Ebook Surgical pathology of the head and neck (Vol 1 - 3/E): Part 2

7
Cancer of the Oral Cavity and Oropharynx
Samir K. El-Mofty and James S. Lewis, Jr.
Department of Pathology and Immunology, Washington University, St. Louis,
Missouri, U.S.A.

I. INTRODUCTION
The most common type of cancer affecting the oral
cavity and oropharynx is squamous cell carcinoma
(SCC), which is estimated to constitute approximately
94% of all oral malignancies (1). Because of this
dominance, the term ‘‘oral cancer’’ is used synonymously with oral SCC (2). Others, less commonly
encountered carcinomas, are malignant melanoma
and neuroendocrine carcinoma, which will be discussed later in this chapter. Carcinomas of minor
salivary glands are detailed in the respective chapter
in the text.
SCC occurring at different anatomic subsites in
the oral cavity and oropharynx vary considerably in
their epidemiologic, demographic, pathologic, and
clinical features. Consequently, it is not possible to
address these various tumors collectively. The following discussion will address in details each individual
carcinoma by its respective site of incidence. The
following is a list of these entities:
SCC of the oral cavity:
1.
2.
3.
4.
5.
6.

SCC of the lip
SCC of the buccal mucosa
SCC of the floor of the mouth (FOM) and oral
tongue (OT)
SCC of the gingival and alveolar mucosa
SCC of the hard palate
SCC of the retromolar trigon
SCC of the oropharynx:

1.
2.
3.

SCC of soft palate and uvula
SCC of the oropharyngeal wall
SCC of tonsils and base of tongue

Keratinizing squamous cell carcinoma (KSCC) is
the prototype and the most common SCC. However,
there is a range of distinct morphologic variants, of this
neoplasm, that are of clinical significance. Differences
in clinical, pathologic, demographic and epidemiologic features of these variants will be addressed here.
The following is a list of these variants:
1.
2.
3.

Nonkeratinizing squamous cell carcinoma (NKCa)
Basaloid squamous carcinoma (BSC)
Adenosquamous carcinoma (ASC)

4.
5.
6.
7.

Adenoid squamous carcinoma
Verrucous carcinoma (VC)
Papillary squamous carcinoma
Spindle cell (sarcomatoid) carcinoma

II.

ANATOMY OF THE ORAL CAVITY
AND OROPHARYNX

According to the American Joint Committee on Cancer Staging, the oral cavity extends from the skin
vermilion junction of the lips to the junction of the
hard and soft palate above and to the line of the
circumvallate papillae of the tongue below (Fig. 1). It
can be divided into eight areas: lip mucosa, buccal
mucosa, lower alveolar ridge, upper alveolar ridge,
retromolar gingival [retromolar trigone (RMT)], FOM,
hard palate, and anterior two-thirds of the tongue
(the OT) (Figs. 1, 2).
The oropharynx extends from the plane of the
hard palate superiorly to the plane of the hyoid bone
inferiorly (Fig. 3), and is continuous with the oral
cavity through an opening called the faucial isthmus.
The oropharynx is separated from the oral cavity

by the junction of the soft and hard palates superiorly,
the line of the circumvallate papillae inferiorly, and
the anterior pillars of the faucies laterally.
The oropharynx encompasses three main
regions—the palatine arch, the base of tongue, and
the lateral and posterior pharyngeal walls. The palatine
arch constitutes the inferior surface of the soft palate
and uvula, the palatine tonsils, and their anterior and
posterior pillars (Fig. 4). Although the RMT is technically a component of the oral cavity, carcinomas in this
location often involve adjacent oropharyngeal sites and
behave more like oropharyngeal tumors (Fig. 4).

III.

EPIDEMIOLOGY AND ETIOLOGY

Oral cancer is an important global health concern
accounting for an estimated 275,000 cases and
128,000 deaths annually (3–5). Cancer of the mouth
and pharynx ranks sixth overall in the world. Its
incidence varies markedly by geographic region.


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Figure 1 Diagram showing the relationships of the oral
cavity anatomic subsites.

Figure 2 Diagram illustrating the anatomic relationship of the
OT, FOM, alveolar ridge, and lower lip. Abbreviations: OT, oral
tongue; FOM, floor of the mouth.

Two-thirds of all cases are observed in developing
countries. The Indian subcontinent accounts for onethird of the global burden. Men are affected two-tothree times as often as women. The oral cavity/
oropharynx is the third most common site for cancer
among males in developing countries (3–5). However,
the incidence of oral cancer for women can be equal
to, or even greater than, that of men in high incidence
areas where both sexes are equally exposed to the
same risk factors (4).
In the United States, approximately 24,000 men
and 10,000 women are diagnosed with oral and oropharyngeal carcinomas annually, representing 3.2% of
all newly diagnosed cancers (6,7). The majority of the
carcinomas develop predominantly between the fifth
and eight decades of life. Women tend to develop the

disease 10 years later than men (8). Changes in
incidence-age have been observed during an approximately 30-year period. Using the 1973–2001 surveillance, epidemiology, and end results (SEER) database,
a statistically significant increase in oropharyngeal
carcinoma in young patients of 20 to 44 years was
observed. No similar increase was evident in oral SCC
(9). Another study found a significant annual increase
in tonsillar SCC in men, but not women, who are
younger than 60 years. Again, no similar increase was
observed in oral nontonsillar sites (10). The total
incidence rates of oral cavity and oropharynx are
found to be higher among blacks than whites. Considerable racial and ethnic differences in the prevalence of oral/pharynx cancer may be related to social
and cultural practices as well as socioeconomic

factors.
Risk factors for oral/pharynx cancer can be
generally classified into several categories including
chemical carcinogens, oncogenic viruses, sunlight,
oral hygiene, nutritional factors, genetic predisposition, and immunocompromise.

A.

Chemical Carcinogens

The most important chemical carcinogens are related
to tobacco and alcohol abuse. Through a large number
of epidemiologic studies, a strong link has been established between the use of tobacco and oral/pharynx
SCC. Alcohol is an independent risk factor for the
disease, but it may have synergistic effect when combined with tobacco (7). The risk of development of
cancer is three to nine times greater in those who
smoke or drink, and as much as 100 times greater in
those who smoke and drink heavily, than those who
neither smoke nor drink (11). It has been estimated
that approximately 75% of oral cancers are related to
prolonged and heavy smoking and alcohol abuse (12).
Cigar and pipe smoking pose similar risk as cigarette
smoking. Tobacco and alcohol abuse has been


Chapter 7: Cancer of the Oral Cavity and Oropharynx

287

Figure 3 Anatomical boundaries of the oropharynx as defined by the American Joint Committee on

Cancer staging. The tip of the epiglottis is considered the inferior border of the oropharynx by some
surgeons.

Figure 4 Diagram showing the relationship of the
RMT to the various components of the oropharynx.
Abbreviation: RMT, retromolar trigone.

implicated in the higher rates and earlier onset of
cancer among men in general and African American
men in particular (8,12,13).
In addition to cigarettes, cigars, and pipes,
tobacco is commonly smoked in other forms, in particular in parts of India and South Asia. Bidi, made of
low-grade tobacco wrapped in tender leaf tobacco is
popular among rural folk and urban poor. The concentrations of nicotine, tar, and other toxic agents in
the smoke are higher in bidi than other cigarettes, with
a higher risk for development of oral cancer (14).
Reverse chutta smoking, with the lighted end of the
cigar placed inside the mouth, is associated with
particularly high rates of oral cancer of the palatal
mucosa (1,15), a site with otherwise very low cancer
incidence.
The primary cause of the very high incidence of
oral cancer in South Asia is, however, the widespread
habit of chewing betel quid or paan and related Areca
nut use. An estimated 200 to 400 million people practice the habit worldwide (16). The components of the
betel quid vary between different populations, but the
main ingredients are the leaf of the vine Piper betel—
which is not botanically related to the Betel palm, Areca
nut, slaked lime (calcium hydroxide), and spices,

which may include cloves and cardamom. Betel chewing is a tradition that goes back thousands of years.
Tobacco was added to betel quid sometime after its
introduction to South Asia by Europeans in the seventeenth century. Although Areca nut is carcinogenic in
itself, the addition of tobacco increased the risk (17,18).
As in the case of smoking, the risk for oral cancer
is dependent on dose and duration of use (19). Much
of the tobacco consumption in the world is without
combustion. In India, up to 40% of tobacco use is in
smokeless forms, mostly of the species Nicotiana rustica, while most smoking tobacco is Nicotiana tabacum
(20). Samples of N. rustica have been found to contain
higher concentrates of tobacco-specific nitrosamines
than N. tabacum (21). The tobacco is placed in direct
contact with the mucosa. In the developing countries,
tobacco is mostly consumed mixed with other ingredients, in addition to betel nut. Lime, molasses, oils,
and spices are used. Snuff is common in Scandinavia
and the United States. Tobacco is also prepared in
blocks or flakes for chewing. ‘‘Snuff dipper cancer’’
described in the southeastern United States is due to
the habit of placing snuff in the labial sulcus (22,23).
Females in this geographic area have high prevalence
of snuff dipping and oral cancer (24).


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Traditional values in some countries do not
favor smoking by women and the young, but there
is no such taboo against using smokeless tobacco.

Most women who use tobacco use it in its smokeless
form. The acquisition of tobacco habits, in whatever
form, starts at an early age. In one study, one-third to
one-half of children younger than 10 years in three
rural areas in India had experimented with smoking
or smokeless tobacco (25). Children have been known
to choke to death on betel nuts. Pakistan’s new laws
forbid the selling of betel nut to children younger than
five years.
More than 300 carcinogens have been identified
in tobacco smoke or in its water-soluble components
that will leach into saliva (26). The most important of
these is the aromatic hydrocarbon benz-pyrene and
other tar derivatives as well as the tobacco-specific
nitrosamines such as nitroso-nor-nicotine (NNN),
nitrosopyrrollidine (NPYR), nitrosodimethylamine.
These aromatic hydrocarbons are identifiable in
tobacco smoke as well as in smokeless tobacco. They
damage DNA by producing adducts, principally O6methylguanine.
Metabolism of these carcinogens usually involves
oxygenation by p450 enzymes in cytochromes, and
their conjugation, in which the enzyme glutathione S
transferase (GST) is involved. Polymorphism of the
p450 and GST genes is under active study in search
of genetic markers of susceptibility to head and neck
cancer and other tobacco-related cancers (27).
Alcohol is the second major risk factor for oral
cancer. In the West, 75% to 80% of patients frequently
consume alcohol. For nonsmokers, it is the most important risk factor. If above 30 g of alcohol is consumed per
day, the risk increases linearly with the amount of

alcohol consumed (28,29). As mentioned before, people
who smoke and drink have much greater risk of oral
cancer than those who only smoke or drink. The risk in
all cases is dose dependent.
Pure ethanol has never been shown to be carcinogenic in vitro or in animal studies (30). It is presumed to act in concert with other, more direct
carcinogens, so called congeners that are found in
the liquor, or from other sources such as tobacco.
Nevertheless, alcohol drinking alone is an independent risk for upper aerodigestive tract carcinoma (29).
The increase in oral cancer in the Western world
has been related to rising alcohol use. In England and
Wales, alcohol consumption more than doubled during the second half of the 20th century, which closely
matched oral cancer mortality and, by inference, incidence. There is strong circumstantial evidence that
alcohol rather than tobacco is the major factor in the
observed trend (4,31). Similar data have been reported
from Denmark (32). All forms of alcoholic drinks are
dangerous if heavily consumed with evidence for the
role of beer, wine, and spirits (12,33–36). The risk
becomes detectable when consumption exceeds 50
drinks per week.
In 1979, a combined case-control study and case
series raised concern that alcohol-containing mouthwash is a risk for oral/pharyngeal cancer (37). More
recently, extensive reviews of epidemiologic studies on

the subject did not corroborate earlier reports. It is
concluded that the risk of developing oral cancer
because of the use of alcohol-containing mouthwash is
unlikely (38). Interestingly, however, dental products
such as toothpaste and mouthwash containing sanguinarine (such as Viadent), which is the principle alkaloid
extract of the bloodroot plant (Sanguinaria Canadensis
L.), an antibacterial agent, is found to increase the risk of

leukoplakia of the maxillary vestibule (39,40).

B.

Ultraviolet Light

Chronic exposure to sunlight (actinic radiation) is
considered to be the most important factor in causation of lip cancer, the vast majority of which occurs in
the lower lip (41–46). This proposal is supported by
the observations that cancer of the lip is more common
in individuals who have fair complexion and who are
more exposed to sunlight because of outdoor occupations or who live near the equator. The propensity of
the lip vermilion border for solar damage is attributable to lack of a pigmentary layer that protects against
UV radiation (47). Other risk factors may play a role in
the causation of cancer of the lip, most notably pipe
smoking (45,48–50). It is suggested that the heat and
trauma of the pipe stem as well as the tobacco
combustion products may play a role in the induction
of malignancy.

C.

Oncogenic Viruses

Accumulating evidence during the last two decades
has linked high-risk human papillomavirus (HPV),
particularly type 16, with some upper aerodigestive
tract carcinomas. The virus, which is a prerequisite for
cervical cancer, is also found to be an important
etiologic factor for a distinct, nonkeratinizing type of

SCC, which occurs in the oropharynx and more specifically in the palatine tonsils and base of tongue. The
virus is very rarely identified in carcinoma of the oral
cavity proper (51–57). Substantial epidemiologic, clinical, microscopic, and molecular evidence strongly
support the connection between oropharyngeal cancer
and HPV. HPV-related oropharyngeal carcinoma is
identified in subjects, with or without the established
risk factors of tobacco and alcohol use (51–57). No
other type of oncogenic viruses has been convincingly
shown to play a strong and direct role in the etiology
of oral/pharyngeal SCC.

D.

Dental Factors and Chronic Inflammation

An association between poor oral hygiene and poor
dentition and oral cancer has been reported in several
studies (4,36,58,59). Experimental evidence in animals
shows localization of chemical carcinogens–induced
tumors to the sites of repeated mucosal traumatization.
An increase in yield and shortened latent period for
the development of the cancers are also observed in
these sites (4). Clinical observations in human cases
describe carcinomas developing at sites of chronic trauma
caused by a broken teeth or ill-constructed dental


Chapter 7: Cancer of the Oral Cavity and Oropharynx

appliances (4,59,60). It is certain that the role of inflammation, whether caused by poor hygiene, infections or

mechanical trauma, in the etiology of carcinoma, is
compounded by known carcinogens such as tobacco
and alcohol abuse, nutritional deficiencies, and other
risks. However, during the current decade, the possibility of a connection between chronic inflammation and
cancer has received intensive scrutiny and has moved to
center stage in cancer research. It has been stated by
some researchers that ‘‘genetic damage is the match that
lights the fire of the malignant process, and inflammation is the fuel that feeds it’’ (61). Recent clinical studies
and experimental mouse models highlight a paradoxical role for the immune system as crucial regulator of
cancer development (62). Tumor-associated macrophages (TAM), which are ubiquitous in the stroma of
virtually all tumors, release a distinct repertoire of
growth factors, cytokines, chemokines, and enzymes
that are known to regulate tumor growth, angiogenesis,
invasion, and/or metastasis (61–64).
The risk for malignancy associated with oral
lichen planus, a chronic inflammatory dermatologic
disease, remains a subject of debate (1,65). Candidal
hyphae are commonly observed to superficially
invade premalignant and malignant oral lesions.
That such an association may be causally related,
rather than an effect of the malignant process, has
been suggested (4,63,66). Some strains of candida
were shown to produce hyperkeratotic lesions in the
dorsal rat tongue (1). In other studies, it was demonstrated that some strains of Candida albicans produce
the chemical carcinogen nitrosamine from dietary
amines substrates (1,67).

E. Nutritional Deficiencies
Numerous studies report a significant preventive effect
of proper diet on oral/pharyngeal cancer (68–72). The

antioxidant or free radical-scavenging vitamins A, C,
and E as well as iron and trace elements, such as zink and
selenium, share a proven protective effect. High incidence of upper gastrointestinal tract carcinoma is seen
in middle-aged women with chronic iron deficiency
anemia, glossitis, and mucosal atrophy, a condition
known as the Plummer-Vinson syndrome. In animals
rendered iron deficient by venesection and low-iron
diets, there developed epithelial atrophy and increased
cancer risk, which was clearly shown when such animals
were challenged with chemical carcinogens (71).
An important study in China found a strong
protective effect for carotenoid and vitamin C and
fiber intake in oral cancer risk (72).

F. Altered Immunity
A similarity in the pattern of increased risk for cancer
in both HIV/AIDS populations and immunosuppressed organ transplant recipients suggests that the
immune deficiency rather than other risk factors for
cancer is responsible for the increased risk (73). In both
of these two populations, there is significant increase
of incidence, predominantly in cancers with known
infectious cause (73–75). These include all three types

289

of AIDS-defining cancers: Kaposi’s sarcoma, nonHodgkin’s lymphoma, and cervical cancer as well as
all HPV-related cancers and Hodgkin’s lymphoma.
An increased incidence in oral/pharyngeal cancer is
observed in both HIV/AIDS patients as well as in
transplant recipients (73). Although incidence of cancer of the lower lip is increased in both populations,

the increase was more marked in the transplantrecipient group (73). A similar pattern is observed in
nonmelanoma skin cancer. While there is no known
connection between lip cancer in renal transplant
recipients and HPV or other viral infections, the risk
factors were found to be related to exposure to UV
radiation and tobacco products (74,75).

IV. MOLECULAR BIOLOGY AND GENETICS
OF ORAL CANCER
Oral SCC, like many other epithelial cancers, evolves
through the accumulation of multiple genetic and
epigenetic alterations in a multistep process (7,76).
Genetic changes commonly involved in oral cancer
include loss of heterozygosity (LOH) at the sites of
known or suspected tumor suppressor genes, mutation, and de novo promoter methylation of tumor
suppressor genes, amplification or overexpression of
oncogenes, and alterations in expression of DNA
repair genes. Common LOHs are observed at 3p, 9p,
and 17p. The deletion of two genes located on the
short arm of chromosome 3; FHIT tumor suppressor
gene and retinoic acid receptor (RAR)-b may play a
role in development of oral cancer (77). P16INK4a
(p16), which is a tumor suppressor gene and a member of the retinoblastoma pathway, is located at 9p21.
High frequencies of deletions and mutations affecting
this gene are observed in oral SCC (77,78). p16 is also
subject to epigenentic control through hypermethylation of its promoter. TP53 (p53), a tumor suppressor
gene located on the short arm of chromosome 17, is
mutated in the majority of oral cancers and is also
frequently deleted (58,77). Gene amplification and
protein overexpression have also been found in head

and neck carcinomas. Of special significance is epidermal growth factor receptor (EGFR), which has
been targeted as a treatment strategy for oral SCC.
Cyclin D1 and p63 are other genes that are amplified
(79,80). Overexpression of cyclooxygenase-2 (COX-2)
is important in carcinogenesis and may provide
molecular target for treatment (81).
Increased susceptibility to oral cancer is associated with a number of inherited cancer syndromes,
including Li-Fraumeni syndrome, Fanconi’s anemia,
and xeroderma pigmentosum (82). Polymorphism in
genes involved in the metabolism of carcinogens contained in tobacco and alcohol have been linked to
individual susceptibility. These genes encode for such
enzymes as the glutathione-s-transferase, which are
involved in detoxifying some carcinogens in tobacco.
Other enzymes that metabolize carcinogens have also
been implicated in oral cancer such as cytochrome
p450, N-acetyltransferase and alcohol dehydrogenase
(77,83). There is increasing evidence for an inherited
genetic component in oral cancer, possibly associated


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with a greater susceptibility to genetic damage by
environmental mutagens. Those individuals may be
more likely to develop multiple tumors (81,84).

A.

Molecular biology in HPV-Related
Carcinomas

Molecular changes in HPV-related carcinomas may
differ from those induced by other carcinogens. A
large body of studies in cervical, as well as HIVpositive oropharyngeal carcinomas, shows that HPV
oncogenes E6 and E7 act through inactivation of P53
and retinoblastoma tumor suppressor genes, respectively. In addition, E6 can directly activate telomerase,
and E7 induces abnormal centrosome duplication.
Consequent cell cycle deregulation and genomic instability are instrumental factors for the developments of
these distinct carcinomas, see infra (Fig. 35) (85–88).

V. CLINICOPATHOLOGIC CONSIDERATION
As stated above, SCC of the oral/pharyngeal mucosa
constitutes a range of variants. Differences between
these entities are not only morphologic but also clinical and in some cases molecular. The clinical and
pathologic features of the following variants of SCC
will be considered in some detail later in this chapter:
1.
2.
3.
4.
5.
6.
7.
8.

KSCC
Nonkeratinizing carcinoma
BSC

ASC
Adenoid squamous carcinoma
VC
Papillary squamous carcinoma
Spindle cell carcinoma (SpCC) (sarcomatoid
carcinoma)

Staging of Oral/Pharyngeal Carcinoma:
Regardless of morphologic type, all variants of
SCC are staged similarly using the TNM system
(Table 1 and 2).

VI. KERATINIZING SQUAMOUS CELL
CARCINOMA
KSCC is the prototype of SCC and is its most common
type. It may occur at any of the anatomic sites of the
oral cavity and oropharynx. Variations in clinical
presentation, symptomatology, treatment outcome,
and prognosis may to some extent depend on the
anatomic location of the tumors. Because of such
variations, the clinical aspects of carcinomas at various sites will be addressed separately.

A.

Pathologic Features

KSCC bears some resemblance to keratinizing stratified squamous epithelium. The similarities vary
depending on the degree of differentiation. Microscopically, KSSC is composed of sheets, strands, and
nests of squamous cells. The tumor cells show
abundant eosinophilic cytoplasm, well-defined cell

borders, intercellular bridges, and hyperchromatic
nuclei. Varying degrees of nuclear and cellular pleomorphism are seen. A characteristic feature of KSCC
is formation of keratin pearls (round cellular nests
with central keratinization). Traditionally KSCC is
graded as well, moderate, and poorly differentiated
variants. Previously, the grading system, which was
proposed by Broder (90), was based on the amount of
keratin production and pleomorphism of the tumor
cells. Four grades are described, grade I being the
most differentiated with the highest keratin production and minimal cellular pleomorphism (Fig. 5),
while grade IV is poorly differentiated with little or
no keratin formation and marked cellular pleomorphism (Fig. 6). Grades II and III have intermediate
levels of these characteristics (Fig. 7). The purpose of
tumor grading is to provide a tool for predicting its
biologic behavior. However, because the histologic
features may vary considerably from area to area
within the same tumor, the Broders grading system
was found to lack significant prognostic value (91).
Several authors suggested that more useful prognostic
information may be deduced from the invasive fronts
of the tumor where the deepest and presumably most
aggressive cells reside (91–94). An invasive front grading system has been devised in which five histologic
features are graded and assigned points from one to
four. The score for each variant is summed to provide
a total malignancy score for each tumor. The parameters used are degree of keratinization, nuclear pleomorphism, number of mitoses per high-power field,
pattern of invasion, and host response. Accordingly,
the lower score is given to tumors with high keratinization (>50% of cells), little nuclear pleomorphism,
(>75% mature cells), 0–1 mitotic figures/HPF, pushing well-defined invasive front and marked host
response. On the other hand, the highest scores are

given to tumors with little or no keratinization,
extreme nuclear pleomorphism, more than five mitoses/HPF, marked cellular dissociation in small nests
or single cells, and no host response. The intermediate
grade tumors have moderate levels of these features.
This system has been found to be of high prognostic
value for oral cavity carcinomas (91,92,95,96). This
histologic grading of malignancy at deep tumor invasive front was also found to have significant positive
relationship with Ki-67 cell proliferative index (97,98).
Other morphologic features that are found to
have independent prognostic significance are presence of perineural invasion and intralymphatic
tumor emboli (99–101). It has also been shown that
the pattern of invasion, at the advancing front of the
tumor, is a significant and independent predictor of
both local recurrence and overall survival. The most
unfavorable pattern is described as diffuse infiltration
with cellular dissociation, while the most favorable is
well defined with ‘‘pushing’’ border (118).
Many studies have advocated the use of tumor
thickness as a measurable prognostic indicator in
small tumors (T1–T2) (101–104). Tumor thickness was
found to be significant in predicting local recurrence,
nodal metastasis, and survival. However, a ‘‘cut off’’
thickness level that can be used to discriminate


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291

Table 1 TNM—Staging System for Oral Cavity Cancer

Definition of TNM
Primary tumor (T)
TX
T0
Tis
T1
T2
T3
T4 (lip)

Primary tumor cannot be assessed
No evidence of primary tumor
Carcinoma in situ
Tumor 2 cm or less in greatest dimension
Tumor more than 2 cm but not more than 4 cm in greatest dimension
Tumor more than 4 cm in greatest dimension
Tumor invades through cortical bone, inferior alveolar nerve, floor of mouth, or skin of
face, i.e., chin or nose
Tumor invades adjacent structures [e.g., through cortical (oral cavity) bone, into deep
muscles of the tongue (genioglossus, hyoglossus, palatoglossus, and styloglossus),
maxillary sinus, skin of face]
Tumor invades masticator space, pterygoid plates, or skull base and/or encases
internal carotid artery

T4a

T4b
Note: Superficial erosion alone of bone/tooth
socket by gingival primary is not sufficient to
classify a tumor as T4.

Regional lymph nodes (N)
NX
N0
N1
N2

N3

Regional lymph nodes cannot be assessed
No regional lymph node metastasis
Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension
Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm
in greatest dimension; or in multiple ipsilateral lymph nodes, none more than 6 cm in
greatest dimension; or in bilateral or contralateral lymph nodes, none more than
6 cm in greatest dimension
Metastasis in single ipsilateral lymph node more than 3 cm but not more than 6 cm in
greatest dimension
Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest
dimension
Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest
dimension
Metastasis in a lymph node more than 6 cm in greatest dimension

Distant metastasis (M)
MX
M0
M1

Distant metastasis cannot be assessed
No distant metastasis

Distant metastasis

N2a
N2b
N2c

Stage
Stage
Stage
Stage
Stage

grouping
0
I
II
III

Stage IVA

Stage IVB
Stage IVC

Tis
T1
T2
T3
T1
T2
T3

T4a
T4a
T1
T2
T3
T4a
Any T
T4b
Any T

N0
N0
N0
N0
N1
N1
N1
N0
N1
N2
N2
N2
N2
N3
Any N
Any N

M0
M0
M0

M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M1

Source: From Ref. 89.

between favorable and unfavorable prognosis has
varied from 1.5 to 6 mm in various studies (102–
106). The variation in results reported in these studies
might be related to several factors, such as using the
surface of the tumor or the adjacent normal mucosa as
the point for measuring the thickness. More likely, the

variations were related to the size and peculiarity of
the tumors. Studies on FOM and OT tumors showed
cutoff thicknesses of 1.5 and 2.0 mm, respectively
(107,108), while in the case of buccal mucosal carcinomas with marked keratinization, the prognosis was
significantly worse for thicker tumors of more than or

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Table 2 TNM Staging System for Oropharyngeal Cancer
Primary tumor (T)
TX
T0
Tis
T1
T2
T3
T4a
T4b

Primary tumor cannot be assessed
No evidence of primary tumor
Carcinoma in situ
Tumor 2 cm or less in greatest dimension
Tumor more than 2 cm but not more than 4 cm in greatest dimension
Tumor more than 4 cm in greatest dimension
Tumor invades the larynx, deep/extrinsic muscle of tongue, medial pterygoid, hard palate, or mandible
Tumor invades lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, or skull base, or encases carotid
artery

Regional lymph nodes (N)
NX
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastasis

N1
Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension
N2
Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension, or in
multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension, or in bilateral or contralateral
lymph nodes, none more than 6 cm in greatest dimension
N2a
Metastasis in a single ipsilateral lymph node more than 3 cm but not more than 6 cm in greatest dimension
N2b
Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension
N2c
Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension
N3
Metastasis in lymph node more than 6 cm in greatest dimension
Distant metastasis (M)
MX
Distant metastasis cannot be assessed
M0
No distant metastasis
M1
Distant metastasis
Stage
Stage
Stage
Stage
Stage

grouping: Oropharynx
0
I

II
III

Stage IVA

Stage IVB
Stage IVC

Tis
T1
T2
T3
T1
T2
T3
T4a
T4a
T1
T2
T3
T4a
T4b
Any T
Any T

N0
N0
N0
N0
N1

N1
N1
N0
N1
N2
N2
N2
N2
Any N
N3
Any N

M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M0
M1

Source: From Ref. 89.

equal to 6 mm in thickness (106). In a study of 145
cases of oral carcinomas of all sites, O’Brian et al. (102)
found that a 4-mm cutoff for good and poor prognosis
applied to all sites.
KSCC is the most common type of oral/pharyngeal carcinoma of all anatomic subsites. Clinical presentation and etiologic factors may vary according to
anatomic locations.

VII.
A.

SQUAMOUS CELL CARCINOMA OF THE
ORAL CAVITY
Squamous Cell Carcinoma of the Lip

As stated above, chronic exposure to sunlight is the
most important etiologic factor. Lip cancer is more
common in individuals who live in rural areas and

who are involved in outdoor occupations, particularly
those with ruddy or fair complexions. It is also more
prevalent in the Caucasian populations that live near
the equator and is rare in blacks and dark-skinned
persons (44,45,109–112). The incidence of carcinoma of
the lip varies from 24% to 30% of oral cancers (113–
115) and 12% of head and neck cancers (114,115). The
lower lip is involved in 85% to 98% of cases
(45,112,114,116,117) with a male predominance. The
male-to-female ratio varies considerably in different
series from 2:1 to 45:1 (45,113,116–118). The patients’

age ranges from the fifth through the eighth decades
of life (110,116,117,119–121) with a mean age of
between 60.5 and 70 years (113,116,117,119–121).
SCC of the upper lip accounts for 1.8% to 7.7% of
all lip cancers (122,123). Upper lip carcinoma is seen
more frequently in women than in men (121,124). The


Chapter 7: Cancer of the Oral Cavity and Oropharynx

293

Figure 6 Poorly differentiated SCC. Although no keratin identified, the cells show keratinocytic phenotype (200Â). Abbreviation: SCC, squamous cell carcinoma.

Figure 5 Well differentiated, KSCC (100Â). Abbreviation:
KSCC, keratinizing squamous cell carcinoma.

relative overall paucity of lip cancer in women has
been attributed to the use of lipstick and less outdoor
exposure, both of which make women less susceptible
to the cumulative effects of actinic damage (124). Lip
cancer is also virtually unknown in blacks and people
with dark complexions (110). This apparent immunity
is presumably due to the protective effects of melanin
pigmentation against UV light (41,125).
Typically, carcinoma of the lower lip occurs at
the vermilion border at a point midway between the
midline and commissure area (1,23,126). Clinical presentations of the carcinomas vary considerably. Early
lesions may be focal, white, and thick, diffuse mixed
erythematous and white, have areas of chapping and

crusting or fissures that do no heal. More advanced
lesions may present as exophytic, infiltrating masses
but more commonly as an ulcer (1,125–128) (Fig. 8).
Palpable induration around the area of the lesion is an
important diagnostic feature in all forms of the tumor
(126,128).

Figure 7 Moderately differentiated KSCC (100Â). Abbreviation:
KSCC, keratinizing squamous cell carcinoma.

Carcinomas of the lower lip, unlike that of the
upper lip, tend to grow slowly. A considerable amount
of time may elapse before a diagnosis is made (127). If
untreated, the tumor may extend to contiguous structures such as skin, muscles, oral mucosa, and bone.
Some carcinomas have a propensity for involvement of
nerves. These may be associated with numbness of the
lip. Involvement of the mental nerve may be limited,
but on occasions, proximal extension of the malignant
cells may follow the course of the inferior alveolar
nerve within the mandibular canal and even along
the mandibular branch of the trigeminal nerve through
the foramen ovale and eventually intracranially. Such
neurotropic behavior may be observed even when


294

El-Mofty and Lewis

Figure 8 SCC of the lower lip presenting as an ulcer. Abbreviation: SCC, squamous cell carcinoma.

other risk factors, such as tumor grade and stage, are
favorable (129–134). The mechanisms involved in neurotropic behavior of some SCCs are currently
unknown. Neural involvement in lip carcinoma can
be determined clinically by sensory complaints such as
burning, stinging pain, or numbness along the course
of the affected nerve and by radiographic findings of
widening of the osseous canals or erosion of skull
foramina with which the affected nerves are associated
(129). Lymph node metastases from carcinoma of
the lower lip develop late in the course of the
disease. It is identified in 12% or fewer of the cases
(116,117,121,122,124,127). The submental and submandibular lymph nodes (levels Ia and b) are most commonly involved. Contralateral metastasis occurs when
the tumor is near the midline, because of crossdrainage of lymphatics present in this location. The
size of the tumor is an important risk factor for lymph
node metastasis. Carcinomas that are smaller than 2 cm
rarely metastasize, whereas those that are larger disseminate to lymph nodes with the same frequency as
carcinomas of the FOM and tongue (126). In one study,
only 5% of T1 and T2 lesions demonstrated nodal
metastasis. In contrast, 67% of T3 and T4 carcinomas
spread to the cervical lymph nodes (135). In another
series, 7% of 757 patients with T1 cancer demonstrated
cervical metastasis as compared with 16% of 249 of
patients with T2 to T4 tumors (124).
Distant metastasis from lip carcinoma is quite
rare. In a review of 845 cases, systemic spread was
noted in 1.6% of the cases. The lung, liver, heart, and
spleen were the sites most frequently involved (136).
Treatment and Prognosis

Surgery and/or radiation therapy are used with good
results in managing smaller tumors of the lower lip,
both achieving equally high local control rates of more
than 90% (122,137–139).
Radiotherapy is contraindicated in the following
conditions: young patients, recurrence following initial radiation therapy, large tumors with possible
neural involvement, and where there is extensive

solar keratosis affecting the rest of the vermilion
border (140).
Surgical management of smaller lesions is usually
in the form of a wedge or V-shaped resection with
primary closures. Larger defects require reconstructive
procedures. Lip shave and vermilionectomy, in addition to the simple resection, are recommended in
patients with demonstrable premalignant actinic
changes (117,141). Cases in which tumor involves the
mental nerve, efforts are made to prevent the progression of cancer cells along the inferior alveolar nerve
back to the base of the skull. This may involve a
hemimandibulectomy or, if possible, unroofing of the
nerve in the inferior alveolar canal and resecting it with
a free proximal margin (129). In such cases, surgery is
followed by radiation therapy (142,143).
Routine elective node dissection in patients with
clinically negative neck has been largely abandoned
because of low yield of nodal metastasis. A cure rate
of 90% is reported in T1 to T2, N0 carcinomas of the
lower lip (47,116,117,119). However, supraomohyoid
neck dissection is advocated in large T3 and T4
tumors, clinically positive nodes, and carcinomas at
the oral commissure (144).

Neck dissection combined with postoperative
irradiation has been highly successful in regional
control (138,141). Cases in which lymph node metastasis is pathologically proven, the average five-year
survival rate is estimated to be 50% (47,116,119,
120,122,124).
Frierson and Cooper developed a cytologic grading system for lip cancer similar to the grading system
of the advancing front alluded to above. Four grades
are described, which have prognostic implications.
They show a three-year cure rate of 95% for grade I
lip tumors but only 46% and 38% for grades II and III,
respectively (120).

B.

Squamous Cell Carcinoma of the Buccal
Mucosa

Many of the etiologic factors described above have
been implicated in the causation of cancer of the
buccal mucosa, in particular, tobacco habits, both
smoked and nonsmoked, and alcohol abuse. The incidence of SCC of the buccal mucosa varies in different
reports from 1% to 10% of oral/oropharyngeal carcinoma (145–147).
In India, where betel nut and other chewing
habits are prevalent, it constitutes 44% of all SCC of
the oral cavity (148). In a recent study from India
of 100 cases of carcinomas of the buccal mucosa, 95%
of the patients gave a history of abuse of oral tobacco
products (149).
Most cases occur in the sixth and seventh decades of life (147,150,151). The male-to-female ratio
ranges from 2:1 to 9:1 in most investigations

(145,149,150,152). However, in southeastern and
southwestern United States, carcinoma of the buccal
mucosa has occurred as often, if not more frequently,
in women. This has been attributed to the excessive
use of snuff and chewing tobacco by females in those
areas (22,153). Early SCC of the buccal mucosa may


Chapter 7: Cancer of the Oral Cavity and Oropharynx

present as a white plaque (leukoplakia), red plaque or
macule (erythroplakia) (Fig. 9), or exophytic verrucous hyperplasia (VH). The advanced lesions may
appear as a fungating mass with a granular red
surface or as ulcerating infiltrative cancer (Fig. 10).
Marked infiltration of the lamina propria and into the
underlying buccinators muscle and buccal fat is a
characteristic feature even in small T1 lesions
(153,154). VC commonly occurs in the buccal mucosa
and is discussed independently later in this chapter.
The signs and symptoms of the disease are
dependent on the degree to which the cancer has
progressed. Early lesions tend to be asymptomatic
but eventually ‘‘soreness’’ becomes the most prominent initial complaint. As the tumor enlarges, trauma,
superimposed infection, and swelling result in
increased pain. Involvement of the masticator spaces
in the process may lead to trismus. The tumor may
slough and form a foul-smelling mass in the mouth or
may ulcerate and appear externally on the skin. Hemorrhage from the internal maxillary or facial arteries is

Figure 9 SCC of the buccal mucosa presenting as erythroplakia with leukoplakic areas. Abbreviation: SCC, squamous cell

carcinoma.

a potential complication. Paralysis of branches of the
facial nerve may also occur (155,156). Invasion of the
mandible or maxilla may be present in advanced
cases. Death occurs from combination of infection,
malnutrition, and hemorrhage.
Treatment and Prognosis

Primary radiation therapy is a good therapeutic
option for early buccal carcinoma (154,155,157).
Patients with larger tumors show higher rates of
recurrence. Wide local resection even in small T1 to
T2 tumors is associated with high recurrence rates
(154,157), while aggressive composite resection has
better results (157). An improvement of the determinate cure rate from 28% to 42%, when surgery
replaced radiation therapy as the preferred treatment,
was reported in a study from Memorial Sloan-Kettering Cancer Center (145). In this study the presence or
absence of nodal enlargement was the most significant
prognostic factor. Patients treated surgically for residual or recurrent buccal carcinoma have extremely
poor prognosis (155). The question of whether or not
to use surgery or irradiation to manage the neck with
clinically negative nodes has not been resolved. It is
suggested that prophylactic intervention is unwarranted because of the low yield of occult nodal metastasis (157,158).
Chemotherapeutic treatment of buccal carcinoma
using a variety of agents has not been very promising.
Use in larger tumors, T3 to T4, resulted in some tumor
regression in a minority of cases (155,159–161). The
vast majority needed surgical salvage, and nodal
regression was not significant in any case.

Regardless of the type of treatment, locoregional
recurrences are common, usually occurring within
18 months (155,161,162). Several factors affect the
prognosis: tumor size, location, and thickness as well
as presence or absence of nodal metastasis. Carcinomas located anteriorly near the commissure area have
more favorable prognosis than those present posteriorly. The latter have a tendency to invade the oropharynx and bone of the mandible and maxilla (163).
Tumor size is useful in predicting outcome only at the
extremes; (T1 and T4), but that discrimination is lost in
the intermediate sizes T2 and T3 (106). Tumor thickness is suggested as a significant independent variable
in prognosis. The cutoff thickness for buccal cancer is
believed to be 6 mm, with five-year survival rates
significantly better for tumors less than 6-mm thick.
Patients presenting with cervical lymph node metastasis are found to have a five-year cure rate of only
23% compared with 56% for those patients without
nodal disease (164).

C.

Figure 10 SCC of the buccal mucosa presenting as an exophytic mass. Abbreviation: SCC, squamous cell carcinoma.

295

Squamous Cell Carcinoma of the Floor
of the Mouth and Oral Tongue

The FOM and the anterior two-thirds of the tongue
(OT) are the most common sites of oral SCC. They
account for more than 60% of all oral carcinomas
excluding the lips (165). The frequency of carcinoma
of the OT exceeds that of the FOM (165–167). In a

296

El-Mofty and Lewis

review of 58,976 cases of oral cancer extracted from
the National Cancer Database (NCDB), the OT
accounted for 31.9% and the FOM 28.4% of the
cases. These tumors demonstrate locally aggressive
behavior related to lack of anatomic barriers to spread
and a propensity for cervical metastasis (168).
Etiology

Excessive smoking and alcohol abuse are the main
etiologic factors. Prolonged contact of the potential
carcinogens in the salivary reservoir with FOM and
OT mucosa may play a role in targeting these sites
specifically (169). These usual risk factors are not
always apparent, particularly in cases of OT cancer
in patients younger than 40 years. In this population,
other risk factors may be involved, particularly genetic
predisposition (170–172). Many younger patients with
tongue cancer have never smoked or consumed alcohol, and in any case, the exposure to those carcinogens
might be of too short duration for malignant transformation to occur (172,173).

Figure 11 SCC of the tongue in a 19-year-old woman with no
history of smoking or excessive drinking. Abbreviation: SCC,
squamous cell carcinoma.

Clinical Features

Carcinoma of the OT and FOM are predominantly
diseases of the elderly with the greatest majority of
cases occurring in the sixth to the eighth decades of
life with a median age of about 60 years (165,169,
174,175). A small minority of cases occur in young
patients in the second and third decades of life. It has
been estimated that about 3% of carcinomas of the OT
occur in young patients but an increase to 6% to 7%
has been recently recognized (176–178). In the United
States, the incidence of OT cancer has increased in
adults aged 20 to 44 years during the last three
decades (177).
In general, men are affected two to three times as
much as women. However, the gap appears to be
closing during the last several decades in various
parts of the world. The difference seen previously
was probably a reflection of the differences in habits
between males and females. As habits such as smoking and drinking became more socially acceptable
among women, the gap has narrowed (166,172,179–
182). Among young patients with OT cancer, it is
particularly noticeable that the proportion of women
is greater than in the general population of tongue
malignancies, yet a history of smoking and drinking is
less frequently reported (183–187) (Fig. 11). Tongue
carcinoma in patients younger than 40 years may be a
distinct biologic entity but as alluded to above, the
underlying causes remain unknown (170–172).
Early asymptomatic carcinomas clinically present as either leukoplakia or, more commonly, erythroplakia (Fig. 12). Shafer and Waldron found that 50%

of erythroplakia of the FOM were histologically
proven to be invasive carcinoma. The remainder
were either severe dysplasia or carcinoma in situ
(188). However, the typical patient presents with a
painless, indurated ulcer of several months’ duration
(Fig. 13). The lesions are frequently more than 2 cm in
diameter at the time when the true nature of the

Figure 12 Early SCC of the tongue seen as an area of
erythroplakia on the lateral border. Abbreviation: SCC, squamous cell carcinoma.

Figure 13 Typical SCC of the lateral border of the tongue
presenting as a painless indurated ulcer. Abbreviation: SCC,
squamous cell carcinoma.


Chapter 7: Cancer of the Oral Cavity and Oropharynx

297

metastasis (101–104,107,108,208). In any case, most of
the patients have stages III or IV disease at presentation
(181,209).
Distant metastases are unusual, occurring only
in 10% of the patients, with the lungs, liver, and bone
as the sites most commonly affected (181,190,192,205).
Secondary primary carcinomas are known to be associated with FOM and OT carcinomas in 4% to 54% of
the cases. The secondary primary carcinomas may be
synchronous or asynchronous and occur mostly in the
head and neck area (181,189,192,194,205,207,210–212).

Half of these second primaries are detected by two
years from the index tumor presentation, but nonaerodigestive tract tumors are common beyond five
years (213).

Figure 14 SCC of the anterior FOM near the lingual frenulum.
Abbreviations: SCC, squamous cell carcinoma; FOM, floor of the
mouth.

Treatment and Prognosis

disease is established (188–191). In cases of FOM
tumors, the most common site is anteriorly, near the
lingual frenulum (Fig. 14). Seventy-two percent of all
tumors occur in this location, whereas 15% to 30%
develop in the middle third and posterior third,
respectively (189,191–193). However, restriction of
the tumor to the confines of the FOM is generally
found only in the initial stages of the disease. Extension to contiguous structures occur in 50% to 70% of
the cases at the time of diagnosis (194–196). In the case
of the OT, the most common site is the lateral border
of the middle third. About 75% of all tumors occur in
the lateral border followed, in descending order, by
the ventral surface, dorsum, and the tip.
The ulcerated lesions are often only the ‘‘tip of the
iceberg.’’ Manual palpation helps in appreciating the
third dimension of the lesion. Some tumors have exophytic components. More advanced carcinomas are
symptomatic. The patients may experience feelings of
discomfort, pain, excessive salivation, or hemorrhage.
Tongue involvement produces some limitation of
movement, resulting in slurred or difficulty in speech.

Involvement of the base of the tongue may lead to
dysphagia and referred otalgia (188,197,198). Weight
loss is reported by one-third of the patients (198). At the
time of diagnosis, the majority of OT and FOM tumors
are classified as T1 and T2 (54–67%) (175,198–201). The
percent of patients presenting with clinically positive
cervical lymph node metastasis varies from 30% to 63%
(174,175,198,200,202,203). In general, the nodes most
commonly involved are those of the submandibular
and upper jugular (levels I and II). Dissemination to
lymph nodes of levels III, IV, and V occur less often
(195,204,205). Anterior lateral and midline lesions have
a propensity for contralateral nodal involvement (206).
The orderly progression of metastasis from upper to
lower lymph nodes is not always apparent; skip metastases are common. Although some studies have found
a positive correlation between tumor size and metastatic potential (206), others have found that T stage is
of little predictive value (101,207,208). On the other
hand, as mentioned before, tumor thickness has been
advocated as a significant predictor of lymph node

Surgery and radiation, either alone or in combination,
are the prime modalities used in the treatments of
carcinomas of the OT and FOM. Chemotherapy has
been used as initial treatment concurrently with radiotherapy or as adjuvant treatment following surgery or
irradiation. For the most part, early carcinomas (stages
I and II) are treated effectively with either surgery or
radiotherapy alone (174,175,181,200,205).
Involvement of the mandible by carcinoma is an
important consideration in selecting appropriate therapy. Assessment of bone involvement by tumor may
be done by clinical examination and radiographic

studies. Plain radiographs may be helpful in judging
the gross extent of mandibular invasion, but they are
of little or no help in determining early or minimal
intraosseous invasion (214–216). Computed tomography (CT) scans provide good cortical bone detail.
Magnetic resonance imaging (MRI) is generally more
reliable in detecting changes within the marrow cavity. Both of the foregoing procedures have produced
false-negative and false-positive results as well as
under- or overestimation of the depth and width of
the invasion (214,217,218). The concomitant use of
both MRI and CT scans has been suggested (219).
If the mandibular bone is minimally involved, a
marginal resection (excision of the alveolar process
above the mandibular canal) is considered. In patients
with clearly demonstrable clinical or radiographic
evidence of mandibular invasion, a segmental mandibulectomy is needed with a 1 to 2 cm resection
margin (190,195,196,215) (Fig. 15). Tumors that extensively invade bones are usually less amenable to cure
by irradiation alone and are complicated by high
incidence of osteoradionecrosis.
Treatment of the neck is recommended in
patients with clinically positive cervical lymph nodes
at presentation. For N1 metastasis, neck dissection
alone is appropriate. For more advanced neck metastasis, a neck dissection with or without radiotherapy is
needed (220). On the other hand, the question of
treatment of the clinically negative neck is controversial. Recommendations for management of the negative neck in stages I and II disease have included
observation alone or prophylactic neck dissection and
prophylactic irradiation. On the other hand, there is


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El-Mofty and Lewis

Figure 15 Diagrams illustrating (A) marginal and
(B) segmental mandibulectomy.

general agreement on the need to treat the neck in all T3
and T4 tumors (180,181,220–223). Other considerations
that are taken into account in deciding whether or not
to treat the neck prophylactically in cases of T1 and T2
tumors include depth and pattern of invasion, lymph
vascular involvement, perineural invasion, and
patients who are not amenable to follow-up.
The most common causes of treatment failure
are the usual events: large tumors, tumor thickness,
positive margins of excision, perineural invasion,
infiltrating pattern of the advancing front, lymph
node metastasis, extranodal spread of tumor, and
distant metastasis (95,118,224–229). The incidence of
local recurrence following surgery or irradiation
varies from 10% to 40%. Over 90% of the patients
who fail therapy, regardless of the modality
employed, will manifest local or regional recurrence
within two years (181,189,190).
Several reports of large series of cases have
emphasized the importance of early detection for more
favorable prognosis. Figures based on clinical stage of
the tumors have shown a five-year survival rate of 69%
to 90% in stage I disease and 0% to 26% for stage IV
disease (165,174,181,190,192,194–196,200,230–232). As
previously mentioned, some investigators have found

that young patients, less than 40 years of age, with OT
cancer tend to have poorer prognosis (171,172,176,178,
183–185,187,233) even when presenting with early-stage
disease, with a locoregional recurrence of 57% and death
caused by disease in 47% of the cases (234). It was
therefore recommended that an aggressive therapeutic
approach be taken in young patients with carcinoma of
the anterior two-thirds of the tongue.
Distant metastasis, usually to the lung and bone,
is estimated to occur in 5% to 15% of the cases, and of
these, 90% expire within two years. Larger estimates
of distant metastasis below the clavicles are reported
on the basis of autopsy studies (228,235–239). About
20% to 30% of patients will develop a second primary
malignancy during the course of their disease
(220,228,240).

D.

Squamous Cell Carcinoma of the Gingiva
and Alveolar Mucosa

The gingiva is the part of the oral mucosa that covers
the alveolar process of the dentate jaws. Mucosal

covering of the mandibular and maxillary ridges in
edentulous areas is the alveolar mucosa. For the
purpose of the current discussion, both the gingival
and alveolar mucosa will be referred to as gingival
mucosa. Gingival SCC is the third most common

intraoral carcinoma after cancers of the tongue and
FOM. It constitutes 4% to 25% of all oral cancers
(166,167,241–248).
Of particular significance is that gingival SCCs
may clinically simulate inflammatory gum diseases
such as chronic gingivitis, periodontal disease, and
periodontal abscess. Consequently, misdiagnosis and
delayed diagnosis are not uncommon (241,248–251). In
addition, gingival carcinoma is characterized by early,
and sometimes extensive, involvement of underlying
bone with impending poor outcome (250–256).
Etiology

Several investigators have indicated that tobacco use
and, in particular, snuff dipping is a major risk factor in
the etiology of gingival carcinoma (22,241,245,257,258).
Alcohol consumption (246,259) and poor oral hygiene
(245,258) are also important considerations. Other
studies, on the other hand, have suggested that the
risk of alcohol and tobacco usage is not as significant
for gingival carcinoma when compared with that of the
tongue and FOM tumors (12,166,259–261).
The occurrence of gingival SCC in young
patients with HIV/AIDS and in patients with graftversus-host disease following marrow transplants, in
the absence of the usual risk factors, suggests an
etiologic role for immune disorders (262–264). A
genetic bases for gingival carcinoma is postulated on
the basis of the detection of p53 mutations and overexpression in many cases (58,77,265). The high incidence of gingival SCC in patients with proliferative
verrucous leukoplakia (PVL) (266) may also suggest a
genetic basis (see infra).

Clinical Features

Gingival carcinoma is primarily a disease of the elderly,
with the vast majority of cases occurring in individuals of 50 years or older (241,246,267,268). Only a
few cases of gingival carcinoma have been reported in
patients younger than 40 years, (269,270) including
one adolescent patient (271). Data derived from several


Chapter 7: Cancer of the Oral Cavity and Oropharynx

earlier series indicated that this disease usually
involves the mandibular gingival and affects men
more often than women (147,167,241,245–247,268,
269,272). However, more recent findings have shown
a decrease in the male-to-female ratio and even a
reversal in gender presentation (166,243,267,273,274).
Gingival carcinoma can present as an area of
erythema, an ulcer, or an exophytic mass, resembling
hyperplastic granulation tissue and mimicking focal
inflammatory gingival hyperplasia (188,275–277). The
carcinoma is more prevalent posterior to the canine
area, most commonly the mandibular molar area
(278,279). Quite often the lesion is asymptomatic
(246,278). More advanced cases may present with
soreness and pain of the gingiva, toothache, or bleeding (246,278,280). Typically, this cancer extends along
the periodontal membrane with destruction of the
supporting bone, resulting in loosening of the teeth,
closely resembling advanced periodontal disease
(242,277) (Fig. 16). Consequently, it is not unusual

for the involved teeth to be extracted, and the true
nature of the disease becomes apparent when the
tooth sockets and surrounding tissue fail to heal
(241,242,246,278). On the alveolar ridge, the carcinoma
often grows in the form of a flat elongated ulcer (281).
The duration of the symptoms in 187 patients, analyzed by Soo et al. (246), varied from three to more
than six months.
The tumors may spread laterally to involve the
mucobuccal folds, cheek, and lower lip (Fig. 16) or
medially leading to invasion of the hard palate, FOM,
and ventral surface of the tongue (278,282). Involvement of the mandibular or maxillary mucobuccal fold
in edentulous patients who wear dentures may give
rise to a mass that lies in close proximity to the flange
of the denture. The clinical appearance of these lesions
may be identical to inflammatory fibrous hyperplasia
(epulis fissuratum) (279) (Fig. 17).
Because of its proximity to alveolar bone, gingival carcinoma commonly shows evidence of bone
invasion (Fig. 18). Bone is usually involved early in
the course of the disease. Clinical and radiographic

Figure 16 Gingival SCC in the maxillary molar area extending
into the buccal mucosa. Notice destruction of the periodontium
and resemblance to advanced periodontal disease. Abbreviation:
SCC, squamous cell carcinoma.

299

Figure 17 SCC of the lingual alveolar mucosa of edentulous
mandibular ridge, resembling inflammatory fibrous hyperplasia.
Abbreviation: SCC, squamous cell carcinoma.

Figure 18 Dental radiograph showing bone destruction at the
site of gingival SCC in the mandibular molar area. Abbreviation:
SCC, squamous cell carcinoma.

evidence of osseous invasion has been noted in up to
75% of patients (246,253,255,256,283,284). This process
does not appear to correlate with the site of the lesion
or the stage of the disease but is dependent on the
proximity to bone (284,285). Mandibular tumors may
extend to the mandibular canal and the inferior alveolar nerve. Paresthesia of the lower lip may develop.
In the maxilla, penetration of the antrum is a frequent
occurrence (252,253,256,278).
Metastasis to cervical lymph nodes may be influenced by the location of the tumor and the T stage of
the disease. Mandibular tumors metastasize more
readily than maxillary ones. Clinically involved
nodes were found in 30% to 32% of the patients
with mandibular tumors and 9% to 14% in patients
with maxillary carcinomas (246,286).
The relationship between cervical metastasis and
tumor stage was investigated in 109 individuals. The
incidence of nodal involvement was found to increase
with the T stage of the disease (246). Dissemination to


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distant sites developed most often in the presence of

extensive cervical metastasis or in the presence of
bone involvement (246).
Radiography

Although radiography generally provides relatively
reliable indication of bony involvement (Fig. 18), the
absence of detectable changes does not completely
exclude the possibility of invasion. Microscopic evidence of bone invasion is frequently seen in spite of
radiographic findings (252,287). Additional techniques, other than intraoral and extra oral plain film
radiography, are usually needed. CT scans, MRI, and
bone scans are all used for ascertaining bone involvement (252,253,256). CT scans are the most frequently
used and are usually the only necessary radiologic
examination. CT can usually predict areas of bone
invasion with a degree of accuracy (254). MRI has an
advantage in demonstrating malignancy in the bone
marrow and perineural sheath. MRI can also aid in
delineating fluid from soft tissue when the paranasal
sinuses are involved (254). Severe bone destruction
may result in displacement of teeth and their isolation
producing ‘‘floating teeth’’ effect and may induce
pathologic fractures (288).
Treatment and Prognosis

Surgery is the mainstay treatment of gingival carcinoma.
Marginal mandibulectomy in appropriately selected
cases is as effective as segmental jaw resection
(246,289–292), and maintenance of the mandibular continuity results in significant reduction in patient morbidity and good long-term functional results (246,291).
Segmental jaw resection is reserved for cases in which
bone destruction extends to the inferior alveolar canal
on imaging examination (Fig. 15). Hemimandibulectomy is done in patients with unilateral involvement

of the entire inferior alveolar canal (252,290,293,294).
Clinically positive cervical nodes N1 to N3 are
treated with modified or radical neck dissection. For
clinically N0 necks, a supraomohyoid neck dissection
is recommended (246,290). Postoperative radiotherapy is used in patients with cervical metastasis as well
as in patients in whom tumor margins are inadequate
or who have advanced stage disease (i.e., stages III
and IV) (246,290,295). Chemotherapy has been used in
advanced cases (249,295).
Several factors play a determinant role in the
prognosis of gingival SCC. These include the size and
site of the tumor, presence or absence of bone involvement and its extent, the adequacy of the surgical
margins, and presence or absence of metastasis
(241,245,269,291,296). Maxillary carcinomas have better outcomes than mandibular ones with five-year
cures of 52% and 45%, respectively (22).
The main predictor of survival is considered to
be the stage of the tumor at the time of diagnosis
(246,253,256,280). Five-year survival rates decline
from 55% to 75%, for stages I and II patients, to 24%
to 44% in more advanced cases (246,280).

E. Squamous Cell Carcinoma of
the Hard Palate
The hard palate is the rarest site of intraoral SCC. It is,
however, the most common site for minor salivary
gland adenocarcinoma of the mouth. As previously
alluded to, SCC of the hard palate is rather common in
some parts of India where reverse Chutta smoking is
prevalent (1,15,297,298). The hard palate is, however,
not uncommonly involved by extension of maxillary

gingival and alveolar ridge SCC (253,256).
In the United States, the peak incidence of occurrence is between 60 and 70 years of age. Although
some studies have found that it is more common in
men, other studies have indicated that women are
more often involved (299,300). The first sign of the
disease is a lump or an ulcer (Fig. 19) that may or may
not be painful but occasionally bleeds. Exophytic
growths are most common and can result in denture
malfunction in individuals who wear a maxillary
prosthesis. Leukoplakia is detected in one-fourth of
the patients in association with the tumor (301). The
average delay from onset of symptoms to diagnosis
has been as long as four to five months (299,302). The
tumors are fairly well distributed between the two
sides and the center of the palate (301). In reverse
smokers, however, the cancer usually develops as an
ulcer, lateral to the midline in the glandular zone of
the hard palate (297).
At the time of diagnosis, about half of the tumors
are localized to the hard palate, 30% have invaded
adjacent structures, and 15% to 30% are associated
with positive cervical lymph nodes, 5% of which are
bilateral (299,300,302). Close to one-half of the tumors
are less than 4 cm in diameter. From the hard palate,
the cancer may spread to invade the underlying bone,
floors of the maxillary sinus and nasal cavity, gingiva,
and soft palate. Invasion through the bone and into
the maxillary sinus or nasal cavity is usually a late
event. The submandibular and subdigastric lymph
nodes are the first to be involved with metastatic

carcinoma (301,303). Distant metastases are rare.

Figure 19 Ulcerated, exophytic SCC of the hard palate in an
edentulous patient. Abbreviation: SCC, squamous cell carcinoma.


Chapter 7: Cancer of the Oral Cavity and Oropharynx

301

Treatment and Prognosis

Some clinicians prefer surgery over radiotherapy as
the prime therapeutic modality for SCC of the hard
palate (254,302). Others, however, have found irradiation to be equally effective and without significant
complications (299,304). Kovalic and Sympson (305)
were able to achieve good 10-year local control and
disease-free survival rates when surgery was combined with irradiation. The mean overall five-year
determinant survival has ranged from 31% to 59%
(300–302,306). For stages I to IV, the five-year survival
rate was found to be 75%, 46%, 36%, and 11%,
respectively (300), almost 80% of these patients who
fail therapy do so within 18 months after treatment.
Fifty-three percent of the treatment failure occurs in
the primary site, 30% in the neck alone, 10% at both
primary site and neck, and 7% at distant sites along
with locoregional recurrence (300). Because of significant prevalence of cervical metastasis from cancer of
the palate, it is recommended that selective elective
neck dissection should be offered to the patients (307).

VIII.

SQUAMOUS CELL CARCINOMA OF THE
OROPHARYNX

As previously indicated, the oropharynx encompasses
five anatomic areas: palatine tonsils, base of tongue,
soft palate and uvula, oropharyngeal walls, and RMT.
Although the latter is technically a component of the
oral cavity, carcinomas of this area often involve
adjacent sites of the oropharynx and behave more
like oropharyngeal tumors and thus will be discussed
in this section.

A.

Squamous Cell Carcinoma of the RMT

The RMT is anatomically a part of the oral cavity
rather than the oropharynx. It consists of a roughly
triangular strip of mucosa that covers the ascending
ramus of the mandible immediately posterior to the
last molar tooth and ends at the apex of the tuberosity
of the maxilla (Figs. 1, 4). Laterally it merges with the
buccal mucosa, and medially it blends with the anterior tonsillar pillar, soft palate, and FOM. Anteriorly it
is in contact with the mandibular gingiva and posteriorly relates to the muscles of mastication (pterygoid
and masseter) and mandibular bone.
Tumors involving the RMT may be extensions
from subjacent sites such as the buccal mucosa, FOM,
posterior tongue, soft palate, or tonsils. These tumors

are described under their respective sites. Carcinomas
primarily of the RMT are relatively uncommon and
will be discussed here. The tumors have been linked
etiologically to tobacco and alcohol abuse (308,309).
Clinical Features

SCC of the RMT occurs primarily in men of 55 to 70
years of age (309–311). Tumors in this region are
characterized by early invasion of the buccal mucosa,
soft palate, and mandible (309,310) (Fig. 20). They are
often diagnosed at an advanced stage owing to the

Figure 20 Ulcerated SCC of the RMT, involving the soft palate
and mandible. Abbreviations: SCC, squamous cell carcinoma;
RMT, retromolar trigone.

absence of early symptoms. The prognosis tends to be
poor because of late stage at the time of presentation
(308–310). Advanced disease is symptomatic, commonly associated with pain and trismus. The symptoms may result from invasion of the branches of the
mandibular nerve and muscles of mastication.
Referred otalgia is also common. At the time of
diagnosis, 27% to 60% are associated with clinically
positive lymph nodes, especially those of levels I and
II (309–314). In one study of 31 patients with RMT
carcinoma, occult metastasis was found in 64% of
clinically N0 necks (308). Histologically documented
invasion of the underlying mandibular bone was
reported in 14% of the cases in one study and 50%
in another (310,314). MRI was found to be more
sensitive than CT scan in predicting infiltration of

the mandibular marrow by tumor. The respective
sensitivity was 100% and 50% (314,315).
Treatment and Prognosis

The optimal management of carcinoma of the RMT is
not yet clearly determined. While some studies advocate surgical management, others recommend radiotherapy. However, it is generally agreed that small T1
and T2 lesions can usually be treated effectively with
radiation or surgery (316–320). Wide excision is necessary even in the absence of bone invasion. When bone
is involved, marginal or segmental mandibulectomy is
required. Adequate surgical margins improve survival (309,316).
Huang et al. (321) in their review of 65 patients
showed a five-year disease-free survival of 31% with
radiation alone, compared with 90% and 63% with
surgery and pre- or postoperative radiation, respectively. These authors recommended combined surgery and radiotherapy for all stages of disease. In
another study, the five-year overall survival was
40% in patients managed with radiation alone and
56% managed with surgery and radiotherapy (322).
Using multivariate analysis, they found that stage and
treatment modality were significant predictors of


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survival. Concurrent chemotherapy and radiation
therapy are occasionally used for advanced stages,
with some increase in survival rates (316). Distant
metastasis eventually occurs in 8% to 18% of the
patients (312,313). Lymph node status is reported to

significantly influence disease-free survival and distant metastasis rate (321).

B.

Squamous Cell Carcinoma of the Soft Palate
and Uvula

The soft palate is an oropharyngeal structure. It is
contiguous with the tonsillar pillars inferiorly and the
hard palate anteriorly. It separates the nasopharynx
from the oral cavity and oropharynx. It approximates
the posterior pharyngeal wall during swallowing, to
prevent nasopharyngeal regurgitation, and during
speech, to prevent nasal escape of air.

Figure 21 Early SCC of the soft palate presenting as erythroplakia. Abbreviation: SCC, squamous cell carcinoma.

Clinical Features

The soft palate represents 5% to 12% of all oropharyngeal carcinomas (323,324). Although the soft palate is
not an uncommon site for malignant tumors of minor
salivary gland, SCC is the most common malignancy
(324). The majority of the lesions develop on the oral
surface. Epidemiologically, these tumors are associated
with tobacco and alcohol use. SCC of the soft palate
and uvula is two-to-three times more abundant in men
than women and in blacks more than whites and tends
to occur in older individuals with an average age of
about 60 years (323–329). Because of its abundant nerve
supply, most patients (60–80%) present within three

months of onset of symptoms and typically complain
of a persistent sore throat, pain on swallowing, or
referred otalgia (330,331). In a review of 188 cases of
SCC of the soft palate and uvula, Weber et al. (329)
observed that 80% were unilateral and 20% were either
midline or bilateral. The uvula was the site of the
primary in 2.7% of the cases (329). Approximately
30% to 35% of patients (range 23–50%) will have
positive cervical lymph nodes at diagnosis, and of
these, 3% to 13% may be bilateral, especially if the
lesion approaches or crosses the midline (326,327,
329–333). The subdigastric and midjugular lymph
nodes are most often involved.
As the tumor enlarges, it is not uncommon for it
to spread beyond the soft palate to involve other sites,
especially the tonsils, RMT, base of tongue, and pharyngeal wall. The lesions may present as an exophytic
growth, an ulcer, a slightly elevated plaque, or as a
diffuse area of erythroplakia (Figs. 21–23).

Figure 22 Ulcerated SCC of the soft palate extending into the
mucobuccal fold. Abbreviation: SCC, squamous cell carcinoma.

Treatment and Prognosis

The tumor can be treated either by irradiation, surgery, or both. In general, early well-localized lesions
can be safely excised without causing significant functional disability, whereas more diffuse or poorly
defined lesions are best treated with radiation.
Advanced tumors associated with regional lymphadenopathy generally require a combination of both
modalities.

Figure 23 Exophytic SCC of the soft palate. Abbreviation: SCC,
squamous cell carcinoma.


Chapter 7: Cancer of the Oral Cavity and Oropharynx

The five-year determinant survival ranges from
55% to 77% (325,327,329,330,332). Morse and Kerr
(334) found significant disparities in survival between
black males compared with white males. The difference in mortality rates for white and black females
was small.
Local recurrence occurs in 25% to 37% of the
cases, and second primary malignant tumors are not
uncommon (24–42% of the cases) (325,326,328–332).
The incidence of distant metastasis during the course
of the disease has varied from 0% to 22%. Most of
these are to either bones or lungs. It has been pointed
out that despite combined modality therapy with
surgery and radiation, the five-year survival for stages
III and IVa resectable tumors is poor (33–47%)
(329,331,335–337). It has been recently shown that
the reason for the poor outcome in those patients
relates to occult metastatic disease in the parapharyngeal space (324). The parapharyngeal space is outside the surgical boundaries of a peroral resection and
neck dissection. Furthermore, the risk of transverse
myelitis limits the amount of adjuvant radiation that
can be given to this area, in a standard opposing field
anterior-posterior technique (324).
The use of neoadjuvant chemoradiation offers
another therapeutic regimen that may be of benefit in
advanced stage disease (338). Intensity-modulated

radiation therapy (IMRT) may provide higher doses
to and better control of the occult metastatic disease in
the parapharyngeal space without the risk of transverse myelitis (324).

C.

Squamous Cell Carcinoma of the
Oropharyngeal Wall

The posterior and lateral walls of the oro- and hypopharynx are anatomically and functionally one structure. Tumors in this location have similar risk factors,
lymphatic drainage, clinical behavior, and prognosis
and are normally treated in the same manner (339–346).
Clinical Features

Tumors of the oropharyngeal walls are relatively rare.
They are more common in males and affect patients
with a median age of 60 to 65 years (339,342,345–349).
Tumors at this site are usually quite large when first
seen. They tend to have a pattern of submucosal
spread and a known propensity for multiple foci of
origin in the regional mucosa (340). Sixty percent to
80% are T3 or T4 at diagnosis (345,350,351). A sore
throat, dysphagia, and odynophagia are the most
common symptoms. Approximately 40% to 60% of
the patients will either have, or subsequently develop,
positive cervical lymph nodes which may be bilateral
(339,345–349,352). The subdigastric, midjugular, and
retro- and parapharyngeal lymph nodes are those
most often involved.
Tumors of the oropharyngeal wall are especially

prone to spread submucosally and through lymphovascular spaces into the nasopharynx above and hypopharynx below. They often invade prevertebral fascia
but rarely extend into the anterior spinal ligament.

303

Treatment and Prognosis

Management of pharyngeal wall carcinomas varies
significantly by institution with some advocating primary surgical resection, if possible, and others favoring combined surgery with pre- or postoperative
irradiation in advanced lesions (340,347,348,353).
Definitive irradiation alone for tumors of all stages
has also been advocated (340,354–356). It has been
suggested that surgery with or without radiation
does not produce improved results over radiation
alone but is associated with higher morbidity (340,354).
The literature regarding use of chemotherapy is
broad and inconclusive. However, in a study on a
group of patients receiving concurrent chemotherapy
with irradiation (all of whom had stages T3 and T4
tumors), the patients appeared to fare better in overall
two-year local control rate than all patients with stages
T3 and T4 tumors (340). The prognosis of pharyngeal
wall carcinoma is extremely poor, regardless of the
method of treatment. The average overall five-year
survival from several series of cases is 23% (range 3–
38%) (339,345–348,352,356). The incidence of second
primary malignancies in these patients is significant,
varying from 17% to 57% (339,347,348,352). Because of
dismal survival rates, only 10% to 20% of the patients
live long enough to develop distant metastasis

(347,349).

D.

Squamous Cell Carcinoma of the Palatine
Tonsils and Base of Tongue

The palatine tonsils join the posterior third of the
tongue inferiorly through their inferior poles and
form the inferior and anterior component of the oropharynx. The base of the tongue harbors the lingual
tonsils. Both of the palatine and lingual tonsils are
components of the Waldeyer’s ring. Microscopically,
the tonsils show fissures or crypts, lined with nonkeratinized stratified squamous epithelium, that
extend into the lymphoid tissue from the surface
squamous mucosa of the oropharynx. The lymphoid
tissues are composed of germinal centers and diffuse
lymphocytes and plasma cells. The latter typically
involve the epithelial crypt walls (Fig. 24). The intermingling of lymphoid cells with the epithelium may
obscure cytologic features of early carcinomas that
may occasionally not be recognized on biopsy examination. The oropharyngeal tonsils are common sites of
a distinct clinicopathologic variant of SCC, the NKCa,
which is etiologically related to high-risk HPV. This
variant of SCC will be discussed in some detail below.
Clinical Features

SCC of the tonsil and base of tongue is two-to-five
times more common in men and occurs primarily in
the 50–70 year age range (52). However, patients with
HPV-related carcinomas are generally younger than
those who harbor HPV-negative tumors. Significantly,

tonsillar carcinomas in patients younger than 40 years
are overwhelmingly HPV related (52).
Although SCC of the tonsils and base of tongue
has been known to be closely linked to alcohol and


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inability to protrude the tongue. Tonsillar carcinomas
tend to involve the base of tongue, soft palate, and
pharyngeal wall. Earlier lesions may present as erythroplakia or as a slight mucosal granularity.
At the time of presentation, 50% to 80% of the
patients have clinically positive lymph nodes, 20% to
30% base of tongue carcinomas, and those of the
palatine tonsils that involve the tongue base either
have or will develop bilateral or contralateral nodal
metastasis at some time during the course of the
disease (362,368–379).
Treatment and Prognosis

Figure 24 Section in a palatine tonsil showing germinal center
and diffuse lymphocytic infiltrate involving the epithelial lining of a
crypt wall (100Â).

tobacco use, it has been more recently shown that
sexual transmission may play an important etiologic
role in patients with HPV-positive carcinomas. The
latter patients are three times as likely to report having

had oral sex as those with HPV-negative tumors and
were more likely to have had multiple sex partners
(357). It has also been demonstrated that husbands of
women with cervical cancer had a significantly
increased risk of developing tonsillar carcinoma
(358). At the same time, many patients with HPVpositive carcinoma have little or no exposure to the
chemical carcinogens from tobacco and alcohol. HPV
is less frequently detected in cancer biopsies of
patients who are tobacco smokers or paan chewers
(9,10,13,57,171,357,359,360). In a recent, large casecontrol study of oropharyngeal cancer, it was reported
that HPV carcinomas were identified in patients with
and without the established risk factors of tobacco and
alcohol use (51).
The most common presenting symptom is sore
throat. More advanced disease may be associated with
dysphagia, referred otalgia, bleeding, trismus, sensation of a foreign body in the throat, and ‘‘hot potato’’
voice in the case of base of tongue carcinomas (361–
363). It is not uncommon in cases of HPV-related
nonkeratinizing carcinoma that the patient present
with cervical lymphadenopathy in the absence of
clinically identifiable primary tumor (364,365).
Indeed, identification of HPV by in situ hybridization
(ISH) and p16 immunoreactivity in SCC metastases to
cervical lymph nodes was shown to be a reliable way
to establish origin from the tonsils or base of tongue
(366,367). HPV-related nonkeratinizing carcinomas
typically arise within the tonsillar crypts and may
show no mucosal abnormality or any detectable
enlargement. On the other hand, conventional KSCC
presents, on examination, as an ulcer with rolled, firm

margins with infiltrative growth that is palpable. Deep
infiltration into the base of tongue is manifested by

Surgery and radiation either alone, or in combination,
are used for treatment of base of tongue and tonsillar
carcinomas. Numerous papers have been published
on the validity of different treatment modalities.
Generally speaking, a combination of surgery and
radiation and, in selected cases, surgery and chemoradiation are used for advanced disease (T3 and T4),
while T1 and T2 tumors can be safely managed with
either surgery or radiation (380–391).
Key factors in surgical treatment of large base of
tongue carcinoma are the proper management of
the larynx and OT. Partial or total laryngectomy
may be required in some cases (392). The decision to
remove the larynx is based on whether it is involved
with the tumor (Fig. 25), the amount of tongue to be
resected, the status of the hypoglossal nerves, and the
general condition of the patient, especially for respiratory function and ability to tolerate aspiration while
trying to relearn to swallow (393).

Figure 25 Gross specimen showing SCC of the base of tongue
involving the supraglottic larynx, treated by combined glossectomy and laryngectomy. Abbreviation: SCC, squamous cell
carcinoma.


Chapter 7: Cancer of the Oral Cavity and Oropharynx

If less than half of the tongue base is excised,
supraglottic laryngectomy can be performed in otherwise healthy individuals without significant operative

problems. If, on the other hand, a large portion of
the base of the tongue needs to be removed,
with sacrifice of both hypoglossal nerves, a total
laryngectomy is generally indicated to prevent severe
aspiration (393).
Total glossectomy may be required in some
patients to achieve an adequate resection margin
(394). In a few highly selected patients, total glossectomy without total laryngectomy can be performed
(395). For these reasons, some clinicians prefer primary
radiation therapy over surgery. Better survival and
functional outcome is reported after radiation therapy
or chemoradiation in patients with advanced disease
(384,386,391). Radiation alone was also shown to produce significantly improved posttreatment function
and quality of life compared with other modalities
(391).
In a study from Memorial Sloan-Kettering
Cancer Center, it was found that most patients obtain
long-term regional control, with no severe complications, after definitive radiation therapy, of base-oftongue carcinoma, followed by neck dissection for
those patients who present with lymphadenopathy
(386). On the other hand, a study from M.D. Anderson
Cancer Center found that patients whose neck disease
responded completely to radiation, using accelerated
fractionated dose, did not appear to need a planned
neck dissection (388).
Postoperative adjuvant radiation therapy for
patients with stages III or IV SCC of the tonsils who
have undergone complete surgical resection is the
treatment of choice for many clinicians (380,382,390).
The overall five-year survival rate for tonsillar and
base of tongue carcinomas has ranged from 20% to

54% (361,362,369,372,375,380,382,384,391,394–400).
The five-year disease-specific survival rates are stage
dependent. Survival rates for stages I to IV in tonsillar
carcinoma are 93%, 57%, 27%, and 17%, respectively
(362). The five-year survival rates for stages I to IV
base-of-tongue carcinoma are reported as 100%, 57%,
20%, and 0%, respectively (371). Fifteen percent of the
patients develop distant metastasis (401). The most
frequent sites of dissemination, in order of frequency,
are lung, liver, bones, and brain.
The overwhelming cause of treatment failure
and death is local recurrence. Distant metastasis
accounts for only a few cases. The five-year actuarial
risk of distant metastasis in patients whose disease
was controlled locoregionally was 21% in one study
(388) and 7.5% in another (389).
Accumulating body of evidence in the United
States, as well as the international literature, confirms
that HPV-related carcinomas of the tonsils and base of
tongue have a statistically significant better prognosis
than HPV-negative carcinomas. The favorable outcome is evident in disease-free and overall survival
of the patients and is independent of TNM stage,
nodal status, age, or gender (402–407). It is suggested
that the favorable prognosis is attributable to higher
sensitivity toward radiotherapy.

305

E. Pathology of Squamous Cell Carcinoma
Variants

The following variants of KSCC are discussed:
1.
2.
3.
4.
5.
6.
7.

NKCa and nonkeratinizing undifferentiated carcinoma
BSC
ASC
Adenoid squamous carcinoma
VC
Papillary squamous carcinoma
Spindle cell (sarcomatoid) carcinoma

IX. NONKERATINIZING SQUAMOUS CELL
CARCINOMA
NKCa is a distinct type of carcinoma, which is HPV
related. It differs from conventional KSCC, not only
microscopically but also molecularly and clinically.
The role of HPV infection, as a prerequisite for the
development of a great majority of carcinomas of the
uterine cervix, is well established (408) and supported
by molecular, serologic, and epidemiologic evidence.
Similar documentation has also been, more recently,
provided for a role for HPV, particularly type 16, in
the pathogenesis of a subgroup of SCCs of the head
and neck (361,409–411). Genomic DNA of high-risk

HPV is detected in approximately 26% of all SCCs of
the head and neck worldwide (412). Rigorous and
consistent molecular evidence have shown viral integration and the expression of viral oncogenes (E6 and
E7) in nonkeratinizing oropharyngeal carcinomas of
the tonsils and base of tongue (52,54,410,411,413). The
prevalence of HPV DNA, particularly type 16, in
oropharyngeal carcinomas has varied in different
studies from 18% to 90% (52,54–57,411). A variety of
techniques are used to identify HPV in the tumors,
including ISH, polymerase chain reaction (PCR), and
immunohistochemistry. The virus is less frequently
identified in laryngeal and sinonasal carcinomas and
rarely in oral SCC (52–54).
In a review of 235 oropharyngeal carcinomas in
all age groups by El-Mofty and Patil (54), 36% of
tonsillar and 32% of base of tongue carcinomas were
HPV-related NKCa. Alternatively, 91% of tonsillar
carcinomas in young patients (younger than 40
years) were HPV type 16 positive (52). The average
age for patients with NKCa of the tonsil and base of
tongue was found to be 53.6 and 56.6 years, respectively. On the other hand, patients with conventional
KSCC are slightly older with an average age of 56.6
and 58.0 years, for tonsillar and base of tongue,
respectively. The male-to-female ratio for patients
with HPV-related NKCa of the tonsils and base of
tongue is 4:1 (54). Numerous epidemiologic and casecontrol studies provide support for the association of
high-risk sexual behavior with HPV-related oropharyngeal cancer (51,357,414–420).
Patients with HPV-positive tumors were three
times as likely to report having had oral sex as those
with HPV-negative tumors and were also more likely

to have had multiple sex partners (51,357). An analysis


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El-Mofty and Lewis

of the Swedish Cancer Registry data (1958–1996)
showed that husbands of women with cervical cancer
had significantly increased risk of developing tonsillar
cancer (358). Exposure to HPV increases the association with oropharyngeal cancer, regardless of tobacco
and alcohol use. HPV is less frequently detected in
cancer biopsies from patients who are tobacco smokers or paan chewers (9,10,357). These observations
suggest two distinct pathways for the development
of oropharyngeal cancers of the tonsils and base of
tongue. In the case of the KSCC, the process is driven
predominantly by the carcinogenic effects of tobacco
or alcohol (or both). The other pathway, as in the case
of the NKCa, is by HPV-induced genomic instability.

A.

Microscopic Features

HPV-related SCCs are characterized by nonkeratinizing basaloid morphology. The tumor cells are generally
monomorphic, oval, or spindle shaped, with hyperchromatic basophilic nuclei, inconspicuous cytoplasm,
and indistinct cell borders. They form cords, sheets,
and nests with sharply defined borders (Fig. 26). Palisading of the peripheral cells may be present (Fig. 27).
Excessive mitoses and apoptosis as well as comedotype necrosis are commonly observed (Fig. 28). Keratinization and keratin pearl formations are generally
absent, although some trend toward keratinocytic maturation may occasionally be present focally in some

tumors (Fig. 29). In these hybrid lesions, the basaloid
epithelial cells at the center or the periphery of the
neoplastic cell sheets may show keratinocytic rather
than basal cell morphology (Figs. 29, 30). The metaplastic change is manifested by a more prominent
cytoplasm, distinct cell membrane, and intercellular
bridges.
HPV-related nonkeratinizing carcinomas typically start deep in the tonsillar crypts of both the

Figure 27 NKCa. Oval and spindle shaped cells with hyperchromatic nuclei, inconspicuous cytoplasm and indistinct cell
borders (200Â). Abbreviation: NKCa, nonkeratinizing squamous
cell carcinoma.

Figure 28 NKCa showing excessive mitoses and apoptosis
(400Â). Abbreviation: NKCa, nonkeratinizing squamous cell
carcinoma.

Figure 26 NKCa of the oropharynx. Sheets of neoplastic cells
with sharp outline and comedo-type necrosis (100Â). Abbreviation: NKCa, nonkeratinizing squamous cell carcinoma.

palatine and lingual tonsils. Because of such location,
the early lesions may be inaccessible to cytologic
smears and superficial biopsies (Fig. 31). It is not
uncommon that small primary tumors, which are
undetectable on routine clinical and radiographic
examination, are associated with significant cervical
lymph node metastasis. These occult primary carcinomas are typically missed on multiple blind endoscopic
biopsies of suspect sites. However, it has been found
that microscopic identification of HPV-related NKCa
or the detection of HPV by ISH and/or p16 immunostaining in metastatic cervical lymph nodes are

Chapter 7: Cancer of the Oral Cavity and Oropharynx

307

Figure 29 NKCa with focal areas of keratinocytic maturation
(400Â). Abbreviation: NKCa, nonkeratinizing squamous cell
carcinoma.

Figure 31 NKCa arising deep in the wall of a tonsillar crypt
(200Â). Abbreviation: NKCa, nonkeratinizing squamous cell
carcinoma.

Figure 30 NKCa. Notice maturation of the peripheral cells
(200Â). Abbreviation: NKCa, nonkeratinizing squamous cell
carcinoma.

Figure 32 Cystic changes in NKCa metastatic to a cervical
lymph node (100Â). Abbreviation: NKCa, nonkeratinizing squamous cell carcinoma.

reliable techniques for establishment of the origin of
an occult tonsillar carcinoma. These primary carcinomas are best identified in excisional biopsies of the
palatine or lingual tonsils (366,367,421). Identification
of the site of a clinically occult primary carcinoma is
crucial for the proper management of the patients. In
the absence of a known primary tumor, patients with
cervical metastasis are likely to be overtreated with
wide-field irradiation that includes the entire pharyngeal axis and larynx. Such treatment protocols are
associated with severe morbidity (422–424). Nonkeratinizing carcinoma metastasis to lymph nodes commonly exhibits extensive central necrosis leading to

characteristic cystic change. The lining epithelium of
the cystic structures may be so scant and bland
appearing that a misdiagnosis of benign cyst may be
rendered (Fig. 32). Such an error is more likely made
in patients whose primary tumors are occult.

B.

Immunohistochemistry

The immunohistochemical profile of nonkeratinizing
carcinoma differs from that of the conventional KSCC
in several aspects. A major distinction is that nonkeratinizing carcinoma shows a diffuse and strong
reactivity to p16 antibodies (Fig. 33), while KSCC is


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El-Mofty and Lewis

Figure 33 NKCa showing strong and diffuse nuclear and cytoplasmic reactivity for p16 immunostain (200Â). Abbreviation:
NKCa, nonkeratinizing squamous cell carcinoma.

Figure 34 High staining scores for Ki67 in an NKCa (200Â).
Abbreviation: NKCa, nonkeratinizing squamous cell carcinoma.

either negative or weakly and focally positive (52,54).
More over, an inverse staining pattern is observed
with p53 reactivity. KSCC is much more likely to react
positively and strongly to this antibody than nonkeratinizing carcinoma. Another distinction is

observed in immunostaining for Ki67. Nonkeratinizing carcinoma shows much higher staining scores,
with that marker, than KSCC (Fig. 34) (52,54).
Overexpression of p16 has been extensively documented in HPV-related carcinomas of the uterine cervix and anorectal tract (425–428) and more recently, as
stated above, in nonkeratinizing carcinoma of the oropharynx. p16 is considered as a surrogate biomarker
for HPV-related carcinomas.
p16 gene product INK4A protein is a cell cycle
protein associated with the retinoblastoma pathway. It

Figure 35 Schematic representation of the proposed interaction of HPV E6 and E7 oncoprotein with cell cycle regulators p53
and Rb.

prevents the dissociation of E2F transcription factor
from pRb and the subsequent progression of S-phase
of the cell cycle (87,429,430). The paradoxical overexpression of an inhibitory protein in actively replicating neoplastic cells is thought to result from
feedback control secondary to pRb deregulation by
HPV E7 oncoprotein (427,431) (Fig. 35).
The increased mitotic activity of nonkeratinizing
carcinoma as compared with KSCC is well illustrated
microscopically (Fig. 28) and is documented by higher
Ki-67 labeling scores (52,54) (Fig. 34). Ki-67 is a nuclear
protein that is overexpressed in actively proliferating
cells. A high Ki-67 score has also been used as a
surrogate biomarker for HPV-related carcinoma of
the uterine cervix (427,432,433).
The inverse correlation between NKCa and p53
has also been documented in HPV-related carcinomas
in several studies, immunohistochemically as well as
by molecular-sequencing techniques (52–54,431,434). It
is well known that p53 mutations play a significant
role in development of the majority of conventional

KSCC in patients with known environmental risk
factors, such as tobacco and alcohol abuse (434–436).
However, in the case of HPV-related carcinomas, p53
inactivation is achieved by a different process. HPV-E6
oncoprotein interferes with p53 function by targeting it
for ubiquitination and degradation (87,437).

X. NONKERATINIZING UNDIFFERENTIATED
CARCINOMA
Nonkeratinizing undifferentiated carcinoma is a variant of NKCa. It is also known as lymphoepithelioma
and nasopharyngeal-type lymphoepithelial carcinoma.
Undifferentiated carcinoma is rare, accounting for
0.8% to 2% of all oral/pharyngeal carcinomas. More
than 90% of this type of carcinoma occurs in the tonsils
and base of tongue (438–441). The patients may present


Chapter 7: Cancer of the Oral Cavity and Oropharynx

Figure 36 Undifferentiated carcinoma of the palatine tonsil.
Notice morphologic similarities to nasopharyngeal undifferentiated
carcinoma (lymphoepithelial carcinoma) (200Â).

with an oropharyngeal mass or a neck mass. Cervical
lymph node involvement occurs in approximately 70%
of the cases at presentation (439,441,442).
Microscopically, undifferentiated carcinoma of
the oropharynx shows morphologic features that are
indistinguishable from that of the nasopharyngeal
undifferentiated carcinoma (WHO type III). The

tumor is composed of syncytial sheets and clusters of
carcinoma cells with vesicular nuclei and prominent
nucleoli and ill-defined cell borders. A rich lymphocytic infiltrate surrounds the tumor cells (Fig. 36). ISH
for Epstein-Barr virus (EBV)-encoded RNA is usually
negative in Caucasians but may be positive in Chinese
patients (443,444). A relationship of undifferentiated
carcinoma of the oropharynx to HPV is suspected but
presently unconfirmed. The tumor cells are positive for
pan-cytokeratin and epithelial membrane antigen
(EMA) immunostains and are negative for leukocyte
common antigen (CD45).
Undifferentiated carcinoma of the oropharynx is
radiosensitive. Local, regional, and distant failure
occurs in 3%, 5% and 19%, respectively. Distant
metastasis is associated with poor prognosis.

XI. BASALOID SQUAMOUS CARCINOMA
The histologic features of BSC were first defined in
1986 by Wain et al. (445). The tumor is an aggressive
variant of conventional SCC. It is described as having
biphasic morphologic features: a basaloid pattern,
which is intimately associated with KSCC, dysplastic
surface epithelium (Fig. 37), carcinoma in situ, or with
focal areas of squamous differentiation. The squamous differentiation is identified by the presence of
two or more of the following histologic features: (i)
individual cell keratinization, (ii) intercellular bridges,
(iii) keratin pearl formation, and (iv) cells arranged in

309

Figure 37 BSC. Dysplastic surface epithelium at upper right
corner (100Â). Abbreviation: BSC, basaloid squamous carcinoma.

Figure 38 BSC. Closely opposed lobules and sheets forming a
jigsaw puzzle pattern (100Â). Abbreviation: BSC, basaloid squamous carcinoma.

a pavementing pattern. The basaloid component is
described as having the following principle histologic
features: (i) solid groups of cells in a lobular configuration that are closely opposed, producing a jigsaw
puzzle appearance (Fig. 38), (ii) small crowded cells
with scant cytoplasm, (iii) dark hyperchromatic nuclei
without nucleoli, (iv) small gland-like cystic spaces
(Fig. 39), (v) small and large foci of coagulative necrosis within the central areas of the tumor lobules, (vi)
stromal hyalinization and intercellular hyaline deposits (Figs. 40, 41).
BSC occurs predominantly in the upper aerodigestive tract. Seven of the 10 cases originally described