {1838}. The infiltrates typically show perivascular lesions.
Chronic myelogenous leukaemia (CML) and periadnexal accentuation. A charac-
is generally a disease of older adults, teristic feature is the presence of rows of Genetic susceptibility
with a median age between 50 and 60 atypical cells between collagen bundles Patients with Down syndrome, Fanconi
years at presentation {1183}. {2137}. The infiltrate is composed of anaemia, ataxia telangiectasia, Bloom
Skin involvement is reported to occur in medium-sized or large neoplastic cells syndrome, and Kostmann syndrome are
2% to 30% of patients with AML {35,125, with round, oval or folded basophilic predisposed to AML.
649}. Specific skin lesions are equally nuclei. Mitotic figures are usually pres-
common among males and females. It is ent. In CML, the infiltrate is more pleo- Prognosis and predictive factors
found more frequently in patients with morphic and dominated by mature and The prognosis of patients with specific
acute myelomonocytic (AMML) and immature cells of the granulocytic series. skin lesions of AML is generally poor
monoblastic/monocytic leukaemias Cutaneous infiltrates of plasmacytoid {125,805}. In one series, all patients died
(AMOL). Specific cutaneous lesions are monocytes may occur in CMML {297}. within 24 months after onset of skin
less common in chronic myelomonocytic lesions {1172}.
leukaemia (CMML) and CML. Immunoprofile
The majority of the tumour cells shows
Clinical features reactivity for lysozyme, myeloperoxidase,
Specific skin lesions present as solitary CD45, CD43, and CD74. Staining for
or multiple violaceous to red-brown chloroacetate esterase and CD68 is vari-
A B
Fig. 4.71 Acute myeloid leukaemia presenting as Fig. 4.72 Myeloid and monocytic leukaemias. A Acute monocytic leukaemia. Immunohistochemical expres-
generalized erythematous papules and plaques. sion of CD68. B Acute myeloid leukaemia. Positive lysozyme stain.
pseudolymphoma)
Epidemiology Table 4.02 Differentiation between B-pseudolymphoma (B-PSL) and cutaneous B-cell lymphoma (CBCL)
Cutaneous pseudolymphomas affect all Taken from Burg et al. {340}.
age groups with a predilection of
CBCL PSL
Borrelia-induced B-pseudolymphomas in
children and young adults, whereas drug Clinical features
induced T-pseudolymphomas more fre- Number of lesions solitary or multiple usually solitary
quently are seen in adults. Even though Extracutaneous involvement possible absent
Borrelia-induced pseudolymphomas Recurrences likely usually no recurrences
may be precursors for B-cell lymphomas Survival time affected not affected
of the skin, in general cutaneous pseudo-
lymphomas are selfregressing and do Histological features
not affect survival. Pattern of infiltrate diffuse or nodular, nodular (> 90%)
Structure of infiltrate “bottom-heavy” “top-heavy”
Border of the infiltrate convexe, sharply demarcated concave, poorly demarcated
Etiology “infiltrating” between
Pseudolymphomatous proliferations in the collagen bundles
skin may be induced by microbial, physi- Additional cells usually absent eosinophils,plasma cells
cal or chemical agents including Borrelia Transformation may occur never occurs
burgdoferi infection, tattoos and drugs.
Immunophenotype
Localization Immunoglobulin light chains monotypic (kappa or lambda) polytypic expression
In most cases, skin lesions are confined B-cell marker expressing cells >50% cells ≤50% cells
to the site of external irritation, i.e. tick T-cell marker expressing cells usually few >50% cells
CD21-positive dendritic cells mostly absent mostly present
bite. Due to the preferential “docking” of
irregular pattern regular pattern
ticks to body areas where the skin is rel-
atively soft, e.g., scrotum of young boys, Genotype
the mamilla, ear lobes, large skin folds Ig heavy chain gene rearrangementpresent in most cases absent in most cases
are preferentially involved.
A B
Fig. 4.78 Parapsoriasis. A Large plaque parapsoriasis with poikiloderma, showing large teleangiectatic patches and a netlike pigmentation. B Flattening of the epi-
dermal rete ridges. Band like lichenoid infiltrate. Dilated small blood vesels in the upper dermis.
Parapsoriasis 215
Parapsoriasis - Large patch Table 4.03
type, with or without Criteria for distinguishing benign and premalignant forms of parapsoriasis en plaques.
poikiloderma
Benign form (small patch type) Premalignant form (large patch type)
with or without poikiloderma
Definition
Pre-malignant inflammatory disorder with Age distribution Adults All ages
tendency to evolve into mycosis fun-
goides. Some authors consider this Sex incidence (m:f) 5:1 2:1
lesion a manifestation of early cutaneous
T-cell lymphoma (CTCL). Clinical features Small (2-5cm in diameter), mostly Few large patches (>5cm in
oval, or finger-like patches, diameter) pityriasiform scaling
Synonyms slightly erythematous and wrinkled with or without telangiectases
surface (pseudoatrophy) uniformly and netlike pigmentation,
Non-poikilodermatous variant. Parapso-
pinkish or yellowish with sometimes slightly hyperkeratotic
riasis en plaques, premalignant type,
pityriasiform scaling (parakeratosis variegata)
parapsoriasis en grandes plaques sim-
ples. Preferential localizations Trunk and upper extremities Breast and buttocks
Poikilodermatous variant : Prereticulotic
poikiloderma, parapsoriasis en grandes Histological features Patchy parakeratosis, slight Slight epidermal atrophy with loss
plaques poikilodermiques; poikiloderma perivascular patchy infiltrate, of rete ridges, significant band-like
vasculare atrophicans; parapsoriasis no oedema, no significant dermal lymphocytic infiltrate sparing
lichenoides; parakeratosis variegata epidermotropism the subepidermal zone, no significant
epidermotropism, no oedema;
telangiectases may be prominent
Epidemiology
in the poikilodermatous variant
All age groups may be affected with a
slight male preponderance. Prognosis Life expectancy normal; Life expectancy normal in most
no progression to mycosis fungoides cases; progression to mycosis
Localization fungoides occurs
Breast and buttocks are most commonly
involved.
Clinical Features loss of rete ridges, in the poikiloderma- ened telomere length was also detected
Few large (more than 5 cm in diameter) tous form. The subepidermal zone is free in CD4+ T cells from patients with parap-
patches showing pityriasiform scaling of lymphocytes, which accumulate in a soriasis {2552}.
with (poikilodermatous variant), telang- band-like arrangement in the upper der-
iectasia and netlike pigmentation are mis, sparing the papillary region. There is Prognosis and predictive factors
present. There is no palpable infiltration. no significant epidermotropism as usual- There is no significant difference
ly seen in early stages of mycosis fun- between the observed and expected
Tumour spread and staging goides. The poikilodermatous variant of survivals in patients with less than 10%
Lesions may stay unchanged over years the disease in addition shows dilated skin involved. {2575}. However when skin
and decades, or slowly show enlarge- blood vessels in the upper dermis. involvement exceeds10%, as seen in
ment in a few cases. No plaques or LPP, sporadic cases have an increased
tumours occur, except when the disease Somatic genetics risk of transforming into mycosis fun-
evolves into CTCL in some of the cases. T-cell receptor gamma gene rearrange- goides after years or decades {2031}.
ment,which is clonal in about half of the
Histopathology patients with LPP, is probably without any
Under patchy parakeratosis there is prognostic significance {2186}.
slight atrophy of the epidermis, due to Increased telomerase activity and short-
Letterer Siwe First years ~90-100% Fever, weight loss, Acute Mortality
of life lymphadenopathy, rate:
hepatosplenomegaly, 50-66%
pancytopenia, bone
lesions
A B
Fig. 4.81 Langerhans cell histiocytosis. A Typical ground glass (“reticulocytic”} appearance of Langerhans cells. B Langerhans cells with membranous staining
for CD1a .
well as small erosions can also be seen. Eosinophilic granuloma palms and soles, sometimes showing
Nodules are uncommon, but may be The most common site of involvement is central ulceration {217}. The skin lesions
found on the trunk and tend to ulcerate. bone. The uncommon cutaneous lesions tend to involute spontaneously within
Additional symptoms include fever, are deep dermal or subcutaneous nod- weeks to months leaving behind hypo- or
weight loss, rash, lymphadenopathy, ules which are not clinically distinct hyperpigmented macules or patches
hepatosplenomegaly, pancytopenia and {818,1956}. Lesions have to be differenti- {979,1372}. Affected infants are other-
purpura. ated from granuloma eosinophilicum wise well {1369}. Patients should be
faciei, a chronic variant of leukocytoclas- carefully followed since relapses may
Hand – Schüller - Christian tic vasculitis with variable presence of occur, including bone involvement, and
disease eosinophils, but usually no extracuta- the occasional case may progress to
The typical triad includes osteolytic skull neous manifestation {452}. Letterer-Siwe disease {1445}. Some
lesions (100%), hypopituitarism induced cases of CSHRH may be clinically con-
diabetes insipidus (50%), and exophthal- Congenital self-healing reticulo- fused with the blueberry muffin syn-
mos (10%). Otitis media, generalized histiocytosis (CSHRH) drome, congenital leukaemic infiltrates,
lymphoadenopathy, hepatosplenome- CSHRH (synonyms: Hashimoto-Pritzker xanthogranulomas or mast cell disease,
galy, and pulmonary disease may be disease; congenital reticulohistiocytosis; but the microscopic picture brings clarity
additional findings. congenital self-healing Langerhans cell {360}.
Skin lesions occur in about 30% of histiocytosis) {981,2082} is a rare condi-
cases, usually in the intertriginous areas, tion (5% of all LCH), initially seen at birth Histopathology
most often as papules and nodules or in the neonatal period, with solitary, The hallmark and unifying feature of all
which may be ulcerated, erosive and localized to generalized papules, vesi- variants of LCH is a cell with large, pale,
superinfected. cles, or nodules on the trunk, head, folded or lobulated, often reniform, vesic-
Fig. 4.83 Indeterminate cell histiocytosis. Multiple Fig. 4.84 Indeterminate cell histiocytosis. The pro- Fig. 4.85 The proliferating cells reveal an indented
firm, asymptomatic papulonodules on the trunk, liferating cells show an irregular, often reniform, nucleus and an abundant cytoplasm with lyso-
ranging in size from few millimetres to 1 cm, vary- vesicular nucleus, surrounded by abundant pale somes, phagosomes and a well developed endo-
ing in colour from dark red to brownish. cytoplasm. From: R. Caputo {378}. plasmic reticulum. Birbeck granules are absent.
(Rosai-Dorfman disease)
A B
Fig. 4.86 Sinus histiocytosis with massive lymphadenopathy. A Left: Brownish nodule of sinus histiocytosis on the nose. 1595 Right: Clustered brownish papules of
sinus histiocytosis on the trunk. B Left: Sheets of macrophages in sinus histiocytosis positive for S100 protein. Right: Lymphocytes within cytoplasm of histiocytes,
i.e,. emperipolesis.
Histopathology
Early lesions are characterized by a
dense infiltrate of monomorphous, non-
A C lipid containing, macrophages with
Fig. 4.87 Juvenile xanthogranuloma. A Mixed form: this form is characterized by the simultaneous presence
abundant, slightly eosinophilic, cyto-
of both red brown papules and nodules, irregularly scattered throughout the skin. Previously published by plasm {378,824}. With time the cyto-
R. Caputo in "Text Atlas of Histiocytic Syndromes. A Dermatological Perspective" , Martin Dunitz, London plasm of macrophages becomes laden
1998 {378}. B Plaqueform: this cluster of yellow nodules on the back of the neck is the only expression of with lipid and appears foamy.
the disease. C Nodular form: a round, high-domed, yellow brown nodule on the right shoulder. Mature lesions contain foamy cells, for-
eign body giant cells and Touton giant no Langerhans granules (LG) can occa- chromosome 17q11.2 or 22q12. Clinical
cells, mainly distributed in the superficial sionally be observed. In older lesions {1115} and genetic analyses {1056} indi-
dermis and on the border of the infiltrate. there is a predominance of foamy cells, cate that neurilemmomatosis and neu-
In addition to macrophages and foamy the cytoplasm of which is completely rofibromatosis type 2 (NF2) genes are
cells, there may be lymphocytes, eosino- filled with lipid vacuoles, cholesterol identical.
phils, neutrophils and plasma cells scat- clefts, and myeloid bodies. The cells cor-
tered throughout the lesion. In older responding to Touton giant cells are Prognosis and predictive factors
lesions fibrosis replaces the cellular infil- large (150-250 µm) and sometimes con- The papules and nodules of the skin tend
trate, and lipids are not present extracel- tain more than 10 nuclei. At their periph- to flatten with time and both the skin and
lularly. ery, such cells are rich in lipid material, most of the visceral lesions disappear
whereas in their centre, mitochondria spontaneously within 3-6 years. A few
Immunohistochemistry and lysosomes predominate. cases of JXG with fatal evolution, proba-
Immunohistochemically {824,2049} ma- bly due to central nervous system
crophages and Touton cells show a uni- Genetics involvement {378} or fatal liver disease
form positive staining with CD14, CD68, JXG is not linked to any genetic locus, {614}, have been reported. In JXG peri-
HAM56 (markers with specificity for but the association with café-au-lait odic complete blood count and peripher-
macrophages) and vimentin, frequent spots of neurofibromatosis (NF1) {2536} al smears would be judicious during a
positive staining for factor XIII (markers and the occasional association with patient’s first two years of life, which is
of dermal dendrocytes) and for cathep- neurilemmomatosis (NF2) {1115} sug- the time of the peak incidence for juve-
isin B and occasional staining for gests that a JXG locus could reside on nile chronic myeloid leukaemia.
MAC387 (a marker for monocytes and
macrophages).
S100 protein, CD1a (OKT6), CD15 (Leu
M1) and peanut agglutinin (PNA) are not
usually expressed on the macrophages
of JXG.
Electron microscopy
Under the electron microscope {378,
824}, the macrophages that characterize
the early stage of the disease exhibit
pleomorphic nuclei, are rich in pseud-
opods, and contain many elongated and Fig. 4.90 Juvenile xanthogranuloma. Electron
irregular dense bodies. microscopy. This large macrophage exhibits lipid
Clusters of comma-shaped bodies, but droplets, myeloid bodies and cholesterol clefts.
Definition There is no preference for either sex The lesion is often clinically misdiag-
Reticulohistiocytosis of the skin repre- {167,465,1405,1462}. nosed, it occurs without evidence of sys-
sents a spectrum of rare clinical entities, temic involvement, and its onset may be
ranging from the solitary cutaneous form Etiology preceded by trauma.
(SCR) through the generalized cuta- The etiopathogenesis is unknown. Generalized cutaneous histiocytosis
neous form without systemic involvement Reticulohistiocytosis may represent an (GCR) {381,547,847,2363} is a purely
(GCR), to multicentric reticulohistiocyto- abnormal macrophage response to dif- cutaneous form characterized by the
sis with systemic involvement (MR). The ferent stimuli. In solitary forms, local trau- eruption of firm, smooth, asymptomatic
skin lesions in all these conditions ma such as insect bites, folliculitis or rup- papulonodular lesions, 3-10 mm in diam-
demonstrate an identical histological tured infundibular cysts may play a role eter. The colour of the recent lesions is
pattern, characterized by numerous {379}, while in systemic forms the associ- pink-yellow, while the older lesions show
mononucleated or multinucleated macro- ation with autoimmune disorders and a red-brown colour. Joint and visceral
phages with abundant, eosinophilic, internal malignancies suggests an lesions are absent. Possibly, this purely
homogeneous to finely granular cyto- immunological basis for the initiation of cutaneous form could represent an early
plasm with a characteristic ground-glass this reaction {1752}. stage of multicentric reticulohistiocytosis,
appearance. before the appearance of joint or viscer-
Localization al lesions.
Synonyms SCR involves mainly the head and the The term multicentric reticulohistiocytosis
Giant cell reticulohistiocytosis, giant cell neck, but may be found in any cutaneous {167,413,465,1405,1752} is used to indi-
histiocytosis; cutaneous reticulohistiocy- site {382,1082}. In GCR the lesions are cate a form of reticulohistiocytosis char-
toma, reticulomatosis with giant cell histi- widely scattered on the skin {381,547, acterized by the association of a cuta-
ocytes; normocholesterolemic xan- 847,2363}. In MR {167,413,465,1405, neous and mucous membrane papulon-
thomatosis; lipoid dermatoarthritis; lipoid 1752} skin lesions preferentially affect the odular eruption with severe arthropathy
rheumatism; multicentric reticulohistiocy- fingers, the palms and the back of the and other visceral symptoms. The papu-
tosis; non-diabetic cutaneous xan- hands, the juxta-articular regions of the lonodular lesions range in diameter from
thomatosis; reticulohistiocytic granulo- limbs and the face. Oral, nasal and pha- a few mm to 2 cm, and are round,
ma; reticulohistiocytosis of the skin and ryngeal mucosa are involved in 50% of translucent and yellow-rose or yellow-
synovia. cases. Osteoarticular lesions involve brown in colour. Grouping of lesions into
mainly the hands (80%), knee (70%) and plaques can give a cobblestone appear-
Epidemiology wrists (65%). ance, but lesions are mostly scattered
Reticulohistiocytosis mostly occurs in and isolated. They do not tend to ulcer-
adults over 40 years of age, but the dis- Clinical features ate, and are pruritic in about one-third of
ease may appear during adolescence: The solitary cutaneous reticulohistiocyto- cases. Osteoarticular manifestations
SCR and GCR have been also observed sis (SCR) or reticulohistiocytoma cutis cause severe chronic polyarthritis with
in children. In adults, the most frequent {382,1082} is characterized by a single, arthralgias, and are the initial sign of the
variant is MR, with about 50 and GCR firm, rapidly growing nodule varying in disease in about 5-65% of cases {167,
with 10 patients reported in the literature. colour from yellow-brown to dark-red. 465,1405}. The osteoarticular lesions
A B C
Fig. 4.91 Multicentric reticulohistiocytosis. A Purplish-brown, firm nodules characteristically affect the fingers. Periungual papules are arranged about the nail
folds. B Papulonodular lesions are spread on the face, lips and oral mucosa. Mucous membranes are involved in about 50% of cases. C Symmetrical involvement
of the knees. In this patient, osteoarticular manifestations were the initial sign of the disease. From: R. Caputo {378}
show a progressive destructive course of scarlet red, indicating the presence of cytoplasm contains one or more Golgi
6-8 years, and then become stable. glycolipids and/or glycoproteins and apparatus, and is rich in mitochondria,
Other systemic localizations, histopatho- neutral fat {167}. lysosomes, dense bodies, phagosomes
logically documented are very rare. and myelin figures. The cytoplasm of
Muscular {667} (myositis, myotonia and Immunohistochemistry about 5-40% of the cells of the infiltrate in
myoatrophy), cardiopulmonary {532} Macrophages stain with macrophage many cases contains the so-called pleo-
(pericarditis, cardiac insufficiency, pleuri- markers KP1/PGM1 (CD68), Ki-M1p, and morphic cytoplasmic inclusions {380-
tis, pulmonary infiltration), ocular {667} for the mesenchymal epitope of vimentin, 382,532}, varying in number from cell to
(exophthalmos, conjunctival infiltration), and show variable reactivity with HAM56 cell. The pleomorphic cytoplasmic inclu-
gastric (gastric ulcer), thyroid (thyroid and for factor XIIIa, lysozyme and α1- sions are unique and highly complex
nodules) and submandibular salivary antitrypsin {381,382,424,2027,2585}. In structures consisting mainly of unit mem-
gland involvements have occasionally contrast, these cells are usually negative branes, occasionally surrounding elec-
been reported. Fever, weight loss and for CD1α, S100 protein, Leu-M1 (CD15) tron-dense areas containing vesicles.
weakness can be present. In MR there is and MAC387. Rare exceptions have Birbeck granules are absent. About 20%
an association with a variety of autoim- been reported. According to Zelger et al. of all macrophages show collageno-
mune disorders such as dermatomyosi- {2585}, SCR differs histopathologically phagic activity {379,766}, but not pleo-
tis, lupus erythematosus, or Hashimoto and immunohistochemically from MR as morphic cytoplasmic inclusions.
thyroiditis as well as internal malignan- lesions are better circumscribed, multin-
cies in 15-27% of cases {167,413,1405, ucleated giant cells more prominent, Prognosis and predictive factors
1752}. Solid tumours such as bronchial, gigantic and bizarre, and macrophages The purely cutaneous forms of reticulo-
breast, stomach and cervical carcino- regularly negative for factor XIIIa in the histiocytosis (solitary and generalized)
mas are most common. Lymphomas and former entity. may involute spontaneously {382,847}. It
myelodysplastic syndromes have been is possible that the generalized purely
found less frequently. Electron microscopy cutaneous form is an early stage of MR,
The infiltrate is formed by large mononu- before the appearance of joint and vis-
Histopathology clear to multinucleated cells exhibiting ceral lesions {381,847}, In MR, there is no
The histological findings in the three numerous peripheral villi {532,667}. parallelism between the mucocutaneous
types of reticulohistiocytosis and in the Nuclei are irregular and often polylobat- and articular manifestations. The muco-
different tissues are identical {167,465, ed, with nucleoplasm of medium electron cutaneous lesions have an unpredictable
1405,1462}. Early lesions are composed density and one or two nucleoli. The course, and may remit spontaneously. In
of macrophages and lymphocytes, and half of the patients, the osteoarticular
therefore may be confused with other manifestations become stable, while in
histiocytoses of the skin. Older lesions the other half, they show a progressive
show the characteristic histological pat- destructive course {1405}. The prognosis
tern: the presence of numerous large, is favourable for the cutaneous forms.
mononuclear or multinucleated macro- The prognosis of MR is related to the
phages with an abundance of importance of the osteoarticular manifes-
eosinophilic, homogeneous to finely tations and of the underlying immunolog-
granular cytoplasm having a ground ic disorders and neoplasms.
glass appearance. At times, phagocyto-
sis of connective tissue and/or cellular
components may be seen {379,532}.
Histochemically, the granular material in Fig. 4.93 Reticulohistiocytosis. Electron micro-
macrophages and giant cells stains with scopy: the polymorphism of the granules is evident
periodic acid-Schiff, Sudan black and at higher magnification.
Reticulohistocytosis 225
Mastocytosis B.J. Longley
B.M. Henz
Definition telangiectasia macularis eruptiva per- cence. Adult mastocytosis is more likely
Mastocytosis is a heterogeneous group stans (TMEP); diffuse cutaneous masto- to be persistent and may be associated
of disorders characterized by the abnor- cytosis (DCL); solitary mastocytoma with SM, rarely also with aggressive sys-
mal growth and accumulation of a clone {965,2405} 9740/1 temic mastocytosis. There is no clear
of mast cells in one or more organ sys- Indolent systemic mastocytosis gender or ethnic predominance of cases
tem {1448}. Most patients have cuta- 9741/1 {964,1450}.
neous mastocytosis (CM) with indolent Aggressive systemic mastocytosis
disease that is confined to the skin and 9741/3 Etiology
that may regress spontaneously. Mastocytosis with associated The KIT protein is a receptor tyrosine
A minority of patients, usually adults, haematopoietic disorder 9741/3 kinase that is also known as the mast cell
have systemic mastocytosis (SM) that Mast cell leukaemia 9742/3 growth factor receptor. Adult mastocyto-
may rarely be highly aggressive and sis and rare pediatric cases are associ-
associated with multi-system involve- Synonyms ated with somatic mutations in the c-KIT
ment and short survival time, or that may Mast cell disease; mast cell proliferative proto-oncogene that alter the enzymatic
be associated with non-mast-cell disease site of the KIT protein {361,1449}. Rare
haematopoietic malignancies {1450, kindreds with familial mastocytosis have
2372,2405}. Epidemiology germ line c-KIT mutations that affect reg-
Cutaneous mastocytosis may be present ulatory portions of the KIT protein, also
ICD-O Codes at birth and usually first appears before causing constitutive kinase activation.
Cutaneous mastocytosis (CM); macu- six months of age. A second peak inci- These patients may also have gastroin-
lopapular or plaque type mastocytosis, dence is found in young adults in their testinal stromal tumours (GISTs) which
formerly urticaria pigmentosa (UP); 3rd and 4th decades. Paediatric masto- are known to be caused by regulatory
telangiectatic mastocytosis, formerly cytosis usually regresses by adoles- type c-KIT activating mutations {189,
A B C
D E F
Fig. 4.94 Cutaneous mastocytosis. A Wheal and flare of Darier sign. The skin lesions of all forms of cutaneous mastocytosis may urticate when stroked. A palpa-
ble wheal appears a few moments after physical stimulation, due to histamine from the mast cells. B Tense blister containing clear fluid on skin of infant with dif-
fuse cutaneous mastocytosis. The skin may appear thickened and reddish brown with diffuse involvement. Note the blister caused by mast cell degranulation and
histamine release. Blisters may form in infants because the dermal-epidermal junction is not yet well developed. C Large pigmented papules of paediatric urticaria
pigmentosa. D Reddish brown macules, patches and plaques on abdomen and arm of an adult with cutaneous and systemic mastocytosis. E Telangiectasia mac-
ularis eruptiva perstans form of cutaneous mastocytosis in an adult. F Pigmented macules of adult type urticaria pigmentosa. The number of lesions may range from
a few to thousands.
Localization
Eighty percent of patients with mastocy-
tosis have disease confined to the skin.
Conversely, of the 20% of patients with
systemic mastocytosis, about half have
cutaneous involvement. Essentially all
patients with SM are adults and have
involvement of the bone marrow, but any
other organ may also be involved, most
commonly the spleen, lymph nodes, or
gastrointestinal tract {116,580,2224,
2372}.
Clinical features
Cutaneous mastocytosis includes sever- Fig. 4.95 Mastocytoma of the skin. Stains containing toluidine blue stain the mast cell cytoplasmic granules
al distinct clinico-pathologic entities metachromatically purple.
whose morphologies include solitary
tumours (Mastocytoma), maculo-papular have relatively vague constitutional involvement in children may point to the
or plaque-type lesions that are mostly symptoms including fatigue, weight loss, presence of c-KIT activating mutations
symmetrically distributed (UP/TMEP), fever, sweats, and non-specific psychi- {2405}. In adolescents and adults, the
and diffuse cutaneous involvement atric symptoms {964,1450}. individual lesions tend to be more heavi-
(DCM). Patients with SM may have also bone- ly pigmented and macular, rather than
Stroking of any lesion of CM may cause related complaints such as pain, frac- papular, like those of young children. The
mast cell degranulation with localized tures, or arthralgias, secondary to direct term TMEP has been used for these
swelling or urtication (Darier sign). mass effects or generalized osteoporo- macular lesions and for larger, lightly pig-
Clinically normal skin may also urticate sis. mented patches with telangiectasias that
when stroked, (so-called dermo- The diagnosis of cutaneous mastocyto- may rarely occur in adults {964}. Cuta-
graphism). Moderate itching is present in sis is established by skin biopsy that neous involvement in SM usually
about half of the patients {579}. Most demonstrates increased numbers of appears morphologically identical to CM
cutaneous lesions show an increase in mast cells in the dermis. Imaging studies in adults, but may also show larger
epidermal melanin pigment which, com- or biopsy of bone marrow or other inter- plaque like lesions.
bined with the tendency of these lesions nal organs are usually not indicated in
to urticate, has led to the term “urticaria the absence of abnormality of the Histopathology
pigmentosa”, a historic designation that peripheral blood counts or specific signs In haematoxylin and eosin (H&E) stained
has recently been proposed to be aban- or symptoms pointing to internal organ sections, normal mast cells have moder-
doned {2405}. Blistering or bullous mas- involvement. ately abundant, oval or polygonal
tocytosis is not a distinct entity but repre- The clinical presentation of CM may shaped cytoplasms with round to oval
sents an exaggeration of Darier sign range from subtle diffuse erythema to nuclei, sometimes giving the appear-
seen in infants whose dermo-epidermal grossly evident, widespread doughy der- ance of a “fried egg”. The nuclei have
junction is not well developed so that mal thickening with accentuation of cuta- clumped chromatin and indistinct or
accumulation of edema fluid results in neous surface markings, giving a so- inapparent nucleoli. The cytoplasms are
the formation of localized blisters {964}. called “grain leather”, (peau chagrine) or filled with small, faintly visible, eosino-
Other symptoms of mastocytosis may be orange skin (peau d’orange) appear- philic or amphiphilic granules which stain
due to mast cell infiltration of specific ance {964,1449,1450,2430,2525}. Tense metachromatically with the Giemsa or
organs or due to release of mast cell blisters filled with clear fluid, occasional- toluidine blue stains. Occasionally, mast
mediators into the circulation. Organs ly slightly-tinged with blood, may be seen cells may be spindle shaped or show bi-
affected include: the gastrointestinal overlying lesions of any form of cuta- or multi-lobated nuclei {1401,1450,1607,
tract (peptic ulcer disease, diarrhoea neous mastocytosis in infants. 2405}.
and cramping) or the cardio-pulmonary Individual lesions in young children tend In normal skin, individual mast cells are
and cardio-vascular systems (flushing, to be lightly pigmented and occur as soli- found perivascularly and scattered
syncope, headache, seizures, hyperten- tary nodules or multiple papules, or throughout the dermis, without formation
sion, hypotension including anaphylaxis, rarely as large heavily pigmented mac- of clusters. Mast cells in mastocytosis
tachycardia, and respiratory symptoms). ules, large plaques, or diffuse infiltration also tend to accumulate perivascularly,
Patients with extensive involvement may of the skin {964}. Large lesions or diffuse and are most often evident in the super-
Mastocytosis 227
ficial dermis, within the dermal papillae Histogenesis ing mutations may indicate persistent
{1401,1607}. In solitary mastocytomas Mast cells are derived from CD34+ disease in this population, and classifica-
and papular, nodular, or diffuse CM, the haematopoetic precursor cells {1982}. tion of mastocytosis based on both clini-
papillary and/or reticular dermis may cal and molecular genetic features may
show either scanty increases in mast cell Somatic genetics eventually prove to be both prognosti-
numbers or heavy mast cell infiltrates, Mastocytosis is a clonal disease in both cally and therapeutically useful {1446,
and there may be extension into the sub- adults and children {1448,1449}. The 1465}. In adults, although CM may be
cutaneous fat. In CM, individual mast tumour cells of almost all cases of adult symptomatic and persist, overall survival
cells may rarely be found in the lower onset sporadic disease carry somatic is usually not adversely affected, even in
epidermis. Unequivocal diagnosis of point mutations of c-KIT that change the the face of concomitant systemic involve-
cutaneous mastocytosis requires the enzymatic site of the KIT protein, causing ment. Patients having aggressive vari-
demonstration of aggregates of mast constitutive activation {361,1449}. ants of SM, however, may have a rapidly
cells within the dermis, and this may be Paediatric sporadic mastocytosis has progressive downhill course with survival
difficult and require multiple biopsies in also been shown to be clonal, but c-KIT measured in months. In patients with
the TMEP form of adult mastocytosis. activating mutations are rare {361,1449}. associated haematologic malignancies,
Lesions of mastocytosis are usually com- Very rare cases of familial mastocytosis, the prognosis is determined by the
posed of an infiltrate of monomorphous usually associated with GISTs tumours, course of the related haematologic dis-
mast cells, and rarely observed infiltrat- are associated with germ line c-KIT ease {964}.
ing eosinophils should raise the possibil- mutations that activate KIT by affecting
ity of dermal hypersensitivity reaction, regulatory portions of the molecule,
parasitosis or an arthropod bite. rather than the enzymatic site {189,
1447}.
Immunohistochemistry
Mast cells are bone-marrow derived cells Prognosis and predictive factors
and therefore express CD45 (CLA). They Patients with mastocytosis confined to
also express CD117 (the KIT protein) the skin generally have a good progno-
and HLA-DR. Relatively specific mast sis, and cutaneous involvement is usual-
cell markers include highly sulfated gly- ly an indicator of a relatively better prog-
cosaminoglycans like heparin (toluidine nosis in SM. CM in paediatric patients
blue stain), tryptase and chymase. CD-2 with solitary mastocytomas or typical
and/or CD25 may be aberrantly ex- papular and macular rashes usually
pressed in mast cells of SM {934, 2404, regresses by adolescence. The pres-
2405}. ence of enzymatic site type KIT activat-
Lymphatic tumours
Lymphangioma circumscriptum 9170/0
Progressive lymphangioma 9170/0
__________
1
Morphology code of the International Classification of Diseases for Oncology (ICD-O) {786} and the Systematized Nomenclature of Medicine (http://snomed.org).
Behaviour is coded /0 for benign tumours, /3 for malignant tumours, and /1 for borderline or uncertain behaviour.
__________
From references {892,2219}.
Superficial tumour is located exclusively above the superficial fascia without invasion of the fascia; deep tumour is located either exclusively beneath the supeficial fascia, or super-
ficial to the fascia with invasion of or through the fascia. Retroperitoneal, mediastinal and pelvic sarcomas are classified as deep tumours.
Epidemiology complicating longstanding lymphoede- extent of a primary tumour and its rela-
Age-standardized incidence rates of soft ma, especially after radical mastectomy tionship to normal structures, and for
tissue sarcomas, which are fairly con- (Stewart-Treves) might also be due to revealing metastases. Both computer-
stant in most areas covered by cancer local immunosuppression {1995}. ized tomography (CT) and magnetic res-
registration, range from 1-3 per hundred An association between exposure to her- onance imaging (MRI) are used. CT is
thousand population {1781}. Sarcomas bicides, including dioxin, and sarcoma- particularly useful for tumours in body
of cutaneous origin are relatively rare, genesis is controversial and remains cavities, and for detecting pulmonary
and are far outnumbered by carcinomas, unproven. Sarcomas can arise in the metastases. MRI can demonstrate intra-
melanoma and benign mesenchymal field of prior therapeutic irradiation. This tumoural heterogeneity, including pres-
neoplasms of skin and subcutis (superfi- is a dose- and time-related phenomenon, ence of solid, fatty, fibrous, haemorrhag-
cial soft tissue). The most common resulting mostly in subfascial, high-grade ic or necrotic tissue, and the interface
benign tumours are lipomas, fibrous his- pleomorphic sarcomas after an interval between neoplastic and normal tissue
tiocytomas, vascular or smooth muscle of 5 or more years. Following irradiation including involvement of neurovascular
lesions including angioleiomyomas, and for carcinoma of breast, low-grade cuta- bundles.
nerve sheath tumours (schwannoma, neous angiosarcomas have been
neurofibroma). Some of these tumours described after an interval as short as 18 Biopsy
are covered elsewhere {756}. The vast months {1772}. Superficial lesions smaller than 2-5 cm in
majority are located superficially and do diameter can be excised in their entirety.
not exceed 5 cm in diameter. Clinical features Larger ones, and all subfascial and
Sarcomas are mostly found in older Benign and malignant tumours present deep-seated tumours need diagnostic
adults. They arise mainly in the extremi- as usually painless masses, with varying sampling. For this, some practitioners
ties, especially the thigh, followed by growth rate. Cutaneous lesions form a prefer open incisional biopsy with an
trunk, head and neck and retroperi- plaque or elevated nodule that can ulcer- appropriately placed incision that is sub-
toneum. ate when malignant. Large (>5 cm) sequently excised in continuity with the
superficial lesions, and all subfascial or formal resection. Needle core biopsy,
Etiology deep-seated tumours, should be referred preferably using a Trucut or larger needle
Most soft tissue sarcomas arise sponta- to a specialist multidisciplinary centre can provide diagnostic information for
neously and are of unknown etiology. A before surgery and preferably before malignancy, subtype and grade, with
small number arise in rare familial cancer biopsy {180}. high sensitivity and specificity in experi-
syndromes with germline mutations. A enced hands {1021,1040}. Fine-needle
number of other congenital and inherited Pathology aspiration cytology is used in a few cen-
syndromes are associated with benign In general, malignant soft tissue neo- tres where a large volume of cases
and malignant soft tissue tumours; type plasms are characterized by nuclear allows accrual of sufficient experience
examples include Mafucci syndrome pleomorphism, mitotic activity including {46}; it is not particularly sensitive for
(chondroid and vascular tumours) and abnormal forms, necrosis and vascular diagnosing malignancy in differentiated
Cowden disease (lipomas, haeman- invasion. Some benign tumours, howev- adipose or in sub-typing low-grade myx-
giomas). Further details can be found in er, can show one or more of these fea- oid lesions, partly because the sample
the WHO Classification of Tumours of tures. Examples include nuclear atypia in might not be representative.
Soft Tissue and Bone {756}. cutaneous pleomorphic fibroma and
Non-hereditary genetic factors are also atypical benign fibrous histiocytoma Tumour spread and staging
presumed to be pathogenetic in various (which can also display necrosis), and The recent WHO classification of
tumour types which have consistent frequent mitoses in nodular fasciitis. Tumours of Soft Tissue and Bone {756}
chromosomal translocations, although it Detailed diagnostic criteria are provided recognizes three behavioural categories:
is not known how or in what cell these for each subtype. 1. Benign tumours. These rarely recur
rearrangements arise. Viruses associat- locally, and those that recur do so in a
ed with sarcomas include human herpes Diagnostic procedures non-destructive fashion and are usually
virus 8 (HHV8) in Kaposi sarcoma Investigation includes clinical assess- cured by local excision. Exceptionally
{434,2487}, and EBV in some smooth ment of size and depth of tumour, the use rarely, an otherwise (and histologically
muscle tumours in children and adults of imaging modalities, and biopsy. typical) benign tumour, such as cuta-
with immunosuppression, including neous fibrous histiocytoma, can metasta-
transplant recipients and patients with Imaging size.
HIV infection {1390,1547}. Angiosarcoma Imaging is of value for assessing the 2. Intermediate tumours are those that
Introduction 231
are locally aggressive and/or very occa- sis (0, <50%, >50%). A total score count subtype is predictive, but one of the prin-
sionally metastasizing. Locally aggres- of 2 or 3 is classified as grade 1, a score cipal factors in assessing prognosis and
sive tumours, such as fibromatosis, recur count of 4 or 5 as 2, and a score of 6, 7 determining management is the histolog-
locally and infiltrate surrounding tissues. or 8 as grade 3. ical grade. Low-grade sarcomas, howev-
Rarely-metastasizing tumours are gener- er, when located in sites where complete
ally dermal or subcutaneous tumours Staging surgical excision is difficult, such as
which have a low (1-2%) but definite risk A widely used staging system for soft tis- retroperitoneum or head and neck, have
of metastasis, most often to regional sue sarcomas is that of the International a worse outcome than similar tumours in
lymph nodes but occasionally to lung. Union against Cancer (UICC) (TNM sys- the extremities. Molecular genetic find-
Examples are recorded for plexiform tem) and American Joint Commission on ings, especially fusion gene types, might
fibrohistiocytic tumour {2028} and Cancer (AJCC) {892,2219}. Unlike for relate to prognosis.
angiomatoid fibrous histiocytoma {693}. many other tumours, staging of sarco-
3. Malignant tumours infiltrate and recur mas includes histological grading as well
locally and have an appreciable risk of as tumour size and depth from surface,
metastasis (exceeding 20%). regional lymph node involvement and
distant metastasis.
Grading
This is an attempt to predict clinical Prognosis and predictive factors
behaviour based on histological vari- Completeness of excision (assessed by
ables. Grading of a tumour should be clear surgical margins in the excision
done on material from a primary untreat- specimen) is the most important factor in
ed neoplasm, though change (increase) prevention of local recurrence {2376}.
of grade can be noted in recurrent or Some sarcomas, notably epithelioid sar-
metastatic tumour. It is not applicable to coma, are relentlessly recurrent, even
all sarcomas; for example, angiosarco- though they might not metastasize until
ma, clear cell sarcoma and epithelioid late in the course of the disease {2238}.
sarcoma are always considered to be of For metastasis, general adverse factors
high-grade malignancy. Several grading are large tumour size and increasing
systems have been proposed, but that of depth from surface. Thus, cutaneous sar-
the French Cancer Centres is gaining comas have a lower risk of metastasis
wide usage {917}. Briefly, tumours are than those located more deeply {2001};
given a score of 1,2 or 3 depending on indeed, histologically malignant leio-
degree of differentiation; 1, 2 or 3 for myosarcomas confined to skin are
number of mitoses per 10 hpf (<10, 11- essentially non-metastasizing tumours
20, or >20); and 0-2 for amount of necro- {1164}. In some instances, histological
Haemangioma of infancy a fibrofatty residuum. Most develop as including GLUT1, Lewis Y antigen,
focal masses, although some show a dif- FcgRII, and IGF-II {1722,1723,1942}.
Definition fuse, segmentally distributed pattern Basement membranes strongly express
Haemangioma of infancy (HOI) is a pro- {2453}. Although usually solitary, many merosin {1723}.
liferation of benign capillaries character- affected infants have several lesions.
ized by perinatal or congenital onset, Rare cases of “diffuse neonatal haeman- Differential diagnosis
rapid proliferation in the first year, fol- giomatosis” have multiple small skin Proliferative phase HOI must be distin-
lowed by spontaneous regression. lesions accompanied by visceral lesions guished from other cellular vascular pro-
Strong expression of GLUT1 is distinctive. {1454}. Large facial haemangiomas may liferations including congenital non-pro-
be associated with posterior fossa mal- gressive haemangioma, kaposiform hae-
ICD-O code 9131/0 formations, aortic coarctation, cardiac mangioendothelioma, tufted angioma,
defects, arterial abnormalities, eye pyogenic granuloma, and intramuscular
Synonyms abnormalities, and sternal clefting haemangioma. Involuting HOI may
Infantile haemangioma, juvenile haeman- (PHACES syndrome) {1591}. Lumbo- mimic vascular malformations. The cha-
gioma. sacral haemangiomas may be associat- racteristic GLUT1 immunoreactivity of
ed with spinal dysraphism, tethered cord HOI is helpful in routinely fixed speci-
Epidemiology syndrome, and other caudal abnormali- mens {1722}.
HOI is the most common tumour of infan- ties {850}. MRI in the proliferative phase
cy, affecting up to 10-12% of children shows a tumoural mass with flow voids. Somatic genetics
{1051,1119}. There is a predilection for HOI are generally sporadic, although
females (at least 3:1) {1663}, Caucasians Macroscopy autosomal dominant inheritance has
and premature infants {1051,1853}. Proliferative phase lesions show solid tan been suggested in several kindreds
Presentation is exclusively in infants, lobules, are well-defined but not encap- {259}. Monozygotic and dizygotic twins
although involuting lesions persist into sulated. show no significant difference in concor-
childhood. dance for haemangioma development
Histopathology {464}. No cytogenetic abnormalities have
Etiology Proliferative phase lesions are cellular been reported.
The unique immunophenotypic resem- masses of plump endothelial cells and
blance of HOI and placental vessels pericytes with abundant cytoplasm and
suggests shared regulatory mecha- enlarged nuclei that together form capil- Cherry haemangioma
nisms, or possibly a common cellular ori- laries with tiny rounded lumina. Investing
gin {1723}. Two recent studies have basement membranes are multilaminat- Definition
demonstrated endothelial cell clonality in ed; mast cells are numerous. The capil- Cherry haemangioma (CH) is a benign,
HOI {295,2452}, suggesting a possible laries are arranged in delicately defined acquired, well-circumscribed aggregate
role for somatic mutation {2452}. lobules, separated by thin fibrous septi of dilated capillaries and venules in the
or normal intervening tissue. Mitotic fig- superficial dermis.
Localization ures may be numerous; supportive arter-
It most commonly affects the skin and ies and veins are prominent. ICD-O code 9120/0
subcutis of the head and neck, followed During involution, endothelial cells and
by the trunk and extremities. Visceral pericytes flatten, lumina enlarge, and Synonyms
involvement, although rare, is most com- mitotic figures diminish. Capillaries pro- Campbell de Morgan spots, de Morgan
mon in the liver, followed by the lung, gressively drop out and are replaced by spots, senile haemangioma.
brain, and intestine {746}. loose connective tissue. End-stage
lesions often show isolated groups of Epidemiology
Clinical features “ghost” vessels composed of thick, acel- CH is rare before puberty, with a few
Nascent lesions appear as blanched lular basement membrane rings contain- lesions developing in early adulthood.
macules or erythematous patches, often ing apoptotic debris. Number and incidence increase through
with central telangiectasias, typically adulthood, becoming almost universally
around 2 weeks of age. Approximately Immunohistochemistry present with large numbers in some
30% are congenital. Following a rapid All stages are distinguished from other patients. Sex predilection is not a feature,
growth phase of 3-18 months, involution vascular tumours by their strong with the exception of lesions that can
occurs over several years, often leaving endothelial positivity for several antigens, occur in pregnancy {169}.
Synonym
Cavernous haemangioma (erroneous, in
part).
Epidemiology
Most reported cases are in adult women.
Localization
The arms and torso are the most com-
mon sites {366}.
Clinical features
Most sinusoidal haemangiomas are
freely movable deep dermal or subcuta-
neous papules or small nodules. When
deep, they may be colourless or bluish,
but when superficial, they may be red.
Fig. 5.1 Cherry haemangioma. Thickened basement membrane material around some vessels and protu- Histopathology
berant endothelial cells. Sinusoidal haemangiomas are round or
oval and very well circumscribed dermal
Etiology Endothelial cell nuclei may be protuber- or subcutaneous neoplasms {366,1680}.
Age is the most common factor in the ant. Sheaths of hyaline multilayered They are composed of thin walled ves-
development of the majority of lesions. basement membrane material com- sels with capacious round lumena. The
Eruptive cases have been reported after posed of laminin, collagen IV and colla- vessels are very closely apposed to one
exposure to sulphur, mustard gas, bro- gen VI surround most vessels {2317}. another (“back to back appearance”).
mide compounds and 2-butoxyethanol Stromal mast cells may be increased Occasional lesions have smooth muscle
solvent {510,747,1901}. There are two compared to normal skin {938}. The in their walls. Thrombosis of vascular
reports of outbreaks in populations, with- endothelial cells are fenestrated and channels occurs in a proportion of cases.
out definite causes {1058,2145}. CH show high levels of carbonic anhydrase This can lead to intravascular papillary
lesions that develop in pregnancy can {668}. Ki-67 proliferating cell marker is endothelial hyperplasia (a potential stim-
involute in the puerperium and eruptive not positive in endothelial cells of CH ulant of angiosarcoma in a partial biopsy)
lesions have been reported in two {2388}. and calcification may result {1680}.
patients with elevated prolactin levels
suggesting a hormonal factor in some Histogenesis
lesions {169,1924}. Ultrastructural three-dimensional studies Hobnail haemangioma
show that CH is composed of intercon-
Localization nected spherical and tubular dilatations Definition
The majority of lesions are located on the of venous capillaries and postcapillary Hobnail haemangioma (HH) {389,916,
trunk and upper limbs with relative spar- venules in the dermal papillae {303}. 1584,1896,2052} is a benign vascular
ing of the head and neck. There is no proliferation characterized by a wedge-
predilection for exposed skin. Somatic genetics shaped dermal proliferation of irregular
A genetic or angiogenic factor has not vascular channels lined in its superficial
Clinical features yet been implicated in the development portion by endothelial cells with hobnail
CH begins as a barely discernible red of CH. morphology.
macule that enlarges to become a slight-
ly elevated erythematous papule 1-5 mm ICD-O code 9120/0
in diameter. It may resist blanching with Sinusoidal haemangioma
pressure. Synonym
Definition Targetoid haemosiderotic haemangioma
Histopathology Sinusoidal haemangioma is a benign
CH is a tightly grouped, well-circum- vascular neoplasm in which cavernous Epidemiology
scribed collection of capillary vessels appearing vascular spaces occur in a HH is relatively rare and presents mainly
and venules in the superficial dermis with well circumscribed, generally small in young to middle-aged adults with
minimal dilatation of some lumena. papule or nodule. Most clinicians use the predilection for males.
Elevated lesions show epidermal atrophy term cavernous haemangioma to refer to
with loss of rete ridges and sometimes an much larger and more poorly circum- Etiology
epithelial collarette. scribed lesions in infants. Trauma may play a role in the formation
B C
Fig. 5.2 Hobnail haemangioma. A Typical targetoid clinical appearance, only seen in a minority of cases. B Intravascular papillae lined by hobnail endothelial cells
are sometimes seen. C Dilated irregular superficial vascular spaces and prominent haemosiderin deposition.
of these lesions {2052}. One possible ori- nels lined by bland endothelial cells that Prognosis
gin is via trauma to lymphangiomas or appear flat or have hobnail morphology. The lesion is entirely benign and there is
angiokeratomas, resulting in dispersion Some of the vascular channels resemble no tendency for local recurrence.
of endothelial cells and erythrocytes into lymphatics. Focally, intraluminal small
the surrounding dermis. papillary projections with collagenous
cores are occasionally seen. As the vas- Glomeruloid haemangioma
Localization cular channels descend further into the
Most cases occur on the lower limbs with reticular dermis they gradually become Definition
predilection for the thigh followed by the smaller and disappear. Inflammation is Glomeruloid haemangioma is a benign
upper extremities and the trunk. Rare not usually a feature. Haemorrhage and vascular proliferation that occurs inside
lesions have been reported in the oral haemosiderin deposition are prominent ectatic blood vessels, producing a pat-
cavity including the tongue and gingivae. but vary according to the stage of evolu- tern reminiscent of renal glomeruli.
tion. A Perls stain may be useful in high-
Clinical features lighting the haemosiderin. ICD-O code 9120/0
Some lesions show a characteristic
targetoid clinical appearance with vari- Immunohistochemistry Epidemiology
ably pigmented ecchymotic haloes sec- The endothelial cells in HH stain diffuse- This is a very rare vascular proliferation
ondary to bleeding and haemosiderin ly for vascular markers including CD31 that occurs exclusively in patients with
deposition within the tumour {2052}. Most and VWF (von Willebrand factor). CD34 POEMS syndrome (Polyneuropathy,
often however, the clinical presentation is is usually negative or very focal. A layer Organomegaly, Endocrinopathy, Mono-
non-distinctive and the clinical differen- of alpha-smooth muscle actin pericytes clonal paraproteinaemia and Skin
tial diagnosis includes haemangioma, surrounds some of the vascular chan- lesions), which is associated with multi-
naevus or fibrous histiocytoma. HH is nels. The positive staining for vascular centric Castleman disease {440,2562}.
asymptomatic, usually less than 2 cm in endothelial growth factor receptor-3 Multiple haemangiomas occur in 24-44%
diameter and increases in size very slow- (VEGFR-3) in some cases has led to the of all patients with POEMS syndrome,
ly. Patients usually describe cyclic suggestion that HH displays lymphatic with most being cherry-type haeman-
changes {389}. Multiple lesions are differentiation {1584}. VEGFR-3 is howev- giomas, and only some being glomeru-
exceptional. Similar histological changes er, not entirely specific for lymphatic loid haemangiomas {1301,2312,2580}.
may occur after trauma {481}. endothelium. Staining for human herpes The reported cases of glomeruloid hae-
virus 8 is consistently negative {932}. mangiomas show female predominance,
Histopathology with patients ranging in age from 40-68
The most striking low-power feature is Differential diagnosis years {440,1278,1285,1965,2083,2380,
the presence of a wedge-shaped vascu- Kaposi sarcoma differs by the absence 2562}.
lar proliferation consisting of superficial, of dilated blood vessels lined by hobnail
dilated and thin-walled vascular chan- cells.
Etiology endothelium with slightly larger and paler meruloid haemangioma is a reactive vas-
Glomeruloid haemangioma has so far nuclei, and supported by pericytes. cular proliferation, perhaps representing
only been found in patients with POEMS Scattered “interstitial” cells that contain a distinctive form of reactive angioen-
syndrome. Its development may be PAS-positive eosinophilic globules are dotheliomatosis.
mediated by circulating vascular endo- found between the capillary loops, but
thelial factor, which is present at high similar cytoplasmic globules can also be Prognosis and predictive factors
titres in the blood of most patients with seen in some endothelial cells. Glomeruloid haemangioma per se is a
POEMS syndrome {2225,2464}. totally innocuous lesion. The outcome of
Immunohistochemistry the patients depends on the underlying
Localization On immunohistochemical staining, the POEMS syndrome.
The lesions are mainly found on the endothelial cells of the capillary loops
trunk, face and proximal limb, and stain for CD31 and CD34, and they are
exceptionally also in the fingers and well supported by actin-positive peri- Microvenular haemangioma
deep soft tissues {440,1278,1285, cytes. The sinusoidal endothelial cells
1965,2380,2562}. covering the tufts are positive for CD31 Definition
but not CD34, while those lining the Microvenular haemangioma is an
Clinical features ectatic vascular spaces are strongly acquired, slowly growing asymptomatic
The lesions manifest as multiple purplish- CD31 positive but weakly CD34 positive. lesion with an angiomatous appearance
red papules or nodules, ranging in size The eosinophilic globules probably rep- {1080}.
from a few to 15 mm {1278,1285,1965, resent immunoglobulin. The cells that
2380,2562}. They occur in patients contain these globules represent a mix- ICD-O code 9120/0
already known to have POEMS syn- ture of histiocytes (CD68+) and endothe-
drome, or as an early phenomenon lial cells (CD31+). Etiology
before the full-blown syndrome develops A histogenetic relationship between
{1278,1285,1965,2083,2380,2562}. Precursor lesions microvenular haemangioma and hor-
Progression from cellular immature, non- monal factors such as pregnancy and
Histopathology specific, vascular proliferation with slit- hormonal contraceptives has been pos-
Glomeruloid haemangioma is mainly like canals reminiscent of tufted angioma tulated {144,2065}, but this feature has
centred in the upper and mid dermis. It is to classical glomeruloid haemangioma not been corroborated by other authors.
characterized by tufts of proliferated, has been reported {2562}. In addition, An example of microvenular haeman-
coiled capillaries projecting inside thin- cherry-type haemangiomas with minia- gioma has developed in a patient with
walled ectatic blood vessels, mimicking ture glomeruloid structures formation can Wiskott-Aldrich syndrome {1939}. Haem-
renal glomeruli. The “sinusoidal” endo- coexist with glomeruloid haemangiomas angiomas identical to microvenular hae-
thelial cells that line the ectatic vascular in patients with POEMS syndrome {440}. mangioma can be seen in patients with
spaces and the surface the vascular tufts Thus these might represent precursor POEMS syndrome {25}.
possess dark round nuclei. These cells lesions of glomeruloid haemangioma.
also show cleft-like extensions into the Localization
cores of the vascular tufts. The capillary Histogenesis It most commonly affects the upper
loops within the tufts are lined by plump The currently favoured view is that glo- limbs, particularly the forearms.
Angiolymphoid hyperplasia
with eosinophilia
Definition
Angiolymphoid hyperplasia with
eosinophilia (ALHE) is a benign skin or
subcutaneous tumour that is a circum-
scribed combined proliferation of imma-
ture blood vessels and chronic inflamma-
tory infiltrate usually containing eosino-
phils. Endothelial cells have a distinctive
epithelioid or histiocytoid appearance
with ample eosinophilic cytoplasm.
Fig. 5.4 Angiolymphoid hyperplasia with eosinophilia. Lobulated proliferation of small to medium size blood Synonyms
vessels with admixed inflammation and a central prominent vessel. Epithelioid haemangioma, cutaneous
histiocytoid angioma, pseudo- or atypi-
cal pyogenic granuloma, inflammatory
However, lesions on the trunk, face and The main differential diagnosis is with angiomatous nodule, intravenous atypi-
lower limbs have also been recorded Kaposi sarcoma in the patch stage. cal vascular proliferation, nodular
{65,1061}. Kaposi sarcoma shows irregular anasto- angioblastic hyperplasia with eosinophil-
mosing vascular spaces, newly formed ia and lymphofolliculosis {201,1154,
Clinical features ectatic vascular channels surrounding 1967,1968,2381}.
Microvenular haemangiomas appear as pre-existing normal blood vessels and
sharply circumscribed, bright red, soli- adnexa (promontory sign), plasma cells, Epidemiology
tary lesions varying in size from 0.5-2 cm. hyaline (eosinophilic) globules, and ALHE was originally described as a
small interstitial fascicles of spindle cells. lesion commonly found in young women
Histopathology All of these features are absent in on the head and neck {1011}. Recent
Microvenular haemangioma appears as microvenular haemangioma. reviews show a wide age range peaking
a poorly circumscribed proliferation of at 20-50 years without female predomi-
irregularly branched, round to oval, thin- Immunohistochemistry nance {738,1753}. There is no predilec-
walled blood vessels lined by a single Immunohistochemically, the cells lining tion for Asian populations.
layer of endothelial cells. They involve the lumina show positivity for factor VIII-
the entire reticular dermis and a variable related antigen and Ulex europaeus I Etiology
degree of dermal sclerosis is present in lectin {144,1080,2065} which qualifies Reactive vascular proliferation and
the stroma. The lumina of the neoplastic them as endothelial cells. Some smooth inflammation {2441} in a traumatized vas-
blood vessels are inconspicuous and muscle actin positive perithelial cells cular structure is a postulated cause of
often collapsed with only a few erythro- have been also described surrounding some ALHE lesions. History of ante-
cytes within them. this vascular space {65,1061}. cedent trauma, histologic evidence of
A B C
Fig. 5.5 Angiolymphoid hyperplasia with eosinophilia. A Epithelioid endothelial cells with abundant cytoplasms, some of which are vacuolated. B Proliferating imma-
ture vessels with protuberant endothelial nuclei associated with lymphoid and eosinophilic inflammation. C Epithelioid endothelial cells with abundant cytoplasms,
some of which are vacuolated.
Differential diagnosis
Kimura disease is a distinct clinicopatho-
logical entity, characterized by a more
prominent lymphoid proliferation and
less prominent vascular component with
almost complete absence of epithelioid
endothelial cells.
Epidemiology
Presentation is mainly in adults with no
sex predilection. Occurrence in children
is exceptional {304}.
Localization
There is a predilection for the trunk and
limbs.
Clinical features
Clinical presentation is variable and con-
sists of fairly widespread erythematous
macules, papules, nodules and plaques
{1559,2513}. Purpura is a frequent find-
ing. Ulceration is very rare. Many sys-
temic illnesses are related to the devel-
opment of RA and it can be said that this
condition often represents a marker of
systemic disease.
Patients affected with RA not uncommon- A
ly are immunosuppressed as a result of
transplantation. Many conditions have
been associated with reactive angioen-
dotheliomatosis including valvular car-
diac disease, alcoholic cirrhosis,
rheumatoid arthritis, polymyalgia
rheumatica, cryoglobulinaemia, the
antiphospholipid syndrome, and sar-
coidosis {551,1385,1559,2178,
2341,2361}. A more localized variant B C
may be seen in some patients and it is Fig. 5.10 Bacillary angiomatosis. A Low power view of a skin lesion of bacillary angiomatosis shows dome
usually associated with peripheral vas- shaped expansion of the upper dermis due to a proliferation of small well formed vessels. B High power
cular atherosclerosis or iatrogenic arteri- view showing the plump endothelial cells lining the vessels. C A Warthin-Starry stain shows the small
ovenous fistulas {1266,1276,1918}. cocco-bacillary organisms.
Arteriovenous haemangioma
Several examples of multiple arteriove- probably represent ancient arteriove-
Definition nous haemangiomas have been nous haemangiomas with atypical cells
Arteriovenous haemangiomas are described in patients with chronic liver due to degenerative changes that occur
benign, asymptomatic vascular prolifera- disease {47}. in long-standing lesions {1351}.
tions. They are not associated with signif-
icant arterio-venous shunting. Macroscopy Histogenesis
Grossly, lesions of arteriovenous hae- The precise nature of arteriovenous hae-
ICD-O code 9123/0 mangioma present as raised papules mangioma is uncertain. Initially it was
and on sectioning there is an admixture considered to be a multicentric hamar-
Synonyms of white and red to brown areas, which toma of the sub-papillary vascular plexus
Cirsoid aneurysm, acral arteriovenous represent the walls of the thick blood with one or more arteriovenous anasto-
tumour {384,385,528,1811}. vessels containing blood. moses {834}. Other authors have sug-
gested that a hamartoma of the Sucquet-
Epidemiology Histopathology Hoyer canal of the glomus body is the
It occurs mainly in middle-aged adults, Arteriovenous haemangioma is a well- cause of this lesion. The latter interpreta-
with no sex predilection. circumscribed vascular proliferation that tion, however, is unlikely because glomus
involves the upper and mid reticular der- cells are usually absent in arteriovenous
Localization mis. The neoplasm is composed mainly haemangioma, and to date, they have
Arteriovenous haemangioma is a neo- of thick-walled muscle-containing blood been identified in only one example of all
plasm mainly affecting facial skin. vessels, lined by a single layer of the reported cases {1318}.
Intraoral and vulvar examples have been endothelial cells. Intermingled with the
also described {1318,1376,1698,1972}. thick-walled blood vessels are thin- Prognosis
walled dilated blood vessels and vari- Arteriovenous haemangioma is a benign
Clinical features able amounts of mucin. Although the lesion and local excision suffices.
Arteriovenous haemangioma presents as thick-walled blood vessels resemble
a red, purple, or skin coloured asympto- arteries, they lack a well-formed elastic
matic papule measuring 0.5-1.0 cm. internal membrane, and most likely rep- Cutaneous angiosarcoma
Usually the lesions are solitary, although resent ectatic veins {1318}. In about one-
multiple examples have been cited. fourth of the studied cases it is possible Definition
When the lesions are multiple they tend to identify both the arteriovenous shunts Angiosarcoma is a malignant neoplasm
to cluster. Occasionally, they are associ- and the spiralled ascending small mus- of endothelial cells. Differentiation
ated with other abnormalities including cular artery (“feeder” vessel) with serial between lymphangiosarcoma and sarco-
epidermal naevus syndrome, vascular sections {834}. The lesions recently mas with blood vascular differentiation
hamartomas and malformations {372}. described as symplastic haemangioma appears problematic at the current time.
Synonyms
Lymphangiosarcoma, haemangiosarco-
ma.
Epidemiology
There are low-grade forms of angiosar-
coma that can occur outside the circum-
scribed clinical settings detailed herein.
Almost all high-grade angiosarcomas are
in one of the following settings: the head
and neck of predominantly male elderly
patients (the most common setting)
{1046}, the chest of patients who have
undergone mastectomy for breast can-
cer (Stewart-Treves syndrome) {2269}, Fig. 5.14 Cutaneous angiosarcoma. The blood vessels have swollen endothelial cells with hyperchromatic
lymphoedema (congenital or acquired), nuclei.
or post-irradiation {2271}.
Lymphangioma Sometimes purplish areas within the lymphatic dilated cisterns with muscular
circumscriptum lesion are seen due to haemorrhage and walls situated in the subcutaneous fat,
thrombus formation within the blood ves- resulting in swelling of the tissue beneath
Definition sel component. Probably, the superficial the superficial vesicles {1768}. The
Lymphangioma circumscriptum refers to vesicles are the result of saccular dilata- superficial component consists of dilated
a vascular malformation involving the tions of superficial lymphatics secondary lymph vessels, lined by flat endothelial
lymphatic vessels of the superficial der- to raised pressure transmitted from the cells in a discontinuous layer, and situat-
mis. A denomination as superficial lym- underlying pulsating cisterns {2502}. ed in the papillary dermis, and the super-
phatic malformation would be more Magnetic resonance imaging accurately ficial reticular dermis {179,750}.
appropriate to describe this lesion. demonstrates the true extent of involve- Sometimes, the lymphatic vessels are
ment {1541}. In rare instances, superfi- arranged in clusters in the papillary der-
ICD-O code 9170/0 cial lymphatic malformations are associ- mis, resulting in a papillated or verrucous
ated with visceral lymphatic malforma- skin surface. The vessels may contain
Epidemiology tions involving the mediastinum {1643} or homogeneous eosinophilic proteina-
Usually, lymphangioma circumscriptum the bladder wall {1107}. Additional asso- ceous lymph or blood, and occasionally
is present at birth or appears early in life. ciations include Becker naevus {1762}, foamy macrophages. Scattered lympho-
and superficial lymphatic malformations cytes may be seen in the connective tis-
Localization have been described in patients with sue stroma between dilated lymphatic
Lymphangioma circumscriptum may be Maffucci syndrome {2292} and Cobb vessels. In extensive lesions, large irreg-
located in any anatomic site, but has syndrome {2168}. ular lymphatic channels are usually seen
predilection for the axillary folds, shoul- beneath the superficial vessels in deep
ders, neck, proximal parts of the extrem- Macroscopy reticular dermis and subcutaneous fat.
ities and tongue {750,1798,2502}. The excised specimens of lymphan-
Lesions involving eyelids and conjuncti- gioma circumscriptum show dilated vas- Immunohistochemistry
va {841} and genital skin of males and cular spaces involving both the superfi- The usual immunohistochemical markers
females {149,419,2006,2436} have also cial dermis and deeper subcutaneous for endothelial cells, such as factor VIII-
been described. tissue, which correspond to the mal- related antigen, Ulex europaeus, and
formed lymphatic vessels. CD31 do not differentiate between blood
Clinical features and lymphatic vessels {1799}. In these
Clinically, the lesion consists of numer- Histopathology cases, new endothelial cell markers such
ous small vesicle-like lesions, often with a The stereotypical superficial lymphatic as vascular endothelial growth factor
verrucous surface, grouped in a plaque. malformation is accompanied by deep receptor-3 (VEGFR-3) {763,1463}, D2-40
A B
Fig. 5.15 Lymphangioma circumscriptum. A Close-up view of the lesions showed that it consisted of numerous vesicle-like lesions, some of them with a verrucous
surface, grouped in a plaque. Purplish areas are seen due to haemorrhage and thrombus formation within a blood vessel component. B Histopathologically, the
lesion consisted of dilated lymph vessels involving the superficial dermis and covered by hyperplastic epidermis with compact hyperkeratosis.
{1179} and Prox1 {2535) may be helpful, Synonyms monly on the lower extremities, but any
since these markers are expressed by Acquired progressive lymphangioma, region of the skin may be affected {918}.
lymphatic endothelium {763,1463}. benign lymphangioendothelioma.
Clinical features
Histogenesis Epidemiology Lesions usually present themselves as
Lymphangioma circumscriptum results Progressive lymphangioma is rare. It solitary, well-circumscribed, red or viola-
from abnormalities in the embryologic occurs chiefly in middle-aged or older ceous patches or plaques. Although usu-
development of lymphatic vessels of the adults and does not show a sex predilec- ally asymptomatic, patients may com-
skin. Lymphangioma circumscriptum tion {918}. plain of tenderness, pain, or itching.
probably represents sequestrated der- Because of slow growth over years,
mal lymphatic vessels that failed to link Etiology lesions may measure several centimetres
up with the rest of the lymphatic system Progressive lymphangioma has been in diameter {918,1157}.
{2502}. However, an ultrastructural study reported after trauma, such as surgical
suggested that lymphangioma circum- procedures and tick bites. Inflammation Histopathology
scriptum was induced by long-standing secondary to trauma has been claimed Progressive lymphangioma is character-
lymphatic stasis {103}. In some patients, to play a role {2463,2532}. ized by delicate, often widely dilated vas-
lymphangioma circumscriptum has cular spaces lined by a monolayer of
developed after surgery or radiotherapy Localization monomorphous endothelial cells. In
on the involved area {1406,1859}. Lesions have been reported most com- some foci, endothelium-lined papillary
stromal projections extend into those
Prognosis and predictive factors spaces. With progressive extension into
Usually, lymphangioma circumscriptum the deep dermis, vascular spaces
is a localized and superficial lymphatic become narrower. They tend to dissect
malformation that only causes cosmetic between collagen bundles and to sur-
problems and does not require treat- round pre-existing vessels and adnexal
ment. The presence of a deep compo- structures. Endothelial cells are more
nent may explain the tendency of the numerous than in normal lymphatic ves-
lesions to persist after superficial exci- sels and may be closely crowded togeth-
sion. er. Nuclei may be hyperchromatic, but
there is no prominent nuclear atypia.
fers from progressive lymphangioma by a diffuse proliferation of lymphatic ves- consequence of involvement of bones
the presence of plasma cells, the invari- sels that may involve bones, parenchy- {862,1882}.
able presence of HHV-8 and more clas- mal organs, soft tissue, and skin.
sic areas of Kaposi sarcoma elsewhere Histopathology
in the lesion. The so-called atypical vas- Synonyms Cutaneous lesions of lymphangiomatosis
cular proliferation following radiotherapy Generalized lymphangioma, systemic are characterized by markedly dilated
(benign lymphangiomatous papules) dif- cystic angiomatosis, multiple lymphang- lymphatic channels throughout the skin
fers from progressive lymphangioma iectasias. and subcutis that are lined by a single
clinically and histopathologically by pre- attenuated layer of flattened endothelial
senting as tiny vesicles and histopatho- Epidemiology cells and usually appear empty. Those
logically by being associated with much Lymphangiomatosis is a rare disease channels tend to dissect between colla-
wider spaces in the upper dermis. occurring mainly in the first two decades gen bundles and to surround pre-exist-
Moreover, these lesions are thought to of life. There seems to be no sex ing structures in a manner reminiscent of
represent lymphangiectasias, rather than predilection {862,1882}. well-differentiated angiosarcoma. Unlike
a neoplastic process {628,1921}. angiosarcoma, cytologic atypia, endo-
Localization thelial multilayering, and mitotic figures
Histogenesis Lesions occur in the skin and the super- are absent. The stroma often contains
Progressive lymphangioma is consid- ficial soft tissues of the neck, trunk, and numerous siderophages and focal
ered to be a neoplastic proliferation of extremities. Most cases of lymphan- aggregates of lymphocytes. Exceptio-
lymphatic vessels. A neoplastic nature is giomatosis affect bones and parenchy- nally extramedullary haematopoiesis
suggested by its slowly progressive mal organs, especially the lung, pleura, may be seen.
course. Derivation from lymphatic spleen, and liver. Soft tissue involvement
endothelia has been suggested on the occurs in the mediastinum and retroperi- Histogenesis
basis of rare erythrocytes within and toneum. Lymphangiomatosis probably represents
around vascular lumina and absence of a vascular malformation, rather than a
a peripheral ring of actin-positive peri- Clinical features neoplastic process.
cytes in most vessels. Cutaneous and subcutaneous lesions
present themselves as soft, fluctuant Prognosis and predictive factors
Prognosis and predictive factors swellings that can be squeezed from one When present on the neck and trunk,
Following surgical excision, local recur- area to another and that may be associ- lymphangiomatosis of soft tissues is usu-
rences are exceptional. Metastases do ated with tiny vesicles. In patients with ally associated with extensive osseous or
not occur. Regression of lesions after involvement of bones and visceral visceral involvement and carries a grave
systemic therapy with corticosteroids organs, the presenting signs range from prognosis with a high rate of mortality
and in the absence of any treatment has pathologic fractures to chylothorax, chy- {1882}. In lymphangiomatosis of the
been reported {918,1577,2463}. lous ascites, and other symptoms related limbs, involvement of bones and visceral
to particular organs affected by the organs is usually insignificant and prog-
process. The interconnected lymphatic nosis, therefore, favourable {1021}.
Lymphangiomatosis channels can be visualised by lymphan-
giography or direct injection of contrast
Definition media into cystic vascular spaces. Plain
Lymphangiomatosis is characterized by x-rays often reveal osteolytic areas as a
Smooth muscle is found in the skin in the common presentations may include papu- Differential diagnosis
arrector pili muscles, the walls of blood lar follicular lesions {659}, multiple lesions Becker naevus may show dermal
vessels and in ‘genital’ skin, which {915,2200} and the so-called "Michelin tyre changes identical to smooth muscle
includes the scrotum (dartos muscle), baby", the latter typically in boys. Patients hamartoma. It has been suggested that
vulva and nipple (areolar smooth mus- with Michelin tyre syndrome may have var- these lesions may form a spectrum
cle). Each of these sites of smooth mus- ious other associated abnormalities {1145}.
cle can give rise to a tumour. {2093}. A clinical classification has been Pilar leiomyoma differs from smooth mus-
Tumours of striated muscle are exceed- proposed in which type 1 refers to the cle hamartoma in being acquired, fre-
ingly rare in the skin. Only the rhabdomy- usual localized form, type 2 the follicular quently multiple, often painful and com-
omatous mesenchymal hamartoma (stri- variant, type 3 to multiple lesions and type prising less discrete smooth muscle bun-
ated muscle hamartoma) will be consid- 4 to the diffuse variant {819}. dles with intervening collagen.
ered below.
Histopathology Genetic susceptibility
There are increased numbers of variably Rare cases of smooth muscle hamar-
Smooth muscle hamartoma orientated discrete smooth muscle bun- toma have been described in siblings
dles within the dermis and sometimes and in a mother and her children {915}.
Definition the subcutis and these may connect to Xp microdeletion syndrome is character-
Smooth muscle hamartoma is a prolifera- hair follicles {1145,2093}. The overlying ized by an unbalanced translocation
tion of dermal smooth muscle bundles epidermis may show acanthosis and between the X and Y chromosomes lead-
that is usually congenital. basal hyperpigmentation and there may ing to deletion of the distal short arm of
be prominent folliculosebaceous units the X chromosome. Affected infants
Synonyms present, although these do not appear to show microphthalmia, linear skin defects
Arrector pili hamartoma, congenital pilar be increased in number {206,1145}. and sclerocornea. The linear skin defects
and smooth muscle naevus, congenital have been reported to show histological
smooth muscle naevus Immunohistochemistry features similar to smooth muscle hamar-
Lesions have been positive for smooth toma {1794} although this was not
Epidemiology muscle actin and desmin as expected described in another case {686}.
Smooth muscle hamartoma is usually {886,1299,2093}. CD34 positive dendro- A child with a familial paracentric inver-
congenital with only occasional reports cytes have been reported to be an inte- sion of chromosome 7q and Michelin tyre
of lesions with onset in adolescence or gral part of the proliferation {1299}. syndrome with smooth muscle hamar-
adulthood {590,1069}. There is a slight
male predominance. The lesion is
uncommon {1028}.
Localization
The lesions are most often located on the
trunk and extremities, particularly proxi-
mally {1145}. Cases have been reported
involving the head and neck region
{1290}, scrotum {1870} and conjunctiva
{1966}.
Clinical features
The typical presentation is as a solitary
patch or plaque of varying size, usually
between 1 and 10 cm, which may show
hyperpigmentation and/or hypertrichosis
{1145} and which may increase in size
with the growth of the patient {2610}. A
positive pseudo-Darier sign is seen in Fig. 5.19 Pilar leomyoma. Multiple pilar leiomyomas Fig. 5.20 Pilar leiomyoma. There are interlacing
most cases {2610}. Occasional cases of the upper back. The lesions were painful in bundles of smooth muscle fibres forming a nodule.
have an atrophic appearance {886}. Less response to cold.
Histopathology
Pilar leiomyomas are circumscribed (but
not sharply so), non-encapsulated
tumours of the dermis, composed of
bundles of smooth muscle arranged in
an interlacing or haphazard pattern. The
cells have abundant cytoplasm and elon-
gated nuclei with blunt ends. Mitoses are
infrequent or absent {1878}. Atypical
cells, similar to those seen in the sym-
plastic leiomyoma of the uterus, are
uncommon {1486}. Granular cell variants
are extremely rare {1586}.
Small amounts of fibrous stroma are
present between the muscle bundles in
older lesions, but there is usually less Fig. 5.21 Leiomyosarcoma. confined to the dermis. There are bundles of spindle shaped cells and scattered
stromal collagen than in the smooth mus- mitotic figures. Not the nuclear pleomorphism.
Localization
RMH typically arises in the midline of the
head and neck, with a particular
predilection for the nose and chin. There
have also been cases involving the
preauricular region {1902,2010,2122},
lateral forehead {1973}, and cheek
{2320}.
Clinical features
The majority of lesions are described as
papules or polyps, but a few have pre-
sented as nodules {105,1973,2320} or
“sessile masses” {1685}. RMH lesions
are generally asymptomatic, but they
can demonstrate the interesting property
of contractile motion, spontaneously or
Fig. 5.22 Rhabdomyomatous mesenchymal hamartoma. Low power view of rhabdomyomatous mesenchy-
mal hamartoma, showing polypoid configuration, intact epidermis, numerous small vellus follicles, and a during crying or feeding {1973,2010}.
central core containing skeletal muscle. Most patients lack other congenital
anomalies, but there have been associa-
tions with cleft lip and palate, ocular
Immunohistochemistry martoma (RMH) refers to single or multi- abnormalities (coloboma, microph-
The cells express smooth muscle actin. ple, congenital, frequently polypoid thalmia, limbal dermoid), low-set ears,
Desmin is present in the majority of lesions that typically arise near the mid- craniofacial clefts, thyroglossal duct
cases. Pan-muscle actin (HHF-35) is line of the head and neck. They contain sinus, lipoma of the brain, and upper
sometimes present focally. skeletal muscle fibres within the dermis extremity and syndactyly {1008,1902,
{1618}. 1973,2010,2037}. Histologic features of
Histogenesis RMH have been found in the cutaneous
The majority of tumours are derived from Synonyms polyps {2037} of a case of Delleman syn-
the arrector pili muscles. Rare cases Striated muscle hamartoma {1008}, con- drome, which consists of orbital cysts,
derived from areolar smooth muscle in genital midline hamartoma. cerebral malformations, and focal dermal
the nipple {1452} and dartos muscle in hypoplasia as well as cutaneous
the scrotum {758} have been reported. Epidemiology appendages {723}. In addition, a patient
About 25 examples of this lesion have {1902} with RMH in association with ipsi-
Genetics been reported {1973,2320}. Typically, the lateral limbal dermoid and coloboma
An unequivocal genetic fingerprint for lesions have been present since birth or (Goldenhar syndrome), has been report-
these tumours is currently lacking {2175}. early childhood, and most patients are ed.
Various genes have been identified that children. Rare cases have been reported Initially, it was believed that RMH might
are expressed differentially in tumour in adults {2037}. Thus far, the male: be an X-linked disorder, as the first few
and normal tissue. Soft tissue leio- female ratio is 2:1. cases were reported in males, but this
myosarcomas most often show genomic
alterations in the 13q4-q21 region {622}.
Rhabdomyomatous
mesenchymal hamartoma A B
Fig. 5.24 Rhabdomyomatous mesenchymal hamartoma. A In the superficial dermis, small skeletal muscle
Definition fibers surround eccrine sweat ducts. B This high power view shows mature intradermal skeletal muscle
Rhabdomyomatous mesenchymal ha- fibers with cross-striations.
A B C
Fig. 5.27 Dermatomyofibroma. A Neoplastic cells in dermatomyofibroma have typical cytological features of myofibroblasts with an ill-defined, pale eosinophilic
cytoplasm and elongated, tapering nuclei. B Characteristically, elastic fibres are slightly increased and fragmented in dermatomyofibroma in comparison to non-
neoplastic tissue (bottom). C Neoplastic cells in dermatomyofibroma stain variably positive for alpha-smooth muscle actin.
Immunoprofile
Staining for S100 protein, myelin basic
protein and neuron specific enolase and
desmin are negative {1590,1895}.
chromosome 9 and TSC2 on chromo- polypoid, hypocellular dermal prolifera- specific actin, CD34 and rarely alpha-1
some 16 have been identified {582}. tions of spindle and irregularly shaped antichymotrypsin {1188,1988}.
stellate or multinucleate cells. Lesional
cells have scant cytoplasm and large, Differential diagnosis
Pleomorphic fibroma pleomorphic, hyperchromatic nuclei with The histologic differential diagnosis
small nucleoli and rare mitotic figures. includes: atypical fibroxanthoma, vari-
Definition Foam cells are rarely present. ants of dermatofibroma, fibrosarcoma,
Pleomorphic fibroma (PF) is a benign, Haphazardly arranged, hyalinized der- fibrous papule of the face, angiofibroma,
polypoid or dome-shaped cutaneous mal collagen is admixed with moderate giant cell fibroblastoma, desmoplastic
neoplasm with cytologically atypical mucin. The collagenous bundles in pleo- Spitz naevus and fibroepthelial polyp
fibrohistiocytic cells {1188}. morphic sclerotic fibromas are more with monster cells {1188}.
storiform and clefted {458,808,1523}.
ICD-O code 8832/0 Myxoid {1614} and sclerotic variants
have been described {808,1523}. Giant cell fibroblastoma
Epidemiology
PF occurs mostly in adults {39,1188}. Immunoprofile Definition
Lesional cells are positive for muscle Giant cell fibroblastoma (GCF) is a histo-
Localization logic variant of DFSP, which primarily
They are located on the trunk, extremi- affects children.
ties, head {39,1188} and rarely the sub-
ungal region {983}. ICD-O code 8834/1
times be observed as plaque-like areas tumourous tissue. Ulceration may be myofibroblastic proliferation. Occasional
of induration, often with peripheral red or present. The cut surface of the tumour is foci may resemble a low-grade fibrosar-
blue discolouration. These tumours may grey-white and firm, with occasional coma, with longitudinal fascicles of spin-
resemble morphoea (localized sclero- areas showing a gelatinous or translu- dle cells demonstrating more prominent
derma) or a morphoeic basal cell carci- cent appearance, corresponding to nuclear atypia and mitotic activity (but
noma. The lesion expands slowly, and microscopic areas of myxoid change. not greater than 5/10 HPF). Such areas
eventuates in the typical, fully developed Haemorrhage and cystic change are have been seen in a minority of primary
protuberant appearance with single or sometimes seen. However, necrosis, a or recurrent lesions {853}.
multiple nodules on a plaque-like base. common feature of malignant fibrous his-
Fungating ulcerated lesions with satellite tiocytoma, is rarely observed in DFSP. It Immunoprofile
nodules characterize an advanced neo- is unusual to encounter DFSP confined DFSP cells label diffusely and strongly
plasm. solely to subcutaneous tissue without with antibodies to CD34 and vimentin.
Patients with advanced DFSPs do not involvement of the dermis {629}. CD34 positivity may be lost in nodular
exhibit signs and symptoms of chronic regions. P75 (low-affinity nerve growth
wasting, as seen in patients with aggres- Histopathology factor receptor) has been reported posi-
sive, high-grade soft tissue sarcomas. DFSP diffusely infiltrates the dermis, and tive in DFSP cells {853}. Tumour cells are
Previous burns, surgical scars, and invades into subcutaneous tissue, espe- negative for S-100 protein, smooth mus-
antecedent trauma have been reported cially along the fibrous septa of fat. The cle actin, desmin, keratins, and epithelial
in association with this tumour. There are epidermis is usually uninvolved. A grenz membrane antigen. Scattered Factor
reports of DFSP occurring at Bacillle- zone may be present. In a well-sampled XIIIa positive cells may be present.
Calmette-Guérin (BCG) vaccination sites specimen, the tumour shows some varia- Tenascin is negative at the dermoepider-
{1558}, and in association with chronic tion in histologic features. The centre of mal zone (DEZ) in DFSP {1180}. Strome-
arsenism {2176}, acanthosis nigricans, the tumour is typically composed of com- lysin 3 is not expressed in the cells of a
and acrodermatitis enteropathica {2161}. pact, uniform, slender, mildly atypical, DFSP in contrast to dermatofibroma in
The tumour may show rapid enlargement spindle-shaped cells, arranged in a which it is invariably expressed {558}.
during pregnancy {2329}. whorled, storiform, or cartwheel pattern.
The tumour cells tightly encase skin Differential diagnosis
Macroscopy appendages without destroying them. Benign and cellular fibrous histiocytoma
Most excised primary DFSPs are indurat- Nuclear pleomorphism is inconspicuous, or dermatofibroma (DF) can be differenti-
ed plaques with one or more associated and mitotic activity is low-to-moderate ated from DFSP by the presence of epi-
nodules. Multiple discrete, protuberant (<less than 5/10 HPF). Some tumours dermal (sometimes basal cell) hyperpla-
skin and subcutaneous tumours are have a prominent myxoid matrix, and sia, more prominent collagenous stroma,
more characteristic of recurrent neo- microscopic myxoid changes have been collagen trapping, and infiltration of the
plasms. Often, there is evidence of a sur- observed in both primary and recurrent fibrous septa, but minimal extension into
gical scar on the skin surface of the tumours {368}. Superficial areas of the fat lobules. Immunostains are also help-
neoplasm are less cellular, and spindle ful. DF contains a focally but not diffuse-
cells are separated by dermal collagen. ly positive CD34 spindle cell component.
The deep portion of the tumour shows a P75 and stromelysin 3 are negative, and
proliferation of spindle cells which tenascin is positive at the DEZ in DF.
expand fibrous septa and interdigitate Diffuse positivity for S-100 protein and
with fat lobules, resulting in a honeycomb the presence of Meissner-like corpuscles
appearance. In some tumours, giant separate lesions of diffuse neurofibroma
cells similar to those of giant cell fibrob- from DFSP.
lastoma are seen. At times, peculiar Malignant fibrous histiocytoma (MFH)
Fig. 5.33 Dermatofibroma (fibrous histiocytoma) myoid nodules may be present, which exhibits a higher degree of cellular atyp-
Cut surface with distinctive yellow colour. represent a nonneoplastic myointimal or ia, pleomorphism, and mitotic activity
than DFSP. Necrosis is usually not a fea- cells, coarse collagen bundles in hap- Clinical features
ture of DFSP, but is generally seen in hazard array, and variable epidermal, Most lesions are single, round, oval to
MFH. Myxoid liposarcoma is distin- melanocytic and folliculosebaceous targetoid papules. Early lesions are red-
guished from myxoid forms of DFSP by hyperplasia are present. dish, but older ones are brown to skin
the presence of lipoblasts, negative coloured, frequently with a brown rim at
CD34 staining, and deep soft tissue ICD-O code 8832/0 the periphery. They usually evolve rapid-
involvement. ly. Dermatofibromas are moderately well
Synonyms circumscribed; the consistency usually is
Histogenesis Histiocytoma (cutis) {2134}, fibroma hard, but may be cystic, eroded or crust-
DFSP and its variant, giant cell fibroblas- durum, subepidermal nodular fibrosis or ed when secondary changes such as
toma (GCF) are currently classified as sclerosis {1602}, sclerotic or sclerosing prominent haemorrhage, lipidization or
neoplasms derived from fibroblasts. fibroma {1895}, sclerosing haemangioma trauma alter the lesions. Most lesions are
CD34 labelling suggests a close linkage {910}. flat, slightly elevated or show a shallow
to dermal dendrocytes. dell. The “dimpling” sign, when lesions
Epidemiology are squeezed between the thumb and
Somatic genetics Dermatofibroma is a very common lesion index finger, is characteristic.
DFSP and GCF exhibit an identical chro- and may develop at any age, but partic- Occasionally, there may be a few, up to
mosomal translocation. See page 259. ularly during the third and fourth several dozen, sometimes grouped
decades. The gender distribution varies (“agminated”) papules. Multiple der-
Prognosis and predictive factors among different populations. matofibromas are regarded as a marker
As with GCF, DFSP has a significant risk of immune suppression; they have been
of local recurrence. The average recur- Etiology observed in Black females with systemic
rence rate in reported cases treated by The etiology has not been established lupus erythematosus; various other auto-
wide local excision (2-3 cm.) is 18%. A unequivocally. It is controversial whether immune disease such as Sjögren syn-
much higher recurrence rate (43%) is it is an inflammatory {21,2590,2591} or drome, pemphigus vulgaris, myasthenia
reported in tumours treated by superfi- neoplastic process {365,518,522,919}. gravis and ulcerative colitis treated with
cial or incomplete excisions only {853} Dermatofibroma has been reported fol- immunosuppressive drugs; occasionally
Local recurrence usually develops within lowing local injuries such as trauma, in renal graft recipients or AIDS patients.
three years after initial surgery. Meta- insect bites or folliculitis, suggesting an Still other lesions form plaques or nod-
stasis occurs rarely. inflammatory etiology. By contrast some ules to tumours. Dermatofibromas usual-
examples have been reported to be clon- ly are long standing lesions which cause
al, supportive of a neoplastic etiology no symptoms.
Dermatofibroma {457,1078,2422}.
(fibrous histiocytoma) Macroscopy
Localization Gross examination reveals a moderately
Definition Most lesions, including various clinico- well-circumscribed, hard papule, nodule
Dermatofibroma (fibrous histiocytoma) pathological variants, occur on the or tumour. The cut surface reveals a skin-
{21} is an ill-defined, predominantly der- extremities {840,1081,1114,1155,1187, coloured to distinctive yellow colour,
mal lesion characterized by a variable 1346,1786,1895,2115,2587,2592-2594} which may show areas of haemorrhage
number of spindle and/or rounded cells. and trunk {187,370,2403}. Rare cases and lipidization and then become cystic.
A variable admixture of inflammatory occur on the face {1583}.
Neural Tumours
__________
1
Morphology code of the International Classification of Diseases for Oncology (ICD-O) {786} and the Systematized Nomenclature of Medicine (http://snomed.org).
Behaviour is coded /0 for benign tumours, /3 for malignant tumours, and /1 for borderline or uncertain behaviour.
1 For PNET and Ewing sarcoma see TNM table of soft tissue tumours
2
{894,2219}.
3
A help desk for specific questions about the TNM classification is available at www.uicc.org/index.php?id=508 .
A B
Fig. 6.1 Palisaded, encapsulated neuroma. A Multinodular variant of palisaded encapsulated neuroma. B The tumour is formed by compactly arranged fascicles
separated by artificial clefts.
Prognostic factors
PEN and its variants are benign, and sim-
ple excision is a sufficient treatment. The
mucosal neuromas of MEN2b often pre-
cede the manifestation of the other
endocrine tumours. Therefore their cor-
rect recognition is important {1020}.
Traumatic neuroma
Definition
Traumatic neuromas represent reactive
or regenerative proliferation of the nerve
sheath components as an attempt to
reestablish lost nerve integrity after sharp
or blunt physical trauma.
Fig. 6.3 Traumatic neuroma. There is an ill-defined dermal nodule composed of irregularly arranged prolif-
eration of nerve fascicles embedded in a fibrotic (scarred) stroma.
Immunohistochemistry
The constituent spindle cells of the nerve
fascicles are positive for S-100 protein,
collagen type IV, whereas the surround-
ing perineurial cells, when present, stain
for epithelial membrane antigen. Anti-
bodies to neural filaments highlight the
axons, and myelinization can be demon- A C
strated by antibodies to myelin basic Fig. 6.4 Traumatic neuroma. A Supernumerary digit (amputation neuroma). Acral polypoid lesion with pro-
protein and CD57 (Leu-7). liferation of nerve fascicles at the base of stalk. B Higher magnification of the regenerating nerve fasci-
cles in the fibrous stroma. C The regenerating nerve fascicles show variation of diameter and orientation.
Prognostic factors The clear spaces correspond to increased perineurial mucin.
Traumatic neuroma is a reactive lesion,
however it can cause local interference
with adjacent organs and is often symp-
tomatic. The usual treatment is simple
excision.
A B C
Fig. 6.5 Primary PNET/EES of skin. A Tumour composed of sheets of monomorphic small round cells containing hyperchromatic nuclei and scanty cytoplasm.
B Strong membranous CD99 positivity in the neoplastic cells. C Homer-Wright rosettes. They are only rarely seen in these neoplasms.
Electron microscopy
At the Ewing end of the spectrum, the
cells appear rather non-descript with
round nuclei and scanty organelles.
There is usually abundant glycogen. The
PNETs show elongated interdigitating
cytoplasmic processes with a few rudi-
mentary junctions, intermediate fila-
ments, microtubules and sparse mem-
brane bound dense core neurosecretory Fig. 6.6 Primary PNET of skin. Electron microscopy of a cutaneous PNET: the cytoplasmic processes of the
granules (100-250 nm in diameter). No neoplastic cells contain intermediate filaments and microtubules (arrow). The inset shows a neurosecreto-
myofilaments, desmosomes or melano- ry granule.
somes are seen {138}.
Primary malignant peripheral primitive neuroectodermal tumour (PNET) / Extraskeletal Ewing sarcoma (ES) 269
Nerve sheath myxoma / neurothekeoma Z.B. Argenyi
Definition and nodules, whereas the “cellular large “bubbly nuclei” with prominent
These tumours encompass a spectrum types” have a firmer, rather red-tan- nucleoli. In a smaller percentage of the
of neuromesenchymal neoplasms char- brown appearance. Their size ranges cases, the tumour is composed of spin-
acterized by proliferation of nerve sheath between 0.5–2.0 cm. Both types are dle cells with plump or ovoid nuclei form-
cells in a variable myxomatous stroma. commonly asymptomatic, but may ing nests and whorls. In the “cellular
They can be further classified into “clas- become sensitive or tender {73,88,99, type”, cytologic and nuclear atypia are
sic” and “cellular” types. 161,371,1865}. more common and mitotic figures can be
conspicuous. Myxoid material is usually
ICD-O code 9562/0 Histopathology scant or present only around the individ-
The “classic type” is usually a well- ual nests {88,99,161,371}. In both the
Synonyms defined, multilobular or fascicular tumour “classic” and “cellular types”, associated
Cellular neurothekeoma (used exclusive- located in the dermis with or without stromal changes, such as fibrosis, hyalin-
ly for the cellular variant), cutaneous lob- extension to the subcutis. The lobules ization of the collagen, patchy chronic
ular neuromyxoma, myxomatous peri- contain abundant myxomatous stroma, inflammation, and angioplasia can occur.
neuroma which appear to be confined by a thin Changes showing transition between the
fibrous encapsulation. The mucin is con- “classic” and “cellular types” within the
Epidemiology nective tissue type acidic mucopolysac- same lesion have been documented. A
These tumours are rare. The "classic charide and stains strongly with colloidal direct connection with nerve twigs can
type" has been reported in middle-aged iron, which clears after hyaluronidase be demonstrated only rarely.
adults (mean 48.4), with predominance treatment. Within the mucinous stroma,
in females, of the head and neck areas there are sparsely distributed spindle, Immunohistochemistry
and upper extremities {73,1865}. The stellate, and polygonal cells without The stromal cells in the “classic” type
"cellular type" has been observed in appreciable cytologic atypia. Mitotic fig- stains strongly for S-100 protein, colla-
younger adults (mean 24 yrs), more com- ures are rare or absent {73,88,755,1865}. gen type IV and weakly for neuron-spe-
mon in females, predominantly on the The “cellular variant” shows an ill- cific enolase and CD57 (Leu-7). The cap-
head and neck areas {88,99,161,371}. defined, often infiltrative growth pattern sule, when present, may label for epithe-
However, both types can occur at any involving the dermis and subcutis. The lial membrane antigen. The “cellular”
age and at any location {229,418,479, proliferating cells form fascicles and type does not have a specific or consis-
1222,1674,1684,2355}. nests and are arranged in a plexiform or tent phenotype. The cells show variable
multilobular pattern. The constituent cells expression of PGP9.5, collagen type IV,
Clinical features are mainly epithelioid type with ample NK1/C3, CD34, and occasionally smooth
The “classic types” manifest as skin- eosinophilic cytoplasm and indistinct muscle specific actin and CD57 (Leu-7).
coloured, pink, soft, rubbery papules cytoplasmic membranes. The cells have Staining for S-100 protein is rare, and
A B
Fig. 6.7 Nerve sheath myxoma (neurothekeoma). A Cellular neurothekeoma (cellular variant of nerve sheath myxoma). The tumour cells form nests and strands infil-
trating the dermis. B Nerve sheath myxoma "classical type". Lobular and fascicular dermal proliferation with myxomatous stroma.
Prognosis
Both variants are considered benign
tumours, although rare cases of the “cel-
lular” type with concerning cytologic
atypia and mitotic activity have been
reported {231,357}. Both tumours can
recur after incomplete removal; therefore,
a complete excision is recommended for
treatment.
B C
Fig. 6.8 Nerve sheath myxoma (neurothekeoma). A Higher magnification of the lobules shows the mixture
of variable cellularity and myxomatous changes. B The tumour nests are well defined, but not encapsulat-
ed and contain minimal or no mucin. The adjacent stroma is hyalinized. C Stellate, polygonal, and spindled
cells are embedded in a markedly mucinous matrix.
Definition 100,000) and is exceptionally rare in less than 10% of cases. Exceptional
Merkel cell carcinoma is a rare malignant black individuals (0.01 annual age cases on mucosal surfaces have been
primary cutaneous neoplasm with adjusted incidence per 100,000) {1616}. recorded.
epithelial and neuroendocrine differentia- Merkel cell carcinoma is more common
tion. Tumour cells share morphologic, in men than in women with a ratio of Clinical features
immunohistochemical and ultrastructural 2.3:1. This tumour typically occurs on the Most tumours are solitary and present as
features with Merkel cells, but a direct sun- exposed skin of older adults with a a painless dome shaped nodule or
histogenetic link is unproven. median age at presentation of 69 years. indurated plaque that is red, violaceous
or skin-coloured and, at times, ulcerated.
ICD-O code 8247/3 Etiology Growth is typically rapid over a period of
Anatomic and geographic distribution of weeks to months. Most lesions measure
Synonyms Merkel cell carcinoma imply sun expo- less than 2 cm in diameter.
First described in 1972 by Cyril Toker as sure as a major risk factor. A relatively
trabecular carcinoma {2357}. Other syn- high incidence of this neoplasm in solid Tumour spread and staging
onyms include neuroendocrine carcino- organ transplant recipients and in Merkel cell carcinoma has a high inci-
ma of the skin, primary small-cell carci- patients with human immunodeficiency dence of local recurrence, regional
noma of the skin, and cutaneous virus infection point towards an etiologic lymph node metastasis and, ultimately,
APUDoma. role of chronic immunosuppression. haematogenous and/or distant lymphatic
spread {517}. Clinical staging after
Epidemiology Localization histopathologic diagnosis should include
The estimated incidence of Merkel cell The majority of Merkel cell carcinomas at the minimum a chest x-ray and CT of
carcinoma is about 470 new cases per arise on sun-exposed skin. The most fre- the chest and abdomen to exclude other
year in the United States. The tumour quently affected sites are the head and possible primary sites and to evaluate for
most commonly affects Caucasians (0.23 neck (50%) and extremities (40%) {843}. the presence of metastatic disease.
annual age adjusted incidence per The trunk and genitalia are involved in Merkel cell carcinoma in locations other
A B C
Fig. 6.9 Merkel cell carcinoma. A Rapidly growing, violaceous nodule on the forehead (courtesy Dr. Scott Dinehart). B Pagetoid involvement of the epidermis.
C Trabecular growth is one of the architectural patterns of Merkel cell carcinoma.
A B Prognostic factors
Diverse clinical prognostic factors
include older age, location on head and
neck, size greater than 2 cm, immuno-
suppression and advanced disease
stage {517,843,2208}.
Adverse histopathologic and immunolog-
ic features include more than 10 mitotic
figures per single high power field, small
cell size, angiolymphatic invasion, and
C D immunoreactivity for CD44 {1803}.
Fig. 6.10 Cutaneous neuroendocrine carcinoma. A Cytomorphological details. Note pyknotic nuclei and
mitoses. B Cytologic detail of Merkel cell carcinoma: Nuclear membranes are distinct, the chromatin is
finely dispersed and nucleoli are inconspicuous. Mitotic figures and nuclear fragments are numerous.
C Punctate perinuclear staining with CK20. D Staining with anti-cytokeratin 20 reveals a ring-like and
paranuclear dot-like pattern.
A B
C D
Fig. 6.11 Granular cell tumour. A Reactive squamous pseudoepitheliomatous hyperplasia with prominent cytologic atypia mimicking squamous cell carcinoma. The
granular cells are intermingled with squamous epithelial cells. B Granular cell tumour. The brightly eosinophilic granular cells form solid nests and strands infil-
trating the dermis. C Granular cell tumour associated with a peripheral nerve. The granular cells have polygonal shape, distinct cytoplasm and eosinophilic gran-
ular cytoplasm with round, fairly uniform nuclei. D The large, ovoid, brightly eosinophilic globules surrounded by clear halo represent giant lysosomes.
Clinical features
GCT usually presents as an asympto-
matic or occasionally tender or pruritic,
skin-coloured or brown-red, firm dermal A B
or subcutaneous papulo-nodule, ranging
Fig. 6.12 Malignant granular cell tumour. A Malignant granular cell tumour shows cells with polygonal and
in size from 0.5-3.0 cm in diameter. spindled morphology and coarse eosinophilic granularity. B Malignant granular cell tumour with pleomor-
Verrucous changes of the surface epithe- phic cells, single cell necrosis and atypical mitotic figure.
lium are common, whereas ulceration is
uncommon. The cutaneous tumours
grow slowly; most symptoms are related Immunohistochemistry ulceration) with the histologic features
to visceral locations. GCT expresses markers associated with (necrosis, spindling, and lymphocapillary
both neural (S-100 protein, PGP 9.5, neu- invasion) should guide in the diagnosis
Macroscopy ron specific enolase, laminin, NGFR, cal- of malignancy. Additional features cited
GCTs are nodular, but not encapsulated, retinin, peripheral myelin proteins, P2-P0, as useful for predicting malignancy are
and present as firm dermal or subcuta- myelin basic protein, CD57) and histio- vesicular nuclei with large nucleoli and a
neous masses with a thickened or verru- cytic (CD68, a-1-antitrypsin) differentia- mitotic rate greater than 2 mitoses/10
cous epidermal surface. On cut-surface tion. The tumour cells are positive for HPF.
the tumour has a pink-yellow, finely gran- vimentin. Most studies report a negative The second type of malignant GCT is
ular appearance {2084,2490}. reaction for neural filaments and GFAP quite rare; both the primary tumour and
{246,743,1063,1487,1540,1714}. its metastases display histologic and
Histopathology cytologic characteristics of malignancy.
The tumour forms poorly cohesive nests, Variants The immunophenotype of malignant GCT
strands, fascicles, and sheets of polygo- Granular cell epulis of infancy is also similar to that of the benign
nal, pale eosinophilic cells in the dermis This is a rare, polypoid tumour of the tumour, however the proliferation mark-
and subcutis. Commonly, the cells form alveolar ridge of the gingiva of the new- ers (Ki-67) show increased labelling
indistinct delicate fascicles that infiltrate born with a predilection for girls. The indices, and p53 expression is prominent
the dermal collagen and extend to the tumour has cytologic features similar to {2084}.
subcutaneous septa. A variant of GCT GCT, but lacks globular cytoplasmic
with a distinctly plexiform growth pattern inclusions, angulate body histiocytes, Genetics
has been documented {1392}. Perineural and contains a distinct plexiform capil- Only limited genetic studies have been
spread is a common feature. The cells lary pattern. The immunohistochemical performed on malignant GCT of the soft
have an abundant granular, faintly profile is also different; the lesions are tissue. This showed two clonal kary-
eosinophilic cytoplasm with round, small, negative for S-100 protein, NSE, laminin, otypes. One atypical tumour was aneu-
hyperchromatic nuclei. The fine, eosino- MBP, CD57, and α-1-ACT {740,1367, ploid and all 11 benign tumours were
philic, intracytoplasmic granules corre- 1764,2528}. either diploid (9 cases) or hyperdiploid (2
spond to lysosomes, which are PAS pos- cases) {627}.
itive and diastase resistant. Malignant granular cell tumour
Occasional larger, brightly eosinophilic These are extremely rare and comprise Prognosis and predictive factors
ovoid bodies surrounded by a clear halo less than 2% of all granular cell tumours. GCT is benign, however local recurrence
can be identified within the granules rep- The age and sex distribution is similar to is common due to incomplete removal
resenting residual “giant” lysosomes. that of their benign counterparts, but complicated by the typical perineural
Interspersed between the granular cells, they are more common on the extremities spread. The malignant variants are
there are spindle cells with fibroblast-like (particularly on the thighs) rather than the aggressive tumours and usually have
features and histiocyte-like cells often head and neck areas, or the oral numerous local recurrences before dis-
with triangular, coarsely granular eosino- mucosa. Malignant GCTs grow rapidly, tant spread. Their overall prognosis is
philic lysosomes designated as “angu- often ulcerate, invade locally and tend to poor, with metastases developing within
late bodies”. Nuclear pleomorphism, spread via extensive metastases. two years in the majority of cases and
prominent nucleoli, and mitotic figures Histologically and cytologically two forms there is close to 60% mortality within
are uncommon. A characteristic feature can be distinguished: the more common three years {2084,2490}. Because of the
of most cutaneous GCTs is the overlying type of malignant GCT is essentially potential for recurrence and the morpho-
pseudoepitheliomatous hyperplasia, identical to the benign tumour. Since logic overlap between benign and malig-
which can be so extensive that it can cytologic atypia or mitotic activity are not nant GCT, complete excision is recom-
mimic a verruca or a well-differentiated reliable biologic indicators, correlation of mended.
squamous cell carcinoma. clinical data (large size, rapid growth,
Nervous system tumours {860,452A} with a greater effect of DN in gene in numerous familial studies around
Rare families have been described dis- non-carriers than in carriers of CDKN2A the world shows that the frequency of
playing melanoma and neural system mutations in the American sample. CDKN2A mutations is about 20% on
tumours (NSTs) over several generations average but varies from 5-50% depend-
{129,1230}. This has been termed Genetics ing on the criteria for family selection.
melanoma-astrocytoma syndrome due to Gene structure and mutations Homozygotes for CDKN2A germline
the presence of cerebral astrocytomas in Two genes (encoding three proteins) mutation have been described in relation
the first family described. conferring a high risk of developing to a Dutch founder effect; they display
melanoma have been identified to date, similar phenotypes than heterozygous
Uveal melanoma (UM) CDKN2A/p14ARF and CDK4. In addi- individuals {912}. Mutations of the
Certain melanoma-prone kindred have tion, a low-risk melanoma susceptibility CDKN2A gene are detected in approxi-
members affected by either uveal and/or gene has also been identified, the mately 10% of sporadic multiple mela-
cutaneous melanoma. The first CDKN2A melanocortin-1 receptor gene (MC1R). noma cases, without any evidence of de
germline mutation was detected recently novo mutations up to date but in relation
in a melanoma-prone family, where one CDKN2A/p16INK4A gene to the existence of a founder effect for
carrier was affected by UM and the other Linkage analyses, cytogenetic studies some of them {115}. To date, no germ
by a CM (Kannengiesser C. et al., Gene and loss of heterozygosity (LOH) studies line mutations have been found in cases
Chromosome and Cancer, pending). in tumour cells have led researchers to of childhood melanoma (<18-20 years of
Naevus: total number (TN), clinically suspect the existence of a CM suscepti- age) lacking a family CM context {2507}.
atypical (AN), histologically dysplastic bility gene at 9p21 locus. The gene, Most CDKN2A mutations are missense
(DN p16INK4A/CDKN2A, was cloned in 1993 mutations scattered throughout the cod-
These naevus phenotypes are major risk {2140} and formally identified as a ing sequences of exons 1a and 2.
factors for CM but whether they repre- melanoma susceptibility gene in 1994 Functional studies of mutant p16INK4A
sent precursor lesions in the course of {1088,1184}. proteins have been carried out using
tumour development is still unclear. The CDKN2A transcript includes exons several assays displaying various sensi-
There are several lines of evidence sug- 1a, 2 and 3. It encodes the 156 amino- tivity: CDK-binding, kinase activity inhibi-
gesting that distinct genetic factors may acid p16INK4A protein composed of four tion, growth arrest and protein cellular
be involved in CM and number of naevi ankyrin repeats which are motifs involved localisation assays. Two more complex
{309}. CDKN2A does not appear to be a in protein-protein interactions. P16INK4A mutations have been also described: a
“naevus” predisposing gene; this pheno- binds to cyclin-dependent kinase 4 mutation located within CDKN2A 5’UTR,
type was found in only half of the sub- (CDK4) and 6 (CDK6), therefore prevent- creating an aberrant initiation codon
jects with a CDKN2A gene mutation and ing binding of cyclin D1 to the CDKs. {1435} and a deep intronic mutation
who had developed melanoma {2226} Cyclin D1/CDK4/6 complexes participate (IVS2-105A/G) of CDKN2A, leading to
and a study of Australian twins has in the phosphorylation of the retinoblas- aberrant mRNA splicing {956}. Recurrent
reported that a CDKN2A-linked gene toma protein (RB), allowing the cell to mutations described in melanoma-prone
may influence flat moles but has no effect progress beyond the G1 phase of the families from different continents have
on raised or atypical moles {2601}. cell division cycle {2166}. The p16INK4A been shown to be founder mutations
Naevus phenotypes (TN, AN and/or DN) protein inhibits RB-dependant cell cycle {115,488}.
have been shown to influence the pene- and therefore acts as a tumour suppres- Within the International Melanoma
trance of CDKN2A in melanoma-prone sor. Consortium, CDKN2A mutation pene-
North-American and French families The search for mutations of the CDKN2A trance was estimated to be, in a set of 80
CDKN2A/p14ARF gene ing both p16INK4A and p14ARF func- Application of genetic testing in the
In 1995, it was discovered that part of tions, have been described in three CM clinical testing
CDKN2A gene was common to another and NSTs families: two large deletions There is some evidence that non-carrier
transcript. This second transcript (exons involving the INK4A locus {128} and a of CDKN2A mutations in melanoma-
1b, 2 and 3) encodes the human p14ARF CDKN2A splice point mutation, leading prone families may have a higher inci-
protein (ARF meaning “alternative read- to p16INK4A and p14ARF transcripts dence of melanoma than the general
ing frame”) composed of 132 amino- lacking exon2 {1818}. However, it cannot population, presumably due to co-inheri-
acid, encoded by exons 1b and 2. be concluded that both p16INK4A and tance of other low-risk susceptibility
According to the current state of knowl- p14ARF inactivation are necessary for genes and common environmental risk
edge, p14ARF is involved in regulation of melanoma-astrocytoma syndrome as a amongst family members. Therefore,
the cell cycle and apoptosis via the p53 fourth such family has been also genetic testing for melanoma is of limited
and RB pathways, by interacting with described with a germ line deletion clinical utility to date, mainly because a
MDM2 (leading to p53 protein accumula- apparently restricted to the p14ARF - negative genetic test may give danger-
tion and to RB inactivation) and E2F1 specific exon 1b {1890}. ously false security. Testing should be
proteins {1437}. done in research protocols and first-
Mutations in exon 2 potentially affect CDK4 gene degree relatives of high-risk individuals
p16INK4A and p14ARF proteins at the The CDK4 gene on chromosome 12q13 should be engaged in the same pro-
same time. Despite this dual coding is composed of 8 exons within a 5-kilo- grams of melanoma prevention and sur-
capacity of the INK4A/ARF locus, recent bases (kb) segment. The initiation codon veillance, irrespective of the results of
description of three p14ARF germ-line is located in exon 2, the stop codon in any gene testing. However, in countries
alterations involving only exon 1b sug- exon 8. This gene encodes the cyclin- of low melanoma incidence such as most
gests a direct role for p14ARF haploin- dependant kinase 4 (CDK4), a 304 European countries, DNA testing may
sufficiency in melanoma predisposition : amino-acid protein. It has been identified improve compliance with sun protection
(1) a deletion restricted to exon 1b and as a melanoma predisposing gene in and surveillance in identified mutation
segregating with melanoma and neural three families world-wide {2226.2607}. carriers. In such situations, CDKN2A
cell tumours within a family {1890}, (2) a Germline mutations affect Arg-24 residue testing could be proposed after careful
16bp insertion in exon 1b in a sporadic in exon 2, which plays a key role in genetic counselling {1238}.
multiple melanoma case {1945}, (3) a p16INK4A binding. The mutation indu-
splice mutation in exon 1b in a two ces the loss of the cell cycle down-regu-
melanoma-cases family {1022}. lation signal that p16INK4A exerts
through RB phosphorylation. In a “knock-
A role for both p14ARF and in” Cdk4R24C/R24C mouse model, con-
p16INK4A/CDKN2A genes? stitutive Cdk4 activation is oncogenic
Germ-line alterations presumably alter- {1891}.
OMIM Numbers
278700 - XPA
133510 - XPB
278720 - XPC
278730 - XPD
278740 - XPE
278760 - XPF
278780 - XPG
278750 - XP variant
Synonyms
De-Sanctis Cacchione syndrome, pig-
mented xerodermoid, xeroderma pig-
mentosum variant
Epidemiology
Incidence A B
Xeroderma pigmentosum occurs with an
estimated frequency of 1:1,000,000 in
the United States {1322}. It is more com-
mon in Japan, the Middle East and
North-Africa. Patients have been report-
ed worldwide in all races including
Whites, Asians, Blacks, and Native
Americans. Consanguinity is common.
There is no significant difference
between the sexes. C D
Fig. 7.5 Xeroderma pigmentosum. A Face of a 16 year old patient showing dry skin with hyperpigmentation,
Clinical features atrophy and cheilitis. B Posterior view of the same patient showing absence of pigmentary changes on
Abnormalities may be present in the skin, areas protected from sunlight. C Face of a 14 year old patient showing freckle-like lesions with different
eyes, or nervous system. There is a amounts of pigmentation, an actinic keratoses, a basal cell carcinoma and a scar with telangiectasia at the
greatly increased frequency of cancer on site of removal of another neoplasm. D Xeroderma pigmentosum. Eye of the 22 year old patient showing
sun-exposed sites. secondary telangiectasia invading the cloudy cornea, and atrophy and loss of lashes of the lower lid.
Figures from K.H. Kraemer {1319}.
Genetics
Fig. 7.7 DNA repair diseases. Correlation between clinical disorder (yellow letters) and molecular defects The seven complementation groups
(black letters). found for the classical XP correspond to
Treatment
Management of patients with XP is based
on early diagnosis, life-long protection
from UV radiation exposure, and early
detection and treatment of neoplasms
{778}.
A B C
Fig. 7.8 A Multiple naevoid basal cell carcinomas scattered over neck and shoulder. B Multiple bifid ribs. C Desmoplastic medulloblastoma. The pale, reticulin-free
nodules often show focal astrocytic differentiation. GFAP immunohistochemitry. From {1287}. NBCCS is typically associated with this variant.
Diagnostic criteria
The International Cowden Consortium
originally proposed a set of operational
A B diagnostic criteria in 1996 {1694}.
Fig. 7.12 Cowden disease (PTEN). A Multiple confluent papules on the upper lip. B Multiple wart-like Because of new data, the Consortium
lesions on the gingivae. revised the criteria in 2000 {688}, which
A B
Fig. 7.14 A Spotty pigmentation and blue naevus in CNC. Courtesy of Dr. David J. Atherton, London, UK, and reference {111}. B Histological specimen of blue nae-
vus showing large epithelioid melanocytes. Courtesy of Dr. Luis Requena, Madrid, Spain.
ed nodular adrenal disease should be ed gene is present, the regulatory sub- gestive of CNC should be advised to
considered and the patient evaluated for unit is no longer produced. The patients have a general medical evaluation and
CNC, particularly if the patient is young are heterozygous for the mutation: the an echocardiogram. Primary relatives of
or has multiple pigmented skin spots or tumours tend to have LOH of the wild CNC patients should be similarly
lumps. Echocardiography is particularly type allele for this regulatory gene. The advised.
important {2276}. CNC2 gene is less well characterized but
appears to be involved in regulating
Differential diagnosis genomic stability, perhaps via the telom-
When multiple pigmented lesions are eres.
present, LEOPARD syndrome should be
considered but myxomas are absent in Prognosis and predictive factors
this condition and the systemic manifes- The prognosis depends on detecting
tations more protean. Mucosal pigmenta- cardiac myxoma, the most serious com-
tion strongly resembles that of Peutz- plex of CNC. The average age of 22
Jeghers syndrome, but intestinal polyps patients who died as the result of cardiac
are not part of the usual spectrum of causes (cardiac failure from myxoma,
Carney complex. cardiac myxoma emboli or cardiac
arrhythmia) was 31 years. Timely diagno-
Genetics sis of the neoplasms requires an aware-
Carney complex is inherited in an auto- ness of the possible significance of the
somal dominant fashion. The gene for pigmented skin spots, skin tumours, pri-
CNC1, known as PRKAR1A, normally mary pigmented nodular adrenal dis-
encodes the protein kinase A regulatory ease and psammomatous melanotic
subunit R1a {408,1284}. When the mutat- schwannoma. Patients with lesions sug-
Dr. Iftikhar AHMED Dr. Maria G. BERNENGO Dr. Joan N. BREUER-MCHAM Dr. John Andrew CARLSON
Department of Dermatology, East 5 Department of Biomedical Sciences Dept of Dermatology Divisions of Dermatology and
Mayo Clinic and Mayo Foundation and Dermatological Oncology MD Anderson Cancer Center Dermatopathology, Campus Box MC-81
200 First St. S.W. University of Turin 1515 Holcombe Blvd. Unit 434 Albany Medical College
Rochester MN 55905 Via Cherasco 23 Houston, TX 77030 47 New Scotland Ave
USA 10126 Turin, ITALY USA Albany, NY 12208, USA
Tel. +1 507 284 4672 Tel. +39 116335849 Tel. +1 713-792 4754 Tel. +1 518 262 6414
Fax. +1 507 284 2072 Fax. +39 11 67 4034 Fax. +1 713 745 3597 Fax. +1 518 262 6251
ahmed.iftikhar2@mayo.edu mariagrazia.bernengo@unito.it jbreuer@mdanderson.org CarlsoA@mail.amc.edu
Dr. Zsolt B. ARGENYI Dr. Emilio BERTI Dr. Leena BRÜCKNER-TUDERMAN Dr. J. Aidan CARNEY
Director of Dermatopathology Institute of Dermatological Sciences Dept of Dermatology Dept. Lab. Medicine and Pathology
University of Washington Medical University of Milan, I.R.C.C.S University Freiburg Mayo Clinic and Mayo Foundation
Center Via Pace 9 Hauptstrasse 7 200 First Street, S.W.
1959 NE Pacific Street, Box 356100 20122 Milan 79104 Freiburg, GERMANY Rochester, MN 55905
Seattle, WA 98195-6100, USA ITALY Tel. +49 761 2706716 USA
Tel. +1 206 598 2119 Tel. +39 02 55035107 - 5186 Fax. +49 761 2706936 Tel. +1 507 284 2691
Fax. +1 206 5984928 Fax. +39 02 50320779 bruckner_tuderman@haut. Fax. +1 507 284 5036
zsolt@u.washington.edu emilio.berti@unimib.it ukl.uni-freiburg.de carney.aidan@mayo.edu
Dr. S. Sankar BANERJEE Dr. Wojciech BIERNAT* Dr. Stanislaw BUECHNER Dr. Rino CERIO
Consultant Histopathologist Neuropahtology and Molecular Dermatologie Department of Morbid Anatomy
Dept of Histopathology Pathology Universitätsspital Institute of Pathology
Christie Hospital NHS Trust Medical University of Gdansk Petersgraben 4 The Royal London Hospital
Wilmslow Rd, Withington ul. Debinki 1 4031 Basel Whitechapel
Manchester M20 4BX, UK 80-211 Gdansk, POLAND SWITZERLAND London E1 1BB, UK
Tel. +44 161 446 3274 Tel. +48 58 349 34 24 Tel. +41 61 265 5099 Tel. +44 20 7377 7349
Fax. +44 161 446 3300 Fax. +48 58 349 34 74 Fax. +41 61 265 5742/4200 Fax. +44 20 7377 0949
liz.ryan@christie-tr.nwest.nhs.uk biernat@amg.gda.pl stanislaw.buechner@hin.ch r.cerio@mds.qml.ac.uk
Dr. Raymond L. BARNHILL Dr. Karen BLESSING Dr. Gunter BURG* Dr. Lorenzo CERRONI
Global Pathology Laboratory Services Department of Pathology Dermatological Clinic Department of Dermatology
University of Miami Miller School of Western Infirmary University Hospital Zurich Medical University of Graz
Medicine Dumbarton Road Gloriastrasse 31 Auenbruggerplatz 8
16250 NW 59th Ave. Suite 201 Glasgow G12 0PJ, UK 8091 Zurich 8036 Graz
33014 Miami Lakes, Florida Tel. +44 141 211 2473 SWITZERLAND AUSTRIA
USA Fax. +44 141 337 2494 Tel. +41 44 255 25 50 Tel. +43 316 385 2423
RLBarnhill@aol.com karen.blessing@northglasgow.scot.n Fax. +41 44 255 44 03 Fax. +43 316 385 2466
hs.uk G.Burg@usz.ch lorenzo.cerroni@meduni-graz.at
Dr. Boris BASTIAN* Dr. Giovanni BORRONI Dr. Walter BURGDORF* Dr. John K.C. CHAN
Comprehensive Cancer Center and Clinica Dermatologica Traubinger Strasse 45A Department of Pathology
Dept of Dermatology and Pathology University of Pavia 82327 Tutzing Queen Elizabeth Hospital
University of California San Fransisco Ospedale San Matteo, IRCCS GERMANY Wylie Road
Box 0808 Piazzale C. Golgi 2 Tel. +49 8158 7159 Kowloon, Hong Kong
San Francisco, CA 94143, USA 27100 Pavia, ITALY wburgdorf@gmx.de SAR CHINA
Tel. +1 415 476 5132 Tel. +39 0382 503813 Tel. +852 2958 6830
Fax. +1 415 476 8218 Fax. +39 0382 526379 Fax. +852 2 385 2455
bastian@cc.ucsf.edu g.borroni@smatteo.pv.it jkchan@ha.org.hk
Dr. Reuven BERGMAN Dr. Freddie BRAY Dr. Eduardo CALONJE* Dr. Sergio CHIMENTI
Department of Dermatology Cancer Registry of Norway Director of Diagnostic Department of Dermatology
Rambam Medical Center Montebello Dermatopathology University of Rome “Tor Vergata”
POB 9602 Fridtjof Nansens vei 17 St John’s Institute of Dermatology Viale Oxford, N 81
31096 Haifa N-0310 Oslo St Thomas’ Hospital 00133 Roma
ISRAEL NORWAY London SE1 7EH, UK ITALY
Tel. +972 4 854 2610 Tel. +47 23 33 39 83 Tel. + 44 20 7188 6408 Tel. +39 06 20 90 27 43
Fax. +972 4 854 2951 Fax. +47 22 45 13 70 Fax. + 44 20 7188 6382 Fax. +39 06 20 90 27 42
dermatology@rambam.health.gov.il fib@kreftregisteret.no jaime.calonje@kcl.ac.uk chimenti@uniroma2.it
Dr. Brigitte BRESSAC - DE PAILLERETS Dr. Ruggero CAPUTO Dr. Claudio Clemente
Service de Genetique Institute of Dermatologic Sciences Casa di Cura S. Pio X E S. Camillo
Institut Gustave-Roussy University of Milan Via F. Nava 31
39 rue Camille Desmoulins I.R.C.C.S. 20159 Milano
* The asterisk indicates participation 94805 Villejuif Cedex Via Pace 9 ITALY
in the Working Group Meeting on the FRANCE 20122 Milan, ITALY Tel. +39 2 6951 6572
WHO Classification of Skin Tumours Tel. +33 1 42 11 40 23 Tel. +39 02 55035200 Fax. +39 2 6951 6449
that was held in Lyon, France, Sept. Fax. +33 1 42 11 52 67 Fax. +39 02 50320779 cclemente.ap@iol.it
22-25, 2003. bressac@igr.fr ruggero.caputo@unimi.it
Contributors 295
Dr. Jan Willem COEBERGH Dr. José L.. DIAZ-PEREZ Dr. M.A. EVERETT Dr. Joan GUITART
Dept. of Public Health Cruces University Hospital Department of Dermatology Dept of Dermatology and Pathology
Erasmus MC, University Medical Pza. Cruces Sin College of Medicine, Nortwestern University, NMH Galter
Center, P.O. Box 1738 E-48903 Baracaldo-Bilbao University of Oklahoma Health Room 19-150
3000 DR Rotterdam SPAIN Sciences Center 675 N Saint Clair
THE NETHERLANDS Tel. +34 94 6006 149 Post Office Box 26901, BMSB 357 Chicago, IL 60611, USA
Tel. +31 10 40 87721 Fax. +34 94 6006 138 Oklahoma City, OK 73190, USA Tel. +1 312 695-2898
Fax. +31 10 40 89455 jldiaz@hcru.osakidetza.net Tel. +1 405 271 4000 Fax. +1 312 908 0664
j.coebergh@erasmusmc.nl Fax. +1 405 271 3032 j-guitart@northwestern.edu
Dr. Martin G. COOK Dr. Corina DOMMANN-SCHERRER Dr. Josef FEIT Dr. Eckart HANEKE
Department of Pathology Institute of Pathology Institute of Pathology Dermatology Clinic
The Royal Surrey County Hospital Cantonal Hospital Winterthur University Hospital Brno Kaiser-Joseph-Strassse 262
Egerton Road Brauerstrasse 15 Jihlavska 20 79098 Freiburg
Guildford Surrey GU2 7XX 8401 Winterthur 625 00 Brno GERMANY
UNITED KINGDOM SWITZERLAND CZECH REPUBLIC Tel. +49 761 3837 400
Tel. +44 1483 464065 Tel. +41 52 266 2503 Tel. +420 532232005 Fax. +49 761 3837 401
Fax. +44 1483 452718 Fax. +41 52 266 4507 Fax. +420 547192819 haneke@gmx.net
corina.dommann@ksw.ch jfeit@ics.muni.cz
Dr. Richard I. CRAWFORD Dr. Reinhard DUMMER Dr. Cyril FISHER Dr. Nancy Lee HARRIS
Division of Anatomic Pathology Department of Dermatology Dept of Histopathology Department of Pathology , Warren 2
St. Paul’s Hospital and University of University Hospital of Zurich Royal Marsden NHS Trust Massachussetts General Hospital
British Columbia Gloriastrasse 31 Fulham Road Fruit Street
B164 - 1081 Burrard Street 8091 Zurich London SW3 6JJ Boston, MA 02114
Vancouver, BC V6Z 1Y6, CANADA SWITZERLAND UNITED KINGDOM USA
Tel. +1 604 682 2344 Tel. +41 44 255 2507 Tel. +44 207 808 2630 Tel. +1 617 726 5155
Fax. +1 604 806 8326 Fax. +41 44 255 89 88 Fax. +44 207 808 2578 Fax. +1 617 726 7474
richaric@interchange.ubc.ca reinhard.dummer@usz.ch Cyril.fisher@rmh.nhs.uk nlharris@partners.org
Dr. Bernard CRIBIER Dr. Lyn Stuart McDivitt DUNCAN Dr. Michael J. FLAIG Dr. Wolfgang HARTSCHUH
Clinique dermatologique Dermatopathology Unit, WRN 827 Klinik fur Dermatologie und Allergologie Universitaets-Hautklinik
Hôpitaux Universitaires de Strasbourg Massachussetts General Hospital Ludwig-Maximilians-Universität Vosstrasse 2
CHRU - 1, place de l’Hôpital 55 Fruit Street Frauenlobstrasse 9-11, 69115 Heidelberg
67091 Strasbourg Boston MA 02114 80337 Munich GERMANY
FRANCE USA GERMANY Tel. +49 6221 568504
Tel. +33 3 88 11 61 80 Tel. +1 617 726 8890 Tel. +49 89 5160 6327 Fax. +49 6221 56 5945
Fax. +33 3 88 11 60 40 Fax. +1 617 726 8711 Fax. +49 89 5160 6182 wolfgang_hartschuh@med.uni-hei-
bernard.cribier@chru-strasbourg.fr duncan@helix.mgh.harvard.edu michael.flaig@med.uni-muenchen.de delberg.de
Dr. Kerry A. CROTTY Dr. J.C. EHRHART Dr. Philippe GALINIER Dr. Jeff D. HARVELL
Sydney Melanoma Unit Institut Gustave Roussy PR2 Hôpital des enfants Toulouse North Georgia Dermatopathology
Sydney Melanoma Diagnostic Genetic Instability and Cancer, UPR 330 Avenue de Grande 945 Church Street Extension
Centre, Royal Prince Alfred Hospital 2169 CNRS Bretagne Marietta, GA 30060
Camperdown, NSW 39, rue Camille Desmoulins B.P. 3119 USA
AUSTRALIA 94805 Villejuif cedex, FRANCE 31026 Toulouse Cedex 3 Tel. +1 770 426 0827
Tel. +61 2 9515 8537 Tel. +33 42 111 63 30 FRANCE Fax. +1 770 426 9534
Fax. +61 2 9515 5278 Fax. +33 42 11 50 08 Fax. +33 5 34 55 85 41
kerry.crotty@bigpond.com ehrhart@igr.fr galinier.philippe@wanadoo.fr
Dr. Esther DE VRIES Dr. David E. ELDER* Dr. Earl J. GLUSAC* Dr. Catherine A. HARWOOD
Dept. of Public Health Department of Pathology and Department of Dermatology Centre for Cutaneous Research
Erasmus MC, University Medical Laboratory Medicine Yale University School of Medicine Barts and the London Queen Mary’s
Center, P.O. Box 1738 University of Pennsylvania LMP 5031 School of Medicine and Dentistry
3000 DR Rotterdam 3400 Spruce Street 15 York Street - P.O. Box 208059 4, Newark Street
THE NETHERLANDS Philadelphia, PA 19104, USA New Haven, CT 06520-8059, USA E1 2AT London, UK
Tel. +31 10 40 87730 Tel. +1 215 662 6503 Tel. +1 203 785 4094 Tel. +44 20 7882 7173
Fax. +31 10 40 89455 Fax. +1 215 349 8088 Fax. +1 203 785 6869 Fax. +44 20 7882 7171
e.devries@erasmusmc.nl elder@mail.med.upenn.edu earl.glusac@yale.edu caharwood@doctors.org.uk
Dr. Florence DEMENAIS Dr. George W. ELGART Dr. Robert James GORLIN Dr. Peter J. HEENAN
INSERM - Université d’Evry Department of Dermatology and Dept of Oral Sciences-Oral Cutaneous Pathology
EMI 0006, Tour Evry 2 Cutaneous Surgery, 1444 Bldg Pathology 16-206B MoosT 26 Leura Street
523 Place de Terrasses de l’Agora University of Miami School of Medicine University of Minnesota Health Nedlands, WA 6009
91034 Evry 1444 N.W. 9th Avenue, 3rd Floor 515 Delaware St SE AUSTRALIA
FRANCE Miami FL 33136, USA Minneapolis, MN 55455, USA Tel. +61 8 9389 1022
Tel. +33 1 60 87 38 26 Tel. +1 305 243 6272 Tel. +1 612 624 3923 Fax. +61 8 9386 8335
Fax. +33 1 60 87 38 48 Fax. +1 305 243 4628 Fax. +1 612 626 2327 pheenan@cyllene.uwa.edu.au
demenais@evry.inserm.fr gelgart@med.miami.edu gorli002@umn.edu
Dr. Carlos DIAZ-CASCAJO Dr. Ervin H. Jr. EPSTEIN Dr. Christof GROSS Dr. Beate M. HENZ
Center for Dermatopathology Department of Dermatology Institut fur Pathologie Department of Dermatology
Engelbergerstrasse 19 University of California, San Klinikum Kassel GmbH Humboldt Universitat Berlin
79106 Freiburg Francisco Mönchebergstraße 41-43 Schumunnstr. 20-21
GERMANY San Francisco, CA 94143-1214 34125 Kassel 10017 Berlin
Tel. + 49-761-31696 USA GERMANY GERMANY
Fax. + 49-761-39772 Tel. +1 415 647 3992 Tel. +49 5619 80 32 26 Tel. +49 30 450 518 006
Tiengen@t-online.de Fax. +1 415 647 3996 Fax. +49 5619 80 69 83 Fax. +49 30 450 518 900
cd@zdpf.de epsteine@derm.ucsf.edu gross@klinikum-kassel.de magdalena.fuchs@charite.de
296 Contributors
Dr. Jana HERCOGOVA Dr. Hideko KAMINO Dr. Sabine KOHLER* Dr. Jann LÜBBE*
Dept of Dermatology and Venereology Division of Dermatopathology Department of Pathology, L235 Clinique et Policlinique de Dermatologie
2nd MedicalSchool Department of Dermatology Stanford University School of Medicine Hopital Cantonal Universitaire
Bulovka University Hospital NYU Medical Center 300 Pasteur Dr 24 rue Micheli-du-Crest
Budinova 2 550 First Avenue, Suite 7J Stanford, CA 94305-5324 1211 Geneve 14
180 81 Prague, CZECH REPUBLIC New York, NY 10016, USA USA SWITZERLAND
Tel. +420 2 660 823 59 Tel. +1 212 263 7250 Tel. +1 650 498 6991 Tel. +41 22 372 94 40
Fax. +420 2 660 823 50 Fax. +1 212 684 2991 Fax. +1 650 725 6902 Fax. +41 22 372 94 70
dermatology@fnb.cz kaminh01@popmail.med.nyu.edu skohler@stanford.edu jann.lubbe@hcuge.ch
Dr. Mark A. HURT Dr. Grace F. KAO* Dr. Steven KOSSARD Dr. John C. MAIZE
Cutaneous Pathology Dept of Pathology and Laboratory Skin and Cancer Foundation Medical Director
2326 Millpark Drive Medicine, Veterans Affairs Maryland Australia Maize Center for Dermatopathology
Maryland Heights, MO 63043-3530 Health Care System 277 Bourke Street, Darlinghurst 266 West Coleman Blvd, Suite 101
USA 10 North Greene Street NSW 2010 Sydney Mt Pleasant, SC 29464
Tel. +1 314 991 4470 Baltimore, MD 21201-1524, USA AUSTRALIA USA
Fax. +1 314 991 4309 Tel. +1 410 605 7000 ext 5312 Tel. +61 2 8353 3053 Tel. +1 843 388 6911
markhurt@aol.com Fax. +1 410 605 7911 Fax. +61 2 8353 3040 Fax. +1 843 388 6917
grace.Kao@med.va.gov skossard@scfa.edu.au jmaizesr@ameripath.com
Dr. Matilde IORIZZO Dr. Richard C. KASPER* Dr. Kenneth H. KRAEMER Dr. Robin MARKS
Department of Dermatology Department of Pathology Basic Research Laboratory Department of Medicine
University of Bologna University of Calgary National Cancer Institute The University of Melbourne, St
via Massarenti 1 9-3535 Research Road NW Building 37, Room 4002 Vincent’s Hospital
40138 Bologna Calgary, AB T2L 2K8 Bethesda, MD 20892 27 Victoria Parade
ITALY CANADA USA Fitzroy, 3065 Victoria, AUSTRALIA
Tel. 0039051341820 Tel. +1 403 770 3201 Tel. +1 301 496 9033 Tel. +61 3 9288 3293
Fax. 0039051347847 Fax. +1 403 770 3292 Fax. +1 301 594 3409 Fax. +61 3 9288 3292
matildeiorizzo@hotmail.com richard.kasper@cls.ab.ca kraemerk@nih.gov Robin.MARKS@svhm.org.au
Dr. Keiji IWATSUKI Dr. Dmitry V. KAZAKOV Dr. Michael KURRER* Dr. Magdalena MARTINKA
Department of Dermatology Sikl’s Department of Pathology Department of Pathology Vancouver General Hospital
Okayama University Graduate School Charles University Medical Faculty University Hospital Zurich University of British Columbia
of Medicine Hospital Schmelzbergstrasse 12 855 West 12th Avenue
2-5-1 Shikata-cho Alej Svobody 80 8091 Zurich Vancouver, BC V5Z 1M9
700-8558 Okayama, JAPAN 304 60 Pilsen, CZECH REPUBLIC SWITZERLAND CANADA
Tel. +81 86 235 7282 Tel. +420-377104651 Tel. +41 44 255 3922 Tel. +1 604 875 5555, local 68227
Fax. +81 86 235 7283 Fax. +420-377104650 Fax. +41 44 255 4416 Fax. +1 604 875 5707
keijiiwa@cc.okayama-u.ac.jp kazakov@medima.cz michael.kurrer@usz.ch magda.martinka@vch.ca
Dr. Elaine S. JAFFE* Dr. Werner KEMPF* Dr. Heinz KUTZNER Dr. Daniela MASSI
Laboratory of Pathology Department of Dermatology Dermatohistopathology Laboratory Dipartimento di Patologia Umana ed
National Institutes of Health University Hospital Zurich Siemensstrasse 6/1 Oncologia
Bldg 10 Room 2N202 Gloriastrasse 31 88048 Friedrichshafen Università degli Studi di Firenze
10 Center Drive 8091 Zurich GERMANY Viale G.B. Morgagni, 85
Bethesda, MD 20892-1500, USA SWITZERLAND Tel. +49 7541 6044 0 50134 Florence, ITALY
Tel. +1 301 496 0184 Tel. +41 1 255 25 50 Fax. +49 7541 6044 10 Tel. +39 055 4478137
Fax. +1 301 402 2415 Fax. +41 1 255 44 03 kutzner@w-4.de Fax. +39 055 4379868
elainejaffe@nih.gov kempf@derm.unizh.ch daniela.massi@unifi.it
Dr. Craig JAMES Dr. Helmut KERL Dr. Liliane LAROCHE Dr. Timothy H. MCCALMONT
Adelaide Pathology Partners Dept of Dermatology Service de Dermatologie Professor of Clinical Pathology and
46 Sir Donald Bradman Drive Medical University of Graz Hôpital Avicenne Dermatology
Mile End S.A. 5031 Auenbruggerplatz 8 Université de Paris XIII University of California
AUSTRALIA 8036 Graz 125, rue de Stalingrad 1701 Divisadero Street, Room 350
Tel. + 08 8238 9800 AUSTRIA 93009 Bobigny Cedex, FRANCE San Francisco, CA 94115, USA
Fax. + 08 8238 9899 Tel. +43 316 385 2538 Tel. +33 1 48 95 51 85 Tel. +1 415 353 7550
Salvatore.Pala@uniroma1.it Fax. +43 316 385 3424 Fax. +33 1 48 95 51 87 Fax. +1 415 353 7538
helmut.kerl@meduni-graz.at liliane.laroche@avc.ap-hop-paris.fr mccalmo@itsa.ucsf.edu
Dr. Steven KADDU Dr. Paul KLEIHUES* Dr. Philip E. LEBOIT* Dr. William H. MCCARTHY
Department of Dermatology Department of Pathology Dermatopathology Section, Suite 336 Sydney Melanoma Unit
University of Graz University Hospital University of California San Francisco Royal Prince Alfred Hospital
Auenbruggerplatz 8 8091 Zürich 1701 Divisadero Street Missenden Road
8036 Graz SWITZERLAND San Francisco, CA 94115-1790 2050 Camperdown, NSW
AUSTRIA Tel. +41 44 255 35 16 USA AUSTRALIA
Tel. +43 316 385 3424 Fax. +41 44 255 45 51 Tel. +1 415 353 7536 Tel. +61 2 9515 8537
Fax. +43 316 385 2466 paul.kleihues@usz.ch Fax. +1 415 353 7553 Fax. +61 2 9550 6316
steven.kaddu@meduni-graz.at philipl@itsa.ucsf.edu william.mccarthy@email.cs.nsw.gov.au
Dr. Marshall E. KADIN Dr. Robert KNOBLER Dr. King-Chung LEE Dr. Jennifer MCNIFF
Beth Israel Deaconess Medical Center Dept of Dermatology Department of Pathology Director, Yale Dermatopathology
Harvard Medical School Medical University of Vienna Queen Elizabeth Hospital Laboratory
330 Brookline Avenue Währinger Gürtel 18-20 Wylie Road Yale University School of Medicine
Boston, MA 02215 1090 Wien Kowloon, Hong Kong PO Box 208059
USA AUSTRIA SAR CHINA New Haven, CT 06520-8059, USA
Tel. +1 401 624 2715 Tel. +43 1 40 400 77 02 Tel. +852 295 86816 Tel. +1 203 785 4094
Fax. +1 617 667 4533 Fax. +43 1 408 12 87 Fax. +852 238 52455 Fax. +1 203 785 6869
mkadin@caregroup.harvard.edu robert.knobler@meduniwien.ac.at leekc@ha.org.hk jennifer.mcniff@yale.edu
Contributors 297
Dr. Neil Scott MCNUTT Dr. Wolter J. MOOI Dr. Rita O. PICHARDO Dr. Pierre RUDOLPH
Department of Dermatopathology Department of Pathology Department of Dermatology Pathologie Institut Enge
Weill Medical College of Cornell Free University medical centre Wake Forest University, School of Tödistrasse 48
University Medical Center De Boelelaan 1117 Medicine, The Bowman Gray Campus 8039 Zürich
1300 York Avenue 1081 HV Amsterdam Medical Center Boulevard SWITZERLAND
New York NY 10022, USA THE NETHERLANDS Winston-Salem, NC 27157-1072 Tel. +41 1 287 38 38
Tel. +1 212 746 6434 Tel. +31 20 4444788 USA Fax. +41 1 287 38 39
Fax. +1 212 746 8570 Fax. +31 20 4442964 Tel. +1 336 716-2768 rudolphp@patho.ch
nsmcnutt@med.cornell.edu WJ.Mooi@vumc.nl Fax. +1 336 716-7732
Dr. Chris J.L.M. MEIJER* Dr. Michael B. MORGAN Dr. Nicola PIMPINELLI Dr. Dirk RUITER
Department of Pathology Departments of Pathology and Department of Dermatological Dept. of Pathology
Vrije Universiteit Medical Center Dermatology Sciences University Medical Center St. Radboud
De Boelelaan 1117, PO Box 7057 Veterans Affairs Medical Center University of Florence P.O. Box 9101
1007 MB Amsterdam 1300 Bruce B. Downs Blvd Via degli Alfani, 37 6500 HB Nijmegen
THE NETHERLANDS Tampa, FL 33612, USA 50121 Florence, ITALY THE NETHERLANDS
Tel. +31 20 44 44070 Tel. +1 813 971 0775 Tel. +39 055 234 4422 Tel. +31 24 3614825
Fax. +31 20 44 42964 Fax. +1 813 971 6675 Fax. +39 055 275 8757 Fax. +31 24 3540520
cjlm.meijer@vumc.nl mbkmmorgan@aol.com pimpi@unifi.it d.ruiter@pathol.umcn.nl
Dr. Yebabe M. MENGESHA Dr. Rohan J. MORTIMORE Dr. Elizabeth RALFKIAER* Dr. Robin RUSSELL-JONES
Department of Dermatology Queensland Medical Laboratory Department of Pathology 5444 St. John’s Institute of Dermatology
Wake Forest University School of P.O. Box 5410 University of Copenhagen St. Thomas ‘s Hospital
Medicine QLD 4101 West End Brisbane Rigshospitalet Frederik V’s vej 11 Lambeth Palace Road
Winston-Salem, North Carolina AUSTRALIA 2100 Copenhagen O London SE1 7EH
USA Tel. +61 7 3840 4698 DENMARK UNITED KINGDOM
yebabe@hotmail.com Fax. +61 7 3840 4476 Tel. +45 354 55346 Tel. +44 20 7928 1333
rm21@qml.com.au Fax. +45 354 56380 Fax. +44 20 7922 8138
e.ralfkiaer@rh.dk russelljones@btinternet.com
Dr. Darius Mehregan Dr. Eduardo NAGORE Dr. Ronald P. RAPINI Dr. Arno RÜTTEN
Pinkus Dermatopathology Departments of Dermatology Department of Dermatology Dermatohistopathology Laboratory
Laboratories, PC Instituto Valenciano de Oncología University of Texas Medical School Dermatologisches Einsendelabor
1314 N. Macomb Street c/ Profesor Beltrán Báguena, 8 and MD Anderson Cancer Center Siemenstrasse 6/1
Monroe, MI 48162 46009 Valencia 6431 Fannin Street, MSB1.204 88048 Freidrichshafen
USA SPAIN Houston, TX 77030, USA GERMANY
Tel. +1 800 746-5870 Tel. +34 961114015 Tel. +1 713 500 7170 Tel. +49 7541 6044 60
Fax. +1 734 242-4962 Fax. +34 961114341 Fax. +1 713 500 7173 Fax. +49 7541 6044 10
darmehregan@pinkuslab.com eduyame@meditex.es Ronald.P.Rapini@uth.tmc.edu ruetten@w-4.de
Dr. David Mehregan Dr. Paula NORTH Dr. Luis REQUENA Dr. Ruth SALOM
Pinkus Dermatopathology Department of Pathology Department of Dermatology Department of Anatomical Pathology
Laboratories, PC Children’s Hospital of Wisconsin Fundacion Jimenez Diaz, Royal Women’s Hospital
1314 N. Macomb Street Milwaukee WI Clinic, Universidad Autonoma 132 Grattan Street
Monroe, MI 48162 USA Avda. Reyes Catolicos 2 Carlton, Victoria 3053
USA Tel. +1 414 266 6288 28040 Madrid, SPAIN AUSTRALIA
Tel. +1 800 746-5870 Fax. +1 414 266 2779 Tel. +34 91 554 7039 Ruth.Salom@med.monash.edu.au
Fax. +1 734 242-4962 pnorth@mew.edu Fax. +34 91 549 4764
davmehregan@pinkuslab.com lrequena@fjd.es
Dr. Thomas MENTZEL Dr. Hiroko OHGAKI Dr. Margaret Haskell RINKER Dr. Ignacio SANCHEZ-CARPINTERO
Dermatohistopathologisches International Agency for Research 1016 Ponce de Leon Boulevard Departamento de Dermatologia
Gemeinschaftslabor on Cancer (IARC) Suite 7 Clinica Universitaria de Navarra
Siemenstrasse 6/1 150, cours Albert Thomas Belleair, FL 35616 Universidad de Navarra
D-88048 Friedrichshafen 69008 Lyon USA Pio XII, 36
GERMANY FRANCE Tel. +1 727 584 2131 31080 Pamplona, SPAIN
Tel. +49 7541 60440 Tel. +33 4 72 73 85 34 Fax. +1 727 585 8683 Tel. +34 94825 5400
Fax. +49 7541 604410 Fax. +33 4 72 73 85 64 Fax. +34 94829 6500
tmentzel@w-4.de ohgaki@iarc.fr isanchezc@unav.es
Dr. Sonja MICHAELIS Dr. Salvatore PALA Dr. Christian ROSE Dr. Christian A. SANDER
Dermatologische Klinik Universita degli Studi La Sapienza Department of Dermatology Department of Dermatology
Universitätsspital Zürich Istituto di Clinica Dermatosifilopatica University of Lübeck General Hospital St. Georg
Gloriastrasse 31 - Policlinico Umberto I Ratzeburger Allee 160 Lohmühlenstr. 5
8091 Zürich Viale del Policlinico, 155 23538 Lübeck 20099 Hamburg
SWITZERLAND 00100 Roma, ITALY GERMANY GERMANY
Tel. +41 1 255 87 33 Tel. +39 337 795577 mobile Tel. +49 451 500 2515 Tel. +49 40 1818 85 2220
Fax. +41 1 255 44 03 Fax. +39 06 44740763 Fax. +49 541 500 5092 Fax. +49 40 1818 85 2462
sonja.michaelis@usz.ch Salvatore.Pala@uniroma1.it christian.rose@derma.uni-luebeck.de christian.sander@ak-stgeorg.lbk-hh.de
Dr. Martin C. Jr MIHM Dr. James W. PATTERSON Dr. Renato ROSSO Dr. Omar P. SANGUEZA*
Dermatopathology Department of Pathology Diparimento di Patologia Umana Dept of Pathology and Dermatology
Harvard Medical School University of Virginia Health System Università di Pavia e Ospedale Wake Forest University, School of
c/o Massachusetts General Hospital PO Box 800214 Policlinico San Matteo Medicine
55 Fruit Street, Warren 827 Charlottesville, VA 22908 Via Forlanini 14 Medical Center Boulevard
Boston, MA 02114-3117, USA USA 27100 Pavia, ITALY Winston-Salem, NC 27157-1072, USA
Tel. +1 617 724 1350 Tel. +1 434 982 4402 Tel. +39 0382 501242 Tel. +1 336 716 4096
Fax. +1 617 726 5626 Fax. +1 434 243 6757 Fax. +39 0382 525866 Fax. +1 336 716 7595
mmihm@partners.org jwp9e@virginia.edu rosso@unipv.it osanguez@wfubmc.edu
298 Contributors
Dr. Daniel Jose SANTA CRUZ Dr. Kathleen J. SMITH Dr. John F. THOMPSON Dr. Janine WECHSLER
Cutaneous Pathology Dept of Anatomic Pathology Sydney Cancer Centre Departement d’Anatomie
2326 Millpark Dr Quest Diagnostics Royal Prince Alfred Hospital Pathologique
St Louis, MO 63043-3530 Tucker, GA 30084 Missenden Road, Camperdown Hopital Henri Mondor
USA USA NSW 2050 Sydney 51 av Mar de Lattre de Tassigny
Tel. +1 314 991 4470 Tel. +1 678 406 1509 AUSTRALIA 94010 Creteil Cedex, FRANCE
Fax. +1 314 991 4309 ksmith@path.uab.edu Tel. + 61 2 9515 7185 Tel. +33 1 49 81 27 38
dsantacruz@aol.com Fax. + 61 2 9550 6316 Fax. +33 1 49 81 27 33
john@mel.rpa.cs.nsw.gov.au janine.wechsler@hmn.ap-hop-paris.fr
Dr. Marco SANTUCCI Dr. Bruce R. SMOLLER Dr. Yoshiki TOKURA Dr. David WEEDON*
Dept of Human Pathology and Oncology Department of Pathology Department of Dermatology 134 Whitmore Street
University of Florence Medical UAMS Medical Center University of Occupational and Taringa, P.O. Box 344
School 4301 West Markham Street, Slot 517 Environmental Health Indooroopilly, Queensland 4068
Viale G.B. Morgagni, 85 Little Rock, AR 72205 1-1 Iseigaoka, Yahatanishi-ku AUSTRALIA
50134 Florence, ITALY USA Kitakyushu 807-8555, JAPAN Tel. +61 7 3377 8776
Tel. +39 055 4478105 Tel. +1 501 686 5170 Tel. +81 93 691 7445 Fax. +61 7 3371 6563
Fax. +39 055 432144 Fax. +1 501 296 1184 Fax. +81 93 691 0907 d_weedon@snp.com.au
marco.santucci@unifi.it smollerbrucer@uams.edu tokuray@hama-med.ac.jp
Dr. Alain SARASIN Dr. Leslie H. SOBIN Dr. Massimo TOMMASINO Dr. Wolfgang WEYERS
Institut Gustave Roussy PR2 Department of Hepatic and Infection and Cancer Biology Group Zentrum für Dermatopathologie
UPR 2169 CNRS Gastrointestinal Pathology International Agency for Research Center for Dermatopathology
39, rue Camille Desmoulins Armed Forces Institute of Pathology on Cancer Engelbergerstr. 19
94805 Villejuif cedex 14th Street and Alaska Avenue 150, cours Albert Thomas 79106 Freiburg
FRANCE Washington, DC 20306-6000, USA 69008 Lyon, FRANCE GERMANY
Tel. +33 1 42 11 63 28 Tel. +1 202 782 2880 Tel. +33 4 72 73 81 91 Tel. +49 761 31696
Fax. +33 1 42 11 50 08 Fax. +1 202 782 9020 Fax. +33 4 72 73 84 42 Fax. +49 761 39772
sarasin@igr.fr sobin@afip.osd.mil tommasino@iarc.fr ww@zdpf.de
Dr. Ulrico SCHMID Dr. Alan SPATZ* Dr. Jorge Toro Dr. Wain L. WHITE
Department of Pathology Department of Pathology Genetics and Epidemiology Branch Greensboro Pathology Associates
Kantonsspital St. Gallen Institut Gustave-Roussy IGR National Cancer Institute, EPS Suite 104
Rorschacherstrasse 95 39, rue Camille Desmoulins 6120 Executive Bld., MSC, Room 7125 706 Green Valley Road
9007 St. Gallen 94805 Villejuif Cedex Rockville, MD 20852-7236 Greensboro NC 27415-3508
SWITZERLAND FRANCE USA USA
Tel. +41 71 494 21 02 Tel. +33 1 42 11 44 62 or 53 Tel. +1 301 451-4562 Tel. +1 336 387-2544
Fax. +41 71 494 28 94 Fax. +33 1 42 11 52 63 Fax +1 301 402-4489 Fax. +1 3336 387-2501
ulrico.schmid@kssg.ch spatz@igr.fr toroj@mail.nih.gov
Dr. Tilman SCHULZ Dr. Wolfram STERRY Dr. Antonella TOSTI Dr. Sean J. WHITTAKER
Institute for Pathology Clinic for Dermatology, Allergology Department of Dermatology Head of Service
Escherichstrasse 6 and Venerology S Orsola Hospital St. John’s Institute of Dermatology
91522 Ansbach Humboldt University University of Bologna St. Thomas’ Hospital
GERMANY Schumannstr. 20/21 Via Massarenti 1 Lambeth Palace Rd
Fax. +49 0981 4888310 10117 Berlin, GERMANY 40138 Bologna, ITALY London SE1 7EM, UK
schulz@pathologie-ansbach.com Tel. +49 30 450 518 061 Tel. +39 051 341820 Tel. +44 207 188 6396
Fax. +49 30 450 518 911 Fax. +39 051 347847 Fax. +44 207 118 6257
wolfram.sterry@charite.de tosti@almadns.unibo.it sean.whittaker@kcl.ac.uk
Dr. Richard SCOLYER Dr. Geoffrey STRUTTON Dr. Goos N.P. VAN MUIJEN Dr. Mark R. WICK
Department of Anatomical Pathology Anatomical Pathology, Dept. of Pathology Division of Surgical Pathology and
Royal Prince Alfred Hospital Princess Alexandra Hospital University Medical Center St. Radboud Cytopathology, University Hospital
Missenden Road Ipswich Road P.O. Box 9101 University of Virginia Health System
NSW 2050 Camperdown Qld 4102 Woolloongabba, Brisbane 6500 HB Nijmegen 1215 Lee Street
AUSTRALIA AUSTRALIA THE NETHERLANDS Charlottesville, VA 22908-0214, USA
Tel. +61 9515 7011 Tel. +617 3240 2480 Tel. +31 24 3614399 Tel. +1 434 924 9038
Fax. +61 9515 8405 Fax. +617 3240 2930 Fax. +31 24 3540520 Fax. +1 434 924 0217
richard.scolyer@email.cs.nsw.gov.au geoff_strutton@health.qld.gov.au g.vanmuijen@pathol.umcn.nl mrwick1@usa.net
Dr. Ratnam K. SHANMUGARATNAM Dr. Daniel W.P. SU Dr. James VARDIMAN Dr. Robb E. WILENTZ
Department of Pathology Department of Dermatology Department of Pathology Department of Dermatology and
National University Hospital Mayo Medical School University of Chicago Medical Center Cutraneous Surgery
Lower Kent Ridge Road 200 First St. SW 5841 South Maryland Ave.MC0008 / University of Miami School of
119074 Singapore Rochester, MN 55905-0001 TW-055 Medicine
SINGAPORE USA Chicago, IL 60637-1470, USA 1444 N.W. 9th Avenue, 3rd Floor
Tel. +65 6772 43 12 Tel. +1 507 284 2511 Tel. +1 773 702 6196 Miami, FL 33136
Fax. +65 6778 06 71 Fax. +1 507 284 0161 Fax. +1 773 702 1200 USA
patshanm@nus.eud.sg su.daniel@mayo.edu jvardima@mcis.bsd.uchicago.edu
Dr. Henry G. SKELTON Dr. Steven H. SWERDLOW* Dr. Camilla VASSALLO Dr. Rein WILLEMZE*
Dept of Anatomic Pathology University of Pittsburgh Department of Dermatology Department of Dermatology, B1-Q-93
Quest Diagnostics UPMC Presbyterian Pathology Dept University of Pavia Policlinico S Leiden University Medical Center
Tucker, GA 30084 Room C606.1 Matteo-IRCCS Albinusdreef 2, PO Box 9600
USA 200 Lothrop Street Piazzale Golgi 2 2300 RC Leiden
Tel. +1 678 406 1509 Pittsburgh, PA 15213, USA 27100 Pavia, ITALY THE NETHERLANDS
henry.g.skelton@questdiagnostics.com Tel. +1 412 647 5191 Tel. +39 0382 503813 Tel. +31 71 5262421
Fax. +1 412 647 4008 Fax. +39 0382 526379 Fax. +31 71 5248106
swerdlowsh@upmc.edu cvassallo@yahoo.com willemze.dermatology@lumc.nl
Contributors 299
Dr. Richard M. WILLIAMSON Dr. Lawrence L. YU*
Sullivan Nicolaides Pathology School of Surgery and Pathology
134 Whitmore Street University of Western Australia
Taringa, QLD 4068 Queen Elizabeth II Medical Centre
AUSTRALIA Hospital Avenue
Tel. +61 7 3377 9765 Nedlands, WA 6009, AUSTRALIA
Fax. +61 7 3377 8724 Tel. +61 8 9346 3329
richard_williamson@snp.com.au Fax. +61 8 9346 2891
lawrence@cyllene.uwa.edu.au
Dr. Xiaowei XU
Dept of Pathology and Laboratory
Medicine
University of Pennsylvania
3400 Spruce Street
Philadelphia, PA 19104, USA
Tel. +1 215 662 6503
Fax. +1 215 349 5910
xug@mail.med.upenn.edu
300 Contributors
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Subject index
C
A typical naevus 105 BHD gene 158
A typical nodular melanocytic pro- Birbeck granules 217, 219-221,
liferation 85 225
A typical pigmented spindle cell nae- Birds-eye cells 38 C to T mutation 11
vus 117 Birt-Hogg-Dubé syndrome (BHD) CA15.3 161
A typical proliferative nodules in 157, 158, 278 Café-au-lait spots 222, 223, 289
giant congenital naevi 93 B-K mole syndrome 105, 109, 279 Calcification 19, 46, 140, 149,
Blastic NK-cell lymphoma 2 0 8 151, 214, 234, 253, 256, 286,
B
Blastoid NK-cell lymphoma 208 287
Bloom syndrome 30, 211, 278 Calcifying epithelioma of Malherbe
Blue naevi 9 5-99 153
Bacillary angiomatosis 2 4 0 Blue naevus-like melanoma 79 Calcitonin 273
Bacille Calmette-Guérin (BCG) vac- Blueberry muffin syndrome 218 C-ALCL 179, 180, 181
cine 55, 260 BMPR1A 290 Callus 75
Back to back appearance 234 Bombesin 273 Calretinin 275
Bannayan–Riley–Ruvalcaba syn- Bone morphogenic protein receptor CAM 5.2 21, 22, 28, 75, 131,
drome (BRRS) 288 type 1A gene (BMPR1A) 290 135, 136, 138, 273
Bartonella bacteria 240 Borrelia 195, 206, 212, 213 Campbell de Morgan spots 233
Basal cell carcinoma 1 3-19, 285 Borrelia burgdorferi 194, 206, Candidiasis 23
212, 213 Caput Medusae pattern 156
G
199, 202 Fanconi anaemia 211
ERCC1 278 Faulty hair matrix 154
ERCC2 278 FCC 196, 197
ERCC4 278 FcgRII 233 Ganglion of the distal interpha-
ERCC5 278 FCL 196, 197 langeal joint 257
Eruptive syringoma 140 Ferguson Smith type keratoacan- Gardner syndrome 154, 278
Erythema 55, 105, 114, 137, thoma 45 Gasoline 11
189, 192, 200, 212, 214, 227 Ferguson Smith type of “multiple Gastrin 273
Erythematous nodule 17, 77, 125 self-healing epitheliomas” 46 Gastrointestinal stromal tumours
Erythematous scaly patches 137 Fetal rhabdomyoma 253, 285, 286 (GISTs) 226
Erythroderma 169, 175-177, Fibrocytokines 78 Gata-3 177
189, 193 Fibroepithelial polyp 253 GCDFP-15 125, 132, 138
Erythrodermic CTCL 175 Fibroepithelioma of Pinkus 17 Gene rearrangement of
Erythroplasia of Queyrat (EPQ) 27 Fibroepithelioma 15, 17 immunoglobulin heavy chain
Ewing sarcoma 264, 268 Fibroepithelial basal celll carcinoma genes, and T-cell receptor genes
EWS gene 269 17 210
Exophthalmos 218, 225 Fibroepithelial polyp 258 Generalized cutaneous histiocytosis
Expansile pattern of growth 68 Fibrofolliculoma 157, 1 5 8, 159 (GCR) 224
Extramammary Paget disease 71, Fibroma durum 261 Generalized lymphangioma 249
136 Fibroma 286 Genital melanosis/lentiginosis 103
Extramammary Paget’s cells 17 Fibromatous Tumours of the Skin Genital naevus 1 1 0, 111
Extramedullary myeloid sarcoma 279 Genital naevus with unusual histo-
211 Fibromin 278 logic features 110
Extranodal marginal zone B-cell Fibroplasia 69, 71, 78 Genodermatosis 36, 256, 285
lymphoma 194 Fibrosarcoma 78, 258, 260 Germinative cells 13, 14, 16, 148
Extranodal NK/T-cell lymphoma Fibrosclerosis 221 Germline 39, 163, 191, 192, 209,
183, 191, 192 Fibrous hamartoma of infancy 253 280, 287-290
Extranodal NK/T-cell lymphoma, Fibrous histiocytoma 78, 231, Germline mutations 231
nasal-type 1 9 1 232, 235, 260, 261 GFAP 269, 275
Extraskeletal Ewing sarcoma 2 6 8 Fibrous papule of the face 258 Ghost vessels 233
Eyelid hidrocystoma 142 FIGO (Fédération Internationale de Giant cell fibroblastoma 2 5 8,
Gynécologie et d’Obstétrique) 260, 261
137 Giant cell histiocytosis 224
F Fine-needle aspiration cytology Giant cell reticulohistiocytosis 224
231 Giant condyloma acuminata
Fabry disease 244, 245 FISH 75, 177, 204, 269 (Buschke-Lowenstein tumour)
Factor VIII 24, 237, 243, 247 Fitzpatrick skin types 66 36
Factor VIII-related antigen 24, Flat macule 56 Giant condyloma acuminatum 22
237, 247 Flat seborrhoeic keratosis 42, 44 Giant congenital naevus (GCN) 83
Factor XIII 223 Flat wart 38 Giant hair matrix tumour 150
Factor XIIIa 220, 221, 225, 262 FLI-1 246, 268, 269 Giant keratoacanthoma 45
Fluorouracil 28 Glabrous skin 26, 27, 46, 74
H
HLA-DR 180, 181, 220, 228 syringoma 148
HLA-DR5 172 Hyalinization 256, 270
HLA-DRB1*11 172 Hyalinizing Spitz naevus 115
Haemangioma 16, 114, 233-237, HLA-DRB1*1104 172 Hyaluronidase resistance 148
239, 242, 243, 245, 258, 289, HMB-45 63, 69, 75, 78, 81, 87, Hydroa vacciniforme-like cutaneous
262 95, 98, 107, 119, 269 T-cell lymphoma 1 9 2
Haemangioma of infancy 2 3 3 HMSH2 163, 278 Hydrolase alpha-galactosidase A.
Haemangioma unilateralis naevi- Hobnail haemangioma 2 3 4 244
forme 242 Hodgkin disease 207 Hyperchromasia 12, 21, 30, 81,
Haemangiopericytoma-like fibrous Hodgkin lymphoma (HL) 178, 206, 104
histiocytoma 262 207 Hypergammaglobulinemia 193
Haemangiosarcoma 246 HOGG1 81 Hyperkeratotic seborrhoeic kerato-
Haematopoietic stem cells 211 HOI 233 sis 42
Haemophagocytic syndrome 182, Homer Wright rosettes 268 Hypermelanotic naevi 58
183, 185, 191, 192 Hormonal contraceptives 236 Hypersensitivity to insect bites
Hailey-Hailey disease 40 Horn cysts 19, 42, 141 192
Hair disk (Haarscheibe) 158 HOXC5 181 Hypertension 227
Hair follicle hamartoma 279 Hypertrophic scar 2 5 4, 255
I
26 Keratocystic odontogenic tumours
Intraepidermal Merkel cell carcinoma 286
138 Keratoses 12, 32, 33, 40-43, 57,
Iatrogenic arteriovenous fistulas Intra-epidermal proliferative disor- 119, 155, 289
241 ders (dysplasias) 11 Keratosis follicularis inversa 156
ICAM-1 112 Intramuscular haemangioma 233 Keratotic basal cell carcinoma 1 9
IgA 123, 146, 172 Intravascular large B-cell lym- Keratotic haemangioma 242
IgE 172, 254 phoma (IL) 2 0 0 Ketron-Goodman type 185
IGF-II 233 Intravascular lymphoma 200, 241 Ki-67 60, 69, 81, 87, 107, 127,
IgG 146 Intravascular lymphomatosis 200 234, 238, 275
IKH-4 146 Intravenous atypical vascular pro- Kimura disease 238
IL-4 172 liferation 237 KIN See Keratinocyte intraepider-
IL-5 172 Invasive hair matrix tumour of the mal neoplasia 30
IL-10 172 scalp 150 KIR receptors 209
Immature trichoepithelioma 18 Invasive pilomatrixoma 149 KIT 226-228, 273
Immunoglobulin 195, 198, 202, Inverted type A naevus 100 Klippel-Trenaunay syndrome 239
204, 205, 206, 214, 236 Involucrin 21, 28, 32, 44 Klippel-Trenaunay-Weber syndrome
Immunosuppression 20, 31, 36- Ionizing radiation 13, 14, 23, 231, 244
38, 40, 45, 47, 68, 231, 240, 246, 283 Koebner phenomenon 36, 38
272, 273 Irregular acanthosis 112 Koilocytes 29, 36, 37
In situ hybridization 12, 26, 191, Irritated seborrhoeic keratosis 42 Koilocytosis 38, 43
203, 204 Isochromosome 11p 116 Kostmann syndrome 211
Indeterminate cell histiocytosis Isolated dyskeratosis follicularis KP1 220, 221, 225, 262
(ICH) 2 2 0 39 K-ras 11
Indolent systemic mastocytosis Ixodes ricinus 213 Kyphoscoliosis 286
226
J
Industrial carcinogens 20
Infantile haemangioma 233 L
Infantile melanoma (birth to one-
year of age) 84 JH translocation 198 Labial lentigo 103
Infantile myofibromatosis 2 5 6 Jun D 278 Labial melanotic macule 103
Infiltrating basal cell carcinoma Juvenile chronic myeloid leukaemia Labial/oral melanosis 103
17 222, 223 Lactate dehydrogenase (LDH) 58
Inflammatory angiomatous nodule Juvenile haemangioma 233 LAMB syndrome 103, 291
237 Juvenile polyposis syndrome 290 Laminin 78, 115, 148, 234, 275
Inflammatory molluscum contagio- Juvenile xanthogranuloma (JXG) Langerhans cell disease 217
sum 212 2 2 2, 223 Langerhans cell granules 219
Inflammatory myofibroblastic JXG See Juvenile xanthogranuloma Langerhans cell granulomatosis
pseudotumour 213 217
Inflammatory pseudotumour (IPT) Langerhans cell histiocytosis (LCH)
213 K 138, 2 1 7
Infundibular tumour 158 Langerhans cells 144, 213, 217,
Infundibulocystic basal cell carcino- K1 and K10 genes 39 219, 220
ma 19 Kamino bodies 59, 115, 117 Large cell acanthoma 39-41, 4 4,
Infundibuloisthmicoma 157 Kaposi sarcoma 231, 235, 237, 47
Ingrown toenail 75 239, 241, 246, 249, 262 Large cell lymphoma (Richter
Inguinal hernia 244 Kaposiform haemangioendothelioma syndrome) 206
Inherited tumour syndromes 277 233 Large plantar wart 38
Ink spot 40 Kasabach-Merritt syndrome 240 Latitudes 11, 13
Ink spot lentigo 103 Keloid scar 2 5 4, 255 Laugier-Hunziker syndrome 103
INK4a 11 Keratin cysts 19 LDH 58