ORL 2001;63:187

Preface

Having already organized two other Special Issues – one on ‘Neuroendo-

crine Neoplasms of the Larynx’ in 1991 and the other on ‘Cancer of the
Larynx: Current Concepts in the Treatment of the Neck’ in 2000, co-edited by
Professor Wolfgang Arnold (Munich) – it gives me great pleasure to present a
Special Issue devoted to ‘Distant Metastases from Head and Neck Cancer: A
Multi-Institutional View’, as this highly-specialized topic is of growing scien-
tific and clinical interest.
Decisions regarding the radical resection of primary tumors and appro-
priate reconstruction depend largely on the presence or absence of distant
metastases. It is therefore essential to search thoroughly for any presence of
these metastases before implementing any treatment.
The contributors have been selected for their standing in their respective
subspecialist fields. It has been a pleasure to cooperate with these distin-
guished authorities and there has been a fruitful, continuous exchange of opin-
ions and information during the preparation of this publication.
Our hope is that this Special Issue will prove a useful tool for all physicians
particularly interested in the diagnosis, treatment and prognosis of distant
metastases from head and neck cancer.
A. Ferlito, MD

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Distant Metastases
from Head and Neck
Cancer
A Multi-Institutional View

Guest Editor
A. Ferlito, Udine, Italy

1 figure, 24 tables, 2001

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 Vol. 63, No. 4, 2001

Contents

187 Preface 229 Distant Metastases from Cervical Esophagus Cancer

Bresadola, F.; Terrosu, G.; Uzzau, A.; Bresadola, V. (Udine)
189 General Considerations on Distant Metastases from 233 Distant Metastases from Salivary Glands Cancer
Head and Neck Cancer Bradley, P.J. (Nottingham)
Ferlito, A.; Rinaldo, A. (Udine); Buckley, J.G. (Leeds); Mondin, V.
(Udine) 243 Distant Metastases from Thyroid and Parathyroid
Cancer
192 The Biology of Distant Metastases in Head and Neck Shaha, A.R. (New York, N.Y.); Ferlito, A.; Rinaldo, A. (Udine)
Cancer
Petruzzelli, G.J. (Maywood, Ill.) 250 Distant Metastases from Ear and Temporal Bone
Cancer
202 Incidence and Sites of Distant Metastases from Head Sasaki, C.T. (New Haven, Conn.)
and Neck Cancer
Ferlito, A. (Udine); Shaha, A.R. (New York, N.Y.); Silver, C.E. 252 Noncervical Lymph Node Metastasis from Head and
(Bronx, N.Y.); Rinaldo, A.; Mondin, V. (Udine) Neck Cancer
Kowalski, L.P. (São Paulo)
207 Screening Tests to Evaluate Distant Metastases in
Head and Neck Cancer 256 Proposal of Standardization on Screening Tests for
Ferlito, A. (Udine); Buckley, J.G. (Leeds); Rinaldo, A.; Mondin, V. Detection of Distant Metastases from Head and Neck
(Udine) Cancer
Johnson, J.T. (Pittsburgh, Pa.)
212 Distant Metastases from Sinonasal Cancer
Lund, V.J. (London) 259 The Treatment of Distant Metastases in Head and
Neck Cancer – Present and Future
214 Distant Metastases from Nasopharyngeal Cancer Buckley, J.G. (Leeds); Ferlito, A. (Udine); Shaha, A.R.
Chiesa, F.; De Paoli, F. (Milan) (New York, N.Y.); Rinaldo, A. (Udine)
217 Distant Metastases from Lip and Oral Cavity Cancer
Betka, J. (Prague)
265 Author Index
222 Distant Metastases from Oropharyngeal Cancer 266 Subject Index
Goodwin, J.W. (Miami, Fla.)

224 Distant Metastases from Laryngeal and

Hypopharyngeal Cancer
Spector, G.J. (St. Louis, Mo.)

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 ORL 2001;63:189–191
General Considerations on Distant
Metastases from Head and Neck Cancer
Alfio Ferlito a Alessandra Rinaldo a J. Graham Buckley b Vanni Mondin a
Departments of Otolaryngology – Head and Neck Surgery, a University of Udine, Italy and
b Leeds
General Infirmary, Leeds, UK
Key Words
Distant metastases W Head and neck cancer W
Classification and terminology of metastases
Abstract
Mortality in head and neck cancer is due to locoregional
disease, distant metastases or intercurrent disease. As
treatment of the primary tumor and cervical metastases
has improved, the proportion of deaths from co-morbidi-
ty and from distant metastases has increased. Distant
metastases almost invariably herald a poor prognosis in
head and neck cancer with an average survival of 4.3–7.3
months and treatment is usually palliative. Reliable de-
tection is important to prevent inappropriate treatment.
The risk is related to the site, stage and histology of the
primary tumor and the presence of cervical metastases.
Early detection and treatment of cervical metastases
may prevent distant metastases. Accurate staging of
tumors helps to identify high-risk tumors that should be
specifically investigated for distant metastases.
Copyright © 2001 S. Karger AG, Basel
Treatment selection for any patient with malignant
disease requires knowledge of the local, regional and dis-
tant spread of the tumor. At the present time it is rarely
possible to offer curative treatment for distant metastases
and so reliable detection is particularly important.
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‘The ultimate event that leads to the mortality of can-
cer is metastasis’ [1]. This statement is true of many
tumors but is complicated by high locoregional recurrence
and co-morbidity in head and neck cancer. Most tumors
of the head and neck initially metastasize to the regional
lymph nodes. The presence of cervical metastases is the
most significant oncological factor in the prognosis of
head and neck squamous cell carcinoma (SCC) because
early detection and treatment may prevent distant metas-
tases [2]. Despite the great advances in cancer treatment,
most patients die of distant metastatic disease.
Presentation of distant metastases is usually late in the
course of the disease and almost invariably means a poor
prognosis. The average survival in this situation ranges
between 4.3 [3] and 7.3 [4] months. Patients with distant
metastases are generally not considered curable and
usually receive only palliative support [5]. Cancers of the
head and neck area are at risk of developing a distant
metastasis before, during or after treatment. The risk is
principally related to site, stage and histology and one of
the roles of this issue is to offer guidelines on investigation
of different tumors. It is recognized that pharyngeal SCC,
for example, has a high rate of metastasis and requires
investigation. Conversely there would be little point in
extensive investigation of a patient with laryngeal verru-
cous carcinoma, which does not metastasize [6], or poly-
morphous low-grade adenocarcinoma of salivary origin,
which has a low metastatic potential [7].
The presence of metastatic disease and its automatic
stage IV status raises interesting and complex manage-
Alfio Ferlito, MD
Department of Otolaryngology-Head and Neck Surgery
University of Udine, Policlinico Universitario
Piazzale S. Maria della Misericordia, I–33100 Udine (Italy)
Tel. +39 0432 559301, Fax +39 0432 559337, E-Mail clorl@dsc.uniud.it
ment decisions for the clinician involved in the treatment
of patients with head and neck cancers [8]. The preva-
lence of metastases at autopsy (37–57%) is much higher
than in clinical studies (4–26%) [9]. This suggests that dis-
tant metastases in head and neck cancer are often asymp-
tomatic, which raises the question of screening. Any
investigations used for screening need to be sensitive,
highly specific, inexpensive, noninvasive and readily
available [4]. Thyroglobulin and calcitonin are valuable
serum markers in thyroid cancer but there is, as yet, no
equivalent test for SCC. The value of repeat chest X-rays
is highly debatable. In the absence of useful screening
tests, metastases are usually detected by specific investiga-
tion of suspicious symptoms. Plain X-rays, computed
tomography (CT) and bone scanning are the most fre-
quently used investigations.
Tumor staging of patients with malignancies of the
head and the neck is essential prior to definitive treat-
ment. Identification of high-risk patients allows for a
more focused search for metastases. Diagnosis of meta-
static disease at the time of initial evaluation should avoid
inappropriate intervention. Re-evaluation is equally im-
portant when considering curative treatment in patients
with recurrence of locoregional disease. The diagnostic
and staging procedures used for head and neck cancer are
sometimes equivalent and sometimes complementary.
The available methods for the assessment of tumor status
include: (1) conventional radiographs (X-rays); (2) sec-
tional imaging – CT, magnetic resonance imaging (MRI),
positron emission tomography (PET); (3) ultrasound and
ultrasound-guided fine needle biopsy; (4) radionuclide
scanning; (5) endoscopic examination and (6) histological
and cytological investigations – conventional histology,
semiserial sections, immunohistochemistry, molecular
analysis and techniques of cell culture.
Tumor mapping and staging at the time of the patient’s
initial evaluation is very important for initiating a correct
and appropriate treatment plan but evaluation of the
patients tumor status should continue throughout the
course of their life. T-staging is useful for summarizing
information for data comparison but has its limitations. It
is clear that measuring of the surface extent of a tongue
tumor may be of less prognostic significance than its
depth. Similarly, the staging of glottic carcinoma has
attracted a lot of criticism because it often fails to put
patients into appropriate prognostic groups. Failure to
understand the heterogeneity of T3 glottic cancer, for
example, has resulted in a pointless debate on whether
treatment should be laryngectomy or radiotherapy. It has
been shown that the T3 stage includes tumors with a 10-
190 ORL 2001;63:189–191
fold range of volume, from 1.7 to 17 ml [10]. The blanket
use of a single philosophy of treatment for such a dispa-
rate group is inappropriate. Accurate tumor mapping
using photography or standardized staging forms, com-
bined with radiological, or other, assessment of tumor
depth has an important long-term function. Staging sys-
tems change and evolve. Retrospective staging may be
impossible unless the exact extent of the tumor has been
recorded.
The method of assessment of treatment and prognosis
is a complex issue. Survival is obviously important. Many
investigators use determinate or disease-specific survival
because of the high death rate from intercurrent illness in
this patient population. Although it may be useful for
comparison of treatment modalities, it has an element of
subjectivity – not least because of the unreliability of
death certificate information. Absolute survival is the
most important issue from the perspective of the patient.
It also has the merit of objectivity. The quality of that sur-
vival is the other important factor but is not easy to assess
[11]. It is also interesting that survival is at the top of the
list when patients are asked to rank the issues that are
most important after treatment of head and neck cancer
[12]. There is also some variation in the timing of assess-
ment. Conventionally, outcomes are measured after 5
years for most cancer sites. This convention has been
adopted in most head and neck cancer studies but is not
necessarily the most appropriate. Survival in salivary can-
cer can decline over a 15- to 20-year time scale. SCC is the
most common malignant tumor in the head and neck.
Recurrent locoregional disease or metastases rarely occur
after 3 years and if a universal standard were adopted, this
would be the most appropriate time interval. Survival is
related both to control of primary tumor and prevention
of the development of distant metastases. The proportion
of deaths from locoregional disease may have fallen but is
offset by the ‘long-term’ occurrence of distant metastases
particularly in supraglottic and pharyngeal cancer [11]. In
addition, a high proportion of patients with distant metas-
tases also have persistent or recurrent locoregional dis-
ease. A recent retrospective study examined patients with
locoregionally-controlled carcinoma of the oral cavity,
pharynx and larynx for the cause of death. It was attribut-
ed to the development of distant metastases in only 5%
[9]. In a sense, improved locoregional control may allow
more time for the development of distant metastases or
second primary tumors.
The development of a second primary cancer is not an
unusual observation in patients who have already been
diagnosed with a head and neck cancer. In general, the
Ferlito/Rinaldo/Buckley/Mondin
possibility of developing a second primary cancer is
reported to be associated with a risk of 10–35% [13]. The
risk is cumulative and the precise figure depends on the
timing of the assessment. This association of multiple
cancer development in the head and neck is likely to be a
consequence of genetic predisposition [14] and exposure
to environmental carcinogens. These may be recreational
(e.g., tobacco and alcohol), occupational (e.g., asbestos
and hardwood dust) or prior radiation. Locoregional con-
trol is still an important goal in the management of head
and neck cancer. If we are to improve survival, we now
need to consider how we prevent or eradicate metastatic
disease.
Table 1 summarizes the classification and the termi-
nology usually used in the current literature regarding the
metastases from head and neck cancers. It is imperative
that among clinicians who treat head and neck cancer,
there is no misinterpretation or confusion of the terms
used when reporting results.
Table 1. Classification and terminology of metastases from head
and neck cancer
Regional lymph node metastasis
Distant lymph node metastasis (metastasis in any lymph node other
than regional is classified as a distant metastasis)
Distant nonlymphatic metastasis
Clinical metastasis
Established metastasis (usually detected by routine histopathology
and is typically larger than micrometastasis)
Subclinical metastasis (indicated also as occult metastasis or occult
disease)
Subpathological metastasis (indicated also as occult micrometastasis,
minimal residual disease, minimal residual cancer or micromet-
astatic disease)
Molecular metastasis (metastasis revealed by molecular tests)
Skip metastasis (when the tumor cells escape the first draining lymph
node and metastasize to other lymph nodes)
Delayed metastasis

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Distant Metastases ORL 2001;63:189–191 191

 ORL 2001;63:192–201
The Biology of Distant Metastases in
Head and Neck Cancer
Guy J. Petruzzelli
Departments of Otolaryngology, Head and Neck Surgery and General Surgery, and Head and Neck Oncology
Program, Cardinal Bernardin Cancer Center, Loyola University Medical Center, Maywood, Ill., USA
Key Words
Cancer invasion W Angiogenesis W Metastasis
Abstract
The detection and treatment of metastatic cancer contin-
ues to be a challenge for the head and neck oncologist.
Unfortunately, head and neck cancer patients who devel-
op distant metastases commonly present late in their
course and rapidly succumb to their disease, despite
advances in imaging technologies and increased sophis-
tication of biochemical analyses. The development of a
rational approach to detection and treatment of meta-
static head and neck cancers should begin with an under-
standing of how these tumors occur and which patients
are at greatest risk for developing them. This article
presents an overview of the biological processes result-
ing in the speed of a malignancy from one site to anoth-
er, with particular attention to head and neck carcino-
mas. The basic histopathologic, immunology and bio-
chemical abnormalities associated with the develop-
ment of these secondary tumors are also discussed.
Copyright © 2001 S. Karger AG, Basel
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Cancer describes a group of diseases having in com-
mon the uncontrolled growth of aberrant cells, invasion of
normal organs through direct extension, and metastasis.
Metastasis defined as the spread of disease from one
organ or part to another not directly connected with it
through the blood, lymph, or serosal surfaces [1]. All head
and neck cancers invade or metastasize and the proper
screening, diagnosis and treatment of these metastases are
based on the unique biologic properties of the primary
tumor. Many of these aberrant biologic properties have
been characterized and include particular genetic muta-
tions, chromosomal translocations, expression of unique
cell surface antigens, or the inappropriate secretion of hor-
mones, enzymes or other molecules.
This chapter will review the basic biological mecha-
nisms of metastasis, which are common to all head and
neck malignancies. Using head and neck squamous cell
carcinoma (HNSCC) as a model, we will present the histo-
pathologic features that predict the development of dis-
tant metastases, and finally survey the literature regarding
clinically revenant tumor markers for head and neck
malignancies.
Guy J. Petruzzelli, MD, PhD, FACS
Head and Neck Oncology Program, Cardinal Bernardin Cancer Center
2160 S. First Ave, Bldg 112, Rm 270
Maywood, IL 60153 (USA)
Tel. +1 708 327 3315, Fax +1 708 327 3248, E-Mail gpetruz@wpo.it.luc.edu
 Biological Processes of the Metastatic Cascade
Not all tumors, regardless of the size of the primary,
will develop distant metastases. Tumor metastasis is ulti-
mately the result of an imbalance between forces favoring
and opposing the development of secondary tumors. Fac-
tors which favor the development of metastases include
the primary tumors ability to activate oncogenes, down-
regulate tumor suppressor genes, express cell-surface ad-
hesion molecules, synthesize and respond to autocrine
and paracrine growth and motility factors, secrete pro-
teases, and produce angiogenic and immunosuppressive
cytokines. Factors opposing the development of metas-
tases include activated tumor suppressor and antimetas-
tasis genes, enhanced host immune responses, synthesis of
protease and angiogenesis inhibitors by both the tumor
and the host, and anatomic and structural barriers.
All of these phenomena are the result of multiple gene
mutations culminating in the development of secondary
tumors at distant sites.
Within a given tumor, subpopulations of cells exist
which differ in their sensitivity to chemotherapy or ioniz-
ing radiation, growth rates, growth factor production, and
other biologic properties including the ability to invade
and metastasize. Fidler and colleagues [2, 3] articulated
this principal of tumor heterogeneity, which is now widely
accepted. Therefore, propensity for the development of
distant metastases ultimately depends on the degree to
which the tumor is populated by these metastatic clones.
The development of local-regional and distant metas-
tases begins with the initiation of the primary tumor and
ends with the establishment of metastatic clones through-
out the host. Several processes including the differential
expression of cell adhesion molecules, release of metallo-
proteinases, and angiogenesis occur at multiple points in
the metastatic cascade. The following examination of the
mechanisms of tumorigenesis, invasion and metastasis
will principally relate to squamous cell carcinoma (SCC)
of the upper aerodigestive tract. However, similar mecha-
nisms exist for the other neoplasms reviewed in this text.
Transformation of Normal Cells into Tumor Cells
The development of a solid tumor is result of a series of
specific genetic alterations, which impart to the neoplastic
cells particular growth advantages. These mutations can
be spontaneous, inherited, or induced by the action(s) of
some chemical, viral, or radiation-induced DNA damage.
This process has been referred to as the acquisition of the
metastatic phenotype.
Biology of Distant Metastases
Epithelial tumors demonstrate a stepwise transition
from normal to malignant, and frequently these changes
can be induced by exposure to known carcinogens. In
1990, Fearon and Vogelstein [4] reported the sequence of
genetic events resulting in invasive colorectal cancer.
Many laboratories are examining the molecular pathogen-
esis of head and neck malignancies in the context of
tumor suppressor gene inactivation, proto-oncogene acti-
vation, and growth factor production [5–7].
Some of the perturbations in normal growth control,
which have been reported in head and neck malignancies,
include inactivation of tumor suppressor genes (p53 and
retinoblastoma, RB) resulting in failure to recognize nor-
mal signals for growth control and apoptosis [8–10]. Un-
der expression of kinase inhibitor protein p27 gene may
lead to increased G1-S transition and loss of cell cycle
control [11–13]. Additionally, the up-regulation of cycle-
activating proteins (cyclin D-1) and the overexpression of
the epidermal growth factor receptor (EGF-R) have been
demonstrated [14].
The susceptibility of the host to the development of
these mutations is another factor that must be considered
in the development of the primary tumor [15, 16]. In
HNSCC the use of tobacco products has been associated
with the development of cancer in the vast majority of
cases. However, in 10–15% of cases, SCC will develop de
novo in the absence of any tobacco exposure. In 1989,
Schantz et al. [17] established that lymphocytes collected
from young individuals with HNSCC without a signifi-
cant history of tobacco use had significantly increased
numbers of bleomycin-induced chromosome breaks than
control populations. These authors hypothesized that the
increased chromosome fragility demonstrated in these
patients may reflect an increased genetic susceptibility to
the development of malignancy. Recently, Koch et al. [18]
examined specific mutations present in HNSCC of smok-
ers and nonsmokers, hypothesizing that two different mo-
lecular mechanisms were involved. These studies demon-
strated that HNSCC developing in patients with a strong
tobacco history tended to have a higher frequency of p563
mutations and loss of heterozygosity at chromosomes 3p,
4q and 11q13. Using polymerase chain reaction probes,
human papilloma virus DNA was more frequently identi-
fied in nonsmokers. Taken together, these and other stud-
ies indicate that alternative molecular pathways may exist
for the development of malignant head and neck tumors
[18, 19].
In summary, the first steps in the development of dis-
tant metastases involve (1) the initiation of the primary
tumor in a genetically susceptible host, (2) the promotion
ORL 2001;63:192–201 193
and progression of malignant cell gene mutations favoring
clone expansion, and (3) uncontrolled proliferation of
these malignant clones of cells due to the actions of
autocrine growth factors and growth factor receptors
(EGF-R).
Angiogenesis
Following the initiation and growth of the primary
tumor, the second step in the establishment of distant
metastases is the development of an intratumor vascular
system. These blood vessels are formed from host-derived
endothelial cells that are recruited into the tumor, stimu-
lated to divide, and assemble into microtubules (i.e.
tumor angiogenesis). Once assembled, these vessels per-
form two main functions: (1) allow for increased growth
of the primary and (2) provide tumor microemboli access
to the host vascular system.
Folkman first proposed the dependence of tumor
growth and metastasis on an intact vascular system in
1971. In the absence of an intact vascular system, tumor
growth is limited to 2 mm in diameter by the diffusion of
oxygen and nutrients into and carbon dioxide and meta-
bolic wastes out of the tumor. Using a variety of experi-
mental models and clinical observations in several human
tumor systems, Folkman [20, 21] and others [22–24] have
clearly demonstrated that tumor angiogenesis appears to
be a crucial rate-limiting step in the development of dis-
tant metastases.
Of all head and neck malignancies, the angiogenic
mechanisms of HNSCC have been studied in greatest
detail. Our laboratory has been investigating the relation-
ship between HNSCC and endothelial cells in an effort to
more clearly understand the sequence of events associated
with tumor-induced new blood vessel formation. We
began by first demonstrating that HNSCC could stimu-
late an angiogenic response in an immunologically privi-
leged embryonic model [25]. Subsequent studies in own
and other laboratories have identified several cytokines
produced by HNSCC that could stimulate endothelial cell
proliferation and migration and alter the expression of
cell surface receptors. These cytokines include basic fibro-
blast growth factor (b-FGF), vascular endothelial cell
growth factor (VEGF) and transforming growth factor-ß
(TGF-ß). Unfortunately, neither serum nor urinary mea-
surement of these cytokines has been consistently shown
to predict tumor recurrence [26–29].
The association between the ability of a tumor to stim-
ulate angiogenic reposes and the potential for lymph node
metastasis has been studied in several solid tumor systems
including HNSCC and differentiated thyroid carcinoma.
194 ORL 2001;63:192–201
The initial studies of Srivastava et al. [30] in 1986 demon-
strated that, in intermediate thickness melanoma, the
greater the intratumor vascular area the greater the likeli-
hood of lymph node metastasis. In 1991, using immuno-
cytochemistry for human factor VIII as an endothelial cell
marker, Weidner et al. [31] correlated intratumor micro-
vessel density with nodal metastasis and clinical outcome
in breast carcinoma. A clear and significant correlation
between microvessel density (angiogenesis) and nodal
metastasis (outcome) was demonstrated in invasive
breast carcinoma. Subsequent studies by these and many
other authors have confirmed the relationship between
tumor microvessel density and nodal metastasis in early
and late stage breast carcinoma, ovarian and endometrial
carcinomas, non-small cell lung carcinomas, prostate car-
cinoma, adenocarcinoma of the colon, and SCC of the
esophagus [32–39].
Data regarding microvessel density as a predictor of
nodal metastasis, survival, or response to treatment in
HNSCC remains conflicting. In 1993, Gasparini et al.
[40] evaluated microvessel densities using the CD-31
endothelial monoclonal antibody in biopsy specimens of
70 patients with advanced head and neck cancer treated
nonsurgically. Patients with microvessel densities 125
per 200! field had a significantly higher (p ! 0.0046)
incidence of local or distant metastases. In this study,
tumor vascularity was not predictive of the response of a
tumor to chemoradiotherapy [40]. Tumor angiogenesis
has shown to positively correlate with nodal metastasis in
carcinoma of the tongue floor of mouth and nasopharynx
[41–46]. However, tumor microvessel density has been
reported to not serve as a predictor of lymph node metas-
tasis by several authors examining tumors from various
sites in the head and neck. Specifically, the tongue supra-
glottic larynx, thyroid and tonsil have been examined
independently, and no significant differences in vasculari-
ty at the tumor-host interface have been demonstrated
between metastatic and nonmetastatic tumors [47–54].
In summary: (1) tumor angiogenesis in required for
growth of the primary tumor to exceed 2 mm in diameter;
(2) tumors produce cytokines which stimulate endothelial
cell proliferation, migration and assembly; (3) the demon-
stration of intratumor blood vessels coincides with the
identification of distant metastases, and (4) quantifica-
tion of tumor angiogenesis can predict the likelihood of
nodal metastases in many solid tumor systems.
Invasion into Local Stroma and Vascular System
In addition to cytokines active on host endothelial
cells, tumors also produce a variety of proteinases active
Petruzzelli
on the components of the extracellular matrix. These pro-
teinases are critical at two points in the metastatic cas-
cade. The first is during intravasation into blood vessels
and lymphatic channels at the site of the primary tumor;
the second is during the extravasation of tumor cells at the
site of the distant metastasis. Whether at the primary or a
distant site the sequence of events associated with tumor
invasion follows the model articulated by Liotta and co-
workers [55, 56]; tumor attachment to basement mem-
brane components, degradation of extracellular matrix
and migration into the surrounding stroma.
The first step of tumor invasions involves attachment
to components in the subdermal extracellular matrix, par-
ticularly laminin. Laminin is composed of three long poly-
peptide chains held together by disulfide bonds in a cross-
like configuration. The functional domains of laminin
serve as receptors or binding site for other laminin mole-
cules, collagen, enctatin and the epithelial cell surface.
Tumor adherence to laminin is medial by a transmem-
brane laminin receptor protein. Malignant epithelial tu-
mors of the breast and colon have been shown to have
higher levels of cell surface lamina receptors than normal
epithelia [57–59].
The role of laminin and laminin receptor interactions
in HNSCC has also been investigated in some detail. In
1986, Carey and co-workers [60–62] identified a mem-
brane-associated protein unique to head and neck carci-
nomas. This antigen (A-9) was present in low levels in
normal keratinocytes but in much higher levels in
HNSCC. Ultrastructural studies indicated that the anti-
gen was located on the basal pole of the malignant epithe-
lial cells and led to speculation that it may have a role in
cell adhesion. The presence of increased expression of the
A-9 antigen was shown to significantly correlate with early
recurrence and reduced diseases-free survival in patients.
Biochemical and structural analysis of the A-9 antigen
identified it as an ·6-ß4 integrin. Integrins are a class
of high-molecular-weight transmembrane glycoproteins
composed of two noncovalently bound subunits (· and ß),
which attach to extracellular matrix and cytoskeletal com-
ponents. Both the ·6 and ß4 integrin subunits can func-
tion as laminin receptor and bind laminin. Experimental
studies using monoclonal antibodies to the ·- or ß-sub-
units and laminin receptor analogs have shown inhibition
of attachment to laminin in vitro and reduced metastasis
formation in vivo [63].
Work in our laboratory has shown that the pattern of
integrin expression in tumor cells can be influenced by
endothelial cells and cytokines. While several studies
have addressed the issue of alterations in endothelial cell
Biology of Distant Metastases
integrin expression, little attention has been directed to
changes in integrin expression on tumor cells. Soluble fac-
tors derived from endothelial cells transiently increase
adherence of HNSCC to fibronectin and vitronectin and
increase surface expression of the ß integrins 1 and 4, but
not 3 [64]. Alterations in tumor cell adherence and the
expression of these cell surface ligands may facilitate inva-
sion, metastasis and neovascularization. These studies
continue to elucidate the mechanisms of HNSCC local
invasion.
Following attachment to lamina molecules in the base-
ment membrane invasion of malignant cells is facilitated
by the secretion of several classes of enzymes that degrade
particular components of the extracellular matrix. The
production of these enzymes is not unique to malignant
cells nor is it an all-or-none phenomenon. Matrix degra-
dation by tumor occurs in an organized fashion such that
an appropriate scaffold of collagen and laminin remain to
provide enough retraction to allow invading tumor cells to
continue their migration into the extracellular matrix
[65]. In order to limit the activity of tumor-derived pro-
teinases, tumors also produce proteinase inhibitors. Tis-
sue-derived metalloproteinases inhibitors (TIMP-1 and
TIMP-2) have also been identified. These proteins bind to
specific activated MMP and prevent matrix degradation.
General classes of these proteolytic molecules include
the matrix metalloproteinases (MMP), named for their
dependence on Zn2+ as a catalyst, and the plasmino-
gen activators. MMP can be further subdivided based
on their respective substrates into (1) interstitial collage-
nases, (2) stromelysins and (3) gelatinases [66]. Specific
HNSCC-derived MMP responsible for the degradation of
fibrillar collagen (collagens I, II, III, V), laminins and oth-
er basement membrane components (collagen IV, gelatin)
have been identified. Using immunoblot analysis and
gelatin enzymography activity of MMP types 1, 2, 3 and 9
have been identified in HNSCC in vitro and in vivo [67–
75]. Charous et al. [76] attempted to demonstrate MMP
proteins using in-situ hybridization. Although expression
of MMP-2 and TIMP-1 was consistent in 21 primary
HNSCC tested, expression of MMP-1 and 9 was variable.
Stromelysins 2 and 3 have also been identified in both
HNSCC and chemically induced SCC, and up-regulation
of MMP m-RNA is positively correlated with increased
stromal invasion.
Another class of proteases, which have been studied in
HNSCC invasion and metastasis, are the plasminogen
activators [77]. These neutral serine proteases catalyze the
synthesis of plasmin from plasminogen and were initially
described in the thrombolytic cycle. Plasmin is a fibrino-
ORL 2001;63:192–201 195
lytic enzyme that also is active in degrading type IV colla-
gen and laminin. Although two forms of PA exist, the uro-
kinase type (u-PA) has been shown by several investiga-
tors to be important in HNSCC invasion and metastasis
[78]. Zymographic gel studies from several laboratories
have demonstrated u-PA production and activity [79].
Clayman et al. [80] have shown that increased invasion on
artificial basement membranes in vitro is correlated with
high levels of u-PA production and up-regulation of u-PA
mRNA. A specific antibody directed against the u-PA
catalytic site prevented invasion of basement membrane
coated filters by HNSCC. Although u-PA is produced by
several primary HNSCC cultures, u-PA levels are signifi-
cantly reduced with time [81].
Migration of tumor cells through the degraded base-
ment membrane into the stroma is the final step in the
sequence of tumor invasion. This process is also observed
as tumors invade vascular or lymphatic channels (intra-
vasation) or exits these channels at distant sites (extrava-
sation).
The ability of tumors to migrate through the extracellu-
lar matrix has been correlated with their metastatic poten-
tial in several experimental tumor systems. By comparing
both metastatic and nonmetastatic variants of the Lewis
lung carcinoma (LLC), Young and co-workers [82–85]
have demonstrated that differences in cytoplasmic cyto-
skeletal architecture may result in the observed differ-
ences in metastatic capabilities. These authors have
shown that lower levels of cytoskeletal organization are
associated with higher levels of invasiveness and in-
creased frequency of metastasis. The polymerization and
depolymerization of the cytoskeletal, hence cellular motil-
ity, is regulated in part by the binding of microtubular
associated proteins (MAPs). The phosphorylation of
MAP-2 by protein kinase A (PKA) will depolymerize
microtubules and destabilize the cytoskeleton. Hence the
observation that the more metastatic variants of the LLC
have increased PKA activity and reduced protein phos-
phatase-2A (PP-2A) compared to nonmetastatic clones.
Manipulation of the PP-2A and PKA axis can alter the
metastatic capabilities of the LLC. Manipulation of PP-
2A activity in HNSCC has also been shown to affect
migration and invasion in HNSCC in vitro. Inhibition of
PP-2A with okadaic acid reduced increased invasion of
HNSCCC lines through laminin and vitronectin. Increas-
ing PP-2A activity with either ceramide or dihydroxyvita-
min D3 decreased invasion through these matrix compo-
nents [86, 87].
In summary, the process of tumor invasion involves
attachment of the tumor to the basement membrane, deg-
196 ORL 2001;63:192–201
radation of extracellular matrix components, and migra-
tion of the malignant cells into the surrounding stroma.
We will refer again the process when we consider the
establishment of the tumor at a secondary (distant) site.
Circulation of the Tumor and Arrest at the Distant Site
Although a significant percentage of malignant tumors
may gain access to the vascular system via the thin walls
of the venous capillaries and lymphatic channels, few go
on to develop distant metastases. As mentioned above,
not all malignant cells are capable of developing metas-
tases and it is estimated that only 0.1% of all circulating
tumor cells eventually develop into secondary tumors.
Tumors will exist in the circulation as single cells, small
tumor microemboli with a fibrin ’cocoon’, or tumor cells
in aggregates with host lymphocytes and platelets. Form-
ing a fibrin shell around tumor microemboli is one mech-
anism by which tumors can prevent detection by circulat-
ing host immune surveillance. While the vast majority of
circulating tumor cells will either not survive host im-
mune defense mechanisms, be destroyed by mechanical
trauma of the circulatory system, or be carried to an unfa-
vorable secondary site, some will survive to establish
metastases [2].
Metastatic tumors, regardless of how they exist in the
circulation, will establish distant metastases either by
mechanical impaction or attachment to the endothelial
cell surfaces. Mechanical impaction of the tumor/lympho-
cyte/platelet emboli will occur when the diameter of the
embolus approaches that of the vessel. The tumor will
then adhere to the lumen surface of endothelial cells and
begin to grow. The second mechanism is the attachment
of single tumor cells to exposed basement membrane on
the subendothelial side of the capillary lumen.
The time course by which blood vessels extravasate
from the vascular lumen to the stroma is dependent of the
local of the attachment to the vascular tree. Tumors
adhering to the thin wall venules will rapidly stimulate
endothelial cell retraction and tumor pseudopodia can be
seen extending into the subendothelial cell space in 1–4 h.
Local dissolution of the basement membrane occurs rap-
idly and tumors can move into the stroma within 24 h.
Tumors adhering on arteriolar endothelium can remain
intravascular for up to 3 weeks and can become covered
by a layer of host endothelial cells. The internal elastic
lamina of arteriolar endothelial cells resists the rapid
retraction of arteriolar endothelial cells and allows for the
development of these intra-arterial microtumors. In time,
enough endothelial cell damage will occur to allow for
exposure of the subendothelial basement membrane, en-
Petruzzelli
dothelial cell retraction, production of proteases, and
extravasation of tumors into the surrounding stroma.
Using mechanisms similar to those of local invasion,
tumors egress from the circulation and proceed to invade
the parenchyma of the target organ [22, 55].
Colony Formation at the Secondary Site
The extravasation of tumors at the secondary site leads
to the development of micrometastases and eventually
fatal macrometastases. The proliferation of these tumors
within the substance of the target organ duplicates the
events seen at the primary including attachment to ma-
trix, production of proteinases, and angiogenesis.
The common theoretical mechanisms exist for deter-
mining the locations of distant metastases were first arti-
culated by Fidler as the ‘seed and soil hypothesis’ of
tumor metastasis. These mechanisms include: (1) tumor
metastasis equally to all organs, but preferentially only
grow in locations which provide appropriate growth fac-
tors (soil); (2) circulating tumor cells have receptors spe-
cific for the endothelial cells of only certain target organs
(seed), and (3) circulating tumors have receptors for spe-
cific chemotactic factors produced by the target organ.
These factors result in the preferential attraction of the
tumors to the target organ (seed soil) [77].
The distribution of the target organs in various malig-
nancies is not random; rather it is a reflection of both the
biology and location of the tumor. Many tumors in the
head and neck have predictable anatomic patterns of
metastases. For example, HNSCC and thyroid malignan-
cies most commonly metastasize to the lung which is the
first capillary bed to be encountered by circulating tumor
cells. Only rarely will metastases appear in the liver or
bone. Adenoid cystic carcinomas (regardless of the site)
will spread along nerve sheaths (perineural extension) and
will present with proximal lesion along cranial nerves.
The uses of orthotopic transplantation models of HNSCC
have shown that cervical lymph node and pulmonary
metastases are seen with greater frequency when com-
pared to tumor growth in the flank [88–90].
Biological Predictors of Metastasis
Thus far we have reviewed the molecular and cellular
events involved in tumor invasion and metastasis. We
have highlighted particular genes and gene products that
appear to play important roles in various times in the met-
astatic cascade. The identification of particular genes or
gene products (proteins), which can consistently predict
Biology of Distant Metastases
Table 1. Histological factors influencing
prognosis
Tumor thickness
Differentiation
Pattern of invasion
Host inflammatory response
Perineural spread
Vascular and/or lymphatic invasion
Bone and/or cartilage invasion
Lymph node metastasis
Extracapsular lymphatic extension
Surgical margin status
the aggressiveness, metastatic potential or occurrence of
distant metastases, would be of great clinical importance,
because, despite tremendous advances in reconstruction,
improved radiotherapy techniques and increased sophis-
tication in organ-sparing surgical techniques of head and
neck malignancies, in particular head and neck SCC, con-
tinue to have high rates of metastasis. The increased use
of systemic therapies including maintenance chemothera-
py has been shown to decrease the development of sec-
ondary tumors and clinical trails continue. These thera-
pies are toxic, expensive and, in some cases, unnecessary.
However, the lack of a reliable histological predictor of
metastasis and the high rate of distant failure justify their
continued use.
In general, two categories of potential tumors markers
can be discussed, those obtained from a histological
assessment of the primary tumor and/or regional nodes
and serum tumor markers. Histological data obtained
from the primary tumor (either biopsy or definitive resec-
tion) and regional nodes is most useful in the prognosis of
the development of distant metastases; serum markers
can be effective in screening for metastasis in asymptotic
patients. This section will examine some of the currently
used pathologic features, serum assay and potential im-
munological markers which have been shown to be useful
in predicting patients at risk for the development of meta-
static disease.
Traditionally, surgical pathologists have used an as-
sessment of the primary tumor in relationship to sur-
rounding host tissues to gauge the aggressiveness and
potential for metastasis (table 1). Such factors as tumor
thickness of cutaneous and epithelial malignancies, peri-
neural spread particularly of salivary gland tumors, an-
gioinvasion, extrathyroidal extension of endocrine tu-
mors, and extracapsular extension of metastatic SCC
ORL 2001;63:192–201 197
have all been correlated with the development of distant
metastasis [91].
One of the most widely accepted paradigms for prog-
nostic significance of histopathologic data are the staging
systems in use for differentiated thyroid carcinoma. Mul-
tiple analyses have examined the relationship of the
extent of thyroid capsular invasion and regional nodal
metastases to the development of pulmonary metastases
[92]. The AMES, DAMES and AGES systems all generate
relevant indices of metastases and are reviewed later in
this volume.
In HNSCC, the strongest histopathologic predictor of
distant metastases is the presence of extracapsular exten-
sion in the cervical lymph nodes. Clinical studies in the
1970s demonstrated the correlation between extracapsu-
lar extension and poor prognosis [93]. Since then, investi-
gators at the University of Pittsburgh and other centers
have confirmed this relationship [94–96]. Retrospective
data from the University of Pittsburgh indicate the strong
correlation between the presence of extracapsular exten-
sion in neck dissection specimens and the eventual devel-
opment of distant metastases. A review of 130 stage III
and IV patients treated with primary surgery revealed 30
patients with distant metastases as the only site of failure.
Of these, 88% had extracapsular extension in the cervical
nodes of which only 4 were clinically staged as N3. The
presence of three or more histologically positive nodes
was also associated with a significantly higher incidence
of distance metastasis [97].
In an attempt to stratify extracapsular extension, de
Carvalho [98] reviewed 170 patients with laryngeal or
hypopharyngeal SCC. Sixty-four percent (109/170) of pa-
tients had histopathological confirmation of metastatic
adenopathy in the neck dissection specimen. These pa-
tients were stratified into those with node-positive pa-
tients with no capsular invasion, capsular invasion with-
out extracapsular extension, capsular invasion with mi-
croscopic extracapsular extension, macroscopic extracap-
sular extension. Patients with macroscopic extracapsular
extension had significantly decreased overall survival and
a threefold increased risk of recurrence.
We have reviewed our experience at the Loyola Uni-
versity Medical Center with 157 previously untreated
patients with HNSCC and minimum 2-year follow-up. In
these patients the rate of the development of distant
metastasis in node-positive extracapsular spread positive
patients was 23% compared to 6.7% in node-positive
extracapsular spread negative and 1.9% in node-negative
patients (p = 0.001). Rates of isolated local recurrences
showed no statistical differences and were 4.6, 6.7 and
198 ORL 2001;63:192–201
3.8% respectively. The consistent pattern of distant fail-
ure observed in these patients has led to a renewed inter-
est in postoperative chemotherapy in these high-risk pa-
tients. Hopefully, data from the recently completed
RTOG 9501 trial comparing adjuvant radiotherapy alone
to concurrent radiotherapy plus cisplatin will provide use-
ful clinical information as to the benefit of system ther-
apy.
With the increased availability of molecular diagnostic
techniques, surgical pathologists have shifted the focus
away from the relationship between the tumor and the
surrounding tissue to more precisely examining the tumor
itself to provide accurate prognostic information. It is
beyond the scope of this commentary to completely
review the expanding body of literature concerning mo-
lecular prognosis in head and neck tumors. Mutations of
several key cell cycles regulating protein including p53,
cyclin D1 and p27 have shown consistently strong correla-
tions with the development of distant metastases, while
mutations in the Ki-67, retinoblastoma gene (Rb), Bcl-2,
Bax and Bak protein were less predictive [8, 99–101].
However, not all head and neck malignancies contain suf-
ficient numbers of these mutations. Therefore, the vari-
able expression of these mutations limits their usefulness
as routine prognostic indicators of metastasis.
Serum tumor markers have shown great utility as
screening tools for the development of local recurrences
and distant metastases in a variety of tumor systems. The
overproduction of thyroglobulin by differentiated thyroid
carcinoma is an example of how a particular gene product
can be effectively used to monitor tumor recurrence.
Yearly, thyroglobulin determination in conjunction with
131I scan has increased the sensitivity and specificity in
detection of recurrent and metastatic carcinoma [102,
103]. Unfortunately, a sensitive and specific serum mark-
er for HNSCC has yet to be identified [104, 105]. One
potentially exciting new area for tumor surveillance in
HNSCC is in the area of immunological markers. The
immune suppressive effects of HNSCC are well known
and are due to the production of immunosuppressive
cytokines and the induction of a population of CD34+
natural suppressor cells [106]. We have demonstrated that
high intratumoral CD34+ content and synthesis of high
levels of granulocyte-macrophage colony-stimulating fac-
tor correlate significantly with local recurrence and dis-
tant metastasis [107]. We are currently investigating po-
tential mechanisms to assess the immunological state of
patients as a potential screening tool.
Petruzzelli
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 ORL 2001;63:202–207
Incidence and Sites of Distant
Metastases from Head and Neck Cancer
Alfio Ferlito a Ashok R. Shaha b Carl E. Silver c Alessandra Rinaldo a
Vanni Mondin a
a Department of Otolaryngology-Head and Neck Surgery, University of Udine, Italy;
b Head and Neck Service, Memorial Sloan-Kettering Cancer Center, New York, N.Y., and
c Department of Surgery, Albert Einstein College of Medicine, Montefiore Medical Center, Bronx, N.Y., USA
Key Words
Head and neck cancer W Visceral metastases
Abstract
The incidence of distant metastases in head and neck
squamous cell carcinoma (SCC) is relatively small in
comparison to other malignancies. Distant metastases
adversely impact survival and may significantly affect
treatment planning. The incidence of distant metastases
is influenced by location of the primary tumor, initial T
and N stage of the neoplasm, and the presence or
absence of regional control above the clavicle. Patients
with advanced nodal disease have a high incidence of
distant metastases, particularly in the presence of jugu-
lar vein invasion or extensive soft tissue disease in the
neck. Primary tumors of advanced T stages in the hypo-
pharynx, oropharynx and oral cavity are associated with
the highest incidence of distant metastases. Pulmonary
metastases are the most frequent in SCC, accounting for
66% of distant metastases. It may be difficult to distin-
guish pulmonary metastasis from a new primary tumor,
particularly if solitary. Other metastatic sites include
bone (22%), liver (10%), skin, mediastinum and bone
marrow. An important question remains as to how
© 2001 S. Karger AG, Basel
ABC 0301–1569/01/0634–0202$17.50/0
Fax + 41 61 306 12 34
E-Mail karger@karger.ch Accessible online at:
www.karger.com www.karger.com/journals/orl
intensely pre- and postoperative screening for distant
metastases should be performed. Preoperative chest X-
ray is warranted in all cases. If the primary tumor and
nodal status place the patient at high risk for pulmonary
metastasis, then preoperative computed tomography
scan of the chest should be done. Screening for distant
metastases at other sites is usually not indicated in SCC
of the upper aerodigestive tract. Postoperatively, annual
X-rays of the chest are usually sufficient, but in high-risk
situations a chest X-ray performed every 3–6 months
may be beneficial. Certain histologic types of primary
tumor have greater or lesser propensity to metastasize
distantly, and have a different natural history. Adenoid
cystic carcinoma metastasizes frequently, even in the
absence of extensive local or regional disease. Basaloid
squamous cell carcinoma and neuroendocrine carcino-
mas also metastasize widely. Extensive evaluation for
distant metastases is justified for these tumors. Knowl-
edge of the natural history of various neoplasms and the
factors that contribute to distant metastases as well as
good judgement are essential for cost-effective treat-
ment planning and decision-making with regard to pre-
and postoperative evaluation for distant metastases in
cancer of the head and neck.
Copyright © 2001 S. Karger AG, Basel
Alfio Ferlito, MD
Department of Otolaryngology-Head and Neck Surgery
University of Udine, Policlinico Universitario
Piazzale S. Maria della Misericordia, I–33100 Udine (Italy)
Tel. +39 0432 559301, Fax +39 0432 559337, E-Mail clorl@dsc.uniud.it
 The incidence of distant metastases in head and neck
primaries is relatively small in comparison to other malig-
nancies such as stomach, pancreas, lung, breast or kidney.
Once distant metastases are discovered, however, long-
term survival is generally poor. Experience related to
metastasectomy is limited in head and neck malignancies
and decisions regarding radical resection of the primary
tumor and appropriate reconstruction rests heavily on the
presence or absence of distant metastases. Enthusiasm for
radical surgery dampens if the surgeon is aware of the
presence of distant metastases. In selected circumstances,
such as an advanced fungating tumor or airway occlusive
tumor, appropriate surgical treatment may be considered
for best palliation.
The incidence of distant metastases of the head and
neck tumors is significantly influenced by location of the
primary tumor, initial T and N stage of the neoplasm, and
the presence or absence of regional control above the
clavicle.
The incidence of distant metastases is directly related
to the stage of the tumor, with high incidence of distant
metastases in stage IV tumors, particularly in patients
who present with advanced nodal disease. The incidence
of pulmonary metastases is extremely high in patients
who present with bilateral N3 disease. Every attempt
should be made for appropriate evaluation, including rou-
tine chest X-ray, computed tomography (CT) scan of the
chest, and other appropriate tests to rule out pulmonary
metastases.
Distant metastases in the absence of nodal metastases
is quite rare in head and neck tumors, except for adenoid
cystic carcinoma (ACC). The natural history of this tumor
is a long, indolent course characterized by progressive
local recurrence and unexplained neurotropism. Distant
metastases occur frequently in ACC. The neoplasm fre-
quently metastasizes to the lungs and, less frequently, to
bones, liver and other organs, without lymph node in-
volvement. ACC of all sites can invade lymph nodes by
direct extension, but true embolic metastases are excep-
tional [1]. However, even in the presence of pulmonary
metastases (but not when metastases occur in bone, par-
ticularly the spine [2]), long-term outcome is quite good in
patients with ACC. The similar is true for differentiated
thyroid carcinoma. The incidence of pulmonary metas-
tases in high-risk follicular or Hürthle cell neoplasms is as
high as 25–30%, and overall long-term survival exceeds
50% [3]. Conversely, cervical and distant metastases have
not been reported in unirradiated cases of true verrucous
carcinoma of the head and neck. Lymph nodes are usually
normal in these patients and the histological examination
Incidence and Sites of Distant Metastases
of any enlarged node revealed only reactive changes [4].
Therefore, a limited work-up is sufficient. The propensity
of basaloid squamous cell carcinoma (SCC) and neuroen-
docrine carcinomas of the head and neck to metastasize
widely justifies an extensive metastatic work-up [5, 6].
It is also important to appreciate that patterns of nodal
and soft tissue recurrence in the neck change after initial
treatment, which may include neck dissection and radia-
tion therapy. New lymphatic channels may open up or
aberrant lymphatic channels may develop after initial
treatment.
The appearance of regional dermal metastases, which is
also related to aberrant lymphatic spread, is a sign of
advanced recurrent disease with extremely poor long-term
control [7, 8]. Hematogenous metastasis to skin is a rare
occurrence which has prognostic significance similar to
distant metastasis to other areas [9]. In clinical studies,
skin is the fourth most common site of distant metastases
in patients with head and neck cancer. The development
of skin metastasis is most closely related to the presence of
two or more cervical metastases and or extracapsular
spread of tumor in the cervical lymph nodes [9]. Skin
metastases occur in 1–2% of all patients with squamous
cell carcinoma (SCC) of the head and neck and account for
fewer than 10% of all distant metastases [10, 11]. In the
head and neck area, the most frequent tumor which metas-
tasizes to the skin is the atypical carcinoid. Twenty-two
percent of reported cases of laryngeal atypical carcinoid
metastasized to the skin or subcutaneous sites [12]. Skin
involvement due to direct extension or iatrogenic implan-
tation should not be considered as skin metastasis.
Controversy remains as to whether mediastinal node
involvement may be regarded as distant metastasis. Para-
tracheal or mediastinal nodal disease is difficult to treat
surgically and control with radiation therapy is quite lim-
ited.
A variety of screening techniques are employed in rou-
tine practice. The most commonly performed test is an
X-ray of the chest. If the chest film is normal, other inves-
tigations – such as liver scan or positron emission tomog-
raphy (PET) scan – are rarely conducted in head and neck
practice. If there is a high likelihood of pulmonary metas-
tases, a CT scan of the chest may be more informative
than a chest X-ray alone. In follow-up of these patients, it
is important to review the chest film and compare it to
previous studies. Any abnormality in the chest radiograph
should be screened by further PET or CT scan. The inci-
dence of a new primary tumor in the head and neck is
approximately 3–5% every year for at least an initial 3–5
years [13]. The diligence with which the lungs should be
ORL 2001;63:202–207 203
Table 1. Reported incidence of clinically detected distant metastases in patients with head and neck cancer

Authors Year Patients Incidence Type of Remarks

% tumor

Rubenfeld et al. [14] 1962 132 21.2 SCC 57.1% lung, 60.7% bone
Berger and Fletcher [15] 1971 243 23.8 SCC The series excluded patients with clinical evidence of DMs, primary and/or
initial neck disease recurring after therapy, and new neck disease after initial
therapy
Probert et al. [16] 1974 779 9.6 SCC, LE, TCC, 54.6% lung, 32% bone, 8% liver
ACC and AcCC
Merino et al. [17] 1977 5,019 10.8 SCC, LE of DMs at presentation and at autopsy were excluded. 52% lung, 20.3% bone,
nasopharynx 6% liver
Black et al. [18] 1984 121 12.3 SCC 12.3% of DMs at presentation, detected after extensive metastatic work-up in
patients with advanced diseases
Vikram et al. [19] 1984 114 17.5 SCC DMs detected after treatment in patients with advanced disease
(III and IV stages)
Initial sites of DMs were lung (60%) and spine (35%)
Shingaki et al. [20] 1986 17 58.8 ACC DMs detected after treatment (surgical or radiation therapy)
Bhatia and Bahadur [21] 1987 1,127 4.2 SCC, ACC, 1.1% of DMs at presentation; 68.7% lung, 18.7% bone, 6.2% liver
RMS, MM
Calhoun et al. [22] 1994 727 11.4 SCC 83.4% lung, 31.3% bone, 6% liver
Troell and Terris [23] 1995 97 14.4 SCC 71.4% lung, 35.7% bone, 14.2% liver
Alvi and Johnson [11] 1997 130 23 SCC DMs detected after treatment in patients with advanced disease
(III and IV stages); 66.6% lung
Spiro [24] 1997 196 37.7 ACC 90.5% lung
Jäckel and Rausch [25] 1999 1,087 11.9 SCC 1.5% of DMs at presentation; 68.5% lung, 23.8% liver, 20% bone
de Bree et al. [26] 2000 101 16.8 SCC 16.8% of DMs at presentation, detected after extensive metastatic work-up in
patients with advanced disease
70.5% lung, 23.5% bone, 5.8% liver
Holsinger et al. [27] 2000 622 15.1 SCC 65.9% lung, 22.3% bone, 9.5% liver
Kim et al. [28] 2000 95 44.2 ACC 73.8% lung, 19% bone
León et al. [29] 2000 1,880 9.5 SCC 50% isolated pulmonary metastases, and an additional 35% had pulmonary
metastases together with metastases in other locations
Bone metastases were the second most frequent locations followed by the liver

ACC = Adenoid cystic carcinoma; AcCC = acinic cell carcinoma; DMs = distant metastases; LE = lymphoepithelioma;
MM = malignant melanoma; RMS = rhabdomyosarcoma; SCC = squamous cell carcinoma; TCC = transitional cell carcinoma.

evaluated remains controversial. Many physicians rou-
tinely use a yearly chest X-ray. However, in high-risk
patients (those who give a history of heavy smoking),
chest radiography performed every 3–6 months to assess
any gross pulmonary abnormality may be beneficial. Rou-
tine bronchoscopy and bronchial washings are generally
not indicated in the head and neck unless gross abnormal-
ities appear in the chest X-ray or CT scan. If the pulmo-
nary lesion is peripheral and easily accessible, fine-needle
aspiration biopsy with CT guidance may be helpful in
making a diagnosis.
The incidence of bone metastases is quite low in the
head and neck. However, in advanced stage or massive
nodal disease, metastases to the hip, long bones or verte-
bral column are not uncommon. Appropriate investiga-
tions – including a bone scan, PET scan and magnetic res-
onance imaging (MRI) – may be of benefit.
The variation in the reported incidence of distant
metastasis as detected by clinical or postmortem exami-
nation depends on the site, stage and phenotype of the
primary tumor and on methods used for evaluation of dis-
tant metastasis. Metastasis in any lymph node other than
regional is classified as a distant metastasis. Clinical data
report an incidence of 4.2–23.8% of distant metastases
prevalently in SCC (table 1) [11, 14–29] and about 37.7–
58.8% in ACC in all salivary sites [20, 24, 28, 30], while

204 ORL 2001;63:202–207 Ferlito/Shaha/Silver/Rinaldo/Mondin

Table 2. Reported incidence of distant metastases at autopsy in patients with head and neck cancer

Authors Year Patients Incidence Type of Remarks

% tumor

Hitchings 1923 4,500 !1 SCC

(quoted by Crile [31])
Price [32] 1934 87 11 SCC
Burke [33] 1937 54 26 SCC
Braund and Martin [34] 1941 174 20 SCC
Peltier et al. [35] 1951 200 17 SCC
Gowen and Desuto-Nagy [36] 1963 61 57 SCC
Abramson et al. [37] 1971 75 34.6 SCC 80.7% lung, 34.6% bone, 26.9% liver
O’Brien et al. [38] 1971 122 46.7 SCC 72% lung, 38.6% liver, 23% bone
Bruger et al. [39] 1972 220 42 SCC
Dennington et al. [40] 1980 64 40.6 SCC 7.8% of patients had DMs clinically diagnosed at presentation
Kotwall et al. [41] 1987 832 46.5 SCC Hypopharynx and base tongue cancer had the highest incidence of DMs
(60.1 and 52.7% respectively); 80.1% lung, 30.7% liver, 30.4% bone
Zbären and Lehmann [42] 1987 101 39.6 SCC 10.8% of patients had DMs clinically diagnosed before autopsy;
70% lung, 42.5% liver, 15% bone
Nishijima et al. [43] 1993 112 36.6 SCC 85.3% lung, 31.7% liver, 29.2% bone

DMs = Distant metastases; SCC = squamous cell carcinoma.

autopsy studies have demonstrated the incidence of dis-
tant metastasis to be as high as 57% in SCC (table 2) [31–
43]. Kotwall et al. [41], in their study, noted that hypo-
pharynx had the highest incidence of distant metastases
(60.1%), followed by the base of the tongue (52.7%) and
the anterior tongue (49.4%). In a recent paper, Holsinger
et al. [27], from the M.D. Anderson Cancer Center in
Houston, provided a panel of clinical and histopatholog-
ical predictors that may identify patients at the greatest
risk for development of distant metastases in head and
neck SCC. In their study, the 5-year incidence of distant
metastasis was 15.1% (94/622). Pulmonary metastases
were most commonly found: 65.9% to the lung, 4.2% to
the mediastinum, 2.1% to the pleura. Metastases to bone
(22.3%) and to the liver (9.5%) were the next most com-
monly encountered. Thirty (31.9%) patients with distant
metastases presented with more than one metastatic site.
Lung was the most common site for solitary metastasis.
The most common site for bony metastasis was the spine
(12.7%), followed by skull (4.2%), rib (3.1%), and axial
bones (femur, humerus; 2.1%). More than half of patients
with osseous metastases presented with multiple sites. Of
213 patients with oral cavity SCC, 33 (15.4%) developed
distant metastases; 26 of 146 (17.8%) patients with oro-
pharyngeal SCC, 21 of 194 (10.8%) patients with laryn-
geal SCC, and 14 of 69 (20.2%) patients with hypopharyn-
geal SCC developed distant metastases [27]. Disease stage
showed a striking correlation with the risk for distant
metastases (as follows): stage I, 1%; stage II, 14%; stage
III, 15%; stage IV, 20% (p ! 0.0003). Advanced disease (T
stage 13 and N stage 12a) was significantly correlated sta-
tistically with the development of distant metastases (p !
0.003). The authors found that certain clinical features
(extent of cervical metastasis or N stage) and histopatho-
logic data (evidence of lymphatic or vascular invasion and
extension beyond the confines of the lymph node) are
associated with significantly increased rates of distant
metastases.
Bone marrow metastasis from small cell carcinoma of
the head and neck is unusual but can occur [44]. Signifi-
cant distant metastases have been found at autopsy in
patients who died with no clinically evident cancer and
who might therefore have been reported as cured [45].
Recently, Jennings and Bradley [46] have demonstrated
that autopsy yields new information about the extent of
the cancer than was considered premortem and hence
should be performed more often.
The incidence of distant metastases at presentation
varies from 1.5 to 16.8% of patients with head and neck
SCC [18, 25, 26, 40]. The lungs, bones (especially the ver-

Incidence and Sites of Distant Metastases ORL 2001;63:202–207 205

tebrae, ribs, and skull) and the liver are the most common
sites of hematogenous distant metastases from head and
neck SCC. Distant spread to other sites is less frequent.
SCC is the most common type of head and neck cancer
representing 90% of all malignancies of these areas. Half
of all distant metastases are detected clinically within 9
months of treatment and 80% within 2 years [17]. Proba-
bly the different reported incidence depends on the selec-
tion criteria of screening for distant metastases and the
characteristics of the patients included [29].
Usual screening tests for distant metastases may fail to
detect metastases to infraclavicular lymph nodes (axillary,
inguinal, anterior intercostal lymph nodes) [47]. Rarely,
cancers of the head and neck metastasize to axillary
lymph nodes [47–49], but nasopharyngeal cancer is fre-
quently associated with mediastinal and hilar lymphade-
nopathy [49, 50].
The time interval between the diagnosis of distant
metastases and death is less than 2 years in more than
90% of patients [16]. Tumors of the hypopharynx, naso-
pharynx, oropharynx and supraglottis have a larger pro-
pensity to metastasize than those of the glottis, nose and
paranasal sinuses and ear.
The risk of subpathological distant metastases has also
to be considered. New and highly sensitive investigations
(immunohistochemistry, molecular analysis and tech-
niques of cell culture) and serial sectioning of nonregional
lymph nodes and at risk organs may increase the detec-
tion of distant micrometastases in head and neck cancer
patients.
Individual disseminated tumor cells were detected in
bone marrow aspirates in 41 of 108 patients (37.9%) with
SCC of the head and neck region. This contamination of
the bone marrow by individual metastatic carcinoma cells
was demonstrated by the use of immunocytochemistry,
relying on monoclonal antibodies raised against cytokera-
tin No. 19. Patients who were shown to possess these
tumor cells within their bone marrow sustained a signifi-
cantly shorter disease-free survival period than did those
patients without immunohistochemically demonstrated
bone marrow involvement by tumor cells (p = 0.002)
[51].

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 ORL 2001;63:208–211
Screening Tests to Evaluate Distant
Metastases in Head and Neck Cancer
Alfio Ferlito a J. Graham Buckley b Alessandra Rinaldo a Vanni Mondin a
Departments of Otolaryngology-Head and Neck Surgery, a University of Udine, Italy and
b Leeds
General Infirmary, Leeds, UK
Key Words
Distant metastases W Head and neck cancer W Screening
Abstract
Investigation for distant metastases is part of the staging
process of a primary tumor or recurrent disease before
treatment. The lung is the most frequent site followed by
bone and liver. Advanced stage and cervical metastases
are the most important predictors of metastases. Almost
all distant metastases are associated with lung metas-
tases. Computed tomography scan of the chest is the sin-
gle most effective investigation. The value of routine
screening tests is questionable and merits further inves-
tigation.
Copyright © 2001 S. Karger AG, Basel
Head and neck cancers usually spread first to the
regional lymph nodes but more rarely may metastasize to
distant sites. Initial diagnosis is typically at about 12
months and 84% are diagnosed within 2 years [1]. Lung,
bone, liver and brain are the only metastatic sites of dis-
tant metastases commonly clinically diagnosed with
screening tests, but other sites, including skin, kidney,
small bowel, colon, pancreas, spleen, gallbladder, heart,
adrenals, pituitary, mesentery, bone marrow could be
involved by malignant neoplasms of the head and neck.
Calhoun et al. [1] carried out a retrospective analysis of
© 2001 S. Karger AG, Basel
ABC 0301–1569/01/0634–0208$17.50/0
Fax + 41 61 306 12 34
E-Mail karger@karger.ch Accessible online at:
www.karger.com www.karger.com/journals/orl
727 head and neck cancer patients for distant metastases.
Lung was the most common site (83.4%), then bone
(31.3%) and liver (6%). Liver metastases appear to be
much more frequent at autopsy. A study of 101 patients
found that the most common sites were the lungs (70%),
the liver (42.5%) and the bones (15%) [2]. Identification
of metastases before treatment is important because of the
impact on the quality of remaining life. The issue of sub-
sequent screening in this high-risk group of patients is
very difficult. The most sensitive tests may involve a rela-
tively high radiation dose making frequent examinations
impractical. Screening tests would have to be repeated at
frequent intervals to confer any real benefit. It is evident
that identification of distant metastases before treatment
may avoid an impact on quality of life when there is no
prospect of cure. There is, however, a question of whether
it benefits patients after treatment has been carried out.
There are two aspects to this question. Firstly whether the
prognostic information is useful. As survival is usually
very short in this situation, it may be essential for some
patients to have this information for practical reasons.
This can only be judged on an individual basis. Secondly
whether any treatment is possible. Usually curative treat-
ment is not possible but there are exceptions, for example
in solitary lung metastases. Early knowledge also helps to
plan effective palliative treatment. An example would be
the early stabilization of lytic metastases in weight-bear-
ing areas.
Alfio Ferlito, MD
Department of Otolaryngology-Head and Neck Surgery
University of Udine, Policlinico Universitario
Piazzale S. Maria della Misericordia, I–33100 Udine (Italy)
Tel. +39 0432 559301, Fax +39 0432 559337, E-Mail clorl@dsc.uniud.it
 It would be helpful to focus attention on those patients
that are at highest risk. The most important predictor of
distant metastases is the nodal stage [1, 3, 4]. Some
tumors have a higher rate of nodal metastasis and this is
principally governed by tumor site. Pharyngeal and supra-
glottic laryngeal tumors have the highest rates of nodal
and distant metastasis [5]. Other factors that may have
predictive value are T-stage or size of primary tumor [1,
6], differentiation [6], tumor invasion front, evidence of
perineural or vascular invasion and evidence of angiogen-
esis [7].
Evaluation of the Lung
Both in autopsy and clinical studies, the lung is the
most common site of distant metastases from head and
neck cancer. The primary screening examination for pul-
monary metastasis has traditionally been chest X-ray [8],
with a sensitivity of 50% and a specificity of 94% [6].
According to most studies, computed tomography (CT)
scan is more sensitive than standard radiology in identi-
fying intrapulmonary lesions [3]. The prevalence of posi-
tive finding on CT scan is 22% (B3.3%) [3, 8–14]. CT
scan and chest X-ray have been compared in some studies.
Most find CT much more sensitive than chest X-ray. Rei-
ner et al. [13] studied 189 patients of whom 66 had posi-
tive CT scans. Only 17 of these were visible on chest X-
ray. Halpern [12] identified 9 positive scans in 24 patients
[8 with squamous cell carcinoma (SCC)], all of whom were
X-ray-negative. Ong et al. [11] found 24 positive scans in
138 patients. Only 9 had positive plain X-rays. Similarly,
Houghton et al. [10] identified 14 positive CT scans in 81
patients. The sensitivity of chest X-ray in comparison was
21%. de Bree et al. [3] found that CT scan detected malig-
nant lesions in the thorax in 18 patients (12 lung metas-
tases, 4 mediastinal metastases, and 2 primary broncho-
genic carcinomas); 13 (72.2%) of these were not seen on
chest X-ray. This finding has not, however, been universal.
Two studies of 25 [8] and 57 patients [14] found that CT
scan offered no advantage. This may, at least in part, be
explained by the very low prevalence of positive findings
in both studies. Overall the evidence strongly supports the
view that CT scan is currently the single most sensitive
diagnostic technique for the detection of distant metas-
tases to the thorax and should therefore be the preferred
investigation, at least in high-risk patients [3, 10, 15]. In
addition to pulmonary metastases, CT scan also detects
mediastinal lymph node metastases, primary lung cancer
and bone metastases in the vertebrae and ribs [3].
Screening Tests for Distant Metastases in
Head and Neck Cancer
Evaluation of the Bone
In clinical studies, bone is the second most common
site of distant metastases in patients with head and neck
SCC. Bone metastases frequently involve more than one
bone and are almost invariably associated with lung me-
tastases [3].
Plasma bone-specific alkaline phosphatase (AP) is not
very sensitive for detecting bone metastases from head
and neck cancers because these metastases are usually
osteolytic, while the AP level is a sensitive and reliable
measure of osteoblastic activity [16]. Therefore, eleva-
tions in this enzyme are much more useful for monitoring
disease in osteosarcomas [16] and for screening for bone
metastases from prostate cancer [17]. Overall, measure-
ment of AP has a sensitivity of 20% and a specificity of
98% for detection of bone metastases [16].
Bone scintigraphy is the most sensitive diagnostic tech-
nique for detecting bone metastases, but a positive bone
scintigram is nonspecific [18]. CT scan and magnetic res-
onance imaging (MRI) and open or needle biopsy may be
helpful in determining the nature of the lesion. The value
of routine pretreatment bone scanning was evaluated in
172 consecutive patients. The management was changed
in only 3. The authors concluded that routine use of bone
scans for investigation of metastases was not necessary
[19]. de Bree et al. [3] identified 4 bone metastases in a
series of 101 patients with head and neck cancer. All were
associated with lung metastases.
Evaluation of the Liver
In clinical studies, the liver is the third most common
site of distant metastases in patients with head and neck
cancers, but at autopsy it is the second most common
site.
Liver metastases rarely occur in the absence of other
distant metastases, particularly lung metastases [6]. Most
patients with head and neck cancer have lung and bone
metastases before they are found to have liver metastases
[20, 21].
Laboratory biochemical investigations as screening
tests to identify liver metastases are not very sensitive and
are extremely nonspecific [6]. The majority of serum liver
function tests measure enzyme levels; alanine amino-
transferase (ALT), aspartate aminotransferase (AST), lac-
tic dehydrogenase (LDH), alkaline phosphatase and Á-glu-
tamyltransferase (ÁGT) are the most frequently mea-
sured. Korver et al. [22] found that serum liver function
ORL 2001;63:208–211 209
tests are of little value in identifying metastatic liver dis-
ease in the initial pretreatment assessment. Abnormal
serum liver function tests are more likely to indicate alco-
hol consumption, and may result from disorders of other
organ systems. Performing further studies in pursuit of
these abnormal findings may not only add to the cost of
patient care, but more particularly cause significant de-
lays in instituting treatment [22].
Ultrasound, CT scan and MRI of the liver are reliable
techniques for detection of liver metastases. Wernecke et
al. [23] recommend CT scan with intravenous contrast
agents. However, the liver is rarely the first site of metas-
tases, although it is commonly involved in the presence of
widespread distant metastases. Imaging of the liver is
therefore unlikely to be useful in the majority of patients.
A liver ultrasound is probably a sufficient confirmatory
study if there is a clinical suspicion of metastases and a
normal chest X-ray or CT scan [6]. The cost of a liver
ultrasound is approximately USD 550, while abdominal
CT scan costs USD 1,000 and MRI costs USD 1,500 [6].
Evaluation of the Brain
Brain metastases are a rare occurrence in SCC of the
head and neck, however they represent the fifth site in
clinical studies, after lung, bone, liver and skin. Contrast-
enhanced CT scan and MRI are indicated to reveal brain
metastases. Neurological manifestations have been re-
ported to be associated with neuroendocrine carcinomas
of the head and neck. In particular, brain, epidural and
spinal metastases have been reported. Therefore, CT scan
and MRI are indicated in these tumors for the detection of
metastatic brain disease. The appearance of brain metas-
tases of neuroendocrine carcinomas on CT scan and MRI
does not differ from that of other types of tumor [24].
Paraneoplastic syndromes have occasionally been re-
ported in association with head and neck small cell neu-
roendocrine carcinomas [25].
Evaluation of Metastases at Other Sites
Cutaneous metastases from SCC of the upper aerodi-
gestive tract account for less than 10% of all distant me-
tastases [26]. Skin metastases may be confused with pri-
mary skin tumors, direct spread from primary site or
nodal metastases or dermal lymphatic permeation. Con-
sequently, some reports may overestimate their occur-
rence. A retrospective analysis of 2,491 patients identified
210 ORL 2001;63:208–211
skin metastases in 19 (0.8%) patients. The median time to
occurrence was 6 months and 90% died of disease within
3 months (1–16 months) of diagnosis [27]. The prognostic
significance is therefore the same as for distant metastases
at other sites. The presence of two or more cervical metas-
tases and/or extracapsular spread were the main predic-
tive factors [27]. Confirmation of skin metastases is by
aspiration cytology or biopsy. Treatment of skin lesions
by surgical excision is very unlikely to impact on progno-
sis but may improve quality of life and symptom control
in some situations [28].
Metastasis to other lymph node groups is a rare event
except in the presence of advanced locoregional disease.
This can, however, be altered by previous treatment. A
retrospective study identified 5 patients with metastases
to distant lymphatic sites. All had combined surgery and
radiotherapy to primary site and lymph nodes and all
developed a local recurrence. Metastases were to the axil-
lary, inguinal, or anterior intercostal lymph nodes [29].
Which Screening Test?
There is a difference between investigation of a patient
before treatment and screening although the terms are
often used interchangeably. Investigation before treat-
ment is part of the staging process and requires the most
sensitive investigation to avoid inappropriate treatment
of a patient with metastases. A battery of tests is not likely
to confer any advantage in the search for metastases.
Almost all distant metastases are associated with lung
metastases. Using thoracic CT scan as a single investiga-
tion in a study of 101 patients would have only missed one
distant metastasis in the liver (1%) [3]. This is confirmed
by other studies [4, 6]. This suggests that using thoracic
CT scan alone in high-risk patients would be a very effec-
tive strategy. Another possible approach would be to use
radioisotope scanning. 67Ga-citrate whole-body scintigra-
phy was used to investigate 83 patients with head and
neck SCC. Scintigraphy correctly diagnosed all 12 distant
metastases as well as 86 of 90 cases of no metastasis,
resulting in a sensitivity of 100% and a specificity of 96%.
In 5 patients, distant metastases were initially detected by
67Ga scintigraphy. An additional benefit is the high sensi-
tivity and specificity for recurrent disease (87% and a
specificity of 91% compared to CT scan = 80 and 62%,
respectively) [30]. A drawback is that those cases with
lung metastases (almost all) would need further investiga-
tion (initially CT scan) to differentiate metastases from
synchronous lung primary tumors.
Ferlito/Buckley/Rinaldo/Mondin
 Screening for distant metastases in those patients who
have been treated is a different issue. If treatment is
planned for locally recurrent disease then specific investi-
gation should be carried out as above. If patients are dis-
ease-free and have no symptoms to suggest distant metas-
tases, then the benefits of screening are questionable. A
questionnaire study in 1993 highlighted that most Ameri-
can head and neck surgeons used annual chest X-ray for
screening, reserving CT scan, barium swallow or endosco-
py for specific symptoms [31]. The value of routine fol-
low-up in breast cancer has been questioned. A study
from Nijmegen looked at locoregional recurrence, distant
metastases and second primary tumors detected at follow-
up. It is interesting that the detection rate at routine fol-
low-up was 1 in 34, whereas for self-referrals it was 1 in
2.7. They noted that chest X-rays were only useful for
laryngeal primary tumors [32]. There needs to be more
research on the impact to patients of discovering meta-
static disease on follow-up.

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7 Sauter ER, Nesbit M, Watson JC, Klein-Szanto
A, Litwin S, Herlyn M: Vascular endothelial
growth factor is a marker of tumor invasion
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the head and neck. Clin Cancer Res 1999;5:
775–782.
8 Tan LKS, Greener CC, Seikaly H, Rassekh
CH, Calhoun LH: Role of screening chest com-
puted tomography in patients with advanced
head and neck cancer. Otolaryngol Head Neck
Surg 1999;120:689–692.
9 Dinkel E, Mundinger A, Schopp D, Grosser G,
Hauenstein KH: Diagnostic imaging in meta-
static lung disease. Lung 1990;169(suppl):
1129–1136.
10 Houghton DJ, Hughes ML, Garvey C, Beasley
NJP, Hamilton JW, Gerlinger I, Jones AS:
Role of the chest CT scanning in the manage-
ment of patients presenting with head and neck
cancer. Head Neck 1998;20:614–618.
11 Ong TK, Kerawala CJ, Martin IC, Stafford
FW: The role of thorax imaging in staging head
and neck squamous cell carcinoma. J Cranio-
maxillofac Surg 1999;27:339–344.
12 Halpern J: The value of chest CT scan in the
work-up of head and neck cancers. J Med 1997;
28:191–198.
13 Reiner B, Siegel E, Sawyer R, Brocato RM,
Maroney M, Hooper F: The impact of routine
CT of the chest on the diagnosis and manage-
ment of newly diagnosed squamous cell carci-
noma of the head and neck. AJR Am J Roent-
genol 1997;169:667–671.
14 Nilssen EL, Murthy P, McClymont L, Den-
holm S: Radiological staging of the chest and
abdomen in head and neck squamous cell car-
cinoma – Are computed tomography and ultra-
sound necessary? J Laryngol Otol 1999;113:
152–154.
15 Houghton DJ, McGarry G, Stewart I, Wilson
JA, MacKenzie K: Chest computerized tomog-
raphy scanning in patients presenting with
head and neck cancer. Clin Otolaryngol 1998;
23:348–350.
16 Leung KS, Fung KP, Sher AH, Li CK, Lee KM:
Plasma bone-specific alkaline phosphatase as
an indicator of osteoblastic activity. J Bone
Joint Surg Br 1993;75:288–292.
17 Gerber G, Chodak GW: Assessment of value of
routine bone scans in patients with newly diag-
nosed prostate cancer. Urology 1991;37:418–
422.
18 Belson TP, Lehman RH, Chobanian SL, Malin
TC: Bone and liver scans in patients with head
and neck carcinoma. Laryngoscope 1980;90:
1291–1296.
19 Brown DH, Leakos M: The value of a routine
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1998;27:187–189.
20 Probert JC, Thompson RW, Bagshaw MA: Pat-
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21 Merino OR, Lindberg RD, Fletcher GH: An
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McCulloch T, Funk GF: Liver function studies
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24 Deleu D, De Geeter F: Neurological manifesta-
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1991;53:520–528.
25 Mineta H, Miura K, Takebayashi S, Araki K,
Ueda Y, Harada H, Misawa K: Immunohisto-
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Laryngol 2001;110:76–82.
26 Alvi A, Johnson JT: Development of distant
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27 Pitman KT, Johnson JT: Skin metastases from
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29 Alavi S, Namazie A, Sercarz JA, Wang MB,
Blackwell KE: Distant lymphatic metastasis
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yngol 1999;108:860–863.
30 Murata Y, Ishida R, Umehara I, Ishikawa N,
Komatsuzaki A, Kurabayashi T, Ishii Y, Ogura
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31 Marchant FE, Lowry LD, Moffitt JJ, Sabbagh
R: Current national trends in the posttreatment
follow-up of patients with squamous cell carci-
noma of the head and neck. Am J Otolaryngol
1993;14:88–93.
32 de Visscher AV, Manni JJ: Routine long-term
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Screening Tests for Distant Metastases in ORL 2001;63:208–211 211

Head and Neck Cancer
 ORL 2001;63:212–213

Distant Metastases from Sinonasal

Cancer
Valerie J. Lund
Institute of Laryngology and Otology, Royal National Throat Nose and Ear Hospital, London, UK

Key Words
Distant metastases W Sinonasal cancer
Abstract
Distant metastases from sinonasal malignancy are gen-
erally a rare event except in the terminal stages of the
diseases and many patients die from recurrence before
the secondaries become clinically manifest. Sinonasal
neoplasia covers a diverse range of pathologies, some of
which have a greater tendency to spread than others, in
particular adenoid cystic carcinoma, malignant melano-
ma and some of the sarcomas. Notwithstanding this, the
frequency with which systemic metastases occurs is
such that screening at presentation could not be re-
garded as cost-effective and is consequently only insti-
tuted in the presence of specific symptoms.
Copyright © 2001 S. Karger AG, Basel
tant spread, the patient may die of local disease before this
becomes evident. Indeed, the control of local disease, i.e.
by craniofacial resection, may increase the apparent fre-
quency of distant metastases [1]. It should also be remem-
bered that the sinonasal region may be the site of second-
ary deposits itself, e.g. kidney, breast, thyroid and pan-
creas.
Such is the rarity of secondary disease that few centers
adopt a universal strategy of systemic investigation,
though may do so for individual histologies. The tumors
more commonly associated with metastases are shown in
table 1, though the exact frequency with which this occurs
remains to be established. Metastases, when they occur,
Table 1. Malignant sinonasal neoplasia more often associated with
distant metastases

Epithelial Mesenchymal
The sinonasal area is affected by the greatest histologi-
Poorly differentiated squamous Lymphoma/plasmacytoma
cal diversity of neoplasia, with every sort of tissue repre- cell carcinoma Rhabdomyosarcoma
sented, although some are more common than others such Adenoid cystic carcinoma Malignant fibrous histiocytoma
as squamous cell carcinoma (SCC), adenocarcinoma and Malignant melanoma Ewing’s sarcoma
olfactory neuroblastoma. All of these histological types Primitive and olfactory Alveolar soft part sarcoma
neuroblastoma Osteogenic sarcoma
have their own individual natural histories but the inci-
Neuroendocrine carcinoma Mesenchymal chondrosarcoma
dence of distant metastases is generally extremely low at Leiomyosarcoma
presentation and even in those with a propensity for dis-

© 2001 S. Karger AG, Basel Valerie J. Lund

ABC 0301–1569/01/0634–0212$17.50/0 Professorial Unit Institute of Laryngology and Otology
Fax + 41 61 306 12 34 Surgeon Royal National Throat, Nose & Ear Hospital
E-Mail karger@karger.ch Accessible online at: 330-332 Gray’s Inn Road, London WC1X 8DA (UK)
www.karger.com www.karger.com/journals/orl Tel. +44 207 915 1619, Fax +44 207 833 9480, E-Mail v.lund@ucl.ac.uk
involve the same areas as other head and neck cancers, i.e.
lung, bone, brain, liver. Occasionally skin lesions may be
seen, e.g. primary neuroectodermal tumors. Protocols for
detection rely upon the presumed site (table 2) and may
be followed by image-guided biopsy. A full lymphoreticu-
lar work-up will be required in all cases of lymphoma and
plasmacytoma. Urinary metabolites such as vanillylman-
delic acid and melanin may be found but offer only a loose
correlation with tumor mass rather than the presence of
metastasis per se.
In sinonasal malignancy, distant metastases are happi-
ly a feature of late end-stage disease for reasons that
remain unclear. This is particularly true in poorly differ-
entiated (anaplastic) SCC.
In the case of adenoid cystic carcinoma the tumor’s
capacity for spread along the perineural lymphatics ren-
ders it particularly difficult to control locally. The fre-
quency of systemic metastases has been quoted to be
between 20 and 41% [2–4]. The lung is most frequently
affected. Whilst 5% of patients have evidence of secon-
daries at initial presentation, metastatic disease may man-
ifest itself up to 22 years later as a consequence of which
patients can never be regarded as cured of this particular
tumor and 5-year survival figures are rendered meaning-
less. However, it is important to recognize that the pres-
ence of metastases does not necessarily imply a rapid
demise and patients may live several years with dissemi-
Table 2. Detection of distant metastases in sinonasal neoplasia
Computed tomography (CT) – brain, thorax, abdomen
Magnetic resonance imaging (MRI) – thorax, abdomen
Bone scan
Ultrasound – liver
Bone marrow (part of lymphoma screen)
nated disease. This has led to an increasing trend towards
radical treatment of metastatic disease, e.g. by pulmonary
lobectomy.
Olfactory neuroblastoma is more frequently associated
with local recurrence than secondary spread though an
incidence of 28% was quoted for the latter in one series
[5]. Primitive neuroblastoma and neuroendocrine carci-
noma, though much rarer, are more frequently associated
with disseminated disease as is malignant melanoma.
Widely dispersed metastases can occur at any stage of this
disease, even in the absence of local recurrence, and are
associated with the rapid decline of the patient.
However, the frequency with which systemic metas-
tases occur in association with sinonasal malignancy gen-
erally is such that screening at presentation could not be
regarded as cost-effective and is consequently only insti-
tuted in the presence of specific symptoms.

References 1 Lund VJ, Howard DJ, Wei WI, Cheesman AD: 4 Harrison DFN, Lund VJ: Tumours of the Up-
Craniofacial resection for tumors of the nasal per Jaw. Edinburgh, Churchill Livingstone,
cavity and paranasal sinuses – A 17-year expe- 1993.
rience. Head Neck 1998;20:97–105. 5 Appelblatt NH, McClatchey KD: Olfactory
2 Conley J, Dingman DL: Adenoid cystic carci- neuroblastoma: A retrospective clinicopatho-
noma in the head and neck (cylindroma). Arch logic study. Head Neck Surg 1982;5:108–113.
Otolaryngol 1974;100:81–90.
3 Chilla R, Schroth R, Eysholdt U, Droese M:
Adenoid cystic carcinoma of the head and
neck. Controllable and uncontrollable factors
in treatment and prognosis. ORL J Otorhino-
laryngol Relat Spec 1980;42:346–367.

Sinonasal Cancer ORL 2001;63:212–213 213

 ORL 2001;63:214–216
Distant Metastases from
Nasopharyngeal Cancer
Fausto Chiesa Fiora De Paoli
Head and Neck Division, European Institute of Oncology, Milan, Italy
Key Words
Distant metastases W Nasopharyngeal cancer
Abstract
Undifferentiated carcinoma is the most frequent naso-
pharyngeal cancer; it has a typical pathognomonic histo-
logical pattern, a close relationship to Epstein-Barr virus
(EBV), a peculiar natural history and a good prognosis. It
has an early tendency to locally spread to the parapha-
ryngeal space. Nodal involvement is highly frequent (70–
90%) and bulky regardless of the size of the primary. Lit-
erature reports up to 11% distant metastases at presen-
tation and up to 87% at autoptic studies. Pretreatment
work-up should include: personal history, clinical and
fiberscopic examination, magnetic resonance imaging
(MRI) or computed tomography (CT) scan of the base of
the skull and neck, histology of the primary and cytology
of neck lumps, bone marrow aspiration and biopsy, and
EBV serological profile. Clinical and pathological factors
predicting possible distant spread are primary tumor and
node extension, and treatment failure. Up to now no reli-
able predictive biological markers have been identified.
After treatment, distant metastases are found in about
30% of patients within 5 years and generally have a bad
prognosis. Metastatic nodes above the clavicle, in ab-
sence of locoregional failure, aggressively treated with
chemoradiotherapy, have a disease-free survival longer
than 5 years. The following is the suggested posttreat-
© 2001 S. Karger AG, Basel
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Fax + 41 61 306 12 34
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ment work-up for early diagnosis of these salvageable
patients: clinical and fiberscopic evaluation every 3
months for 2 years and later on every 6 months; skull
base and neck MRI or CT scan, and chest CT scan at 6, 12,
18, 24, 36, 48 and 60 months; EBV serological evalua-
tion.
Copyright © 2001 S. Karger AG, Basel
Nasopharyngeal cancer is a tumor derived from epi-
thelial cells and accounts for 90% of the malignancies aris-
ing in this anatomical site. Many histological classifica-
tions of this tumor have been proposed in time. They are
based on the degree of differentiation and on prognostic
relevance. From these classifications we can distinguish
two main types of nasopharyngeal cancer: (1) squamous
cell carcinoma (SCC) and (2) undifferentiated carcinoma
(UCNT). The former accounts for about 30% in the low-
risk population, but less than 5% in endemic regions; it is
a typical keratinizing carcinoma similar to those found in
the upper aerodigestive tract. Generally it does bad in
local control and overall survival; its natural history and
diagnostic and therapeutic work-up is very similar to that
of the other pharyngeal SCCs. On the contrary, UCNT
needs a separate analysis because it has a peculiar natural
history, and a better prognosis than SCC [1, 2].
UCNT is characterized by a typical pathognomonic
histological pattern and clinically it has high metastasiz-
ing behavior. It is frequently observed in South China,
Fausto Chiesa, MD
Head & Neck Division, European Institute of Oncology
Via Ripamonti, 435
I–20141 Milan (Italy)
Tel. +39 02 57489490, Fax +39 02 57489491, E-Mail fausto.chiesa@ieo.it
Southeastern Asia, Alaska and in the Mediterranean ba-
sin, where it is endemic. There is a close relationship
between this tumor and Epstein-Barr virus (EBV), a DNA
virus belonging to the Herpes virus group, and the virus
seems to have an important role in its carcinogenesis [2].
UCNT generally arises in the mucosa around the
Rosenmüller fossa and in early stages it is often occult at
clinical and fiberscopic examination. It has an early ten-
dency to locally spread to the parapharyngeal space and
the choanae into the nasal cavity. Nodal involvement is
highly frequent (70–90%) and bulky (up to 40% of UCNT
have nodes 16 cm when diagnosed) regardless of the size
of the primary. Distant metastasization rate is very high:
up to 11% at presentation is reported in the literature and
autoptic studies report distant metastases as high as 38–
87% [2–7].
Pretreatment work-up should include:
(1) Personal history: Early disease is generally asymp-
tomatic, and patients often present with a history of a
node in the upper neck slowly growing over months or
years. Clinicians should look for a long history of nasal
obstruction, hearing loss and recurrent serous otitis. Ad-
vanced diseases often present diplopia and severe head-
ache due to intracranial development of the neoplasia.
(2) Clinical examination: This includes a fiberscopic
exam of the pharynx and larynx, a clinical check of the
oral cavity, of the neck and a careful neurological evalua-
tion of the cranial nerves.
(3) Imaging evaluation: Locoregional staging includes
magnetic resonance imaging (MRI) or computed tomog-
raphy (CT) scan of the base of the skull and neck; MRI is
generally preferred because it allows a better evaluation of
parapharyngeal extension [8]. A CT scan of the chest, as
well as a liver ultrasound exam and a bone scan should
implement this work-up for the search of possible meta-
static disease.
(4) Pathological and serological work-up: (a) Histology
of the primary tumor: an aimed biopsy under fiberscopic
guide must always be taken. In T0 cases, random biopsies
should be done. (b) Cytology: when the primary tumor is
not clinically evident a smear of the entire nasopharyn-
geal mucosa is needed, in addition to the random biop-
sies. Fine-needle aspiration cytology of the neck lumps –
when present – is mandatory. (c) Bone marrow aspiration
and biopsy: this is not performed in all centers, but when
done a 40% detection of subclinical distant metastases in
N3 patients has been reported [2]. (d) EBV serological
profile: this includes assessment of immunoglobulin (Ig),
IgA against viral capside antigen (VCA), early antigen
(EA), and IgG anti-Epstein-Barr nuclear antigen (EBNA).
Nasopharyngeal Cancer
Several retrospective studies evaluated clinical and
pathological factors predicting possible distant spread of
UCNT. In all studies the following factors are considered
as independent determinants both at univariate and mul-
tivariate analysis [2–7]:
(1) Primary tumor extension: Bad outcome and devel-
opment of distant metastases are related to involvement
of parapharyngeal muscles. Recently, Chua et al. [4]
showed a statistically significant relationship between dis-
tant metastases and parapharyngeal extension to the pres-
tyloid space and anterior part of masticatory space.
(2) Node extension: Distant metastases are significant-
ly related to nodes’ size and site, being more frequently
observed in patients with advanced N stage (N3) and low
neck level disease.
(3) Treatment failure: Persistence of neck nodes after
treatment and locoregional failures are significant predic-
tors of distant metastases.
Up to now no reliable biological markers predictive of
development of distant metastases have been identified.
The first and second items are the rationale for planning
more aggressive treatments such as concomitant chemo-
radiotherapy, although there is not yet statistical evidence
that these schedules are more effective in preventing dis-
tant metastases than traditional radiotherapy.
Among the proposed classifications of nasopharyngeal
carcinomas, the most used are the Chinese staging system
(table 1) and the 5th Edition of the UICC staging system
(table 2). Hong et al. [9] in a recent study compared these
two classifications in predicting NPC prognosis. They
found that the predictive power of the Chinese tumor clas-
sification was superior, while the UICC nodal classification
was more reasonable and suggested that a combination of
the two systems should improve their outcome prediction.
After treatment, distant metastases develop in about
30% of patients within 5 years (40% in those with locore-
gional failure and 29% in those with locoregional control)
at a median time of 8 months [3, 6]. Average duration of
their life after diagnosis of distant metastases is very low
(5 months), also if some authors report that a few patients
survived more than 5 years [5, 6]. Distant metastases are
mainly observed in bone (48%), lung (27%), liver (11%),
nodes above the clavicle (10%); the latter, in absence of
locoregional failure, have a long-term disease-free surviv-
al (64–114 months) when treated with aggressive chemo-
radiotherapeutic schedules [5]. An early diagnosis of such
potentially salvageable patients is therefore important.
The following is the suggested posttreatment work-up,
based on the literature findings: (1) Clinical and fiber-
scopic evaluation every 3 months during the first 24
ORL 2001;63:214–216 215
Table 1. The Chinese 1992 staging system (1992) [9] Table 2. The 5th edition of the UICC staging system (1997) [9]

T1 Tumor confined to nasopharynx T1 Tumor confined to nasopharynx

T2 Involvement of nasal cavity, oropharynx, soft palate, anterior T2 Tumor extends to soft tissue of oropharynx and/or nasal
cervical vertebrae soft tissue, and parapharyngeal space exten- fossa
sion before SO line T2a: without parapharyngeal extension
T3 Extension over SO line, involvement of anterior or posterior T2b: with parapharyngeal extension
cranial nerves alone, skull base, pterygoprocess zone, and pte- T3 Tumor invades bony structures and/or paranasal sinuses
rygopalatine fossa T4 Tumor with intracranial extension and/or involvement of
T4 Involvement of both anterior and posterior cranial nerves, cranial nerves, infratemporal fossa hypopharynx or orbit
paranasal sinuses, cavernous sinus, orbit, infratemporal fossa, N0 No regional lymph node metastasis
and direct invasion of first or second cervical vertebra N1 Unilateral metastasis in lymph node(s) measuring up to 6 cm
N0 No enlarged lymph node in greatest dimension above the supraclavicular fossa
N1 The diameter of upper neck lymph node 1 4 cm, movable N2 Bilateral metastasis in lymph node(s) measuring up to 6 cm in
N2 Lower neck lymph node or the diameter between 6 and 7 cm greatest dimension above the supraclavicular fossa
N3 Supraclavicular lymph node or the diameter 1 7 cm or fixed or N3 Metastasis in lymph node(s)
skin infiltration 1 6 cm in greatest dimension
M0 Absence of distant metastasis Extension to the supraclavicula fossa
M1 Presence of distant metastasis M0 No distant metastasis
Stage I T1 N0 M0 M1 Distant metastasis
Stage II T2 N0–1 M0 T1–2 N1 M0 Stage I T1 N0 M0
Stage III T3 N0–2 M0 T1–3 N2 M0 Stage IIA T2a N0 M0
Stage IVA T4 N0–3 M0 T1–4 N3 M0 Stage IIB T1 N1 M0
Stage IVB Any T Any N M1 T2a N0–1 M0
T2b N0–1 M0
SO line: the line connected from the styloid process to the mid- Stage III T1 N2 M0
point on posterior edge of the great occipital foramen. T2 N2 M0
The border between upper and lower neck is the lower margin of T3 N0–2 M0
the cricoid cartilage. Stage IVA T4 N0–2 M0
Stage IVB Any T N3 M0
Stage IVC Any T Any N M1

months after therapy, later on every 6 months. (2) MRI or
CT scan of the skull base and neck at 6, 12, 18, 24, 36, 48
and 60 months. (3) CT scan of the chest at 6, 12, 18, 24,
36, 48 and 60 months. (4) EBV serological evaluation:
there is not general agreement about the usefulness of this
assessment, because initial serological levels and their
posttherapy variations do not always predict the outcome
of the disease. However, their increase after clinical
remission, if obtained, is suggestive of locoregional or sys-
temic relapse of the disease.

References

1 WHO International Histological Classification
of Tumors, No 19: Histological Typing of Up-
per Respiratory Tract Tumors. Geneva, WHO,
1978, pp 32–33.
2 Fandi A, Altun M, Azli N, Armand JP, Cvit-
kovic E: Nasopharyngeal cancer: epidemiology,
staging, and treatment. Semin Oncol 1994;21:
382–397.
3 Kwong D, Sham J, Choy D: The effect of loco-
regional control on distant metastatic dissemi-
nation in carcinoma of the nasopharynx: An
analysis of 1,301 patients. Int J Radiat Oncol
Biol Phys 1994;30:1029–1036.
4 Chua DTT, Sham JST, Kwong DLW, Choy
DTK, Au GKH, Wu PM: Prognostic value of
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geal carcinoma. A significant factor in local
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2423–2431.
6 Geara FB, Sanguineti G, Tucker SL, Garden
AS, Ang KK, Morrison WH, Peters LJ: Carci-
noma of the nasopharynx treated by radiother-
apy alone: determinants of distant metastasis
and survival. Radiother Oncol 1997;43:53–61.
7 Lee AW, Foo W, Law Sc, Poon YF, Sze WM, O
SK, Tung SY, Chappel R, Lau WH, Ho JH:
Recurrent nasopharyngeal carcinoma: The
puzzles of long latency. Int J Radiat Oncol Biol
Phys 1999;44:149–156.
8 Sakata K, Hareyama M, Tamakawa M, Oouchi
A, Sido M, Nagakura H, Akiba H, Koito K,
Himi T, Asakura K: Prognostic factors of naso-
pharynx tumors investigated by MR imaging
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216 ORL 2001;63:214–216 Chiesa/De Paoli

 ORL 2001;63:217–221
Distant Metastases from Lip and
Oral Cavity Cancer
Jan Betka
Department of Otolaryngology – Head and Neck Surgery, Charles University, Prague, Czech Republic
Key Words
Distant metastases W Lip cancer W Oral cancer
Abstract
Distant metastases related to lip carcinomas occur very
exceptionally (0.5–2%) and can be expected in cases of
advanced tumors with advanced regional disease. Dis-
tant metastases from oral cavity carcinomas variy over a
broad interval (8–17%) and depend also on the stage of
disease. The knowledge of the presence of distant me-
tastases is vital for the planning of further treatment.
From a clinical point of view, patients with lip and oral
cavity can be divided into a group where the risk of dis-
tant metastases is low, and into a high-risk one. In low-
risk group patients (stages I, II and III) the risk of the inci-
dence of distant metastases is 3%, and the diagnostic
approach should consist of an X-ray of the lungs and liv-
er tests. Further examinations are necessary if there are
symptoms suggesting the presence of distant metas-
tases or previous examinations are abnormal. The high-
risk group (stage IV) and all patients with locoregional
relapse have a risk of distant metastases of approximate-
ly 10% and the best treatment consists of a positron
emission tomography (PET) scan. If a PET scanner is not
available it is recommended to run a computed tomogra-
phy scan of the lungs and liver tests. If any clinical inves-
tigation is abnormal further tests are necessary.
Copyright © 2001 S. Karger AG, Basel
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Fax + 41 61 306 12 34
E-Mail karger@karger.ch Accessible online at:
www.karger.com www.karger.com/journals/orl
According to the American Cancer Society, about
1,220,100 new cancer cases were expected to be diag-
nosed in 2000 (1.3 million cases of basal and squamous
cell skin cancers are not included). Some 30,200 patients
were expected to contract oral cavity and pharynx in 2000
and it was estimated that 7,800 would die from tumor
that year. Lip and oral cavity carcinoma is fortunately rel-
atively rare [1].
Lip Cancer
In the United States, lip carcinomas account for just
12% of tumors found in the head and neck area, and the
number of male patients is 6 times as high as that of
females. The highest incidence rate of lip carcinomas is in
South Africa (13.3 cases/100,000 inhabitants) and Spain
(11.4/100,000 inhabitants). As to females, it is Thailand
which shows the highest incidence rate (3.8/100,000 in-
habitants). From a histological viewpoint, these carcino-
mas are almost invariably of a squamous or basal cell
type. Distant metastases related to lip carcinomas occur
very exceptionally. As a rule, this is attributable to a gen-
erally early diagnosis of the tumor which, because of its
good accessibility, is identified in initial stages in 93% of
cases [2]. As to regional metastases, they occur in 5–7% of
cases, and are thus relatively rare. Distant metastases are
exceptional (0.5–2%) and can be expected in cases of
Jan Betka, MD, PhD
Department of Otolaryngology – Head and Neck Surgery
I. Medical Faculty Charles University, University Hospital Motol
Vúvalu 84, CZ–150 06 Motol-5, Prague (Czech Republic)
Fax +420 2 290 495, E-Mail jan.betka@lfmotol.cuni.cz
Table 1. Incidence rates of distant metastases

Kotwall Peltier O’Brien Braund and Burke Zbären and Probert Merino Brennan
et al. [6] et al. [7] et al. [8] Martin [9] [10] Lehmann [11] et al. [12] et al. [13] et al. [14]

Patients 832 200 153 284 88 101 779 5,019 769

FU duration Autopsy Autopsy Autopsy Autopsy Autopsy Autopsy 5 years 2 years 2 years
Total number of oral
cavity cases, % 40 32 14 8
Oral cavity bottom, % 43 23 6 17
Tongue, % 49 33 27 25 15
Others, % 32 13 33 36 17

advanced tumors with advanced regional nodal disease
[3]. The global trend is one of a decreasing incidence rate
of lip carcinomas.
Oral Cancer
In the United States, oral cavity carcinomas account
for 7% of diagnosed head and neck tumors. The incidence
rate is twice as high for males as for females, and it is
assumed that the number of oral cavity carcinoma cases is
higher in the old-age population. There are significant dif-
ferences in the oral cavity carcinoma incidence rates from
one country to another, the top countries in this respect
being Bermuda (incidence rate 16.3/100,000 ) and India.
As to Europe, the highest incidence rate among males is in
France (incidence rate 13.5/100,000) while the opposite
end belongs to Japanese females (incidence rate 0.13/
100,000). Squamous cell carcinomas (SCCs) account for
more than 90% of oral cavity tumors. Other oral cavity
tumors are represented by those of small salivary glands,
of which the adenoid cystic carcinoma is the most fre-
quent type (it accounts for 42% of tumors affecting small
salivary glands, but less than 1% of all head and neck
tumors). The adenoid cystic carcinoma exhibits a tenden-
cy toward producing distant metastases (up to 58.8%). In
rare instances, nonepithelial tumors can be found as well,
namely soft tissue sarcomas (incidence rate 1/100,000)
and Kaposi's sarcoma (50% of patients with AIDS devel-
op Kaposi's sarcomas in the oral cavity). Malignant mela-
nomas are found more frequently among Blacks and Japa-
nese; some 0.2–0.8% of these tumors are found in the oral
cavity. Cases of lymphomas located in the oral cavity are
extremely rare (0.2%).
The first to note the possibility of distant metastases
associated with head and neck carcinomas was Crile [4].
In his study in which he presented the results of his analy-
sis of autopsy findings, he found distant metastases relat-
ed to oral cavity carcinomas only exceptionally. Most of
the patients died of a locoregional relapse or because of
the tumor persistence. Shaha et al. [5] mention a 13%
incidence rate of distant metastases related to carcinomas
of the oral cavity tumors in their study of a group of 320
patients. They view the advancement of the disease and
relapses of the primary process or metastases as the most
important risk factors. It is interesting to note that inci-
dence rates of distant metastases based on both autopsy
documents and clinical studies vary over a broad interval,
ranging between 6 and 43% in the autopsy case and 8 and
17% in clinical studies (table 1) [6–14].
Relation between the Primary Tumor Extent
and the Incidence Rate of Distant Metastases
Most authors present evidence corroborating the exis-
tence of a relation between the advancement of the prima-
ry process and the incidence rate of distant metastases
[15]. They submit proof indicating that the larger or more
advanced the primary process is, the higher the probabili-
ty of occurrences of distant metastases (tables 2, 3) [6, 13,
16–19]. As to advanced tumor development stages, rele-
vant publications mention incidence rates of distant me-
tastases ranging between 20 and 40%.
Relation between the Condition of Regional
Lymphatic Node Metastases and the Incidence
Rate of Distant Metastases
There is a great deal of evidence that there exists a cor-
relation between the extent of lymph node metastases
involvement and incidence rate of distant metastases. It is
interesting to note that autopsy studies present higher

218 ORL 2001;63:217–221 Betka

Table 2. Disease stage versus the incidence of distant metastases Table 3. Primary tumor size versus the incidence rate (%) of distant
metastases
Merino et al. [13] Kotwall et al. [6] Vikram et al. [16]
(clinical study) (autopsy study) (clinical study) Merino Berger and Loree and Cerezo
et al. [13] Fletcher [17] Strong [18] et al. [19]
Stage I 2 42
Stage II 6 35 T1 5 25 15 35
Stage III 9 43 20 T2 10 20 27 37
Stage IV 20 55 T3 13 23 31 23
T4 16 30 40 38
p ! 0.05 NS p ! 0.05 NS

Table 4. Incidence rates (%) of distant metastases for different N-stages

Merino Berger and Vikram Arons and Loree and Kotwall Zbären and
et al. [13] Fletcher [17] et al. [16] Smith [22] Strong [18] et al. [6] Lehmann [11]
(autopsy) (autopsy)

N0 5 9 4 12 3 (I, II) 42 24
4 (III, IV)
N1 12 17 18 34 (N1–N2)
N2 22 26 (2a) 25 (N1–N3) 28 (N1–N3) 24 (N1–N3) 40 (N2–N3)
23 (2b)
N3 27 38 (3a) 54
33 (3b)

incidence rates than clinical studies [20, 21]. This may be Table 5. Localization of distant metastases (%)
attributable to the former studies being focused on pa-
Autopsy study Clinical study
tients with a negative prognosis; however, it is also possi-
[6–9, 11, 29–31] [12, 13, 16, 32–35]
ble that a process of hematogenous spread and the forma-
tion of metastases precedes the formation of regional Lung 71 54
metastases (table 4) [6, 11, 13, 16–18, 22]. Some authors Liver 36 10
view the effect of extracapsular spread is the most impor- Bones 15 22
Mediastinum 23 3.4
tant prediction factor, along with the existence of more
Distant nodes 16 Sporadic
than four positive lymph node metastases [23–26]. Suprarenal glands 14 Sporadic
Kidney 14 Sporadic
Heart 13 Sporadic
Distant Metastases – Incidence and Brain 12 Sporadic
Localization

The incidence of distant metastases at the time of diag-

nosis varies from 2 to 17% of patients with head and neck
SCC [27, 28]. Distant metastases from oral cavity tumors
can be expected on the lower end of this scale. Distant
metastases most frequently attack lungs (54%), as well as
bones and liver, etc. (table 5) [6–9, 11–13, 16, 29–35].
According to autopsy studies and clinical studies, there
exists a 2–3 times higher incidence in autopsy.
Clinical Management
Lip tumors very rarely produce distant metastases.
Oral cavity tumors exhibit a relatively low tendency
toward creating distant metastases. The probability of the
formation of a distant metastasis depends on: (1) histolog-
ical composition of the tumor; (2) extent of the primary

Lip and Oral Cavity Cancer ORL 2001;63:217–221 219

Table 6. Diagnostics and treatment of distant metastases

Location of metastases Clinical symptoms Examination methods Treatment Forecast

Lungs – solitary, Asymptomatic cough,
multiple pain, hemoptysis, difficult
breathing, weight loss
Bones – the most Aches, especially at night,
frequently affected ones ebbing when the patient
include the femur, moves, pathological frac-
pelvis, spine, ribs tures
Liver Hepatomegaly. Pains in
the liver area, hepatitis,
fever, weight loss
Brain Headaches, nausea,
neurological symptoms,
psychical changes
Lung X-ray (capable of identifying only
metastases 11 cm); a vague finding is an
indication for an additional CT or MRI
examination; the sensitivity of the cyto-
logical analysis of sputum is just 5–20%.
Bronchoscopy needed to eliminate the
possibility of duplication
Increased ALP (bone isoenzyme) Bone
X-ray (50% sensitivity). Radionuclide
scanning of the skeleton (80–95% sensi-
tivity). CT, MRI examination
Increased liver and ALP tests. Ultrasonic
scanning (80% sensitivity). CT and MRI
examination (90% sensitivity) CT +
arterial portography (95% sensitivity).
Biopsy needed to eliminate the possibility
of duplication
Contrast CT, contrast MRI, brain
angiography
Surgical wedge resection
(subject to the patient being
in a good shape and having
good lung functions, and to
the metastases being surgi-
cally accessible). Palliative
radiotherapy if the bronchus
is obstructed
Palliative
Exceptionally a resection of
metastases. Palliative
Treatment of solitary
metastases using the Leksell
gammaknife, exceptionally
surgical exstirpation.
Multiple metastases – palliative
The surgical removal is
possible for just 5–15% of
patients, of whom 30%
survive more than 5 years
after the operation.
Otherwise, the prognosis
is unfavorable
Unfavorable
Unfavorable
Unfavorable

tumor; (3) extent of regional lymphatic nodes disease, and
(4) locoregional persistence or relapse.
The knowledge of the presence of distant metastases is
vital for the planning of further treatment. From a clinical
viewpoint, patients suffering from a lip or oral cavity car-
cinoma can be divided into a group where the risk of the
incidence of distant metastases is low, and into a high-risk
one. As to the latter group, it comprises patients having a
T4 tumor and/or manifesting N2b–N3 regional nodes (i.e.
those falling into stage IV), and all patients showing a
locoregional relapse. Insofar as the low-risk patients are
concerned, the risk of the incidence of distant metastases
at the time the primary process is diagnosed is between 2
and 3%; consequently, the treatment should consist in an
X-ray of the lungs and liver tests rather than in an exagger-
ated diagnostic tracking of distant metastases. Further
examinations are necessary if there are symptoms suggest-
ing the presence of distant metastases and/or if the results
of previous examinations are abnormal. As to FU, it is
recommended to take a lung X-ray once a year and to con-
duct clinical checks.
As to the high-risk patients, the risk of the incidence of
distant metastases is approximately 10%. The riskiest
group of patients comprises those diagnosed for an N3
lymphatic node condition or suffering from a locoregional
relapse.
Although there exists a higher risk of the formation of a
distant metastasis in this group of patients, an extensive
screening is neither generally recommended, nor econom-
ically efficient. With the disease in an advanced stage, the
best current treatment consists in a positron emission
tomography (PET) scan and/or in targeted examinations
(table 6). Insofar as locoregional relapses are concerned,
when an extensive surgery is planned, it is recommended
to run a PET scan which will can give us early information
of a distant metastasis, thus sparing us a disappointment
after a demanding operation. However, distant metas-
tases can also appear as a result of clinical manifestations
of micrometastases. If a PET scanner is not routinely
available, it is necessary to run a computed tomography
scan of the lungs. Further examinations depend on the
clinical finding of the patient. As to FU, it is recom-
mended to take a lung X-ray twice a year and to repeat
liver tests once a year. The monitoring of the two groups
of patients referred to above spans their whole lifetime,
not just because of a risk of a local or distant relapse of the
disease, but also due to a threat of a tumor duplication.

220 ORL 2001;63:217–221 Betka

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 ORL 2001;63:222–223
Distant Metastases from Oropharyngeal
Cancer
W. Jarrard Goodwin
Department of Otolaryngology, University of Miami, Fla., USA
Key Words
Distant metastases W Oropharyngeal cancer
Abstract
Distant metastasis is a significant problem in patients
with carcinoma of the oropharynx, occurring in approxi-
mately 15–20% off all patients over the course of the dis-
ease. It is, however, a relatively uncommon first site of
failure, as compared to local and regional recurrence.
Distant spread occurs most commonly to the lungs, in
patients who present with advanced disease, and espe-
cially in those with pathologically proven lymph nodes at
multiple levels of the neck or in the lower neck. Metasta-
sis to distant sites also occurs more often in patients who
recur locally or in the neck.
Copyright © 2001 S. Karger AG, Basel
The oropharynx includes the soft palate, tonsillar fos-
sae, tongue base and the pharyngeal walls from the level of
the soft palate cephalad to the level of the epiglottis cau-
dad. Perhaps its most distinguishing anatomical charac-
teristic is as the location for most of the Waldeyer’s lym-
phatic ring, including the palatine tonsils and the lingual
tonsils. Additional pertinent anatomic features include a
complex muscular structure that is critical to speech, mas-
tication and swallowing, and a rich blood supply.
Most tumors occurring in the region are malignant,
and squamous cell carcinoma (SCC) is, by far, the most
common of these. The SCCs seen here tend to be less well
differentiated than those occurring in the oral cavity or
© 2001 S. Karger AG, Basel
ABC 0301–1569/01/0634–0222$17.50/0
Fax + 41 61 306 12 34
E-Mail karger@karger.ch Accessible online at:
www.karger.com www.karger.com/journals/orl
the larynx. Interestingly, the degree of differentiation does
not seem to have a significant impact on overall survival.
Lymphomas (more commonly of the non-Hodgkin’s type)
and malignant salivary gland tumors also occur here with
some frequency.
Lymph node metastases from SCC are common, oc-
curring in approximately 40% of patients at the time of
original presentation. Approximately 15% of patients
present with spread to bilateral lymph nodes.
TNM staging is a critical determinant of prognosis.
Prognosis is especially poor in patients who have T4 pri-
mary cancers due to deep invasion of the pterygoid mus-
cles or the muscles at the root of the tongue, and/or N3
neck disease. Unfortunately, cancers at this site often
cause few symptoms until late in the course of the disease,
and the majority of patients in most series have stage III
or IV disease when first diagnosed.
Because of many of the factors discussed above, most
notably the advanced stage at the time of diagnosis, the
rich vascular supply of the region, and the relatively com-
mon occurrence of poorly differentiated cancers, one
might expect distant spread from oropharyngeal cancers
to occur relatively commonly. Indeed, that is the case,
with most reported experiences indicating an incidence,
which is more common than cancer of the larynx and can-
cer of the oral cavity, but slightly less than that of cancer
of the hypopharynx.
Merino et al. [1] reviewed a 25-year experience for
patients treated at M.D. Anderson Hospital and Tumor
Institute from 1948 to 1973, and found that distant
spread occurred in 110 of 717 (15.5%) patients with can-
cer of the ‘oropharynx proper’. They differentiated the
W. Jarrard Goodwin, MD, FACS
Department of Otolaryngology – Head and Neck Surgery
University of Miami, Sylvester Comprehensive Cancer Center
1475 NW 12 Avenue, Suite 4037, Miami, FL 33136 (USA)
Tel. +1 305 243 4387, Fax +1 305 243 4901, E-Mail jgoodwin@miami.edu
oropharynx proper (tonsillar fossae, base of tongue and
pharyngeal walls) from the faucial arch, and found that
distant spread was twice as common in the former. The
lungs were the most common site of distant spread, occur-
ring in 62 patients (56%), followed by bone in 15%, and
liver in 12%. Liver metastases were relatively common
for this site when compared to the incidence from all oth-
er head and neck sites (5%). For the series as a whole, the
incidence of distant spread was correlated with advanced
T stage, and even more strongly related to an advanced N
stage. Nearly half of occurrences of distant metastases
became apparent within 1 year of treatment, and 80%
became apparent within 2 years. The incidence of distant
spread did not vary with mode of therapy, occurring in 85
of 543 patients (15.7%) of patients treated with radiother-
apy alone, and in 16 of 133 patients (12%) treated by sur-
gery alone.
In a more current study from the same institution, Hol-
singer et al. [2] found a fairly similar incidence of distant
spread, occurring in 17.8% of 146 patients treated for oro-
pharyngeal cancer. Once again, T stage and N stage had a
strong impact on incidence of distant spread. Extension of
disease beyond the confines of a lymph node, and evi-
dence of lymphatic or vascular invasion at the primary
site, also predicted distant spread. In a separate study of
65 patients with carcinoma of the oropharynx and oral
cavity, Close et al. [3] also found a strong correlation
between the occurrence of vascular invasion at the prima-
ry site and the incidence of distant metastases.
The location and pattern of lymph node metastases
may also predict the incidence of distant spread. Vikram
et al. [4] studied 114 patients treated for newly diagnosed
stage III/IV cancer of the mouth and throat between 1975
and 1980. Distant spread occurred in 35% of patients who
had pathologic evidence of positive nodes at multiple lev-
els in the neck, as opposed to just 5% of patients who were
found to have negative nodes or positive nodes at just one
level. In a study of 455 patients with metastatic adenopa-
thy from head and neck SCC (all sites), treated between
1964 and 1985, Ellis et al. [5] found that the most impor-
tant predictors of distant spread were N stage and location
of metastatic nodes in the lower neck.
Many patients who develop distant spread have al-
ready recurred at the local site. Indeed, local-regional
recurrence is another predictor for distant spread. Beer et
al. [6] treated 139 patients for oropharyngeal cancer
between 1990 and 1998, and found that distant spread
occurred in 14/62 patients (23%) with local-regional fail-
ure, and just 4/77 patients (5%) who were controlled at
the primary site and in the neck. Similarly, Leibel et al. [7]
reviewed 2,648 patient records in the RTOG head and
neck database, and found that distant spread occurred in
19% of patients who failed locally or in the neck, and in
just 7% of patients who maintained local-regional control.
Viewed in another way, Fein et al. [8] reviewed an exten-
sive experience from the University of Florida with 785
oropharyngeal cancer patients treated primarily with ra-
diation therapy from 1964 to 1991, and found that 27% of
patients recurred locally, while 15% recurred in the neck,
and just 11% developed distant metastases as the first or
only site of failure.
In summary, distant spread is a significant problem in
patients with carcinoma of the oropharynx, but is a rela-
tively uncommon first site of failure, as compared to local
and regional recurrence. It occurs more commonly in the
lungs, in patients who present with advanced disease,
especially those with pathologically proven lymph nodes
at multiple levels or in the lower neck. Distant spread also
occurs more often in patients who recur locally or in the
neck.

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Oropharyngeal Cancer ORL 2001;63:222–223 223

 ORL 2001;63:224–228
Distant Metastases from Laryngeal and
Hypopharyngeal Cancer
Gershon J. Spector
Department of Otolaryngology – Head and Neck Surgery, Washington University, St. Louis, Mo., USA
Key Words
Distant metastases W Laryngeal cancer W Hypopharyngeal
cancer
Abstract
A retrospective tumor registry analysis of patients with
squamous cell carcinoma (SCC) of the larynx and hypo-
pharynx who were treated with curative intent in the
Department of Otolaryngology – Head and Neck Surgery
at Washington University School of Medicine and
Barnes Hospital between January 1971 and December
1991. In 2,550 patients, the mean age, sex and tumor dif-
ferentiation did not affect the incidence of distant metas-
tases. The overall incidence of distant metastases was
8.5% (217/2,550 patients) with the following distribution:
glottis 4.4%, supraglottis 3.6%, subglottis 14%, aryepi-
glottic fold 16%, pyriform sinus 17% and posterior hypo-
pharynx 17.6%. The overall 5-year disease-specific sur-
vival for distant metastases was 6.4%. Distant metas-
tases were related to advanced local disease (T3 + T4),
lymph node metastases at presentation (N+), tumor loca-
tion (hypopharynx) and locoregional tumor recurrence
(p ^ 0.028). A meta-analysis of variables which predis-
pose to a higher incidence of distant metastases indicate
that tumor location (hypopharynx 1 larynx), advanced
primary disease (T3 + T4), regional disease (N+), locore-
gional recurrences, and advanced regional metastases
(N2 + N3) are statistically significant.
Copyright © 2001 S. Karger AG, Basel
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Methods
A retrospective review of patients in the tumor registry
of the Department of Otolaryngology – Head and Neck
Surgery of Washington University in St. Louis revealed
2,550 patients with primary squamous cell carcinoma
(SCC) of the larynx and hypopharynx (1971–1991). All
had biopsy-proven, previously untreated tumors and were
managed with curative intent. All patients were eligible
for 5-year follow-up. Tumors were staged utilizing the
1992 AJCC/UICC criteria for the pretreatment TNM
classification. Tumor differentiation was based on post-
treatment pathologic analysis.
Distant metastases were defined as tumor spread to
other organ systems. The tumor spread may be of two
types: (1) nonlymphatic metastases (hematogenous
spread) to other organs, the most common being pul-
monary parenchymal metastases (skin, bone, etc.) or
(2) lymph node metastases to other than regional lymph
nodes, the most common are mediastinal, abdominal and
axillary node metastases. Furthermore, distant metastases
can be seen at initial presentation (M1 disease) or as
delayed disease (most common; 1 year posttreatment).
For the purpose of this study, the cure rate means that
a lesion is cured for 5 years or longer (NED) post defini-
tive therapy. In the current report, only disease-specific
5-year survival rate (DSS) or determinate survival rate is
used in order to assess the impact of the distant metas-
tases on survival (tumor death). Standard analysis meth-
Gershon J. Spector, MD FACS
Department of Otolaryngology – Head and Neck Surgery
Washington University School of Medicine
660 South Euclid Avenue, Campus Box 8115, St. Louis, MO 63110 (USA)
Tel. +1 314 362 8626, Fax +1 314 367 7346, E-Mail spectorg@msnotes.wustl.edu
Table 1. SCC of the larynx and
hypopharynx: incidence of distant Location Patients OM1, % DM % Cured %
metastases
Larynx
Glottis 1,119 6.8 50 4.4 2/50 4
Supraglottic 520 16 19 3.6 0/19 0
Subglottic 28 29 4 14.2 0/4 0
Hypopharynx
Aryepiglottic fold 315 22 51 16.1 1/51 1.92
Pyriform sinus 408 31 70 17.1 11/70 15.73
Post wall 130 34.7 23 17.6 0/23 0
Total 2,550 23.2 217 8.5 14/217 6.4

1 OM – occult metastases: number pathologic positive nodes – number clinical positive

nodes/number total positive nodes !100 = % occult metastases.
2 Distant metastases in 6 patients at presentation.
3 Distant metastases in 11 patients at presentation.

ods include the Kaplan-Meier method for actuarial sur-
vival, the ¯2-Fischer exact test and log rank in order to
determine statistical significance. Events that are de-
scribed as significant in the text indicate that the event
achieved a statistical significant p value ^ 0.05 with the
subsequent p value listed. Tumors are subdivided by their
anatomic locations and pretreatment TNM staging.
Results
Overall Data
In 2,550 patients with laryngeal and hypopharyngeal
cancers, the median age 59.8 years (range 21–94), male:fe-
male ratio (8.5:1), ethnic group (71% Caucasians, 20%
African-American, 9% other groups) and degree of tumor
differentiation (11 B 3% poorly differentiated tumors)
were not statistically significant in the development of
distant metastases.
The overall incidence of distant metastases was 8.5%
(217/2,550 patients). Only hypopharyngeal tumors pre-
sented with M1 disease (17/853 patients; 1.9%). Distant
metastatic disease was significantly related to advanced
primary disease (T4), locoregional recurrence, presenting
regional lymph node metastases (N+ disease), delayed
regional lymph node metastases (2 years posttreatment)
(N+ disease; p ^ 0.05). Advanced regional lymph node
metastases (N2 + N3) increased by 3-fold the incidence of
distant metastases (p = 0.001). The incidence of distant
metastases in glottic and supraglottic cancers was 4.4 and
3.6% respectively, and was significantly less than in can-
cers of the subglottis (14.2%), aryepiglottic fold (16.1%),
pyriform fossa (17.1%) and posterior hypopharyngeal
wall (17.6%) (p = 0.023) (table 1). Delayed regional me-
tastases predisposed to distant metastases (p = 0.028).
The incidence of distant metastases was not related to
locoregional salvage rate (p = 0.73). The most common
distant metastasis occurred to the lung and mediastinum
(53%), bone (15%), skin (7%), CNS (3%), and other organ
systems (22%).
The overall salvage rate for distant metastases was
poor (6.4%) with the highest cure rate found in pyriform
sinus carcinomas (15.7%; 11/70 patients) due to a propen-
sity for early single focal distant metastases. Delayed dif-
fuse pulmonary, cutaneous or bone metastases was not
cured (0%).
Larynx
Lesions of the larynx are subdivided by anatomic loca-
tion as glottic, supraglottic and subglottic carcinomas.
Glottic Carcinoma. The incidence of distant metas-
tases in 1,119 glottic carcinoma patients was 4.4% (50
patients). Advancing tumor stages increased the incidence
of distant metastases (table 2). Distant metastases in-
creased with poorer locoregional control rate and de-
creased salvage rate in stage IV disease (64 and 13%
respectively) in a significant manner (p = 0.018). The
highest incidence of distant metastases occurred in T4N1
(22.2%) and T2–3N2–3 (18.1%) disease and was signifi-
cantly related to the highest incidence of delayed regional
lymph node metastases in T4N1 (22%), T4N2–3 (27%)
and T2–3N2–3 (27%) disease stages. Thus, both ad-

Laryngeal and Hypopharyngeal Cancer ORL 2001;63:224–228 225

Table 2. SCC of the glottis and distant metastases Table 3. Aryepiglottic carcinoma: distant metastases vs. tumor stage
and locoregional control
Stage Patients DM1 % Time, years2
Stage Patients L/R1 % DM %
T1N0M0 659 8 1.2 3–8 salvage
T2N0M0 134 3 2.2 2–8
T3N0M0 203 23 11.3 2–16 T1N0 22 1/1 100 4 18.1
T1N1M0 4 0 0 0–0 T2N0 31 6/7 86 3 9.6
T2-3N1M0 47 6 12.7 1–7 T3N0 64 10/24 41.6 7 10.9
T2-3N2-3M0 11 2 18.1 2–7 T1-3N1 64 8/23 34.7 10 15.6
T4N0M0 37 5 13.5 2–3 T4N0-1 70 14/27 51.8 8 11.4
T4N1M0 9 2 22.2 1–3 TXN2-3 58 4/19 21 13 22.4
T4N2-3M0 15 1 6.6 1–2 TXNXM1 6 0 0 62 100
Total 1,119 50 4.4 1.5–6 Total 315 43/101 42.5 51 16.1
DSS3 2/50 4.0 3.2 DSS3 26/694 (38%)4 1/51 1.95

1 DM – distant metastases confirmed histologically, radiological-
ly or clinically.
2 Time – initial diagnosis of distant metastases from the time of
primary tumor diagnosis.
3 DSS –5 year NED cause-specific survival.
1 L/R salvage – locoregional recurrences (101) and therapeutic sal-
vage (43).
2 Six patients presented with distant metastases. None was cured.
3 DSS – cause-specific survival at 5-year NED.
4 Delayed regional metastases occurred in 69/101 patients (68.3%)
and 38% were salvaged.
5 One patient survived salvage therapy for distant metastases.

vanced primary disease (T stage) and regional lymph
node metastases (N+ disease) predispose to distant metas-
tases (p = 0.0371). The distant metastatic disease oc-
curred at a mean of ^3.2 years following primary tumor
therapy. The cure rate was 4% (2/50 patients).
Supraglottic Carcinoma. The incidence of distant me-
tastases in 520 patients with supraglottic carcinomas was
3.6% (19/520 patients). These occurred at 1–75 months
following treatment of the primary disease with a mean of
23.3 months for central epiglottic tumors; 17.6 months for
marginal (lateral) supraglottic tumors, and 10 months for
lesions extending to the vallecula or base of the tongue.
The incidence of distant metastases was not related to pri-
mary tumor stage (T stage) which was as follows: T1 0.9%,
T2 5.7%, T3 2.2% and T4 5%. Distant metastatic disease
was related to the degree of regional lymph node involve-
ment (N+ disease) as follows: N0 2.3%, N1 1.3%, N2
6.4% and N3 20% (p = 0.031). Regional ipsilateral clinical
lymph node involvement was 32% (pathologically 43%,
e.g. 11% occult disease). In N2 and N3 disease contralat-
eral metastases were 42% and were the most common
cause of death (15%). The overall death rate from distant
metastases was 3.7%.
Subglottic Carcinoma. Primary subglottic SCC oc-
curred in 28 patients and had a 14.2% (4 patients) distant
metastatic rate. These were not TNM stage-related (p =
0.92). All patients died of their disease at a mean of 3.6
years following diagnosis of the primary tumor. Only
patients treated by unimodality therapy developed dis-
tant metastases. Clinically, subglottic carcinomas had a
21% incidence of regional lymph node metastases at pre-
sentation. Following resection, the pathologic N+ regional
lymph node metastatic rate was 50% (29% occult metas-
tases). Patients who survived 5 years (NED) following pri-
mary therapy (46.4%; 13/28 patients) had a 19% inci-
dence of distant metastases with a mean occurrence of 2.8
years following primary therapy.
Hypopharynx
Lesions of the hypopharynx are subdivided by their
TNM stages and anatomic locations into aryepiglottic
fold, pyriform sinus and posterolateral hypopharyngeal
wall. Postcricoid cancers were mostly advanced pyriform
sinus tumors and were tabulated with the two/three wall-
apex pyriform sinus tumors (advanced disease).
Aryepiglottic Fold Carcinoma. At presentation, 315
patients with aryepiglottic fold tumors had 80.5% T3 and
T4 disease, 56.3% regional metastases and 1.9% (6 pa-
tients) distant metastases (M1 disease). The overall inci-
dence of distant metastases was 16.1% (51 patients). All
but 1 died of the disease (1/51 patients; 1.9%). Although
the incidence of distant metastases rose with increased

226 ORL 2001;63:224–228 Spector

Table 4. Pyriform sinus carcinoma: distant metastases vs. tumor
location and locoregional control/salvage

Tumor Patients L/R1 % DM %2

location salvage

One wall 48 6/9 66.6 7 14.5

Medial wall 267 29/83 34.9 39 14.6
2–3 walls/apex 93 13/35 37.1 24 25.8
Total 408 127 38 70 17.1
DSS3 48/1271 37.7 9/70 12.82

1 L/R salvage – locoregional recurrence (127 patients) and 48 sal-

Fig. 1. The incidence of hypopharyngeal tu-
vaged.
2 mor (130 patients) treatment failures are due
Eleven patients presented with distant metastases and 2 were
to tumor recurrences at the original site (pri-
cured at 5-year NED (18.1%) and 9 of 70 delayed distant were cured
mary), delayed neck node metastases (re-
(12.8%). The overall cure rate is 13.5%.
3 gional) and delayed distant metastases (dis-
DSS –5 year NED disease-specific survival.
tant). Refer to text for discussion.

TNM stage, locoregional failure, reduced salvage rates,
delayed regional lymph node metastases and advanced
regional node disease (N2 + N3), the data failed to reach
statistical significance (p = 0.278) in differentiating arye-
piglottic tumor parameters that lead towards distant me-
tastases. This was due to a high proportion of advanced
disease patients (table 3).
Pyriform Sinus Carcinoma. At presentation in 408
patients with pyriform sinus cancers, 67% had T3 + T4
disease, 69% had regional node metastases and 2.6% (11
patients) had distant metastases (M1 disease), e.g. 87%
had stage III or IV disease. The overall incidence of dis-
tant metastases was 17.1% (70/408 patients). The tumors
were subdivided into three groups based on tumor loca-
tion within the pyriform sinus with the following 5-year
(NED) cause-specific survival rates: one wall tumors
(73%), medial wall tumors (63%) and two/three wall-apex
tumors (49%). Advanced two/three wall-apex tumors had
a significant increase in distant metastases as compared to
one wall or medial wall tumors (25.8 vs. 14.6%) (p =
0.046). However, the incidence did not correlate with
locoregional control rate, salvage rate, second primary
tumors or delayed regional metastases (table 4). Since
most pyriform sinus lesions were advanced disease, two/
three wall-apex tumors which had a high regional lymph
node metastatic rate at presentation (678%) of which
31% were occult (pathologic) metastases failed to demon-
strate statistically a predisposition of regional metastatic
disease (N+ disease) to distant metastases over the other
two groups of pyriform sinus cancers (p = 0.089).
Posterolateral Hypopharyngeal Wall Carcinoma. In
130 patients with posterolateral hypopharyngeal wall can-
cer, combined therapy had a significantly higher 5-year
cause-specific cure rate (49%) than radiation alone (7%)
(p = 0.031). Stage III and stage IV disease predominated
(82%) with a regional metastatic rate of 72% and T3 and
T4 primary disease of 68% at presentation. The overall
5-year cure rate (NED) was 31% with lateral wall tumors
having a higher survival rate than posterior wall tumors
(p = 0.039). T stage was predictive of survival (p = 0.015).
Combined therapy patients who had higher doses of post-
operative radiation (6,500 +cGy) had fewer distant me-
tastases (8.3%) than those treated with radiation alone
(18%) or low-dose combined preoperative radiation and
surgery (24%). There were 23 patients (17.6%) with dis-
tant metastases. 43.4% (10 patients) were associated with
locoregional tumor recurrence at the primary site. 34.7%
with positive ipsilateral node disease at presentation had
delayed contralateral neck node metastases (fig. 1). In
56.5% of distant metastatic tumor patients, the primary
and regional lymph node disease was controlled. Statisti-
cally, the incidence of distant metastases is related posi-
tively with regional metastatic disease (N+ disease) and
advanced primary disease (T4 stage) (p = 0.049).

Laryngeal and Hypopharyngeal Cancer ORL 2001;63:224–228 227

 Conclusions
To conclude: (1) The overall incidence of distant me-
tastases was 8.5% (217/2,550 patients) in cancers of the
larynx and hypopharynx. (2) Distant metastases were
related to advanced primary disease (T4 stage) regional
lymph metastases (N+ disease) and tumor location (hypo-
pharynx) (p = 0.028). (3) Advanced regional lymph node
metastases (N2 + N3 disease) increased the incidence of
distant metastases by 3-fold (p = 0.017). (4) The highest
incidence of distant metastases occurred in hypopharyn-
228 ORL 2001;63:224–228
geal tumors and was 3 times greater than in laryngeal glot-
tic cancers (p = 0.028). This was related to more advanced
initial tumor presentation in hypopharyngeal cancers as
compared to laryngeal cancers (p = 0.039). (5) The salvage
rate for distant metastases was poor (6.4%) and signifi-
cantly worse than the salvage rate for delayed regional
node metastases (42%) or second primary malignancies
(38%) (p = 0.001). (6) The incidence of distant metastases
was greatest between 1.5 and 6 years post initial treatment
with a mean of ^3.2 years.
Spector
 ORL 2001;63:229–232
Distant Metastases from Cervical
Esophagus Cancer
Fabrizio Bresadola Giovanni Terrosu Alessandro Uzzau Vittorio Bresadola
Department of General Surgery, University of Udine, Italy
Key Words
Distant metastases W Cervical esophagus
Abstract
Cancer of the cervical esophagus has a poor prognosis in
relation to stage. Correct staging is thus essential in
order to establish the prognosis and the treatment pro-
gram. Distant metastases can involve the lymph nodes
(mediastinal and celiac lymph nodes) or they can be
extranodal visceral types. Correct lymph node staging
can be performed with esophageal endoscopic ultraso-
nography, computed tomography (CT) scan and, cur-
rently, with positron emission tomography (PET) and
minimally invasive surgery. For hematogenous metas-
tases, CT scan and PET are mainly used, as well as mini-
mally invasive surgery, with the eventual aid of intra-
operative ultrasonography.
Copyright © 2001 S. Karger AG, Basel
Introduction
The cervical esophagus is the initial segment of the
esophagus, located between the lower edge of the cricoid
cartilage and the thoracic inlet, corresponding to the
suprasternal fossa, about 18–20 cm from the dental arch.
Moving upward is the direct continuation of the lower
© 2001 S. Karger AG, Basel
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part of the hypopharynx, meaning the pharyngoesopha-
geal junction or postcricoid area, which extends from the
arytenoid cartilages and the folds uniting them to the low-
er edge of the cricoid cartilage [1].
Given the direct continuation of the hypopharynx with
the esophagus, the vicinity of the larynx, the same diag-
nostic work-up is followed for tumors in this region. This
is also the reason that when locally advanced tumors are
involved, it may be impossible to determine the site in
which the cancer originated.
In Italy, the incidence of esophageal cancer is 5 cases/
100,000 inhabitants. Within the framework of esophageal
tumors, the rate of cancer of the cervical esophagus is
13.4% in selected cases studies [2].
Diagnosis
Cancer of the cervical esophagus is often diagnosed
late, during an advanced stage, and as a result the progno-
sis is poor. In 20% of cases, the illness can initially present
itself when already in a metastatic stage [3]. Moreover, in
a large percentage of cases there are multiple, synchro-
nous or metachronous tumors of the initial air and diges-
tive passages (6–28%) [4]. Therefore, accurate preopera-
tive staging is essential for selecting patients not only in
terms of prognosis but above all for therapeutic pur-
poses.
Fabrizio Bresadola, MD
Department of General Surgery, University of Udine, Policlinico Universitario
Piazzale S. Maria della Misericordia, I–33100 Udine (Italy)
Tel. +39 0432 559557, Fax +39 0432 559555
E-Mail fabrizio.bresadola@dsc.uniud.it
 In most cases, the advanced stage of cancer of the cer-
vical esophagus and hypopharynx is connected with local
extension of the illness, involving the adjacent organs and
the regional satellite lymph nodes. In this case, the region-
al lymph nodes are the superficial and deep lymph nodes
of the neck, while the mediastinal and celiac lymph nodes
are considered to represent the involvement of distant
metastases [1]. Surgical treatment cannot be used in these
cases.
Lymph Node Metastases
The spread of the cancer to the mediastinal and celiac
lymph nodes is currently studied with various techniques
and with different results: endoscopic ultrasonography
(EUS), thoracoabdominal computerized tomography
(CT) scan, positron emission tomography (PET) and min-
imally invasive surgery.
EUS makes it possible to examine the periesophageal
and celiac lymph nodes, defining not only their shape and
size but, using the latest equipment, also the intrinsic
characteristics of the lymph nodes themselves, distin-
guishing between reactive ones and neoplastic ones. This
method is limited by the need for a guaranteed esophageal
passage and above all, by the fact that it is an operator-
dependent examination. Therefore, the results can vary
according to the operator’s level of experience.
Recently, Catalano et al. [5] reported the results of
EUS performed in 149 patients with esophageal carcino-
ma who had undergone surgery. The criteria defining a
neoplastic lymph node were: diameter 61 cm, circular
shape, uniform hypoechogenic morphology, sharp and
clear margins. With regard to the mediastinal lymph node
involvement (N), the study showed a sensitivity of 79%, a
specificity of 63% and an accuracy of 73%, while for the
celiac ones the rates were 83, 98 and 96%, respectively, in
relation to the postoperative pathological staging.
Other authors have also confirmed the accuracy of
lymph node staging via EUS with values ranging from 65
to 87% [6–10], generally higher than the ones obtained via
CT scan. Giovannini et al. [11] reported even higher
results using an endoscopic ultrasound-guided biopsy
(sensitivity 97% and specificity 100%) to examine distant
lymph nodes. The puncture of the lymph node is handled
percutaneously and is guided by an ultrasound endo-
scope. This is contraindicated for lymph nodes !5 mm,
when the distance from the probe is 16–7 cm, and when
there is interposition of the great vessels.
230 ORL 2001;63:229–232
The thoracoabdominal CT scan permits complete stag-
ing of cancer of the cervical esophagus, not only for the
mediastinal and celiac lymph node involvement (N), but
also for metastases to other organs.
With regard to examination of the lymph nodes, how-
ever, the results are generally inferior as compared to
EUS, due to the fact that CT scan offers lower definition
(1 cm) than EUS (3–4 mm) and to the ability of EUS to
distinguish the morphological characteristics of the lymph
node as well. Diagnostic accuracy ranges from 39 to 55%
[6, 7].
PET is a diagnostic examination that makes it possible
to identify the areas in the organism with a high metabo-
lism, as is the case with tumors, which take up the posi-
tron-emitting tracer injected in the patients. The tracer
that has been used to date in the literature is 18F-2-fluo-
rodeoxyglucose (FDG).
Several studies in the literature have compared PET
with CT scan, evaluating the site of the primary tumor,
involvement of the mediastinal and celiac lymph nodes,
and the presence of other distant metastases. The results
in terms of lymph node involvement have shown a sensi-
tivity of 45%, a specificity of 100% and an accuracy of
48–76% [8, 12–14]. In many cases of false negatives, it
has been demonstrated that there were micrometastases
to the lymph nodes that were revealed only by a histologi-
cal examination. Thus, it is likely that the limitation of
PET lies in the fact that it is still unable to detect occult
metastases to the lymph nodes [8]. Nevertheless, even
now it offers better results than CT scan examinations
and new paths might be opened by the development of
new tracer elements.
The concept of staging through minimally invasive sur-
gery was introduced recently. While on the one hand it is
indeed an invasive method, on the other it has proven to
be superior to all the other conventional diagnostic imag-
ing techniques, enabling more accurate orientation of the
treatment of patients according to the stage of the disease.
Krasna et al. [15] compared lymph node staging with CT
scan and EUS in 88 patients with esophageal carcinoma,
using thoracoscopy and/or diagnostic laparoscopy. The
sensitivity, specificity and positive predictive values
were, respectively: for thoracoscopy 62.5, 100 and 100%;
for esophageal EUS 0, 51.4 and 5.5%; for thoracic CT
scan 75, 75.6 and 23.1%. Instead, as far as diagnostic
laparoscopy is concerned, the respective values were 84.6,
100 and 100%, as opposed to 0, 97.1 and 0 for the abdom-
inal CT scan and 22.2, 81.5 and 28.6% for the abdominal
EUS.
Bresadola/Terrosu/Uzzau/Bresadola
 The reliability of staging with minimally invasive sur-
gery was also confirmed by Luketich et al. [16], who
reported a change in the radiological clinical staging
(CT+EUS) in 32% of cases of esophageal cancer.
Extranodal Metastases
The incidence of distant metastases in cancer of the
cervical esophagus is influenced by the T stage and the N
stage of the neoplasm: a higher stage corresponds to a
higher incidence of distant metastases.
Hematogenous metastases are localized above all in
the lungs, bones and liver. Hepatic involvement is often
manifested as part of a picture of multiorgan metastases.
In terms of noninvasive diagnosis and staging, PET cur-
rently seems to be the most reliable examination and has
proven to be more accurate than CT scan in detecting dis-
tant metastases in 100 cases of esophageal cancer [17].
PET has documented distant metastases in 27 of 39
patients, with a sensitivity of 69%, a specificity of 93.4%
and an accuracy of 84%, as opposed to 46.1, 73.8 and 63%
respectively for CT scan. Nevertheless, the authors con-
cluded by affirming the superiority of invasive staging via
laparoscopic surgery. This superiority was also confirmed
by other authors [12] who, on the basis of PET, modified
the therapeutic orientation of patients who were M+
(17/58). CT has nevertheless maintained its role in staging
cancer of the cervical esophagus not only because the
examination is more easily accessible to a large segment of
the population than PET, but also because it continues to
show good specificity for hepatic lesions and sensitivity in
terms of pleuropulmonary ones.
Lastly, as far as invasive staging through laparoscopic
surgery is concerned, the experiences and results set forth
concerning lymph node staging hold true. Undoubtedly, a
first-hand view of the splanchnic organs, together with the
possibility of performing ultrasonography and/or a biop-
sy, enhances the accuracy of this method. On the other
hand, the low incidence of solitary celiac and hepatic
lymph node metastases from cancer of the cervical esoph-
agus and hypopharynx does not justify its application on a
large scale, also considering the good reliability of other
noninvasive methods.
Treatment
It is well known that patients with cancer of the cervi-
cal esophagus have a low average survival rate, often
because the illness is diagnosed late and is in an advanced
stage. Surgery is indicated in cases that are in a locore-
gional stage and it has a morbidity rate of 31–48% and a
mortality of 10–30% [2, 3, 18–20], with a long-term sur-
vival rate of 21–34% [2, 19]. Although they have im-
proved over the years, these results achieved in the dis-
ease in the locoregional stage suggest that surgery is not
indicated for tumors with distant metastases, due also to
the impairment that may sometimes be involved (laryn-
gectomy), which seriously impairs the quality of life.

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 ORL 2001;63:233–242
Distant Metastases from Salivary
Glands Cancer
Patrick J. Bradley
Department of Otorhinolaryngology – Head and Neck Surgery, Queens Medical Centre, Nottingham, UK
Key Words
Distant metastases W Salivary gland cancer
Abstract
Patients who present with malignant salivary glands
should at their initial assessment have an X-ray of the
chest to exclude the possibility of distant metastases.
Patients who have other symptoms, bone pain etc.,
should be appropriately investigated. The likelihood of
patients developing distant metastases is associated
with high-grade tumors, most commonly adenoid cystic
carcinoma, high-grade mucoepidermoid carcinoma, sal-
ivary duct carcinoma and tumors sited in the submandib-
ular gland, posterior tongue and pharyngeal tumors.
Patients who have had a high-grade tumor treated and
survived without locoregional recurrence have the same
risk of developing distant metastases as those patients
who have locoregional recurrence. Other histological
types of salivary tumors are associated with a lower risk
of developing distant metastases but a real risk remains
lifelong. It is recommended that all patients who have a
malignant salivary gland tumor treated, any histology,
should be followed up and clinically assessed at least
once every 12 months for life.
Copyright © 2001 S. Karger AG, Basel
© 2001 S. Karger AG, Basel
ABC 0301–1569/01/0634–0233$17.50/0
Fax + 41 61 306 12 34
E-Mail karger@karger.ch Accessible online at:
www.karger.com www.karger.com/journals/orl
Recently the World Health Organisation’s histologic
classification of salivary tumors was updated, and in the
group of carcinomas, the classification now includes new-
ly described tumors and separates carcinomas not only
according to morphologic characteristics but also on the
basis of biologic behavior, prognosis and treatment results
[1]. The carcinomas of salivary origin are therefore best
considered to behave biologically according to the grade
of the tumor, high-grade and ‘non-high-grade’ malignan-
cy, regardless of the specific histologic diagnosis (table 1).
However, some of the malignant tumors may be difficult
to grade and their aggressiveness may thus be difficult for
the clinician to predict. The agreed treatment of choice of
a malignant salivary neoplasm is wide surgical excision
with removal of the surrounding soft tissue and the drain-
ing lymphatics if clinically involved. The distribution of
salivary tissue in the head and neck is in the major sali-
vary glands (parotid, submandibular gland) and minor
salivary glands including the sublingual gland, most fre-
quently located in the oral cavity but are found in all ana-
tomical areas of the head and neck.
Survival in malignant disease is determined more
favorable should the tumor arise in the parotid gland, the
palate, or other mouth sites, and were less favorable when
the submandibular gland, the nasal cavity, or paranasal
sinuses were involved. ‘Cure’ rates are low in patients
Patrick J. Bradley, MB
Department of Otorhinolaryngology – Head and Neck Surgery
Queens Medical Centre, 32A Ropewalk
Nottingham NG1 5EH (UK)
Fax +44 115 9709748, E-Mail z0001227@zoo.co.uk
Table 1. Classification of salivary gland
malignancy – high-grade and ‘non-high-
grade’ [from 1]
High-grade Non-high-grade
High-grade mucoepidermoid Acinic cell carcinoma
Adenoid cystic carcinoma Polymorphous low-grade adenocarcinoma
Salivary duct carcinoma Epithelial-myoepithelial carcinoma
Adenocarcinoma NOS Basal cell carcinoma
Carcinoma ex-pleomorphic adenoma
Small cell carcinoma
Squamous cell carcinoma
Undifferentiated carcinoma

with submandibular gland primaries because they are General Comments

most usually a high-grade tumor [2, 3]. Patients with sero-
mucinous gland tumors of the larynx had the lowest
reported survival [4]. Almost 90% of patients with low-
grade malignant tumors are alive 10 years after treatment,
whereas only 25% with high-grade tumors survive the
same time interval. However, no correlation of survival
could be established between the histological grade, pri-
mary site, margins of excision in adenoid cystic carcino-
ma (ACC) and the development of distant metastases [3].
Overall the incidence of distant metastasis occurring is
reported by site to be 17% of the patients with parotid
tumor, 37% of those with a submandibular tumor, and
24% of those with a lesion arising in a minor salivary
gland [2].
Assessment
In patients with carcinoma of the major and minor
salivary glands, the incidence of failures at distant sites is
20–40% according to different histotypes (table 2) [3, 5–
35]. Each patient should have a routine X-ray of the chest,
supplemented when necessary by a computed tomogra-
phy (CT) scan of the thorax. Special investigations such as
bronchoscopy with sputum cytology, bone scanning, se-
rum liver function tests, abdominal ultrasound scanning
and brain scans, should be performed when indicated
[8].
To distinguish lung metastases from primary parotid
carcinoma and a second primary lung carcinoma, the fol-
lowing statements should be considered: (1) a period 15
years for the development of a lung lesion, in the presence
of a parotid squamous cell carcinoma (SCC); (2) CT imag-
ing of a pulmonary lesion compatible with a distant dis-
ease, and (3) histopathologic analysis of biopsy specimens
obtained during bronchoscopy [8].
Generally acknowledged that salivary gland survival
should not be reported in terms of 5-year survival but
should be reported more in longer period of survival and
periods of 15–20 years should now be the norm. The rea-
sons for recommending this protracted patient observa-
tion period is that the risk of locoregional recurrence and/
or the development of distant metastases remains possi-
ble and real for the duration of the treated patient’s life.
In a review of 405 patients with carcinoma of salivary
glands, major and minor sites, followed up over 15 years,
the incidence of distant metastases was reported to be
11.1% (45 patients) [5], whereas in a series of 103 parotid
cancer patients treated and followed up over a 40-year
period it was 24.2% (25 patients) [7]. The location of the
primary site of the tumor and the histological type of the
malignancy had an important association with the devel-
opment of distant metastases. Considering the interval
between initial diagnosis and the appearance of distant
metastases, the Amsterdam Group [8] found no signifi-
cant difference between low-grade and high-grade carci-
nomas (mean 7.1, range 3–18 months vs. mean 6.3, range
0–32 months, respectively) (p = 0.747). In this series,
patients with undifferentiated parotid carcinoma showed
the highest incidence of distant metastases (63.6%)
whereas those with mucoepidermoid carcinoma had the
lowest risk (17.2%). Overall, patients with high-grade car-
cinoma had a higher occurrence of distant metastases
than those with low-grade carcinoma (30.6 vs. 17.9%; p =
0.033). The lungs were the preferential site for SCC (4/5)
and ACC (4/6). The commonest site of distant metastases
overall was the lung 75–90%, followed by long bones, liv-
er, brain; other sites reportedly involved were vertebrae,
skull, ribs, thyroid, subcutaneous, ileum and the peritone-
um [3]. According to histologic type, ACC had the highest
rate of distant metastases, with the other histologic types

234 ORL 2001;63:233–242 Bradley

Table 2. Reported incidence of distant metastases associated with salivary gland tumors

Authors Year Pa- Histo- Site Duration follow-up Number (%) of Sites of distant
tients pathology period of review, years distant metastases metastases cited

Yu and Ma [5] 1987 405 Mixed Mixed 3 years minimum F/U 45 (11.1%) Lung 40 (10%),
1960–1983 liver 3, bone 2
Teo et al. [6] 2000 50 Mixed Mixed 5 years minimum F/U 11 (22%) Lung 3 (6%),
1984–1993 bone 2, liver 2
Renehan et al. [7] 1999 103 Mixed Parotid 12 years median F/U 25 (24%) Lung 17 (16%),
Range 5–32 years bone 5, brain 4
1952–1992
Gallo et al. [8] 1997 124 Mixed Parotid 5 years minimum F/U 33 (26.6%) Lung 14 (11%), brain 4,
1970–1990 liver 3 , skin 3,
bone 3, multiple 5,
unknown 1
Van der Poorten et al. [9] 1999 135 Mixed Parotid 1973–1994 35 (30%) Lung 56 (42%),
first recurrence DM skeleton 21%,
48 (35.5%) multiple sites 19%,
eventually developed DM others
Andersen et al. [10] 1991 95 Mixed Submandibular, 1960–1985 4 (4%) at presentation N/R
sublingual, Lung 19 (20%)
minor salivary
Garden et al. [11] 1994 160 Mixed Minor salivary 1961–1990 43 (26.8%) N/R
Spiro et al. [12] 1991 378 Mixed Minor salivary 10 years minimum F/U 12 (19%) N/R
1939–1983
Anderson et al. [13] 1995 95 Mixed Minor salivary 1956–1991 12 (13%) N/R
Koka et al. [3] 1989 51 ACC Mixed 1969–1987 19 (39%) Lung 12 (23%),
+ other sites
Spiro [14] 1997 196 ACC Mixed 10 years minimum F/U 74 (38%) 5 (3%) Lung 67/74 (90%),
1939–1986 at presentation bone 5, disseminated 2
Fordice et al. [15] 1999 160 ACC Mixed 1977–1996 35 (21.9%) Lung 107 (67%),
liver 12%
Jones et al. [16] 1997 108 ACC Mixed 5 years minimum F/U 14 (13%) N/R
1963–1993
Huang et al. [17] 1997 91 ACC Mixed More than 10 years 29 (32%) Lung 26 (28%), liver 2,
1960–1982 bone 1
Sur et al. [18] 1997 50 ACC Mixed 5 years minimum F/U 9 (18%) 5 (10%) Lung 7 (15%), brain 1,
1983–1992 at presentation multiple 1
Kim et al. [19] 1994 67 ACC Mixed 1979–1991 27 (40%) Lung 21 (31%)
Howard and Lund [20] 1985 20 ACC Nasal/sinus 5 years minimum 5 (25%) Lung 5 (25%), + bone 2,
liver 1, pericardium 1
Plambeck et al. [21] 1996 55 Muco- Mixed 1965–1995 2 (3%) Lung 4 (7%), other sites
epidermoid at presentation N+
Colmenero et al. [22] 1991 20 AcCC Mixed 1966–1989 2 (10%) Lung 2 (10%)
Timon et al. [23] 1994 45 AcCC Mixed Median F/U 89 months 4 (8.8%) N/R
Lewis et al. [24] 1991 63 AcCC Mixed 1915–1978 13 (20.6%) Lung most frequent,
bone
Hoffman et al. [25] 1999 310 AcCC Mixed 1985–1990 10 (3.1%) N/R
at presentation
15 (4.8%) developed DM
Martinez-Barba et al. [26] 1997 9 SDC Parotid 1968–1996 3 (33.3%) Lung, bone, brain
Lewis et al. [27] 1996 26 SDC Parotid and 1960–1989 16 (61.5%) Lung, bone, brain
submandibular

Salivary Glands Cancer ORL 2001;63:233–242 235

Table 2 (continued)

Authors Year Pa- Histo- Site Duration follow-up Number (%) of Sites of distant
tients pathology period of review, years distant metastases metastases cited

Guzzo et al. [28] 1997 26 SDC Parotid 1975–1994 2 (8%) at presentation Liver, lung, bone,
10 (38%) during brain, skin
follow-up
Sykes et al. [29] 1999 30 Mixed Submandibular 1980–1993 6 (20%) Lung 4 ,
+ other sites 2 (20%)
Gaughan et al. [30] 1992 18 SCC Parotid 5 years minimum F/U Zero
1960–1988
Wang et al. [31] 1991 6 MM Parotid 5 years minimum F/U Zero
Klijanienko et al. [32] 1997 2 PA Parotid 1 Both till death All palate tumor Lung 2 (100%),
Palate 1 metastasized 16 months vertebrae, skull
after surgery; parotid
tumor 2 years
Hoorweg et al. [33] 1998 3 PA Parotid 2 10 years minimum F/U All Lung, scalp, vertebrae
Submandibular 1
Aberle et al. [34] 1985 20 PLGA Minor salivary Since 1966 Zero
Gaughan et al. [30] 1992 18 PLGA Minor salivary Since 1969 Zero
Castle et al. [35] 1999 164 PLGA Minor salivary Average F/U One patient Lung
115.4 months

DM = Distant metastasis; SCC = squamous cell carcinoma; ACC = adenoid cystic carcinoma; AcCC = acinic cell carcinoma;
PLGA = polymorphous low-grade adenocarcinoma; PA = pleomorphic adenoma; MM = malignant melanoma; SDC = salivary duct carcinoma.

more rare. According to location of the primary, the
tumors of the tongue and submandibular gland had high-
est rates of distant metastases [5], in one series all patients
with a solid-type ACC died of distant metastases [3].
Another review of 135 cases of parotid malignancy, recur-
rence occurred in 57 patients; the first sign of recurrence
was locoregional in 18 patients and regional and distant in
4 patients, whereas 35 patients showed distant metastasis
as the first site of recurrence. Forty-eight patients devel-
oped distant metastases, 42% showing isolated pulmo-
nary metastases, 21% showing isolated skeletal metas-
tases, 19% showing multiple sites, and the remaining
patients showed liver, brain, bone marrow and retropha-
ryngeal lymph node infiltration [9].
In a comprehensive study of parotid malignancy [7],
the risk of development of distant metastases and the
influence of tumor factors were analyzed. On univariant
analysis of the group, by tumor size (T1 = 0%, T2 = 5%,
T3 = 38%, and T4 = 73%, p ! 0.0001) and grade (low 2%,
intermediate 44%, and high 36%, p ! 0.001) and on mul-
tivariate analysis, the risk of distant metastases were best
predicted by tumor size, presence of cervical nodes, local
soft tissue extension and tumor grade. Despite apparent
local cure in 77 patients, 20 (25.9%) patients developed
distant metastases, suggesting that in many patients, mi-
croscopic dissemination may have already occurred at the
time of presentation.
In a series of 50 patients initially treated for nondissem-
inated carcinomas over a 10-year period [6], no difference
was found in the time to relapse after primary treatment
between the three types of failure – primary, regional and
distant metastases: in addition, there was no predisposi-
tion to any particular failure between the different histo-
logic types. Among the 11 (19%) patients who developed
distant metastases with and without locoregional failure,
the main site of metastasis was the lung (4: 36.3%), fol-
lowed by bone (2: 18.1%) and liver (2: 18.1%). In 4
(36.3%) patients they developed distant metastases be-
tween 0.24 and 6.48 months after the diagnosis of primary
and/or regional failure. The median survival time after
diagnosis of distant metastases was 21.8 months (range
4.6–90.0) despite the low response to chemotherapy.
Distant metastases were demonstrated clinically in 33
(26.6%) of 124 patients with carcinoma of the parotid
gland [8]. Twenty-one patients were men (63.6%), and 12
were women (36.4%). Twenty of the patients with distant
metastases (60.6%) were aged 150 years (p = 0.485). Five
patients (4%) had distant metastases at multiple loca-

236 ORL 2001;63:233–242 Bradley

tions. The presence or absence of positive lymph nodes in
the dissected neck significantly influenced the develop-
ment of subsequent distant metastases in this series (68.2
vs. 23.7%) (p = 0.007). There was also evidence that the
number of involved nodes was prognostically significant:
patients with 12 positive nodes had a higher risk of devel-
oping subsequent distant metastases than those with 1
positive cervical node (p = 0.014). Clinical signs of local
tumor extension such as skin, soft tissue, or bone involve-
ment, and particularly facial nerve paralysis, were found
to be associated with a higher rate of distant metastases.
Greater than 50% of parotid carcinoma with a facial
nerve impairment developed subsequent distant metas-
tases compared with 33% of patients with other signs of
local extension and with 22.8% of patients with no signs
of local aggressiveness (p = 0.011). The histology of the
primary tumor to time to the development of distant
metastases was not found statistically significant but sug-
gestive in the high-grade tumors when ACC was included.
ACC patient survival after a diagnosis of distant metas-
tases was median 78.5 months (mean 73, range 5–142). It
was noted that locoregional tumor control [8] in parotid
carcinomas did not appear to affect the risk of distant
metastases in both univariate and multivariate models,
despite its significant prognostic impact on overall surviv-
al. The majority of distant metastases (21/33: 63.6%)
occurred in patients with locoregional control. Consid-
ering the risk of distant metastases in patients who did
and did not receive postoperative radiotherapy, a higher
incidence of distant metastases was found in the radio-
therapy group than in those patients treated with surgery
alone (16/41 (39%) vs. 17/83 (20.5%); p = 0.028).
The patients who experienced a distant metastases
represented 63.6% of those who died of the disease, sug-
gesting that distant metastasis represents a major problem
in patients with carcinoma of the parotid gland [8]. These
authors reported a lack of correlation between locoregion-
al failure and the occurrence of distant metastases in a
series of 124 consecutive patients with parotid carcinoma,
suggesting a possible difference between the biologic be-
havior of salivary gland carcinoma and other carcinomas
of the head and neck area. Suggested is the probability of
locoregional control and distant metastases are frequently
independent in patients with parotid gland carcinoma
and other sites, with the consequences that the proportion
of patients who achieve local control is frequently in-
creased by the use of more effective local treatment (e.g.,
higher radiation doses). The treatment to date of adjuvant
methods in the management of malignant salivary gland
tumors is limited to palliation [36].
Salivary Glands Cancer
Adenoid Cystic Carcinoma
ACC accounts for one quarter of malignant salivary
gland tumors in most series and constitutes about 10–
15% of all parotid malignancies [14, 18]. This cancer is
more common in minor than in the major salivary glands.
Patients with a pathologic solid type of ACC are more
likely to develop distant metastases and die of their dis-
ease should they live a long period of time after treatment
[19]. There is a high rate of metastases associated with
ACC of the submandibular gland, tongue and maxillary
antrum with a rate of 47.1, 50 and 40% respectively;
metastases of the palate region is associated with the low-
est rate of distant metastases [17, 21].
In a series of 196 patients with ACC selected for fol-
low-up [14], 10 years or more have been analyzed, the
majority had been treated by surgery alone, with 22.4%
(44 patients) given adjuvant radiotherapy. Distant metas-
tases was recorded in 74 patients (37.7% of total and 59%
of treatment failures). Most often, this occurred in asso-
ciation with local and/or regional recurrence (51 patients),
but 23 of the 74 had distant metastases in the absence of
failure elsewhere. Five patients had lung metastases when
first seen. The lung was involved in 67 (90.5%) of the 74
patients with distant metastases. This was the only indica-
tion of distant spread in 50 patients, whereas bone, vis-
cera and brain metastases were associated with lung nod-
ules in 11, 5 and 1 others, respectively. Bone was the only
site of distant metastases in 5, and the remaining 2 had
disseminated disease. Comparing 122 patients who never
had distant metastases with 74 with known distant
spread, there was no significant difference by age, gender,
site of origin, duration of symptoms, or tumor grade.
Tumor size in excess of 3 cm was highly predictive of dis-
tant metastases, as was locoregional recurrence and cervi-
cal node involvement. Survival after appearance of dis-
tant metastases, 40 patients (54%) died within 3 years, 7
(9.4%) survived from 10 to as long as 16 years. Spiro [14]
suggests that the incidence of other sites being involved by
distant metastases is likely to be more common because in
some patients, once lung metastases are detected, no fur-
ther metastatic work-up is initiated. Lung metastases are
rarely solitary and with time the normal lung parenchyma
is slowly replaced by confluent metastatic masses. Surgi-
cal resection may be considered for isolated pulmonary
metastases, although no survival benefit has yet been
demonstrated [15]. Once symptoms develop or visceral
metastases appear, patients seldom survive more than a
year or two. The larger the tumor size at presentation and
the development of locoregional treatment failure are the
ORL 2001;63:233–242 237
two factors most predictive of distant metastases. It seems
of little sense to institute potentially morbid chemothera-
py unless there are symptoms to palliate [14, 15]. When
bone metastases occur, especially in the spine, the course
of disease is usually rapidly fulminant [15].
It has been suggested that some factors leading to dis-
tant metastasis must also exist other than locoregional
failure and that tumor cells must travel an independent
pathway to get to the distant site [15]. Consistent thera-
peutic treatments of the primary site disease may close the
pathways leading to distant failure, these advances most
likely await the advent of effective chemotherapeutic
agents in the management of salivary gland malignancy.
Mucoepidermoid
Major Salivary Glands
Seven hundred and fourteen cases diagnosed as mu-
coepidermoid carcinoma [2] of a major salivary gland
were obtained for evaluation from the Register of Oral
Pathology at the Armed Forces Institute of Pathology
(AFIP). The pathology and case histories were available
for 250 cases and the histopathologic features were re-
viewed. Most mucoepidermoid carcinomas of the major
salivary glands are low grade and had a favorable out-
come. However, patients with a high-grade tumor of small
size (no larger than 3 cm) who had been treated aggres-
sively enjoyed long survival. Grading of the tumor was
considered important by this group.
Minor Salivary Glands
A review of 818 cases of mucoepidermoid carcinoma
of an intraoral minor salivary gland reviewed at the AFIP
emphasized the need for grading of the tumors, but states
that not all patients followed a predictive clinical pattern
once graded [37]. Patients with a high score were more
likely to develop regional and distant metastases, usually
the lung, when compared with the less aggressive low
scored tumors.
Mixed Sites
In a group of 55 patients with mucoepidermoid carci-
noma [21] – 22 major (parotid and submandibular gland)
and 33 minor salivary gland location – 2 patients at pre-
sentation had distant metastases and both had N+ dis-
ease. Distant metastases without local recurrence were
found in 2 patients. Distant metastases occurred in a total
of 4 patients during a follow-up period from surgery (1–22
years). The distant metastases were located in the lungs,
238 ORL 2001;63:233–242
liver, bone and abdominal wall. This paper proposed that
the stage grouping according to the TNM classification
provides a better estimation of the likely clinical behavior
than the histological subtyping of the tumors.
Acinic Cell Carcinoma
Acinic cell carcinoma [22] is considered a slow and
indolently growing low-grade malignancy, with only ‘oc-
casional’ and a small number of cases developing primary
recurrence, nodal and distant metastasis. In a review of 20
cases of mixed salivary sites, 17 parotid and 3 minor
glands (oral cavity 2, antrum 1), 2 patients developed dis-
tant metastases of lung and bones; at 6 and 16 months
both patients had local recurrence. Recently a review of
acinic cell carcinoma (mixed sites) from the National
Cancer Data Base (NCDB) [25] identified 1,353 cases in
the head and neck for the years 1985–1995. Worse surviv-
al was associated with high grade, age 630 years and the
presence of metastatic disease. It was identified that there
was an aggressive subset of acinic cell carcinoma which is
characterized as high grade and advanced, and rarely
occurs in patients younger than 30 years. In the patients
diagnosed in the period 1985–1990, minimum 5-year sur-
vival, of 591 patients, 10 presented with distant metas-
tases, of the 15 patients who developed distant metas-
tases, 9 were dead with a median follow-up of 31.0
months from the time of diagnosis.
In a series of 45 cases of acinic cell carcinoma reported
from Toronto [23], 42 cases were located in the parotid
gland (93.3%) 1 buccal, 1 submaxillary gland and 1 in the
neck. Local recurrence occurred in 15 (33.3%) of the 45
cases. Two patients subsequently developed distant me-
tastases and received chemotherapy. In total, distant me-
tastases developed in 4 patients.
In a series of 63 acinic cell carcinomas treated at the
Mayo Clinic, 20.6% developed distant metastases. Nei-
ther morphologic pattern nor cell composition was a pre-
dictive feature [24]. The time from treatment to develop-
ment of recurrence or metastases can be as much as 30
years! – The median time to developing distant metas-
tases was 3 years. The lung was the most common site of
hematogenous spread, followed by bone. In all patients
who developed a distant metastases they had also devel-
oped a local recurrence prior to making the diagnosis.
Bradley
 Salivary Duct Carcinoma
Salivary duct carcinoma is a distinctive and aggressive
[26] tumor. This neoplasm is characterized histologically
by a striking resemblance to mammary duct carcinoma
and occurs most often in the parotid gland of middle-aged
and older men. Nine cases presented three developed sys-
temic metastatic diseases (33.3%) after recurrence locore-
gionally. Luna et al. [38] and Brandwein et al. [39]
reported distant metastases in 66% of 30 patients and
57% of 58 patients respectively, which subsequently in-
creased to 82% [40]. In another series of 26 cases treated
[27], 23 patients’ tumor was located to the parotid and 3
submandibular gland, 16 cases (61.5%) developed distant
metastases; the most frequent sites involved were in order
of occurrence the lungs, bone and brain. A thorough
review of salivary duct carcinoma [28] adding 26 new
cases and reviewing the literature of 86 cases up to 1994
came to the conclusion that most patients died of dissemi-
nated disease in spite of aggressive and often successful
locoregional treatment. At the time of diagnosis, 2 (8%)
cases had distant metastases already, and 10/26 (38%)
developed distant metastases during follow-up. Distant
metastases were located in several organs: liver, lung,
bone, brain and skin. Relapses became evident at 3–37
months (median 10) after the first treatment. They con-
clude that salivary duct carcinoma has two different pat-
terns of presentation. Most patients present with a rapid
onset and progression of the tumor, whereas other pa-
tients have a more indolent course in the context of a
preexisting pleomorphic adenoma, which gives rise to the
more aggressive tumor. It therefore appears valid to
assume that in the latter cases the salivary duct carcinoma
is in fact a carcinoma ex-pleomorphic adenoma. Further-
more, it is recognized that the most common histologic
type of carcinoma arising is a pleomorphic adenoma. Dis-
tant spread did not seem to be related to the T stage of
disease at presentation, but more related to the presence
of lymph node metastases. It was therefore suggested that
in this disease prophylactic ipsilateral neck dissection
possibly has a preventative role when the patient presents
N0 and may prevent the possibility of distant metastases.
Submandibular Tumors
ACC is the most common malignant tumor of the sub-
mandibular gland followed by mucoepidermoid carcino-
ma. When follow-up is extended for the patient’s lifetime,
studies have shown that disease-related deaths can occur
Salivary Glands Cancer
at 20 years or more after treatment. The clinical course of
submandibular gland malignancy is typically less pro-
tracted, more aggressive, than salivary gland malignancies
of other sites. The incidence of distant metastases re-
portedly as high as 40% from ACC, suggests that chemo-
therapy may play an important role in distant metastases
prevention, however this would need to be conducted in a
multicenter study [41].
In another review of 70 cases, 24 patients were females
and 46 males with a mean age at presentation 64 years
(range 17–94). ACC has been found the most common,
followed by carcinoma ex-pleomorphic adenoma and ad-
enocarcinoma. No mention of distant metastases was
reported in patients who died nor it was commented upon
in survivors! [42]. In another series of 30 patients, with
equal male:female distribution, all patients were managed
by excision and postoperative radiotherapy [29]. Six pa-
tients developed distant metastases to the lung, 2 cases
were associated with uncontrolled recurrences. All 6 cases
who developed distant metastases had ACC. Median sur-
vival following recurrence was 19 months (range 1–106).
Minor Salivary Glands
In a group of 95 patients [13] who had minor salivary
gland carcinomas, distant metastases was identified in
13% of patients occurring more frequently in those with
ACC or in those patients with a pharyngeal primary. The
biological behavior of adenocarcinoma is found to be sim-
ilar to that of ACC with the exception that regional metas-
tases are more common than distant metastases. Acinic
cell carcinoma arose most frequently in the oral cavity
sites with patients showing hematogenous spread to in-
volve the lungs, the abdominal cavity and spinal column.
In 160 patients treated for a minor salivary gland
malignancy at MD Anderson between 1961 and 1990
[11], ACC was present in 113 patients, 25 had a mucoepi-
dermoid carcinoma, and 18 patients had an adenocarci-
noma; the tumor was located in the paranasal sinuses in
46 cases and in the palate in 43 cases. The most common
failure pattern was distant metastases which developed in
43 (26.8%) ACC patients; histologic type, named nerve
invasion, nodal disease and an increased time interval
between surgery and radiotherapy were associated with
an increased risk of distant metastases (p ! 0.05). In most
patients who developed distant metastases (79%) the
occurrence was within the first 5 years of treatment.
The actual incidence of distant metastases remains
uncertain when calculated as a proportion of the 378 who
ORL 2001;63:233–242 239
had a minor salivary gland carcinoma [12], at least 19% of
the patients developed distant spread. The likelihood of
tumor dissemination showed a significant relationship to
the initial status of the neck: 17% when the neck was clini-
cally negative and 31% with enlarged nodes.
In minor salivary gland tumors, distant metastases
developed in 27/87 (31%) of previously untreated pa-
tients [43]. At 12 years the actuarial probability of occur-
rence of distant metastases was 40% in 87 previously
untreated patients with no significant difference noted
according to histologic type (p = 0.46). The probability of
distant metastases as the only site of failure was 19%, with
no significant difference according to histologic type. Dis-
tant metastases developed in 1/8 patients (12.5%) with
clinically positive nodes, compared with 29/87 patients
(33.3%) clinically negative nodes. Time to the develop-
ment of distant metastases did not differ significantly
according to the histologic type. In ACC at the Institut
Gustav Roussy [44] who observed a 38% 5-year survival
rate after the appearances of distant metastases, the inci-
dence of 19% distant metastases as the only site of failure
is also consistent with Memorial Sloan-Kettering Cancer
Center [12].
In a series of 95 minor salivary gland malignant tumors
seen in 25 years [10], ACC was 55 (57.8%) and adenocar-
cinoma 15 (15.7%). The site of tumor location was the
submandibular gland in 38 (40%), sublingual in 6 (6.3%)
and other minor gland sites in 51 patients (53.6%). Dis-
tant metastases occurred in 12/55 (21.8%) patients with
ACC, with 3/15 (20%) who had an adenocarcinoma, and
4/12 (33.3%) carcinoma ex-pleomorphic adenoma. Dis-
tant metastases which occurred were related to site: 11/38
(28.9%) submandibular gland and 4/6 (66.6%) sublingual
gland, 1 each from the hard palate, 1 floor of mouth and 2
from rhinopharynx. At the time of diagnosis, 4 (4.2%)
patients had distant metastases (2 sublingual, 1 subman-
dibular gland and 1 hard palate) to the lungs; 3 at the time
of diagnosis of distant metastases also had nodal disease.
Fifteen patients subsequently developed distant metas-
tases, 10 of whom had ACC. Metastasis most often devel-
oped when the primary was located in the submandibular
gland. Twelve patients (21%) with ACC developed dis-
tant metastases. The median survival of these patients
was 22 months (range 3–83); 3 patients were alive at the
end of investigations 69, 77 and 83 months after treat-
ment.
240 ORL 2001;63:233–242
Pleomorphic Adenoma
Pleomorphic adenoma has been reported to metasta-
size to the neck and distally when associated with fre-
quent and multiple macroscopic recurrences. The metas-
tasis are clinically and histologically similar to the original
primary lesion. There has to date not been any demon-
strable evidence of histological malignancy, nor is there
evidence that metastases were present at first presenta-
tion. Metastasizing pleomorphic adenoma is both histo-
logically and cytologically indistinguishable from typical
pleomorphic adenoma. Flow cytometric analysis and
chromosomal abnormalities have not added further to
identify such patients at risk. These metastasis only be-
come apparent several years after treatment and develop-
ment of locoregional recurrence. Reported sites of metas-
tasis include lungs, bones and other viscera. To date, 45
such cases have been reported in the literature [32, 33].
The hallmark of each of the patients reported is local exci-
sion or enucleation prior to the first presentation of dis-
tant metastases. It has been suggested that previous tumor
manipulation has provided the opportunity of the pleo-
morphic adenoma cells to enter lymphatics or blood ves-
sels, however blood or lymphatic invasion has not been
seen. It is therefore recommended that adequate primary
surgical excision is done of the involved lobe or the gland
of origin with a surrounding margin of normal salivary
gland tissue.
Polymorphous Low-Grade Adenocarcinoma
In a cohort of 164 patients with polymorphous low-
grade adenocarcinoma (PLGA) [35], there was a recur-
rence rate of 9.1% and no evidence of discrete cervical
lymph node metastases. However, 2 patients did die from
the affects of PLGA (biopsy-proven pulmonary metas-
tases and local extension of the tumor to involve vital
structures). Patients need to be followed up for more than
5 years, suggesting that yearly assessment for recurrent
tumor is prudent for the rest of the patient’s life. In a
review of 20 cases of lobular (polymorphous low-grade)
carcinoma of minor salivary glands, no distant metastases
occurred and there was 1 case of regional nodal involve-
ment [34]. Another report of 12 cases [45] reported no
cases of distant metastases.
Bradley
 Others Parotid Carcinomas
Primary SCC of the parotid gland is extremely rare and
in a review of 18 cases [30], the majority of cases was 65
years old. Local recurrence which occurs usually within 12
months, heralds a fatal outcome. No cases were noted to
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 ORL 2001;63:243–249
Distant Metastases from Thyroid and
Parathyroid Cancer
Ashok R. Shaha a Alfio Ferlito b Alessandra Rinaldo b
a Head and Neck Service, Memorial Sloan-Kettering Cancer Center, New York, N.Y., USA;
b Department of Otolaryngology – Head and Neck Surgery, University of Udine, Italy
Key Words
Distant metastases W Thyroid cancer W Parathyroid cancer
Abstract
Thyroid cancer represents a unique biological tumor
where even with the high incidence of distant metas-
tases, the overall prognosis is not as poor as many other
human cancers. The overall long-term survival in pa-
tients presenting initially with distant metastasis is ap-
proximately 50%. The overall incidence of distant metas-
tases varies between 10 and 35%, depending upon the
histology. The overall incidence is directly related to var-
ious histologies – being least in papillary thyroid carcino-
ma (10%) and highest in Hürthle cell tumor (33%). The
incidence of distant metastases is also very high in
patients with medullary and anaplastic thyroid cancer.
The incidence of distant metastases at the time of initial
presentation in differentiated thyroid cancer is approxi-
mately 4%. In high-risk patients – especially in patients
with extrathyroidal extension or massive nodal metasta-
sis – the distant metastases can be evaluated after total
thyroidectomy with radioactive iodine ablation. Pulmo-
nary metastases are very common in young individuals,
but they are extremely well treated and the mortality
from distant metastases in this group is very low. How-
ever, distant metastases in patients with poorly-differen-
tiated carcinoma have a poor prognosis. In high-risk
patients, generally a total thyroidectomy should be un-
© 2001 S. Karger AG, Basel
ABC 0301–1569/01/0634–0243$17.50/0
Fax + 41 61 306 12 34
E-Mail karger@karger.ch Accessible online at:
www.karger.com www.karger.com/journals/orl
dertaken so that the patient can undergo radioactive
iodine dosimetry and ablation as indicated. The surveil-
lance in patients with thyroid cancer includes: close clini-
cal follow-up, chest X-ray, and radioactive iodine dosim-
etry. Thyroglobulin is commonly used as a prognostic
marker in patients having undergone total thyroidecto-
my. The incidence of distant metastases in medullary
thyroid cancer is high, mainly to the lung and liver. Per-
sistent hypercalcitonemia is an indication of regional or
distant metastases. A variety of diagnostic tests are help-
ful, such as octreotide scanning, computed tomography
scan, magnetic resonance imaging and positron emis-
sion tomography scan. Laparoscopy to evaluate the sur-
face of the liver is also an important investigation to
detect distant metastases. The incidence of distant me-
tastases is very high in patients with anaplastic thyroid
cancer, but most of the time the outcome depends on the
locoregional recurrence and massive disease in the cen-
tral compartment. The parathyroid cancer is quite rare,
less than 1%, in patients undergoing parathyroidectomy.
The diagnosis of parathyroid cancer is made by patho-
logical features but the most certain method of diagnosis
of a malignant tumor of the parathyroid is the identifica-
tion of secondary deposits. The incidence of distant
metastasis is difficult to determine due to the rarity of
this condition, but the most common site is the lung.
Patients with distant metastasis have recurrent pro-
gressive hypercalcemia along with high parathormone
level.
Copyright © 2001 S. Karger AG, Basel
Ashok R. Shaha, MD, FACS
Head and Neck Service, Memorial Sloan-Kettering Cancer Center
Cornell University Medical Center
1275 York Avenue, New York, NY 10021 (USA)
Tel. +1 212 629 7649, Fax +1 212 717 3302, E-Mail shahaa@mskcc.org
 Introduction
The subject of thyroid cancer continues to generate
considerable controversy and debate. Most of the contro-
versy is related mainly to the diagnostic work-up of a soli-
tary thyroid nodule and extent of surgery in a patient pre-
senting with unilateral thyroid cancer. There are strong
proponents of routine total thyroidectomy, however,
based on the understanding of the prognostic factors and
risk group analysis, one can tailor the surgical procedure
to the extent of the disease and biology of the thyroid
tumor [1–5]. Approximately 18,000 new patients with
thyroid cancer are expected to be seen in the United
States in the year 2000 [6]. There seems to be a steady
increase in the incidence of thyroid cancer in the United
States with 8,000 patients presenting in 1974 to 18,000 in
the year 2000. There clearly appears to be a steady
increase in the incidence of thyroid cancer in women.
However, the mortality from thyroid cancer has essential-
ly remained unchanged. Approximately 1,225 patients
die of thyroid cancer in the United States every year [7].
Of these, approximately 500 die of anaplastic thyroid can-
cer, 300 die of medullary thyroid cancer, while the death
from differentiated thyroid cancer is quite rare today.
Thyroid cancer represents a unique biological disease
with the spectrum of tumors ranging from relatively com-
mon and indolent papillary carcinoma to the highly ana-
plastic, almost universally fatal spindle and giant cell
tumor of the thyroid [8]. Thyroid cancers can be divided
into well differentiated and the other group. The well-dif-
ferentiated thyroid cancers include papillary, follicular,
mixed and Hürthle cell variety. The other group includes
medullary carcinoma of the thyroid and anaplastic thy-
roid cancer. Some rare forms of thyroid cancer such as
lymphoma, sarcoma and metastatic carcinoma to the thy-
roid also belong to this group. In a large series of 53,856
patients as reported by Hundahl et al. [9] from the
National Cancer Data Base in the United States, the inci-
dence of papillary carcinoma of the thyroid was 78%, fol-
licular cancer 13%, Hürthle cell 3%, and the incidence of
medullary and anaplastic thyroid cancer was 4 and 2%
respectively. They reported an excellent survival in papil-
lary thyroid cancer compared to follicular and Hürthle
cell tumors. Even though Hürthle cell tumors are usually
grouped as a variant of follicular thyroid cancer, the
Hürthle cell cancers represent a distinct histological entity
with specific histological criteria, lack of radioavidity and
high incidence of distant metastasis. Recent review of
Hürthle cell tumors at Memorial Sloan-Kettering Cancer
Center revealed a high incidence of long-term mortality in
244 ORL 2001;63:243–249
high-risk and aggressive Hürthle cell tumors (widely inva-
sive histologic variety) [10].
Prognostic Factors and Risk Group Analysis
The understanding of the prognostic factors has be-
come very clear in the last two decades with a large num-
ber of retrospective reviews from major institutions [2, 3,
11–15]. The Mayo Clinic and the Lahey Clinic initially
described their prognostic factors as AGES and AMES [2,
5]. Upon review of various series, the following prognostic
factors appear to have a major impact in the long-term
outcome: age, grade of the tumor, size of the tumor, extra-
thyroidal extension and distant metastasis. The histology
also appears to be an important prognostic factor. How-
ever, other prognostic factors such as nodal metastasis,
sex, and multicentricity of the tumor do not appear to
have an impact in the long-term outcome. Based on these
prognostic factors, the patients are divided into low- and
high-risk groups. The long-term mortality in the low-risk
group is approximately 2% while the mortality in the
high-risk group is 46%. The review from a large data base
of retrospective study of more than 1,000 patients fol-
lowed for an average duration of 20 years from Memorial
Sloan-Kettering Cancer Center revealed three distinct
risk groups: low-, intermediate- and high-risk groups [3].
Based on these risk groups, the authors were able to
review the long-term survival. In the low-risk group, the
survival was 99%, while in the intermediate- and high-
risk groups it was 87 and 57%, respectively. The under-
standing of the risk groups and prognostic factors appears
to be extremely important in the biology and management
of thyroid cancer, especially related to the extent of thy-
roidectomy [16] and adjuvant forms of therapy.
Distant Metastasis
The distant metastasis in thyroid cancer can be di-
vided into two categories: initial presentation of distant
metastasis and distant metastasis following the initial
treatment of thyroid cancer [17]. Interestingly, if man-
aged appropriately, the long-term survival in patients
with distant metastasis is approximately 43% [18]. The
incidence of distant metastasis in thyroid cancer appears
to be directly related to age of the patient, size of the
tumor, presence or absence of extrathyroidal extension,
and histology. Approximately 4% of patients present ini-
tially with distant metastasis in well-differentiated thy-
Shaha/Ferlito/Rinaldo
roid cancer [18]. However, the incidence of distant metas- Table 1. Incidence of distant metastasis at the time of initial presen-
tasis in medullary and anaplastic thyroid cancer is much tation
higher.
Histology Number with distant metastasis
patients total ! 45 1 45 %
Distant Metastasis at the Time of Initial
Papillary 810 19 11 8 2.35
Presentation Follicular 171 18 1 17 10.5
Hürthle 57 7 1 6 12.2
In a series of 1,038 patients from Memorial Sloan-Ket- Total 1,038 44 13 31 4
tering Cancer Center, 44 patients presented initially with
distant metastasis (4%) [18]. The incidence of distant
metastases was 2.35% for papillary cancer while it was
10.5% for patients with follicular thyroid cancer, and Table 2. Incidence of distant metastasis based on histology
12.2% for Hürthle cell tumors [17]. The highest incidence
Histology Initial presentation Cumulative
of presentation with distant metastasis was noted in
patients above the age of 45 with follicular thyroid carci- Papillary 2% 10%
noma (table 1). The long-term survival in this group was Follicular 11% 22%
43% compared to 86% in patients presenting without dis- Hürthle 12% 33%
tant metastasis (p ! 0.001). The therapeutic approaches to
patients presenting with distant metastasis are essentially
well defined and generally include total thyroidectomy
followed by radioactive iodine dosimetry and ablation, cell cancers. At the time of initial diagnosis, 53% of the
suppressive treatment with L-thyroxine [19–22]. Rarely, patients had metastasis only to the lungs, 20% had metas-
the presence of distant metastasis may be the initial mani- tasis only to the bones, and 16% had multiple organ
festation of thyroid cancer with no gross clinically appar- involvement. The other organ sites involved included
ent disease in the thyroid region. The most common sites brain, mediastinum, skin, liver and eye. The overall mor-
of distant metastasis are lung and bone. The overall out- tality rates at 5 and 10 years were 65 and 75% respective-
come in this group of patients with adequate treatment of ly. Forty-eight percent of all deaths were directly attribut-
primary thyroid cancer and distant metastasis is quite ed to thyroid cancer. The multivariate analysis showed
satisfactory. The usual form of treatment includes routine only age (p 1 0.0001), and involvement of multiple organ
total thyroidectomy in a patient presenting with distant sites (p = 0.0003) was independently associated with can-
metastasis for the primary tumor if the tumor is surgically cer mortality. Bone metastasis was relatively more com-
resectable. Approximately 4–6 weeks after the surgery, mon in Hürthle cell and follicular cancer of the thyroid
the patient will undergo radioactive iodine dosimetry and compared to papillary cancer of the thyroid. The highest
ablation. Usually the maximum allowable dose of ra- risk of death was found in patients who were noted to
dioactive iodine is used. In patients with poorly-differen- have multiple organ involvement at the time of their ini-
tiated thyroid carcinoma, there may not be obvious tial diagnosis.
radioactive iodine avidity in the distant metastasis. Ap-
propriate and adequate management of these patients
with distant metastasis due to poorly-differentiated his- Distant Metastasis Subsequent to Initial
tology generally remains unsatisfactory due to the lack of Treatment
radioavidity. The resection of the entire thyroid facilitates
giving a large dose of radioactive iodine that may concen- The incidence of distant metastasis subsequent to ini-
trate in the distant metastasis. tial treatment depends upon the initial extent of the dis-
Ruegemer et al. [23] from the Mayo Clinic reviewed ease, the risk group, age of the patient, the presence or
their experience of 85 patients who presented with distant absence of extrathyroidal extension, histology, and grade
metastasis either initially at the time of primary evalua- of the tumor. The overall incidence of distant metastasis
tion or subsequently in the follow-up. The incidence of in papillary thyroid cancer is as high as 10% while the
distant metastasis by histology was 7% for papillary carci- incidence in follicular and Hürthle cell tumors is 22 and
noma, 19% for follicular carcinoma, and 34% for Hürthle 33% respectively (table 2). The high-grade tumors have

Thyroid and Parathyroid Cancer ORL 2001;63:243–249 245

Table 3. Incidence of distant metastasis based on risk groups
Risk groups Patients, total Distant metastasis
Low 403 (39%) 2%
Intermediate 403 (39%) 12%
High 232 (22%) 34%
higher incidence of distant metastasis including poorly-
differentiated histology such as tall cell, trabecular, insu-
lar and undifferentiated tumors. The incidence of dis-
tance metastasis in the low-risk tumors is extremely small
and, if a patient in the low-risk tumor group develops dis-
tant metastasis, one should be always on the lookout to see
if the initial histology was of poorly-differentiated type. In
a large series of 403 patients from Memorial Hospital in
the low-risk group, the long-term survival was 99% and
only 4 patients eventually died of thyroid cancer [24] (ta-
ble 3). On re-review of the slides of these 4 patients, it was
noted that 2 had poorly-differentiated histology at their
initial presentation. The incidence of distant metastasis is
very high in elderly patients, especially those who have
had multiple recurrences in the locoregional area. A large
number of these patients generally have nonradioavid
tumors, most of the time with poorly-differentiated histol-
ogy or transformation from well-differentiated to poorly-
differentiated thyroid cancers. The incidence of distant
metastasis is higher in patients presenting with extrathy-
roidal extension of the primary tumor and those patients
who have local recurrence.
Treatment of Distant Metastasis
The diagnosis of distant metastasis is made on the clin-
ical examination, radiological studies, thyroglobulin lev-
els [25], and radioactive iodine avidity of the distant
metastasis. In young patients with massive nodal disease,
there is high incidence of pulmonary metastasis and this
may not be revealed on routine chest X-ray. However, a
large ablative dose of radioactive iodine will show diffuse
pickup in the lungs after a few days of radioactive iodine
ablation. Several investigators have shown that patients
who have microscopic metastatic disease rather than
grossly evident disease on routine chest radiography do
much better and respond very well to radioactive iodine.
A patient presenting with a pulmonary mass with a histo-
ry of thyroid cancer should have appropriate further
work-up including fine-needle aspiration biopsy of the
246 ORL 2001;63:243–249
lung to rule out primary pulmonary neoplasm. Occasion-
ally the diagnosis of pulmonary mass may be difficult
with fine-needle aspiration biopsy and under these cir-
cumstances, appropriate immunohistochemical studies
including thyroglobulin stain will be of great help. The
treatment approaches include radioactive iodine, appro-
priate suppressive therapy with L-thyroxine, external ra-
diation therapy to the localized area – especially to the
bone when it is causing spinal compression and pain. Sur-
gical intervention is rarely undertaken. In patients with
metastatic Hürthle cell tumors to the lung where the dis-
ease has remained stationary, one may occasionally con-
sider surgical intervention. The bony metastasis may
require appropriate stabilization of the bone. Occasional-
ly a patient may present with bony metastasis as initial
presentation and the orthopedic surgeon may undertake
surgical intervention, not realizing that the bony lesion is
a metastatic thyroid cancer. Patients may present with
brain metastasis and neurological symptoms. The surgical
intervention may be undertaken with craniotomy in se-
lected patients with brain metastasis, especially those
causing serious neurological deficits. The role of surgery
in management of distant metastasis from thyroid cancer
appears to be quite limited.
Surveillance in Thyroid Cancer
The surveillance of a patient who has undergone ap-
propriate thyroid surgery for primary tumor depends
mainly on the risk group analysis:
Low-Risk Group
In a young patient with a small primary tumor where
lobectomy or total thyroidectomy is performed, the sur-
veillance is limited to clinical examination: (1) Clinical
examination: (a) every 3–4 months, first 2 years; (b) every
4–6 months for the next 2–3 years; (c) every 6 months
from 5 years onwards. (2) Chest X-ray once a year for the
first 5 years and then once every 2 years. (3) Serum thyro-
globulin level if the patient has undergone total thyroidec-
tomy. (4) Radioactive iodine is generally not indicated as
the prognosis is excellent. (5) Radioactive iodine dosime-
try until at least one negative radioactive iodine scan is
obtained.
High-Risk Group
(1) Clinical examination: (a) every 3 months for the
first year; (b) every 4 months during the second year;
(c) every 4–6 months through the third to fifth years; (d) ev-
Shaha/Ferlito/Rinaldo
ery 6 months from 5 years onwards. (2) Chest X-ray every
year for the first 5 years and every 2 years after that.
(3) Serum thyroglobulin twice a year. (4) Radioactive
iodine dosimetry and ablation until one negative scan.
Medullary Carcinoma of the Thyroid
Medullary carcinoma of the thyroid forms a part of
MEN-I or MEN-II. The sporadic form is also well known.
It is a distinct clinical entity originating in parafollicular
or C cells of the thyroid. The incidence of nodal metasta-
sis is very high. Most of the C cells are located in the supe-
rior portion of the thyroid gland. High calcitonin level is a
hallmark of medullary carcinoma of the thyroid. Occa-
sionally a patient may present with nodal metastasis and
the fine-needle aspiration biopsy or the open biopsy of the
neck node should be reviewed with immunohistochemis-
try for calcitonin. The usual treatment for medullary car-
cinoma of the thyroid is total thyroidectomy and central
compartment node clearance. If there are clinically palpa-
ble or obvious nodes at the time of surgery, appropriate
modified neck dissection should be undertaken. The over-
all survival in medullary carcinoma is much worse com-
pared to well-differentiated carcinoma of the thyroid and
overall 5-year survival is about 60–65%. Postoperatively
these patients should be followed very carefully. The
recent advances in the molecular biology and the genetics
have revealed a major contribution of the RET proto-
oncogene mutation in medullary carcinoma of the thy-
roid. Family members and siblings should be evaluated
carefully with RET studies and should there be a family
member with RET mutation, appropriate total thyroidec-
tomy should be undertaken at an early age. Most of the
young children who have undergone total thyroidectomy
based on RET mutation have been noted to have C-cell
hyperplasia or early medullary carcinoma and they should
be essentially cured of medullary carcinoma of the thy-
roid. Postoperative follow-up in patients with medullary
thyroid cancer includes: (1) Clinical examination: (a) eve-
ry 3 months for the first year; (b) every 4–6 months from
second to fifth year; (c) every 6 months after 5 years.
(2) Chest X-ray every year for the first 5 years, and then
every 2 years. (3) Calcitonin and carcinoembryonic anti-
gen levels every 6 months.
A patient with medullary thyroid cancer and progres-
sive hypercalcitonemia is indicative of recurrent medulla-
ry cancer of the thyroid. The recurrence could be either in
the thyroid bed or generally in the lymph nodes in the
neck or superior mediastinum. If the patient presents with
Thyroid and Parathyroid Cancer
a very high level of calcitonin, one should screen critically
the lungs for pulmonary metastasis and if the lungs are not
the source of high calcitonin, then the liver should be eval-
uated with an ultrasound, liver scan, magnetic resonance
imaging (MRI) and laparoscopy. The laparoscopic evalu-
ation of the liver is extremely important in patients with
rising and persistent hypercalcitonemia. The incidence of
liver metastasis, especially small metastatic disease on the
surface of the liver, is very high in patients with medullary
thyroid cancer and generally these are difficult to evaluate
by any other imaging studies. Percutaneous needle biopsy
with laparoscopic guidance will confirm the presence of
metastatic disease on the surface of the liver.
Anaplastic Thyroid Cancer
The incidence of anaplastic thyroid cancer ranges be-
tween 2 and 3%. There appears to be decreasing incidence
of anaplastic thyroid cancer in the United States, however
it is still a prevalent disease in other parts of the world,
especially in areas where endemic goiter is still very com-
mon. According to the AJCC-UICC classification, all ana-
plastic thyroid cancer patients belong to stage IV because
of the aggressive nature of the disease. The surgeon’s role
in the management of anaplastic thyroid cancer is mainly
to make appropriate diagnosis. Fine-needle aspiration
biopsy will raise suspicion of anaplastic thyroid cancer,
however it is vitally important to rule out small cell ana-
plastic thyroid cancer, lymphoma, and to confirm the
diagnosis of giant and spindle cell anaplastic thyroid can-
cer. Core biopsy or open biopsy is invariably necessary to
confirm the diagnosis. It is also important to rule out high-
grade poorly-differentiated papillary or follicular thyroid
cancer that may be a surgical problem. Appropriate histo-
pathological evaluation and diagnostic studies including
immunohistochemistry are necessary to rule out small cell
anaplastic thyroid cancer or lymphoma. Most of the
patients with anaplastic thyroid cancer present with ad-
vanced local disease. Fifty percent of the patients may
present with lymph node metastasis and the incidence of
pulmonary metastasis at the time of presentation is quite
high. The incidence is also very high during the follow-up.
The follow-up of these patients is invariably of short dura-
tion since most of the patients generally succumb to their
anaplastic thyroid cancer in a matter of months. Surgical
intervention in these patients is futile and local recurrence
is extremely high unless the tumor is very small and well
localized. Most of these patients are now treated with a
combination of chemotherapy and radiation therapy. Ra-
ORL 2001;63:243–249 247
diation therapy is generally utilized in the hyperfraction-
ated scheme. Chemotherapy is invariably added to the
radiation therapy and the commonest drug of choice is
Adriamycin. Recently there appears to be increasing in-
terest in taxol, and cis-platinum and 5-FU are also uti-
lized as a radiosensitizer. Anaplastic thyroid cancer con-
tinues to be a challenge to the treating physicians and the
follow-up should be undertaken every month to evaluate
the locoregional disease including lymph node metastasis.
Chest X-ray may be repeated every 3 months for pulmo-
nary metastasis. Symptoms of dysphagia in patients with
anaplastic thyroid cancer are indicative of involvement of
the esophagus and the subsequent treatment is essentially
palliative. Most of the patients die of uncontrolled local
disease, mainly due to airway difficulty or dysphagia and
cachexia. Due to high incidence of pulmonary metastasis,
patients may succumb to massive pulmonary disease with
pleural effusion and airway distress.
Parathyroid Carcinoma
Parathyroid cancer forms a rare endocrine neoplasm
with more than 700 cases published in the world literature
[26–33]. It forms approximately 1% of diseases of the
parathyroid glands [34]. Persistent hypercalcemia is sug-
gestive of primary hyperparathyroidism. Of the patients
undergoing surgery for primary hyperparathyroidism,
85% are generally single gland adenoma while approxi-
mately 14% represent multiglandular disease. One per-
cent of the parathyroid surgical procedures represents
parathyroid carcinoma. The diagnostic dilemma revolves
around making a definite diagnosis of parathyroid carci-
noma. The clinical suspicion is raised with extremely high
parathormone level and calcium level 114 mg. A clinical-
ly palpable mass or nodal metastasis may occasionally be
noted, however this is more common in recurrent setup.
At the time of surgery, if the parathyroid gland appears to
be infiltrating into the surrounding structure, especially
the thyroid gland and if one cannot separate the thyroid
from the parathyroid, it would be appropriate to remove
ipsilateral thyroid lobe in an effort to get a better onco-
logic margin. Quite often the diagnosis of parathyroid car-
cinoma is a pathological curiosity after excision of the
parathyroid gland. Morphologic features diagnostic of
malignancy in parathyroid lesions are difficult to define,
identify and apply [35]. The distinction between benign
and malignant parathyroid tumors is difficult to make
histologically. Carcinomas cannot be reliably separated
from adenomas by histology alone [33]. In one series of 40
248 ORL 2001;63:243–249
patients with metastatic parathyroid cancer, as many as
50% were thought to have benign disease by the surgeon
and by the pathologist at the initial surgery [31]. Several
histologic findings of parathyroid malignancies, such as
vascular invasion, local invasion, fibrous bands dividing
the lesion, trabecular cellular arrangement, mitoses, ad-
herence to surrounding tissues, may be present in some
degree in benign tumors, or they are easily misinterpreted
[35]. The presence of capsular invasion in and itself can-
not be equated with carcinoma in a parathyroid tumor.
Vascular invasion is difficult to define except if seen out-
side the vicinity of the neoplasm [32]. No single feature is
pathognomonic of malignancy. The most certain method
of diagnosis of a malignant tumor of the parathyroid is the
identification of secondary deposits [35]. Metastases oc-
cur approximately in 30% of the patients with parathy-
roid carcinoma [32] and are unusual at the time of presen-
tation. They may be found in local regional lymph nodes
but usually after local recurrence [26], and their incidence
varies in the literature between 17 and 32% [34]. Pulmo-
nary metastases are by far the most common distant
metastases [31], but other organs may be involved as
bone, liver, kidney, adrenal glands and pancreas. The
final diagnosis depends upon the appropriate histological
evaluation and close follow-up. Metastases are the only
sine qua of malignancy. Death is usually caused by com-
plications of persistent hypercalcemia and its sequelae
and is not due to widespread organ replacement. The
overall 5- and 10-year relative survival rates were 85.5
and 49.1% respectively in the largest series reported in the
literature [26].
Surveillance in Patients with Parathyroid
Carcinoma
The surveillance in patients with parathyroid carcino-
ma is critical to rule out local recurrence, nodal or distant
metastasis. The clinical examination should be undertak-
en every 3 months postoperatively for the first 2 years
along with evaluation of the neck for nodal disease. A
chest X-ray should be undertaken every 6 months to rule
out metastatic disease. The most important follow-up in
patients with parathyroid cancer is regular assay of serum
parathormone and serum calcium. If there is a persis-
tently high parathormone level, recurrence should be sus-
pected and appropriate imaging studies including com-
puted tomography scan, MRI, ultrasonogram, and ses-
tamibi scan may be undertaken. If nodal disease is appar-
ent by imaging studies or by ultrasound, appropriate neck
Shaha/Ferlito/Rinaldo
dissection should be undertaken. Since the overall inci-
dence of parathyroid carcinoma is so low, very little infor-
mation is available on pulmonary metastasectomy in
parathyroid cancer. However, if localized disease is noted
in the lungs for a duration of time, one may consider
metastasectomy. The role of chemotherapy continues to
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tions. Appropriate diuretic therapy, hydration, diphos-
phonates, mithramycin, etidronate, etc., may be of some
help.
13 Hay ID, Bergstralh EJ, Goellner JR, Ebersold
JR, Grant CS: Predicting outcome in papillary
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249
 ORL 2001;63:250–251
Distant Metastases from Ear and
Temporal Bone Cancer
Clarence T. Sasaki
Department of Surgery – Section of Otolaryngology, Yale University, New Haven, Conn., USA
Key Words
Distant metastases W Ear cancer W Temporal bone cancer
Abstract
Cancers of the temporal bone are rare. Cervical metas-
tases occur in approximately 10% of cases and are much
more likely once disease extends beyond the confines of
the temporal bone. Nonlymphatic spread of squamous
cell carcinoma is usually a late event resulting in meta-
static deposits in the lung, bone, liver and brain. This
chapter discusses detection of distant metastases and
provides a recommended schedule for interval patient
evaluation.
Copyright © 2001 S. Karger AG, Basel
Cancers of the temporal bone are rare. Estimates of
incidence are in the range of 6 cases per million, with a
median age of occurrence at 55 years. 60% of malignan-
cies affect the auricle, 28% the external auditory canal
and 12% the middle ear and mastoid. Most tumors of the
auricle are basal cell carcinoma (BCC) in contrast to squa-
mous cell carcinoma (SCC) that affect the external audito-
ry canal and middle ear. However, other cancers of the
temporal bone include adenocarcinoma, melanoma and
© 2001 S. Karger AG, Basel
ABC 0301–1569/01/0634–0250$17.50/0
Fax + 41 61 306 12 34
E-Mail karger@karger.ch Accessible online at:
www.karger.com www.karger.com/journals/orl
sarcoma. Cervical metastases are present in approximate-
ly 10% of cases often involving intraparotid nodes as well
as level I and II lymph nodes [1].
Temporal bone architecture plays a distinct role in the
behavior of tumor extension. For example, lesions affect-
ing the external auditory canal rarely metastasize until
there is direct bony invasion. Extension anteriorly and
inferiorly through the fissures of Santorini or the foramen
of Huschke allows disease to extend to the temporoman-
dibular joint. Tumor metastasis is much more likely once
disease has extended beyond the bony confines of the
temporal bone. Superior extension through the tegmen of
the mastoid or middle ear places disease in direct proxim-
ity to the temporal lobe of the brain in the middle cranial
fossa. Posterior extension places the facial nerve at risk as
tumor extends into the mastoid process. Medial extension
of tumor within the middle ear may cause involvement of
the jugular bulb and carotid artery [2–4]. Distant metasta-
sis, however, is usually an extremely rare event. Nonlym-
phatic or hematogenous spread in SCC is also usually a
late event resulting in metastatic deposits in lung, bone,
liver and brain [5].
Clarence T. Sasaki, MD
Department of Surgery, Section of Otolaryngology
Yale University School of Medicine, Department of Surgery
333 Cedar Street, New Haven, CT 06510 (USA)
Fax +1 203 785 3970, E-Mail frb2@email.med.yale.edu
 Pulmonary Metastasis
Chest computed tomography (CT) scan is clearly the
most sensitive in identifying and localizing pulmonary
metastasis although plain chest radiography serves as a
useful screening tool. Plain chest x-rays are much more
easily available and important cost differential also un-
derlies its universal utility. The cost of noncontrast CT
scan is USD 958.00 compared to plain chest radiograph
of USD 171.00.
Bone Metastasis
Because metastasis to osseous tissue is the second most
common presentation of distant metastases, bone scan is
an important and sensitive test. However, because of its
nonspecificity, CT-directed needle biopsies may be nec-
essary to establish diagnosis. The cost of bone scan is
USD 791.00.
diagnostic CT scan followed by ultrasound-guided needle
biopsy. The cost of ultrasound-guided needle biopsy is
USD 265.00.
Brain Metastasis
Although brain metastasis is a rare occurrence from
head and neck cancer, it is particularly more probable in
tumor involving the temporal bone simply because of its
proximity to the cranial vault. CT scan and magnetic reso-
nance imaging (MRI) provide the highest sensitivity of
screening for intracranial disease well before neurological
manifestations become apparent. The cost of contrast-
enhanced head CT scan is USD 1,032.00 compared to
contrast enhanced MRI USD 1,345.00.
Guidelines for the Detection of Distant
Metastasis in Temporal Bone Cancer

For the detection of distant metastases in temporal

Liver Metastasis
Hematogenous spread to liver rarely occurs without
evidence of pulmonary and bone disease. Although liver
function tests may detect abnormality, elevation in liver
enzymes ordinarily carries low sensitivity or specificity
for liver involvement. Confirmation most often requires a
bone cancer, the following guidelines of Medina [6] are
recommended: (1) Establish initial baseline head CT scan
and chest CT. (2) Repeat chest CT and head CT annually.
(3) Office examination: first year posttreatment: 1–3
months; second year posttreatment: 2–4 months; third
year posttreatment: 3–6 months; fourth and fifth years:
4–6 months; after 5 years: annually.

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ported on 33 patients. Head Neck 1999;21:
461–466.
5 Sasaki CT, Spencer D, Ariyan S: Cancer of the
ear; in Ariyan S (ed): Cancer of the Head and
Neck. St Louis, Mosby, 1987.
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Ear and Temporal Bone Cancer ORL 2001;63:250–251 251

 ORL 2001;63:252–255
Noncervical Lymph Node Metastasis
from Head and Neck Cancer
Luiz P. Kowalski
Head and Neck Surgery and Otorhinolaryngology Department, Hospital do Cancer A.C. Camargo, São Paulo, Brazil
Key Words
Head and neck cancer W Lymph node W Metastases
Abstract
Nonregional lymph node dissemination must be classi-
fied as distant metastasis but axillary and mediastinal
metastases can be part of a regional dissemination of the
disease. Metastases to lymph nodes of the upper medi-
astinum are very common among patients with subglot-
tic, hypopharynx and thyroid carcinomas. Axillary me-
tastases are found at autopsy in 2–9% of the patients
who died of head and neck squamous cell carcinoma
(SCC) and are frequently associated with skin implanta-
tion in aggressive recurrent head and neck carcinomas.
The possible explanations for this location of metastasis
were retrograde dissemination due to lymph system
blockage, further tumor dissemination after a parasto-
mal recurrence, hematogenous dissemination, and me-
tastasis from a second primary tumor. Patients with dis-
tant metastasis have been considered incurable and only
palliative treatment was instituted. Treatment planning
for cases with axillary metastasis must take in consider-
ation the likelihood of other regional recurrences and/or
distant metastasis. Also, the presence of a second prima-
ry tumor must be ruled out. Whenever axilla is the only
site of cancer recurrence, a standard axillary dissection
© 2001 S. Karger AG, Basel
ABC 0301–1569/01/0634–0252$17.50/0
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must be considered. Upper mediastinal metastases from
subglottic and hypopharyngeal cancer are managed by
paratracheal and mediastinal dissection through the
neck and postoperative radiotherapy.
Copyright © 2001 S. Karger AG, Basel
Definition
Nonregional lymph node dissemination must be classi-
fied as distant metastasis according to UICC [1]. How-
ever, axillary and mediastinal metastases can in fact
represent a contiguous regional dissemination of disease.
Metastases to lymph nodes of the upper mediastinum are
very common among patients with subglottic and hypo-
pharyngeal squamous cell carcinoma (SCC) [2–4]. Metas-
tases of thyroid cancer to mediastinal lymph nodes are
classified as regional (N1b), and metastases to inguinal,
peribronchial and abdominal lymph nodes are classified
as distant metastasis (M1).
Incidence
In autopsy as in clinical series, distant metastases to
the noncervical lymph node have rarely been described in
cases of head and neck carcinomas [5–9]. Axillary metas-
Luiz P. Kowalski, MD, PhD
Head and Neck Surgery and Otolaryngology Department
Hospital do Cancer AC Camargo, Rua Professor Antonio Prudente 211
São Paulo 01509-900 (Brazil)
Tel. +55 11 3272 5125, Fax +55 11 3277 6789, E-Mail lp_kowalski@uol.com.br
tases are found at autopsy in 2–9% of the patients who
died of head and neck SCC [6, 7], but the incidence of
such metastasis can be higher because nonpalpable axilla-
ry lymph nodes are not routinely dissected at autopsy,
except in breast cancer and some melanoma patients. In
the autopsy study by Hoye et al. [6] of 42 cases of head
and neck SCC, there were thoracic lymph node metas-
tases in 11 cases (26.1%), abdominal lymph nodes in 5
cases (11.9%) and other distant lymph node metastases in
7 cases (16.7%). Suen [10] pointed out that axillary metas-
tasis is frequently associated with skin implantation in
aggressive recurrent head and neck carcinomas. Sun et al.
[11] reported 1 case of oat cell carcinoma of the larynx
with bilateral neck metastases. The postmortem examina-
tion showed persistent primary tumor, bilateral neck, pul-
monary, central nervous system and axillary metastases.
Alavi et al. [8] reviewed 342 patients with mucosal head
and neck SCC, and 47 (13.7%) had distant metastases.
Five patients (1.5%) had metastases to infraclavicular
lymph nodes (axilla, inguinal and presternal).
Schobinger [12] demonstrated mediastinal metastasis
in 7 out of 40 patients with head and neck cancer at autop-
sy –1 of these patients died due to the tracheal invasion
by the metastatic lymph node. Rucco and Amatulli [13],
Som [14] and DiSantis et al. [15] also showed mediastinal
involvement by head and neck carcinomas. A recent
study by Martins [4] with 35 patients who underwent
upper mediastinal dissection due to tumors located as fol-
lows: cervical esophagus (16 cases), pyriform sinus (7
cases), postcricoid (7 cases), larynx (4 cases) and pharyn-
goesophageal recurrence of a thyroid carcinoma (1 case).
Of the 28 cases who were analyzed, 17 (60.7%) had
mediastinal metastasis: esophagus, 8/13 (61.5%); hypo-
pharynx, 8/11 (72.7%); larynx, 0/3; recurrent thyroid car-
cinoma, 1/1.
Physiopathology
Except for the midline structures of the upper respira-
tory and digestive tracts, the lymph flow is ipsilateral and
the jugular nodes are usually the first echelon on lymph
nodes. Some areas as the subglottis, trachea, hypopha-
rynx, esophagus and thyroid had a lymph drainage to pre-
and paratracheal nodes. These lymph nodes constitute a
wealthy network with those at the upper mediastinum
[16–18], and the anatomic relationships and the lymphat-
ic vessels’ communications at the jugulo-subclavian junc-
tion are complex and variable, being possibly the retro-
grade dissemination both from the head and neck region
Noncervical Lymph Node Metastasis
to the axilla or mediastinum, as well as from infraclavicu-
lar tumors to the neck.
Although communications between cervical and axil-
lary lymphatics exist, the physiologic flow is centripetous
to the jugulo-subclavian junction [16]. A malignant tumor
can promote serious changes at the lymphatic drainage.
Although these modifications are mainly due to the block-
age of lymph nodes consequent to metastasis, fibrosis con-
sequent to surgical manipulation or radiotherapy are oth-
er possible involved factors [17–21]. Fibrosis at the jugu-
lo-subclavian junction and superior mediastinum could
explain the anomalous lymphatic dissemination of a head
and neck cancer to the axilla.
The skin and soft tissues at the level of manubrium
lymphatic flow can be directed to the transverse cervical
chain as well as to axillary lymph nodes, even under nor-
mal conditions [22]. Patients who previously underwent
tracheostomy or with parastomal recurrences are at risk of
axillary lymph node metastasis.
In summary, the possible explanations for this unusual
location of metastasis were: (a) retrograde dissemination
due to lymph system blockage at the jugulo-subclavian
junction; (b) further tumor dissemination after a parasto-
mal recurrence; (c) hematogenous dissemination, and
(d) metastasis from a second primary tumor.
Diagnosis
The high-risk patients for axillary metastasis are those
with massive neck metastasis and those who underwent
tracheostomy or have parastomal recurrences. Routine
palpation of the axilla should be recommended in such
cases during follow-up examinations. Koch [9] identified
the following common characteristics among patients
with axillary metastasis: (a) the initial neck mass or pri-
mary tumor had been successfully treated years prior to
the development of the axillary metastases, (b) the neck
had been treated with both surgery and radiotherapy, and
(c) in all cases there was a new primary tumor or late
recurrent SCC. He also recommended monitoring of axil-
lary lymph nodes (palpation and computed tomography
(CT) scan in suspicious cases) as part of tumor surveil-
lance in patients who developed recurrent or new primary
disease in the upper aerodigestive tract after aggressive
treatment of the neck with surgery and/or radiotherapy.
The mediastinum should be investigated by CT scan in
patients with advanced laryngeal carcinoma with subglot-
tic involvement and in all patients with hypopharyngeal
carcinoma.
ORL 2001;63:252–255 253
Table 1. Distribution of reported nonregional lymph nodes in patients with head and neck cancer detected clinically, according to the tumor
site, stage, histology, prior treatment, treatment and survival

Authors Primary tumor Stage Histology Previous treatment Site of nodal Treatment of Survival
metastases metastases

Ezhov and Larynx TxNxM0 SCC ? Axilla Axillary dissection 6 months, DOC
Andreev [25]
Sun et al. [11] Larynx TxN2cM0 OCC RT Axilla Autopsy finding DOD
Gnepp et al. [26] Larynx TxNxM0 OCC SL+RND Peribronchial Chemotherapy 3 months, DOD
Larynx TxN2cM0 OCC RT Axilla Autopsy finding DOD
Larynx TxN+M0 OCC RT Inguinal No treatment DOD
Pyriform sinus TxN+M0 OCC RT Mediast. + axilla No treatment DOD
Larynx TxN0M0 OCC TL+RND+RT Mediast. No treatment DOD
Nelson and Larynx TxNxM0 SCC RT+TL+RND Bilateral axilla Axillary dissection 24 years, DOC
Sisk [23]
Alavi et al. [8] Oral cavity T3N0M0 SCC Comp. res.+RND+RT Presternal * DOD
Hypopharynx T3N2M0 SCC TL+RND+RT Inguinal * DOD
Oral cavity T2N1M0 SCC Comp. res.+RND+RT Axilla Axillary dissect. +RT NED, 1 year
Oral cavity T2N0M0 SCC Comp. res.+RND+RT Axilla * DOD
Oropharynx T4N0M0 SCC Comp. res.+RND+RT Presternal * DOD
Koch [9] Larynx T1N0M0 SCC RT+RND+2ndP Axilla Axillary dissection ! 24 months, DOD
Larynx T3N0M0 SCC TL+RT+2ndP Bilateral axilla No treatment Lost to follow-up
Larynx T4N0M0 SCC SL+RND+RT+RND+2ndP Axilla Axillary dissection ! 12 months, DOD
Unknown T0NxM0 SCC RT+RND+RND+RT Axilla ? ?

SCC = Squamous cell carcinoma; OCC = oat cell carcinoma; RT = radiotherapy; TL = total laryngectomy;
Comp. res. = composite resection; RND = radical neck dissection; Mediast. = mediastinum; 2ndP = second primary tumor;
SL = supraglottic laryngectomy; DOC = died other causes; DOD = died of disease; NED = nonevidence of disease;
? = no information available.
* Treatment of the distant lymphatic metastases included regional lymphadenectomy and radiotherapy in 2 cases,
local radiotherapy alone in 2 cases, and local radiotherapy combined with chemotherapy in 1 case.

Management showed long-term results of postoperative radiotherapy

Patients with distant metastasis have been considered
incurable and only palliative treatment was instituted.
Although it is possible to perform a lymph node dissection
in cases with such tumor dissemination, it is a sign of poor
prognosis. Treatment planning for cases with axillary me-
tastasis must take the likelihood of other regional recur-
rences and/or distant metastasis into consideration. Also
the presence of a second primary tumor must be ruled out.
Whenever axilla is the only site of cancer recurrence, a
standard axillary dissection must be considered [23]. Up-
per mediastinal metastases from subglottic and hypopha-
ryngeal cancer are managed by paratracheal and mediasti-
nal dissection through the neck [3, 4] and postoperative
radiotherapy. The mediastinal dissection includes all pa-
ratracheal lymph nodes, brachiocephalic artery nodes,
and paraesophageal nodes, down to the aortic arch (the
inferior limit of the dissection). Mirimanoff et al. [24]
including the upper mediastinum in the portals of pa-
tients with advanced laryngeal and hypopharyngeal carci-
noma, showing a significant reduction on the rates of
parastomal recurrences. Metastases from thyroid cancer
are managed by mediastinal dissection followed by a ther-
apeutic doses of 131I. Metastases to lymph nodes at other
sites are managed as systemic disease, usually with che-
motherapy.
Prognosis
The poor prognosis in cases of nonregional metastasis
can result from the high risk of the simultaneous occur-
rence of distant metastasis, which is common to all can-
cers with massive regional dissemination. Nelson and
Sisk [23] reported a 25-year survival after bilateral axilla-
ry dissection due to metastasis from a laryngeal carcino-

254 ORL 2001;63:252–255 Kowalski

ma. In the Russian literature, Ezhov and Andreev [25]
reported 1 patient with axillary metastasis who under-
went axillary dissection and died of other cause (myocar-
dial infarction) after 6 months. Of the 4 cases reported by
Koch [9], 1 was recent, 1 was lost to follow-up and 2 died
within 1–2 years due to bone and pulmonary metastases.
Of the 5 patients reported by Alavi et al. [8], 4 were
treated and only 1 survived more than 1 year. Table 1
shows the long-term results of the treatment of patients
with nonregional metastasis from head and neck carcino-
mas.

References

1 International Union Against Cancer: Sobin
LH, Wittekind Ch (eds): TNM Classification of
Malignant Tumors, ed 5. New York, Wiley-
Liss, 1997.
2 Harrison DFN: The pathology and manage-
ment of subglottic cancer. Ann Otol 1971;80:
6–12.
3 Harrison DFN: Laryngectomy for subglottic le-
sions. Laryngoscope 1975;85:1208–1210.
4 Martins AS: Indications for neck and mediasti-
nal node dissection in pharyngolaryngeal tu-
mors. First World Congress on Head and Neck
Oncology. Bologna, Monduzzi Editore, 1998,
pp 551–555.
5 Peltier LF, Thomas LB, Barclay THC, Kris-
men AN: The incidence of distant metastases
among patients dying with head and neck can-
cer. Surgery 1951;30:827–833.
6 Hoye RC, Herrold KMcD, Smith RR, Thomas
LB: A clinicopathological study of epidermoid
cancer. Cancer 1962;15:741–749.
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sites of distant metastases in head and neck car-
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8 Alavi S, Namazie A, Sercarz JA, Wang MB,
Blackwell KE: Distant lymphatic metastasis
from head neck cancer. Ann Otol Rhinol Lar-
yngol 1999;108:860–863.
9 Koch WM: Axillary nodal metastases in head
and neck cancer. Head Neck 1999;21:269–
272.
10 Suen JY: Cancer of the neck; in Myers EN,
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ed 2. New York, Churchill Livingstone, 1989,
pp 221–254.
11 Sun CC, Hall-Craggs M, Adler B: Oat cell carci-
noma of the larynx. Arch Otolaryngol 1981;
107:506–509.
12 Schobinger R: The rationale for a combined
mediastinal and neck dissection in head and
neck cancer. Pract Otorhinolaryngol 1957;19:
235–242.
13 Rucco B, Amatulli G: Le recidive stomali e le
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ore nelle neoplasie della laringe. Arch Ital Otol
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14 Som ML: Surgical treatment of carcinoma of
the postcricoid region. NY State J Med 1974;
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gectomy: CT study. Radiology 1984;153:713–
717.
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l’homme. Paris, Masson, 1932.
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phatic System. Philadelphia, Saunders, 1968.
18 Welsh LW: The normal human laryngeal lym-
phatics. Ann Otol 1964;73:569–582.
19 Welsh LW, Welsh JJ: Abnormal patterns of the
laryngeal lymphatics. Laryngoscope 1963;73:
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21 Feind CR, Cole RM: Contralateral spread of
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CD, Feind CR, Slanetz CA Jr, Weinberg JAJ
(eds): The Lymphatics in Cancer. Philadelphia,
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23 Nelson WR, Sisk M: Axillary metastases from
carcinoma of the larynx: A 25-year survival.
Head Neck 1994;16:83–87.
24 Mirimanoff RO, Wang CC, Doppke KP: Com-
bined surgery and postoperative radiation ther-
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1985;11:499–504.
25 Ezhov VG, Andreev VG: Metastasis of laryn-
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Noncervical Lymph Node Metastasis ORL 2001;63:252–255 255

 ORL 2001;63:256–258
Proposal of Standardization on
Screening Tests for Detection of Distant
Metastases from Head and Neck Cancer
Jonas T. Johnson
Department of Otolaryngology, University of Pittsburgh, Pa., USA
Key Words
Distant metastases W Head and neck cancer W
Screening tests
Abstract
A standardized approach to screening for distant metas-
tases must be flexible. This reflects the fact that the
issues involved have not been adequately studied to
allow evidence-based recommendations. Effective and
responsible application of screening for distant metasta-
sis would improve our ability to council patients regard-
ing important therapeutic decisions. It would also have
important consequences on healthcare economics.
Screening recommendations should reflect the stage of
the primary tumor and the histologic cell type because
these two parameters most clearly correlate with the risk
for distant metastases. The most commonly encoun-
tered distant metastases are pulmonary. The most sensi-
tive validated screening technique is just computed to-
mography (CT). Advanced technologies such as simulta-
neous positron emission tomography/CT may replace
these prior technologies in the near future. Recommen-
dations for routine screening following curative treat-
ment are subjective at this time. Careful history and
physical examination remains the basis for the follow-up
evaluation. The sensitivity and cost effectiveness of
imaging studies in this setting remains unstudied and
contentious.
Copyright © 2001 S. Karger AG, Basel
© 2001 S. Karger AG, Basel
ABC 0301–1569/01/0634–0256$17.50/0
Fax + 41 61 306 12 34
E-Mail karger@karger.ch Accessible online at:
www.karger.com www.karger.com/journals/orl
A proposal for standardization of approach to screen-
ing for distant metastasis in patients with cancer of the
head and neck must of necessity be placed forward with
some sense of humility. Screening evokes a diverse set of
complex issues, many of which have not been adequately
studied at this time to allow evidence-based recommenda-
tions. It is apparent that the development of metastases is
an important component of management of patients with
cancer of the head and neck. This is substantiated by the
significant observations of distant metastases in patients
evaluated in autopsy series [1–17] and the proliferation of
clinical reports indicating that metastatic disease may
develop as the sole site of recurrence in 4–59% of patients
[18–30].
Our enthusiasm for evaluation of distant metastases
must be balanced against the reality of medical economics
in an environment of increasing cost consciousness. Ef-
forts to identify low-risk groups of individuals are ongoing
and are a required component of any screening recom-
mendation. A well-conceived algorithm for screening,
however, holds the potential for some cost savings from
the current environment in which screening seems to be
random and sometimes ill directed. Additionally, clini-
cians are often frustrated by delays in treatment provoked
and necessitated by incidental findings encountered dur-
ing routine screening. In many circumstances, this repre-
sents identification of a benign pathology previously unre-
cognized. However, we should not lose track of the poten-
tial secondary gain in identification of second primary
cancers in this group of patients with clear risk.
Jonas T. Johnson, MD
Department of Otolaryngology, University of Pittsburgh
Suite 500, 203 Lothrop Street
Pittsburgh, PA 15213 (USA)
Fax +1 412 647 2080, E-Mail jonasj@pitt.edu
 Motivation
Effective and responsible application of a screening
algorithm would assuredly allow for improved counseling
to patients and their families when important therapeutic
decisions must be made. Identification of distant metas-
tases would also facilitate accurate staging and clinical
reporting. This would additionally provide a targeted sub-
set of patients for new therapies. In the last two decades,
irradiation and chemotherapy have rapidly become the
standard for management of advanced head and neck
cancer. Improved local-regional control has been recog-
nized, however, head and neck oncologists have been
frustrated by the difficulty in demonstrating improved
survival. This seems to reflect an increasing incidence of
distant metastases. It is unclear if this is reflective of the
fact that metastatic disease is present, but unrecognized at
the time of initial presentation. It also seems to indicate
that systemic chemotherapy as it is currently employed, is
ineffective in eradicating microscopic distant disease. As
noted before, an important motive for enhanced identifi-
cation of distant metastases is the potential to identify
second primary cancers at an earlier stage.
Tumor Peculiarities
The literature suggests that a variety of factors in-
fluence the risk of distant metastases. An important, but
potentially contentious issue is the site of the primary
tumor. Reports suggest that certain sites (e.g, glottis,
sinonasal tract, and skull base) may be associated with a
reduced risk of distant metastases. It is unclear if this is an
indication of true biologic diversity or only reflective of a
failure on the part of the investigators to adequately sub-
ject their data to multifactorial analysis or, in the case of
skull base and sinonasal tumors, it may be reflective of
difficulty in controlling local-regional disease which
serves to obscure the presence of microscopic distant
metastases.
Stage at presentation seems clearly related to the risk
for distant metastases. This seems scientifically plausible
and suggests that any screening system must acknowledge
the stage of the primary tumor being treated. This is prob-
ably especially important in patients presenting with cer-
vical metastases. The presence of N2 and N3 disease at
diagnosis is a clear indication of biologic aggressiveness
and the interaction between the host and his tumor.
The histology of the primary tumor seems to clearly
correlate with the risk of distant metastases. One extreme
Screening Tests
is adenoid cystic carcinoma, which carries a risk of up to
58.8% of patients developing distant metastases at some
time in their lifetime [7]. In contrast, other cell types such
as verrucous carcinoma, basal cell carcinoma, and low-
grade salivary gland cancers rarely metastasize and exten-
sive routine screening seems an unnecessary use of re-
sources.
Screening at Initial Diagnosis
Every patient who presents with high-grade carcinoma
involving some structure in the head and neck should
undergo a careful history aimed at identification of poten-
tial sites of secondary primary tumors. This evaluation
should be supplemented by a careful physical examina-
tion, inspecting the skin and all the mucosal surfaces of
the upper aerodigestive tract. This approach supple-
mented by screening chest X-ray seems to be the minimal
standard for every patient. Needless to say, this would
include careful palpation and evaluation of the cervical
lymphatics.
Indications for Further Evaluation
Abnormality on chest X-ray (which cannot be docu-
mented to be chronic), presence of bulky (N2 or N3) neck
metastases or advanced primary stage (T3 or T4) may be a
valid justification for further evaluation. The most logical
next test is computed tomography (CT) scan of the chest.
Patients presenting with recurrent cancer after initial
therapy are clearly at increased risk for distant metastases.
Routine screening with chest CT scan seems appropriate
because the increased risk is further magnified by the
need for patients and their families to make especially dif-
ficult therapeutic decisions regarding the appropriateness
of heroic surgery, participation in experimental trials, and
the option for palliative care only. Knowledge regarding
metastatic disease may be an essential determinate in this
decision for many patients and their families.
Symptom-Specific Evaluation
Attentive follow-up is an essential component in the
care of patients who have been treated for carcinoma of
the head and neck. The new onset of pain always deserves
further evaluation. Pain at the site of the primary tumor
may herald recurrence in a submucosal location. Pain in
the back, hips, or a long bone may be an indication of
distant metastases. Radiographic evaluation with plain
ORL 2001;63:256–258 257
film or CT scan is appropriate. Suspicious lesions can be
biopsied.
Weight loss requires further investigation. Surgery and
irradiation treatment to the upper aerodigestive tract is
frequently associated with weight loss attributable to loss
of taste, xerostoma, and fibrosis affecting the muscles of
mastication and deglutition. The potential for either re-
current disease or new primary carcinoma should always
be considered under these circumstances. Evaluation
sometimes requires either barium contrast radiography or
diagnostic endoscopy.
Monitoring following completion of therapy directed
at cancer of the head and neck consists of interval review
of history and physical examination. Recent onset of new
symptoms should elicit an evaluation directed at clari-
fying the origin of the symptom. Careful inspection of the
mucosal surfaces of the upper aerodigestive tract and the
cervical lymphatics is undertaken at regular intervals. The
intervals chosen generally reflect the risk of recurrent dis-
ease. The greatest risk for recurrence is in the first 24–36
months following therapy. Accordingly, most individuals
recommend follow-up evaluations at 1- to 3-month inter-
vals during this high-risk period. Continued follow-up at
6- to 12-month intervals lifelong seems appropriate be-
cause of the high incidence of second primary tumors.
Screening should include an annual chest X-ray.
Routine use of CT scan and magnetic resonance imag-
ing for follow-up screening purposes may be appropriate
for patients with tumors in hard to examine areas such as
the skull base and sinonasal tract. It may also be appro-
priate for patients with difficult to examine anatomy, for
instance, patients receiving chemoradiation in whom
there is severe fibrosis and induration. Positron emission
tomography (PET) scanning may represent a significant
advance in the evaluation and follow-up of these head and
neck patients. Advanced technologies such as simulta-
neous PET/CT scan offer optimism that a more sensitive
tool may be close at hand.

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258 ORL 2001;63:256–258 Johnson

 ORL 2001;63:259–264
The Treatment of Distant Metastases
in Head and Neck Cancer – Present and
Future
J. Graham Buckley a Alfio Ferlito b Ashok R. Shaha c Alessandra Rinaldo b
a Department of Otolaryngology – Head and Neck Surgery, Leeds General Infirmary, Leeds, UK;
b Department of Otolaryngology – Head and Neck Surgery, University of Udine, Italy;
c Head and Neck Service, Memorial Sloan-Kettering Cancer Center, New York, N.Y., USA
Key Words
Distant metastases W Head and neck cancer W Treatment
Abstract
At the present time the occurrence of distant metastases
in patients with head and neck squamous cell carcinoma
means that lifespan is measured in months. In most
instances treatment is purely palliative. Isolated lung
metastasis can be successfully removed with long-term
disease control in selected patients. Radiotherapy can be
useful for palliation of bone metastases and occasionally
lung or brain metastases. Chemotherapy does not have
a major impact at the present time except for the treat-
ment of metastases from nasopharyngeal cancer. Pallia-
tive symptomatic care, along with appropriate pain con-
trol, is essential since pain management is very impor-
tant in these patients. A significant change in the survival
of patients with head and neck cancer is only likely to
occur by the development of new approaches to treat-
ment. Blocking tumor angiogenesis and treatment based
on genetic abnormalities or cell surface receptors offer
the two strategies that are most likely to be successful.
Copyright © 2001 S. Karger AG, Basel
© 2001 S. Karger AG, Basel
ABC 0301–1569/01/0634–0259$17.50/0
Fax + 41 61 306 12 34
E-Mail karger@karger.ch Accessible online at:
www.karger.com www.karger.com/journals/orl
Head and neck cancer survival has not dramatically
improved in the last 30 years despite some notable treat-
ment advances [1]. This is because survival in head and
neck cancer is not related to control of the primary tumor
only. The proportion of deaths related to locoregional dis-
ease may have been reduced but were replaced by deaths
from intercurrent illness, due to the high co-morbidity in
this patient group, or second primary cancer, or from dis-
tant metastases. Distant metastases are particularly im-
portant in supraglottic laryngeal and pharyngeal cancer
[2]. The risk of distant spread is related to primary tumor
site, its local and regional extension, and the phenotype. It
is evident that the next objective for treatment should be
the prevention or treatment of metastases. The aim of this
article is to consider the currently available treatment and
to speculate on likely strategies for the future.
Surgery
Both in autopsy and clinical studies, the lung is the
most common site of distant metastases from head and
neck cancer [3, 4]. The role of metastasectomy is unclear
in head and neck malignancies, although it is extremely
important for a clinician to appreciate that a solitary pul-
monary nodule in patients with head and neck malignan-
J. Graham Buckley, MD
Department of Otolaryngology – Head and Neck Surgery
Leeds General Infirmary
Leeds LS1 3EX (UK)
Tel. +44 113 3928031, Fax +44 113 3923165, E-Mail JGrahamBuckley@compuserve.com
cies is often considered as a new primary pulmonary neo-
plasm rather than metastatic tumor. If the patient has
multiple pulmonary nodules, metastatic head and neck
tumor is more likely than primary lung cancer. It would
be almost impossible to prove histologically whether the
pulmonary squamous cell carcinoma (SCC) represents
primary or metastatic tumor. The presence of in situ com-
ponents in the pulmonary lesion may suggest that the pul-
monary lesion is a new primary tumor rather than a meta-
static tumor. The incidence of pulmonary metastases is
also high in patients who present with extensive soft tissue
extension of the primary or metastatic regional nodal dis-
ease. The patients who present with jugular vein invasion
or extensive soft tissue disease in the neck clearly have a
high incidence of pulmonary metastases. Pulmonary me-
tastasectomy of isolated metastasis has been shown to be
of benefit in selected patients [5]. Therefore, there is some
logic in treating pulmonary metastases surgically because
they can be solitary and therefore potentially resectable.
In an analogous situation, partial liver resection can be
successful in the treatment of solitary metastases in co-
lonic cancer. But considering that lung metastases are
usually multiple, and prolonged survival without treat-
ment is not unusual, resection of pulmonary metastases
may be hard to justify in adenoid cystic carcinoma (ACC)
[6]. However, if isolated, stable metastases from ACC
may be resected with good long-term control.
The Memorial Sloan-Kettering Cancer Center of New
York reported their experience using pulmonary metasta-
sectomy in the treatment of 41 patients with SCC and 36
with glandular carcinoma (mainly thyroid and ACC) of
the head and neck. Survival at 5 years varied according to
histology with a rate of 64% in glandular tumors and 34%
in SCC. Interestingly, patients with ACC fared best, with
an 84% 5-year survival, but none remained disease-free
[4]. However, this is a highly selected group of patients for
surgery. Nibu et al. [7] reported a very similar 5-year sur-
vival of 32% in 32 patients with head and neck SCC
treated by pulmonary metastasectomy. They found that
oral cavity tumors had a significantly lower survival
(15.4%) than other sites (45.2%). Rendina et al. [8]
reported a study of 8 patients with pulmonary metastases
from laryngeal cancer. Curative resection was carried out
in 6 patients. Two patients refused treatment and died
after 10 and 12 months. Four of the remaining 6 survived
over 40 months. The authors concluded that it did not
seem to matter whether the metastases were single or mul-
tiple.
Surgery is sometimes useful in the treatment of bone
metastases, although radiotherapy is the standard first-
260 ORL 2001;63:259–264
line treatment. It is indicated in pain that is unresponsive
to other treatment and in lytic metastases in weight-bear-
ing areas [9].
Surgical resection should also be considered for pa-
tients with solitary brain metastasis and no extracranial
disease or controlled extracranial disease, because phase
III data indicate enhanced survival with such an ap-
proach. Whole-brain radiotherapy is routinely adminis-
tered postoperatively [10].
Radiotherapy
Radiotherapy is unlikely to cure even solitary lung
metastases. However, it may have a palliative role and it
may increase survival when there are a limited number of
foci, small metastases and locoregional control [11]. Chest
pain and hemoptysis are more effectively palliated than
cough and dyspnea. Chest symptoms are common in
patients with locally advanced lung cancer and are effec-
tively palliated with one 10-Gy or two 8.5-Gy one-frac-
tion doses of radiation to the thoracic inlet and mediasti-
num. Eighty percent of patients with vena cava syndrome
due to malignant disease achieve symptom relief with a
brief, fractionated, palliative course of radiotherapy [10].
Approximately 50% of patients with cancer develop
bone metastases, although they are relatively unusual in
head and neck cancer. They can cause pain and affect
weight-bearing areas and consequently have a significant
impact on quality of life. The role of radiotherapy in the
palliation of bone metastases is well supported in the liter-
ature, with reported response rates of around 70–90% [10,
12–15]. The pain relief is complete in nearly half of the
responders [14, 16]. If patients fail to respond to the first
treatment, then they may respond to re-treatment. In a
retrospective analysis of 105 consecutive patients, the
overall response rate to initial treatment was 84% for pain
relief, and at re-treatment was 87% [15]. A single dose of
6–10 Gy is generally thought to be as effective as fraction-
ation [10, 13, 14], although this view is not supported by
all studies [12]. Pain from multiple bone metastases that
is not controlled by analgesics can be managed with a sin-
gle dose of half-body irradiation with a degree of pain
relief in 73% of patients [10]. Pain palliation may also be
achieved by treatment with bone-seeking radiopharma-
ceuticals. Strontium-89 and samarium-153 are licensed
for use and rhenium-186 HEDP and tin-117m diethyl-
enetriamine penta-acetic acid (DTPA) are in phase II/III
trials. Patients with a positive bone scan using techne-
tium-99m methylene diphosphonate are eligible for treat-
Buckley/Ferlito/Shaha/Rinaldo
ment, and indications and contraindications for use are
now well defined. The evidence in the literature now sug-
gests that these agents can significantly reduce pain due to
bone metastasis, delay development of new painful sites
or slow progression and can reduce radiotherapy require-
ments. They are, however, associated with myelosuppres-
sion, and more data is needed on response duration and
treatment toxicity. Re-treatment is possible and appears
to be safe [13, 17].
Recent phase III trials indicate that bisphosphonates
may have a role in reducing bone pain, pathologic frac-
tures and the need for further radiotherapy was decreased
[10]. Intratumoral injection of P-32 chromic phosphate
produced a complete remission in 7/17 patients with
refractory solid tumors or solitary metastases in an early
phase II study. Systemic or local side effects were minimal
and so this modality is likely to receive further attention
in clinical trials [18].
Occasionally, surgical resection of metastases is useful
for metastases that do not respond to radiotherapy and in
weight-bearing or high-stress areas (subtrochanteric re-
gion of the hip, mid-femoral diaphysis, mid-humeral me-
taphysis). Surgical stabilization can improve the remain-
ing quality of life in these patients if it is carried out early
enough [9]. A brief, fractionated course of radiotherapy is
usually given postoperatively [10].
Radiotherapy also has a role in the infrequent patients
with brain metastases. It relieves clinical symptoms in
70–90% of patients [10]. The use of stereotactic radiosur-
gical treatment remains to be defined. It is most often
used to treat solitary metastases in previously irradiated
patients.
Chemotherapy
Head and neck cancer metastases are responsive to
chemotherapy and the use of multiple agents may in-
crease response rate. Unfortunately, neither single agent
nor combinations of drugs have any significant impact on
survival [19]. The exception may be nasopharyngeal car-
cinoma, where platinum-based chemotherapy may in-
crease survival even in the presence of distant metastases
[20].
Taxanes, which combine cytotoxicity and antiangio-
genesis, are being evaluated. Response rates of 23–42%
have been reported in phase I/II trials when docetaxel is
used as a single agent. This increases to 52–100% when it
is used in combination with cisplatin and 5-fluorouracil
(5-FU). A phase III trial of the addition of docetaxel to
Treatment of Distant Metastases
standard neoadjuvant therapy with cisplatin and 5-FU is
now under way [19, 21].
An alternative approach is to improve drug delivery to
the tumor. Stealth liposomal drugs have a reduced clear-
ance with prolonged circulation half-life and there is a
degree of selective accumulation in tumor deposits be-
cause of increased vascular permeability. Biodistribution
studies have shown a selective tumor uptake in patients
with advanced head and neck cancer and a phase I study
has shown a 33% response rate with relatively low toxicity
[22].
Targeting Tumor Angiogenesis
The process of angiogenesis is fundamental to the
growth of both the primary tumor and metastases. Tu-
mors cannot grow more than 2–3 mm without inducing
the formation of new blood vessels [23]. Tumor cells ini-
tiate the process by altering the balance between positive
and negative regulators of microvessel growth. Normal
maturation does not occur and results in leaky vessels, a
high interstitial pressure and eventual vascular compres-
sion and central necrosis. At this stage, shortly after they
are detectable, tumors are much less accessible to chemo-
therapy [24]. Estimation of the degree of angiogenesis
may have prognostic value. Microvessel density can be
measured within tumors and is associated with the risk of
metastasis breast and colorectal [25] and head and neck
cancers [26]. The principal strategies currently being used
to design antiangiogenesis agents are aimed at blocking
angiogenic factors (or enhancing negative regulators) or
acting on endothelial cells to block cell surface receptors
or prevent them from breaking down the surrounding
matrix. Several chemicals have now been found capable
of blocking steps in the process of angiogenesis in animal
tumor models [25]. There are 18 agents undergoing hu-
man trials registered on the National Cancer Institute
database. Six of these agents are at the phase III stage. The
drug thalidomide, which acts by direct endothelial cell
inhibition, is currently under phase II evaluation in head
and neck cancer. It seems unlikely that angiogenesis
inhibitors alone will be useful for established metastatic
disease but they may have a role in combination with oth-
er agents. It seems logical to assume that these agents are
most likely to be effective at a stage of early tumor growth,
before angiogenesis has occurred. It is possible that their
greatest potential may be the prevention of disseminated
disease in those tumors with a propensity to metastasize.
ORL 2001;63:259–264 261
 Strategies Based on Cytogenetic Changes
Genetic changes and abnormal expression of growth
factor receptors on the surface of tumor cells are potential
targets for a ‘magic bullet’ treatment that is specific for
tumor cells. The chance of achieving this will depend on
the identification of specific genetic changes within malig-
nant cells. The mapping of chromosomal abnormalities in
cancer is part of the Cancer Genome Anatomy Project
(CGAP) coordinated by the National Center for Biotech-
nology (NCBI). Significant progress has been made with
the identification of the p53 (and the associated mdm2,
p63 and p73 genes), retinoblastoma and p16 tumor sup-
pressor genes and a number of other oncogene aberrations
(including the ras gene family), all of which play a role in
the pathogenesis of head and neck cancer [27]. This has
far-reaching implications for the management of the pri-
mary tumor and metastases. Subtyping of tumors by
genetic changes may enable better prediction of metastat-
ic potential, prognosis and response to treatment. The
analysis of genetic abnormalities in the surgical margins,
lymph nodes or the bone marrow is possible and may pre-
dict those patients who are likely to recur or may benefit
from systemic therapy [28]. Therapeutic approaches have
been devised to exploit these genetic changes. The tumor
suppressor gene, p53, is implicated in more than 50% of
cancers. It plays a role in cell cycle regulation and in apop-
tosis and is the most frequently identified abnormality in
head and neck cancer. The simplest approach is to replace
the defective gene. Injecting the tumor with an adenoviral
vector possessing wild-type p53 has succeeded in achiev-
ing this goal. Phase I and II trials of p53 gene transfer have
shown a response in patients with advanced, locoregional-
ly recurrent head and neck cancer [29]. Adenoviral p53
was demonstrated to be safe and well tolerated and pro-
duced a 27% control rate at 18 months in 15 incurable
patients [30]. Several randomized studies of adenoviral
p53 are now under way in patients with head and neck
SCC to determine its role as a surgical adjuvant in
untreated disease and in combination with DNA-damag-
ing agents. p53 has also been used as the target in the
development of another type of antitumor viral therapy.
The pathogenicity of adenovirus depends on a 55-kilodal-
ton protein from the E1B region that normally binds to
and inactivates the p53 gene [30]. An E1B gene-attenuat-
ed adenovirus has been engineered. Its replication is
blocked by functional p53 in normal cells. In contrast, a
wide range of human tumor cells, including numerous
carcinoma lines with either mutant or normal p53 gene
sequences, are destroyed. A phase II trial of a combina-
262 ORL 2001;63:259–264
tion of intratumoral ONYX-015 injection with cisplati-
num and 5-FU in patients with recurrent SCC of the head
and neck showed a high proportion of complete re-
sponses. By 6 months, none of the responding tumors had
progressed, whereas all noninjected tumors treated with
chemotherapy alone had progressed. Tumor biopsies ob-
tained after treatment showed tumor-selective viral repli-
cation and necrosis induction [31]. There is also evidence
to suggest that p53 gene therapy acts synergistically with
conventional chemotherapy [32, 33].
Similar manipulations have also incorporated ‘suicide
genes’, for example using herpes simplex virus thymidine
kinase gene to sensitize tumors to the cytotoxic effects of
ganciclovir administration and have been successful in
vitro and in vivo [34, 35]. Both retrovirus and adenovirus
have been used as a vehicle for gene transfer in humans
and the associated toxicity appears to be transient and rel-
atively minor. Similarly nonviral cationic lipid-mediated
gene transfer also appears safe in humans [36]. Combin-
ing an adenoviral vector with cationic liposomes appears
to improve the efficiency of gene transfer in mice. This
may make it possible to deliver a smaller amount of virus
with a reduction in toxicity and immune response to the
virus [37]. One of the limitations of this type of treatment
is the frequent absence of the necessary receptor on the
tumor cells. However, viruses can be manipulated to rec-
ognize SCC markers. Integrins of the ·2ß1 and ·3ß1 class
are frequently overexpressed and have been used as tar-
gets for an engineered adenovirus. This strategy could
potentially achieve preferential augmentation of gene
transfer in tumor cells compared with normal cells [38].
There are several other potential targets for gene-based
therapy. Overexpression of cyclin D1 may play an impor-
tant role in growth rates, biological behavior and response
to chemotherapy of human head and neck cancer. The
ability to suppress the malignant phenotype by down-reg-
ulating cyclin D1 expression may provide a new gene
therapy approach for patients with head and neck cancer
[39]. Similarly, herpes simplex virus has similarly been
used in vitro to transduce the human interleukin-2 gene
into tumor cells. The transduced cells secreted high levels
of interleukin-2 and subsequent transplantation resulted
in a high rejection rate [40]. It has demonstrated signifi-
cant treatment-specific antitumor activity when com-
bined with subtotal surgical resection in a head and neck
cancer murine model. There was no evidence of toxicity
or problems with wound healing [41]. Injection of alloan-
tigen into tumors to induce expression of a foreign class I
major histocompatibility complex protein (HLA-B7) has
been used in a phase I trial on 9 patients with recurrent
Buckley/Ferlito/Shaha/Rinaldo
and refractory head and neck SCC. There were 4 partial
responses and no toxicity [42].
Targeting the products of oncogenes is another promis-
ing strategy. The HER-2/neu (c-erb-B2) oncogene has
been extensively investigated as a prognostic factor in
breast cancer. Combining an anti-HER-2/neu monoclon-
al antibody (trastuzumab) with chemotherapy improves
survival in those patients with overexpression [43]. Some
salivary gland tumors also overexpress HER-2/neu and
this may potentially make them amenable to immunologi-
cal manipulation.
The ras gene is expressed in about 50% of colorectal
cancers and has been used as a target for gene therapy.
There is limited evidence to suggest that p21N-ras may be
important in the early stages of carcinogenesis [44]. Over-
all, however, the expression of members of the ras gene
family is low in head and neck cancer [45–47]. Blocking
the growth-signaling protein produced by the ras gene or
the related epidermal growth factor receptor are both
under investigation and have a potential future role in
head and neck cancer.
Quality of Life/Pain Management and
Supportive Care
Even though the patients with distant metastasis from
head and neck cancer generally do poorly and the avail-
able treatment modalities are limited, we should make
every effort to offer the best palliation to these patients.
The issue of quality of life in these patients remains a
major concern and all efforts should be made to offer
them the best and the treatment approaches chosen
accordingly. Pain is a major concern in these patients,
especially in patients with recurrent tumor near the skull
base with involvement of the cranial nerves and intradu-
ral involvement of the tumor. Appropriate pain manage-
ment is extremely important in making the last few
months of their life as pain-free as possible. Management
of airway and nutrition are also very important. Regard-
ing the former, it should be managed at an appropriate
time and may require an elective or semi-elective tra-
cheostomy. Feeding should be appropriately managed
and may require a percutaneous gastrostomy. If the pa-
tient requires a gastrostomy, it should be performed
before the development of trismus or severe cachexia.
Some patients with recurrent tumor in the retromaxillary
area or near the skull base may develop severe trismus,
which limits their nutritional intake. Depression is a
problem that must be taken seriously in the earlier stages
of cancer treatment, but it improves as the course of fol-
low-up lengthens [48].
Because it may be almost impossible for the family to
adequately care for these patients, assistance from a hos-
pice, Calvary or nursing home is a due consideration.
Some of these patients will prefer to be in hospice care
rather than suffering in the midst of other family mem-
bers. Overall, the management of distant metastasis from
head and neck cancer revolves around the care of the
patient, the care of the disease, the care of the family, and
appropriate palliative support.

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Buckley/Ferlito/Shaha/Rinaldo
 Author Index

Betka, J. 217 Kowalski, L.P. 252

Bradley, P.J. 233 Lund, V.J. 212
Bresadola, F. 229 Mondin, V. 189, 202, 207
Bresadola, V. 229 Petruzzelli, G.J. 192
Buckley, J.G. 189, 207, 259 Rinaldo, A. 189, 202, 207, 243, 259
Chiesa, F. 214 Sasaki, C.T. 250
De Paoli, F. 214 Shaha, A.R. 202, 243, 259
Ferlito, A. 189, 202, 207, 243, 259 Silver, C.E. 202
Goodwin, J.W. 222 Terrosu, G. 229
Johnson, J.T. 256 Uzzau, A. 229

© 2001 S. Karger AG, Basel 265

ABC
Fax + 41 61 306 12 34
E-Mail karger@karger.ch Accessible online at:
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 Subject Index

Angiogenesis 192 Metastases 192, 252

Cancer invasion 192 Nasopharyngeal cancer 214
Cervical esophagus 229 Oral cancer 217
Classification and terminology of metas- Oropharyngeal cancer 222
tases 189 Parathyroid cancer 243
Distant metastases 189, 207, 212, 214, 217, Salivary gland cancer 233
222, 224, 229, 233, 243, 250, 256, 259 Screening 207
Ear cancer 250 – tests 256
Head and neck cancer 189, 202, 207, 252, Sinonasal cancer 212
256, 259 Temporal bone cancer 250
Hypopharyngeal cancer 224 Thyroid cancer 243
Laryngeal cancer 224 Treatment 259
Lip cancer 217 Visceral metastases 202
Lymph node 252

© 2001 S. Karger AG, Basel

ABC
Fax + 41 61 306 12 34
E-Mail karger@karger.ch Accessible online at:
www.karger.com www.karger.com/journals/orl