CHAPTER 32
Oral Cancer: Classification,
Staging, and Diagnosis
G. E. Ghali, DDS, MD
M. Scott Connor, DDS, MD
Estimates indicate that more than
1.3 million new cancers will be diagnosed
in the United States this year, and 27,700
will be located in the mouth and
oropharynx.1 This number represents
approximately 3% of all cancers and is
the eighth most common cancer affecting
males in the United States. Globally, more
than 360,000 new cases of oral cancer will
be diagnosed this year.2 Mortality rates
remain high despite some advances in
locoregional control. There will be
approximately 200,000 deaths worldwide,
of which 7,200 will occur in the United
States. Most patients will present for
diagnosis with either regional or distant
disease. Data have shown a trend for
African Americans to have more
advanced disease compared with white
Americans (68% vs 52%) at the time of
diagnosis. Even more alarming is the fact
that, when compared with equal stages at
the time of diagnosis, African Americans
have a poorer 5-year relative survival rate
compared with other races. A review of
trends in 5-year relative survival rates
over the past three decades has shown a
statistical difference between the time
periods of 1974 to 1976 and 1992 to 1996
(54% vs 59%); the improvement in sur-
vival again fails to hold true for the
African American population.1
Approximately 85 to 95% of all oral
cancer is squamous cell carcinoma
(SCC).3,4 However, multiple other malig-
nant lesions can be found in the oral cavi-
ty such as sarcoma, minor salivary gland
tumors, mucosal melanoma, lymphoma,
or metastatic disease from nearly any site
in the body.
Risk Factors for SCC of the
Oral Cavity
The etiology of SCC of the oral cavity has
been studied extensively. Numerous risk
factors have been suggested as etiologic
agents for the development of these malig-
nancies. While no single causative agent
can be attributed to the development of all
oral cancers, several carcinogens have been
identified, and of those tobacco and alco-
hol appear to have the greatest impact on
malignancy development. Both extrinsic
and intrinsic factors likely play a role in
the development of SCC of the oral cavity.
The risk of oral cancer associated with
tobacco use is noted to be 2 to 12 times
higher than in the nonsmoking popula-
tion, and 90% of individuals with oral
cancer will have a smoking history.5–9 The
combination of various carcinogens with-
in tobacco, combined with the heat, may
lead to a variable number of genetic muta-
tions in the epithelium of the upper
aerodigestive tract. At some point these
continued mutations, coupled with the
patients’ own inherent genetic susceptibil-
ity, expressed in the hetero- or homogene-
ity of certain tumor suppressor genes or
oncogenes (TP53, c-myc), may lead to the
development of a cell line capable of
unregulated growth.
Alcohol in itself is not a recognized
initiator in the development of oral SCC.
However, the role of alcohol as a promot-
er in the development of oral cancer
when coupled with the use of smoking
tobacco has been shown.10 This may be
related to the effects of contaminants in
alcohol and its ability to solubilize car-
cinogens and enhance their penetration
into oral mucosa.5,11
A possible viral etiology has been
demonstrated in oral cancers, especially by
the human papilloma virus (HPV). The
HPV subtypes 16 and 18, similar to those
causing cervical cancer, have been implicat-
ed. Smith and colleagues showed that when
individuals in his study had other risk fac-
tors adjusted, such as smoking, alcohol, and
618 Part 5: Maxillofacial Pathology
age, the presence of HPV in the oral cavity
was associated with a 3.7 times greater
chance of cancer development than in the
noninfected individual.12 Other authors
have noted a unique subset of characteris-
tics in individuals that may develop SCC as
a result of HPV infection, showing less
association with tobacco or alcohol abuse,
frequently involving the tonsils, and having
an improved prognosis.13
The study of the tumor biology of
SCC has exploded in the past decade. The
accepted molecular theory concerning
genetic alterations of SCC is that of a
“multihit” tumorigenesis ultimately lead-
ing to unregulated cell growth and func-
tion.14,15 It is thought that multiple exoge-
nous insults (tobacco, alcohol, viral) can
lead to activation of oncogenes or inacti-
vation of tumor suppressor genes. Onco-
gene dysregulation leads to a gain of func-
tion alteration, and transforming growth
factor alpha (TGF-α) and eukaryotic initi-
ation factor 4E (eIF4E) are two examples
of well-studied genes that have proven up-
regulation in SCC.16 Loss of tumor sup-
pressor gene function requires loss of both
normal alleles, which leads to the inactiva-
tion of the critical function of that gene.
The most studied of the tumor suppressor
genes are TP53 and P16.15,17–19 No single
gene alteration is responsible for carcino-
genesis, but rather a host of altered genes
contribute. Attempts have been made to
use genes and their products to identify
oncologically safe margins operatively
with minimal success.20 Gene therapy tri-
als that target these specific genes hold
better promise.
Premalignant Disease
Premalignant disease can be divided into
that occurring as an isolated lesion or that
associated with a condition. A precancer-
ous lesion is defined as morphologically
altered tissue in which the development of
malignancy is more likely than with nor-
mal mucosa. A precancerous condition is a
condition or generalized disease that does
not necessarily alter the appearance of the
mucosa but may be associated with a
greater risk for the development of can-
cer.21 Precancerous lesions are broadly
classified as leukoplakia and erythroplakia.
Leukoplakia is defined as a white
patch or plaque that cannot be character-
ized clinically or ascribed to any other
pathologic disease.22 Leukoplakia cannot
be scraped or rubbed off and is therefore
primarily a diagnosis of exclusion. Lesions
caused by lichen planus, white sponge
nevus, nicotine stomatitis, or other
plaque-causing diseases do not qualify as
leukoplakia. Leukoplakia is strictly a clini-
cal diagnosis and does not imply any spe-
cific histologic diagnosis. Leukoplakia is
generally asymptomatic and clinically
appears as a white or off-white lesion that
may be flat, slightly elevated, rugated, or
smooth (Figure 32-1). It may be found as
isolated or multifocal lesions and may
change in morphology over time. More
than 70% of the time leukoplakia occurs
on two or more surfaces and has a strong
male predilection.23,24 A more aggressive
variant exists and is referred to as prolifer-
ative verrucous leukoplakia (Figure 32-2).
The lower lip vermilion, buccal mucosa,
and gingiva account for most oral cavity
leukoplakia; however, lesions found on the
tongue and floor of the mouth account for
most lesions exhibiting dysplasia or carci-
noma.23–26 These relative frequencies
change with different geographic locations
and are based on local habits.
FIGURE 32-1 Typical appearance of floor-of-
mouth leukoplakia.
FIGURE 32-2 Common presentation of prolifer-
ative verrucous variant of leukoplakia on gingiva.
The only consistent histology found in
all leukoplakia is the presence of hyperker-
atosis. The underlying epithelium may range
from normal to invasive carcinoma. The true
etiology for the development of leukoplakia
is unknown; however, several causative fac-
tors have been proposed. Tobacco use,
whether smoked or smokeless, is most close-
ly associated with the development of leuko-
plakia, and more than 70% of patients with
leukoplakia are smokers.23 While several
studies have shown elimination of tobacco
use to be associated with resolution or
decrease in the size of the lesion, others have
shown poor improvement with its cessation.
Ultraviolet radiation to the lower lip
is frequently observed in the development
of lower lip vermilion leukoplakia. Indi-
viduals with chronic unprotected expo-
sure to sunlight are at highest risk for
development. These leukoplakia lesions
are frequently associated with actinic
cheilitis (Figure 32-3).27
FIGURE 32-3 Actinic cheilitis of the lower lip
secondary to chronic unprotected sun exposure.

Trauma is also associated with the
development of leukoplakic lesions. Ill-
fitting dentures, sharp edges on oral pros-
theses or teeth, or parafunctional oral
habits with objects such as toothpicks can
be associated with leukoplakia. Obvious
traumatic lesions to the buccal mucosa
such as the development of a linea alba are
not considered leukoplakia.
The frequency of dysplasia and carci-
noma within leukoplakia is most closely
associated with the lesion’s location and
patient’s habits. Waldron and Shafer in
their study of 3,256 lesions submitted to
their respective oral pathology depart-
ments as “leukoplakia” found that 43% of
floor-of-mouth lesions and 24% of both
tongue and lip lesions contained some
degree of dysplasia or carcinoma.25 Sever-
al studies have also looked at malignant
transformation over time and found it to
vary from 0.13 to 17.5%.23–26,28 The results
of these studies vary according to suspect-
ed causes of the leukoplakia (geographic
habits) and the length of follow-up or time
to biopsy of the lesion. The malignant
transformation of these lesions has been
studied extensively by Silverman and col-
leagues.23 They note that, while a definite
rate of transformation cannot be stated,
their 257 patients had a 17.5% transfor-
mation rate with an average follow-up
time of 7.1 years. The second year of
follow-up in their series exhibited the
greatest rate of malignant transformation
at 5%. If those lesions initially noted to be
dysplastic on biopsy were followed, they
had an even higher rate of malignant
transformation, at 36.4%. Earlier studies
by Silverman and colleagues found malig-
nant transformation rates of 0.13% and
6%.26,28 The variability in transformation
rates of most studies is attributed to differ-
ences in ethnicity, drinking alcohol and
tobacco usage, location of the lesions, and
duration of follow-up.
Erythroplakia is a red patch that can-
not be scraped off or characterized clini-
cally or ascribed to any other pathologic
Oral Cancer: Classification, Staging, and Diagnosis 619
disease (Figure 32-4). Almost all true ery-
throplakia demonstrates dysplasia, carci-
noma in situ, or invasive carcinoma.
Shafer and Waldron’s review of biopsies
submitted under this clinical diagnosis
revealed that 51% were invasive SCC, 40%
were carcinoma in situ or severe dysplasia,
and 9% were mild to moderate dysplasia.29
The most common sites of occurrence are
the floor of the mouth and retromolar
trigone. Lesions appear as bright red, are FIGURE 32-5 Typical appearance of ery-
frequently “velvety” in appearance, and throleukoplakia on labial and buccal mucosa.
have a sharply demarcated border. The eti-
ology of these lesions is unknown but and difficulty with speech and swallowing.
thought to be the same as that for leuko- Unlike tobacco pouch keratosis, OSF does
plakia. Frequently these lesions are noted not regress with the cessation of betel quid
to be nonhomogeneous in appearance use. Longitudinal studies have shown a
with adjacent or intralesional leukoplakia. malignant transformation rate of 7.6%
When observed with this morphology, over a 17-year period.32
they are referred to as erythroleukoplakia
or “speckled erythroplakia” (Figure 32-5). Cervical Lymph Node Levels
These lesions also harbor an ominous The neck is divided into six “surgical lev-
potential as rates of malignant transfor- els” based on anatomic structures (Figure
mation have been noted of up to 23%.23 32-6). Each anatomic area of the oral cav-
Oral submucous fibrosis (OSF) is a ity has a predictable lymphatic drainage
precancerous condition seen predomi- pattern to the over 300 lymph nodes in the
nantly in India and Southeast Asia. It is a
chronic, progressive mucosal disorder
most frequently associated with the habit
of chewing betel quids; however, there is
evidence that this lesion is multifactorial
in nature with genetic, immunologic,
nutritional, and autoimmune factors pos-
sibly involved.30,31 The condition is charac-
terized by a mucosal rigidity that leads to
trismus, odynophagia with spicy foods,
I
II
V
VI
III
IV
FIGURE 32-4 Typical appearance of erythro- FIGURE 32-6 Lymph node levels of the neck. Levels I to
plakia located on left posterior soft palate. VI are subdivided and described in text.
620 Part 5: Maxillofacial Pathology
neck.33 By grouping defined nodal groups
into surgical levels, clinicians are afforded
the ability to communicate with each
other. It also allows clinicians to tailor
their surgical management of the neck
based on these known drainage patterns.
Level I includes the submental and
submandibular nodal groups.
Level IA, the submental group, is
bounded by the hyoid bone inferiorly,
the mandibular symphysis superiorly,
and the anterior bellies of the digastric
muscles laterally.
Level IB, the submandibular group, is
bounded by the posterior belly of the
digastric inferiorly, the mandibular body
superiorly, the anterior belly of the digas-
tric muscle anteriorly, and the stylohyoid
muscle posteriorly.34,35
Level II includes upper jugular lymph
nodes surrounding the internal jugular
vein and adjacent spinal accessory nerve.
Level IIA is bounded inferiorly by a
horizontal plane made by the inferior
body of the hyoid bone, superiorly by the
skull base, anteriorly by the stylohyoid
muscle, and posteriorly by a vertical plane
defined by the spinal accessory nerve.
Level IIB is bounded inferiorly by a
horizontal plane made by the inferior
body of the hyoid bone, superiorly by the
skull base, anteriorly by a vertical plane
defined by the spinal accessory nerve, and
posteriorly by the lateral border of the
sternocleidomastoid muscle (SCM).34,35
Level III includes middle jugular
lymph nodes surrounding the internal
jugular vein. It is bounded inferiorly by a
horizontal plane defined by the inferior
border of the cricoid cartilage, superiorly
by the horizontal plane defined by the
inferior body of the hyoid bone, anteriorly
by the lateral border of the sternohyoid
musculature, and posteriorly by the lateral
border of the SCM or sensory branches of
the cervical plexus.34,35
Level IV includes the lower jugular
lymph nodes surrounding the internal
jugular vein. It is bounded inferiorly by the
clavicle, superiorly by the horizontal plane
created by the inferior border of the cricoid
cartilage, anteriorly by the lateral border of
the sternohyoid musculature, and posteri-
orly by the lateral border of the SCM or
sensory branches of the cervical plexus.34,35
Level V includes all the nodes in the
posterior triangle, the spinal accessory and
transverse cervical nodes, and all of the
upper, middle, and lower jugular lymph
nodes on the posterior aspect of the SCM.
Level VA is bounded inferiorly by the
horizontal plane created by the inferior
border of the cricoid cartilage, superiorly
at the apex found at the convergence of
the SCM and trapezius muscles, anterior-
ly by the posterior belly of the SCM or
sensory branches of the cervical plexus,
and posteriorly by the anterior belly of the
trapezius muscle.
Level VB is bounded inferiorly by the
clavicles, superiorly by the horizontal plane
created by the lower border of the hyoid
bone, anteriorly by the posterior belly of
the SCM or sensory branches of the cervi-
cal plexus, and posteriorly by the anterior
border of the trapezius muscle.34,35
Level VI includes the pretracheal,
paratracheal, and prelaryngeal or so-called
Delphian lymph nodes. It is bounded infe-
riorly by the suprasternal notch, superior-
ly by the hyoid bone, and laterally by the
common carotid arteries. This level is also
known as the anterior compartment.34,35
Clinical Correlation
Based on Site
The boundaries of the oral cavity extend
from the vermiliocutaneous junction of
the lips to the junction of the hard and soft
palate posterior-superiorly and to the line
created by the circumvallate papilla poste-
rior-inferiorly. Posterior-laterally the
boundaries are represented by the anterior
faucial pillars. The American Joint Com-
mittee on Cancer (AJCC) has divided the
oral cavity into seven distinct anatomic
locations from which primary lesions may
develop.36 The sites have defined bound-
aries, and in developing these sites the
AJCC has attempted to produce a means
of better studying and treating oral cancer.
Mucosal Lip
The lip begins at the junction of the ver-
milion border with the skin and includes
only the vermilion surface or that portion
of the lip that comes into contact with the
opposing lip. It is well defined into an
upper and lower lip joined at the commis-
sures of the mouth.26 It is supported by the
orbicularis oris muscle and receives its
blood supply from branches of the facial
artery. Sensory innervation is provided by
the mental nerve and motor function via
branches of the facial nerve.
Mucosal lip cancers represent
approximately 2 to 42% of oral cavity
cancers.4,37–41 Mucosal lip cancer is seen
almost exclusively in older white men as
a result of chronic sun exposure (Figure
32-7). Its infrequent occurrence in dark-
skinned races is further evidence of its
etiology. Nodal metastasis in lip cancer is
infrequent, 10% of lower lip cancers and
20% of cancers in the upper lip and com-
missure are found to metastasize to the
nodes.42 Metastasis from the lower lip is
to the submental, submandibular, and
perifacial nodes (level I more commonly
than level II). Preauricular, periparotid,
and submandibular nodes drain cancers
of the upper lip and commissure (level II
more commonly than level I). Bilateral
FIGURE 32-7 Neglected carcinoma of the
lower lip.

neck metastasis may develop if the lower
lip lesion is near or has crossed the mid-
line; however, the upper lip rarely
exhibits crossover between right- and
left-side lymphatics.43
Buccal Mucosa
Buccal mucosa includes all the lining of the
inner surface of the cheeks and lips from
the line of contact of the opposing lips
(mucovermilion junction) to the line of
attachment of mucosa to the alveolar ridge
(upper and lower) and pterygomandibular
raphe.36 The buccal mucosa is supported
by the buccinator muscle posteriorly and
the obicularis oris anteriorly. The vascular
supply to the posterior aspect is derived
from the buccal artery, a branch of the
internal maxillary artery; innervation is
from the buccal branches of the facial
nerve along with the long buccal branch of
the third division of the trigeminal nerve.
Carcinoma of the buccal mucosa rep-
resents 2 to 10% of all SCC of the oral
cavity (Figure 32-8).4,37,38,44 In Central
and Southeast Asia the use of “pan” (a
combination of tobacco, betel nut, and
lime) has been linked to buccal mucosa
carcinoma and represents more than 40%
of all oral cavity SCC.45 First-echelon
lymphatic drainage from the buccal
mucosa is level I followed by level II.46
Cervical metastases are observed in 10 to
27% of presenting patients.44,47,48
Alveolar Ridge
The alveolar ridge mucosa may be divided
into lower (mandibular) and upper (max-
illary) components. The mucosa overlying
the alveolar process of the mandible
extends from the line of attachment of
mucosa in the buccal gutter to the line of
free mucosa of the floor of the mouth.
Posteriorly it extends to the ascending
ramus of the mandible.36 The mucosa
overlying the alveolar process of the max-
illa extends from the line of attachment of
mucosa in the upper gingival buccal gutter
to the junction of the hard palate. Its pos-
Oral Cancer: Classification, Staging, and Diagnosis
FIGURE 32-8 Squamous cell carcinoma of the
left buccal mucosa.
terior margin is the upper end of the
pterygopalatine arch.36
Alveolar ridge or gingival carcinoma
represents 2 to 18% of oral cancers and
occurs predominantly on the mandibular
alveolus (64 to 76%).4,37–41,49,50 At diagno-
sis, approximately one-third of these
tumors exhibit some bony involve-
ment.50,51 Lymph node metastasis tends to
occur more frequently in mandibular
ridge tumors than in maxillary tumors.
Nodal drainage is principally to levels I
and II for both the maxillary and
mandibular lesions and is found in 24 to
28% of patients at diagnosis.46,49-51 Alveo-
lar ridge carcinomas are frequently insidi-
ous tumors masquerading as inflammato-
ry lesions, periodontitis or gingivitis, tooth
abscesses, or denture sores (Figure 32-9).
Retromolar Gingiva
(Retromolar Trigone)
The retromolar gingiva is a triangular
region of attached mucosa overlying the
ascending ramus of the mandible from the
621
level of the posterior surface of the last
molar tooth superiorly to the tuberosity of
the maxilla. Laterally this area merges with
buccal mucosa and medially is in continu-
ity with the soft palate, anterior tonsillar
pillar, and floor of the mouth.36
Tumors of the retromolar trigone fre-
quently involve adjacent anatomic sites at
the time of diagnosis (Figure 32-10). Pri-
mary symptomatic complaints with these
tumors are sore throat, otalgia, and tris-
mus. Tumors of the retromolar trigone
represent 2 to 6% of all oral cavity carci-
nomas.4,38,39 Lymphatic drainage from this
area is predominantly to the submandibu-
lar nodes (level IB) and the upper jugu-
lodigastric nodes (level II).46,52 Lesions of
this region tend to be more aggressive in
nature with regard to developing cervical
metastasis, because 27 to 56% of individu-
als present with metastatic disease.53–55
Floor of the Mouth
The floor of the mouth is a semilunar
space over the mylohyoid and hyoglossus
muscles, extending from the inner surface
of the lower alveolar ridge to the under-
surface of the tongue. Its posterior bound-
ary is the base of the anterior faucial pillar
of the tonsil. It is divided by the frenulum
of the tongue and contains the ostia of the
submandibular and sublingual salivary
glands.36 Anatomically it consists of the
FIGURE 32-9 Biopsy-proven squamous cell car-
cinoma of the mandibular alveolar ridge result-
ing in erosion of underlying bone and loosening
of dentition.
622 Part 5: Maxillofacial Pathology
FIGURE 32-10 Ulcerative carcinoma of left
retromolar trigone with extension towards the
anterior tonsillar pillar.
unattached mucosa overlying the mylohy-
oid and hyoglossus muscles.
Carcinoma of the floor of the mouth
represents 8 to 25% of oral cavity SCC, and
several studies have shown a fairly dramatic
increase in incidence (Figure 32-11).4,38–41
Two distinct lymphatic drainage systems
have been identified in the floor of the
mouth.56 The superficial system drains
bilaterally into the submandibular nodes
(level I), while the deep system drains into
the ipsilateral submandibular, upper and
FIGURE 32-11 Carcinoma of anterior floor of
the mouth presents with induration, ulcera-
tion, and mild tongue fixation.
middle jugulodigastric nodes (levels I, II,
and III). Studies have shown that nearly
one-half of all patients presenting with a
floor-of-mouth carcinoma will have
metastatic disease at presentation.57–59
Shaha and colleagues demonstrated that
60% of individuals with metastatic disease
will have multiple levels involved.57
Hard Palate
The hard palate is between the upper alve-
olar ridge and the mucous membrane cov-
ering the palatine process of the maxillary
bones. It extends from the inner surface of
the posterior edge of the palatine bone and
can be divided into a hard and soft com-
ponent.36 In the United States, only 25% of
palatal SCC occurs in the hard palate with
75% occurring in the soft palate (anatom-
ically a part of the oropharynx).60–62 In
India and Southeast Asia, where reverse
smoking is popular, the proportion of
hard palate lesions is greater.
The hard palate represents 3 to 6% of
all oral cavity SCC (Figure 32-12).4,37–39
There is a paucity of lymphatics to the
hard palate. Approximately 10 to 25% of
individuals present with evidence of
metastasis, generally to levels I and II.61,63
Hard palate lesions may also metastasize
to retropharyngeal nodes or nodes that are
not palpable on a clinical examination or
readily removable with a traditional neck
dissection. Nonhealing ulcers and poor-
fitting dentures are common complaints
FIGURE 32-12 Carcinoma of the hard palate
with extension to alveolar mucosa.
among individuals who develop disease at
this site.
Anterior Two-Thirds of the
Tongue (Oral Tongue)
The anterior two-thirds of the tongue is
the freely mobile portion that extends
anteriorly from the line of circumvallate
papillae to the undersurface of the tongue
at the junction of the floor of the mouth.
It has four areas: the tip, the lateral bor-
ders, the dorsum, and the undersurface
(nonvillous ventral surface of the tongue).
The undersurface of the tongue is consid-
ered a separate category by the World
Health Organization.36 The tongue is
entirely a muscular structure composed of
the extrinsic muscles, the genioglossus,
hyoglossus, styloglossus, and palatoglos-
sus, as well as the intrinsic muscles of the
tongue. Blood supply to the tongue is from
the paired lingual, sublingual, and deep
lingual arteries. The tongue receives motor
innervation via the hypoglossal nerve and
taste and sensation from lingual branches
of the trigeminal nerve.
In the United States, SCC of the
tongue is found mainly on the anterior
two-thirds (75%), versus the posterior
one-third (25%).64 Tongue carcinoma rep-
resents 22 to 49% of all oral cancer diag-
nosed (Figure 32-13).4,37–41 Several epi-
demiologic reviews have shown the
unfortunate trend of an increase in tongue
cancer and an alarming increase in the
FIGURE 32-13 Carcinoma proliferating from
ventral tongue to encompass full thickness of the
tongue.

incidence of those diagnosed before 45
years of age.40,41,65–67 Lymphatic drainage
of the oral tongue is principally to level II,
followed by levels III and I.46,52 Carcinoma
of the lateral border generally metastasizes
ipsilaterally, but SCC of the tip or body of
the tongue may exhibit bilateral metas-
tases. Approximately 40% of patients have
evidence of clinical node metastasis at the
time of diagnosis.68
Staging
The TNM system devised by the AJCC is
designed to stratify cancer patients into
different stages based on the characteris-
tics of the primary tumor (T), regional
lymph node metastasis (N), and distant
metastasis (M). It is an attempt to help
guide treatment and estimate patients’
5-year survivability. T refers to the prima-
ry lesion and is graded on greatest dimen-
sion and presence of adjacent tissue infil-
tration (Table 32-1). N refers to regional
lymph node involvement and is graded on
the presence of nodes, greatest dimension,
and side of involvement in relation to the
primary tumor (Table 32-2). M grades dis-
tant metastasis and is based simply on its
presence (M1) or absence (M0). The AJCC
staging system (Table 32-3) is designed for
clinical use; however, the patient may be
restaged based on final pathology after
Table 32-1 Primary Tumors (T)
Tumor Description
TX Primary tumor cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ
T1 Tumor 2 cm or less in greatest dimension
T2 Tumor more than 2 cm but not more than 4 cm in greatest dimension
T3 Tumor more than 4 cm in greatest dimension
T4a* Tumor invades adjacent structures (eg, through cortical bone, into deep
[extrinsic] muscle of the tongue, maxillary sinus, skin of face) (resectable)
T4b Tumor invades masticator space, pterygoid plates, or skull base or encases
internal carotid artery (unresectable)
*Superficial erosion alone of bone or tooth socket by an alveolar primary is not sufficient to classify a tumor as T4.
Adapted from Greene FL et al.35,36
Oral Cancer: Classification, Staging, and Diagnosis 623
Table 32-2 Regional Lymph Nodes (N)
Node Description
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 a lymph node more than 6 cm in greatest dimension
Adapted from Greene FL et al.35,36
resection and designated with a p prefix measurement of the primary lesion
(pTNM) or at autopsy with an a (aTNM). before biopsy is essential. Often, biopsied
If synchronous tumors are found at pre- SCCs are referred without accurate mea-
sentation, the higher stage tumor should surements, leaving the treating surgeon
be used for stage designation, and an m in a difficult situation relative to proper-
suffix may be used to denote the multiple ly assigning a T group. Additionally,
primary tumors (TmNM).36,69 postbiopsy inflammation could lead to
over- or underestimates of the lesion’s
Assessment of Primary Lesion true dimensions.
Proper lesional assessment is based on a A complete evaluation of all anatomic
thorough clinical evaluation. Accurate locations within the oral cavity must be
performed by visual examination and pal-
pation to detect any mucosal abnormality.
The goal in evaluating the patient is to
detect any abnormal tissue and assess the
extent of disease. Patients may present with
myriad complaints such as a nonhealing
sore in the mouth, loosening of teeth, ill-
fitting dental prosthesis, trismus, otalgia, or
weight loss. Examination of the oral cavity
should include removal of all dental appli-
ances and use of a dental mirror for indi-
rect evaluation of the nasopharynx and
hypopharynx. Bimanual palpation is criti-
cal to assess any involvement of structures
such as the deep musculature of the
tongue, floor of the mouth, buccal mucosa,
salivary structures, or bony mandibular
624 Part 5: Maxillofacial Pathology

Table 32-3 Stage Grouping patients versus patients whose primary an often asymptomatic synchronous
tumor was thick (> 2 mm), who had a lesion. McGuirt reported a synchronous
Stage Characteristics
45.6% failure rate and metastatic node dis- primary lesion rate of 16% in his prospec-
Stage 0 Tis N0 M0 ease was present in 38%. Rarely, primary tive study of 100 head and neck cancer
tumors may be located in areas that are patients.76 The discovery of the synchro-
Stage I T1 N0 M0 difficult to assess or may be painful to nous lesions frequently led to an alteration
assess, requiring an evaluation under anes- in the treatment plan of the index lesion.
Stage II T2 N0 M0
thesia along with panendoscopy. Other reported incidences of synchronous
Panendoscopy, or “triple endoscopy,” primary tumors range from 2 to 9%.77–81
Stage III T3 N0 M0
T1 N1 M0
involves the use of a rigid bronchoscope, Panendoscopy can be performed quickly
T2 N1 M0 esophagoscope, and laryngoscope to and at a minimal price for the patient in
T3 N1 M0 sequentially examine and take biopsies, if terms of cost and added morbidity.
required, from the aerodigestive tract. The availability of flexible endoscopes,
Stage IVA T4a N0 M0 Warren and Gates first described the especially nasopharyngoscopes, has led to
T4a N1 M0 notion of synchronous and metachronous their use in many institutions, along with
T1 N2 M0 tumors in 1932.73 A synchronous tumor is the conversion to flexible bronchoscopes
T2 N2 M0 described as a second histologically con- and esophagoscopes. Additionally with the
T3 N2 M0 firmed malignancy. This malignancy must advent of tomographic imaging, routine
T4a N2 M0 be distinct and geographically separated preoperative panendoscopy is currently
by normal non-neoplastic mucosa and not undergoing reevaluation in many institu-
Stage IVB Any T N3 M0
of metastatic origin from the index lesion. tions. Many authors believe that the low
T4b Any N M0
It must also be discovered at the time of yield of bronchoscopy compared with
Stage IVC Any T Any N M1
initial tumor evaluation. If the second pri- chest imaging should preclude its use,
35,36
mary tumor is discovered at a later time it while others have called for selective
Adapted from Greene FL et al.
is considered a metachronous tumor. endoscopy to investigate only symptom-
Slaughter and colleagues described the driven complaints.81–84 Should multiple
structures. Assessment of the lateral tongue concept of “field cancerization” secondary primary tumors be discovered during
and posterior pharynx is assisted by anteri- to the panmucosal effects of smoked tobac- patient evaluation, each lesion should be
or and lateral traction on the tongue with co irritants and alcohol.74 This theory staged separately.
cotton gauze (Figure 32-14). explains the relatively high prevalence of
The AJCC describes the possible second primary malignancies in the upper Assessment of
growth patterns of a tumor as endophytic, aerodigestive tract and has been described Regional Metastasis
exophytic, or ulcerated.36 These character- on a molecular level.75 Panendoscopy Evaluation of the neck is perhaps the most
istics play no part in staging the primary became the gold standard for discovering critical and difficult aspect of staging oral
tumor. While depth of invasion is not used or any head and neck cancer. The presence
to clinically stage the patient, several stud- of a single lymph node with metastatic dis-
ies have shown that depth of invasion does ease reduces the patient’s 5-year survival by
play a prognostic role in the development 50%. In turn, the presence of extracapsular
of regional metastasis, especially in tongue spread decreases this survival by another
and floor-of-mouth cancers.70–72 The 50%.85 A retrospective study by Snow and
study performed by Spiro and coworkers colleagues showed a surprisingly high rate
at Memorial Sloan-Kettering Cancer Cen- of extracapsular tumor spread in even
ter looked at primary tumor thickness in small lymph nodes. His analysis showed
relation to risk of cervical node metastasis that lymph nodes greater than 3 cm had a
in SCC of the tongue and floor of the 73.7% chance of extracapsular spread, 2 to
mouth.70 They found that patients with 3 cm a 53.3% chance, 1 to 2 cm a 44.3%,
FIGURE 32-14 Anterior manual traction of
thin (< 2 mm) cancer of these respective and less than 1 cm a 28.8% chance.86 Other
the tongue with the aid of a cotton gauze
areas had a failure rate of 1.9% and lymph improves visualization of this lateral and ven- studies have concurred with this high rate
node metastasis present in 7.5% of tral tongue mass. of extracapsular spread.87,88 These drastic

reductions in long-term survival under-
score the importance of preoperative stag-
ing for an appropriate prognosis and treat-
ment plan. It should be noted that staging
depends not on specific lymph node level
involvement, but rather on presence of
nodes, size, number, and whether they are
ipsilateral, contralateral, or bilateral in rela-
tion to the lesion.
Traditionally, the gold standard in
staging the neck has been through digital
palpation of all levels of the neck bilateral-
ly. The neck has a large number of palpa-
ble structures and a large area to be sur-
veyed for the presence of lymph nodes.
While there is no correct order in which to
evaluate the neck, each clinician should
develop a sequence to use consistently to
avoid missing any part of the examination.
Observation of the neck is important to
note any asymmetries or skin changes.
Most clinicians prefer to palpate the neck
standing behind the patient, simultane-
ously palpating each aspect of the neck.
We find it helpful to break the neck down
into muscular triangles and examine them
sequentially from the submandibular tri-
angle to the posterior triangle. Lymph
node chains should be evaluated for the
presence of palpable masses, noting their
size, surgical neck level, and whether the
mass is fixed or moveable. Bending the
patient’s head forward or slightly to the
side will ease taut tissues of the neck allow-
ing for better palpation. Other important
palpable structures of the neck to be eval-
uated in the examination include the
parotid gland, the thyroid gland, and the
postauricular, occipital, and supraclavicu-
lar lymph node chains. The parotid gland
should be evaluated for the presence of
any palpable disease or masses and the
thyroid gland for any nodule, masses, or
thyromegaly. The trachea should be
inspected for any deviation or fixation.
The past decade has seen a relatively
high incidence of observer error. 89,90
Deficiencies have been observed in both
the ability to recognize the presence of a
Oral Cancer: Classification, Staging, and Diagnosis
clinically palpable node and also in the
ability to assess its size. A study by Alder-
son and colleagues showed that both res-
idents and staff involved in the treatment
of head and neck malignancies consis-
tently underestimated the size of smaller
nodes, and accuracy of assessment was
independent of experience.90
With the advent of advanced imaging,
both computed tomography (CT) and mag-
netic resonance imaging (MRI) have been
used as adjuncts to the physical examination
for both evaluating nodal disease and help-
ing to delineate the nodes in relation to vital
structures such as the carotid artery. Studies
have shown that clinically negative tumor-
positive nodes may be detected on CT or
MRI in 7.5 to 19% of cases.91–96
Computed Tomography
CT is generally performed preoperatively
with intravenous contrast to help delineate
vascular from lymph structures. The scan
generally involves 3- to 5-mm slices from
the skull base to the clavicles. Important
radiographic markers for the presence of
suspicious adenopathy include lymph node
size, shape, and central necrosis. A lymph
node is considered abnormal when it is
greater than 1.5 cm in the jugulodigastric
region or greater than 1 cm in other regions
of the neck.92,96 Shape has been suggested as
a criterion to help distinguish pathologic
nodes. The shape of a normal or hyperplas-
tic lymph node resembles a bean, as
opposed to round or sphere-like metastatic
nodes frequently present. Next to size, the
most specific indicator of metastatic nodal
disease on tomographic imaging is the
presence of intranodal necrosis, indepen-
dent of size and shape (Figure 32-15). Only
an intranodal abscess or fatty hilar metapla-
sia can simulate central tumor necrosis.
Magnetic Resonance Imaging
MRI is another method of neck imaging
that has gained popularity in the past
decade. With superior soft tissue detail,
one would expect better delineation of
625
FIGURE 32-15 Axial computed tomography
scan with contrast demonstrates large right cer-
vical node with criteria for regional metastasis.
lymph node pathology; however, the fat
that surrounds the cervical lymph nodes
can interfere with imaging detection. The
T1-weighted, fat-suppressed contrast-
enhanced image is perhaps the optimal
sequence to evaluate cervical metastatic
disease.92,97 MRI provides the distinct
advantage of viewing the neck and prima-
ry tumor in planes not available by CT.
Difficulty with the use of MRI concerns
both the time and motionlessness
required for an acceptable study to be per-
formed. Individuals with oral cancer fre-
quently have large lesions that may com-
promise the airway while supine for
extended periods of time. When using
MRI for evaluating the neck the same cri-
teria concerning nodal size, shape, and
central necrosis should be applied as
when evaluating with CT.
Ultrasound
Ultrasound (US) evaluation of the neck
has become increasingly popular in Euro-
pean countries. Sonography is relatively
inexpensive and is tolerated well. It may be
used as an initial study to help guide the
clinician in deciding whether further imag-
ing studies of the neck may be required.
This is especially true in the clinically N0
neck. Sensitivity of sonography in the
detection of cervical lymph node metasta-
sis is 89 to 95%, and specificity is 80 to
626 Part 5: Maxillofacial Pathology
95%.98–100 This specificity can be increased
with the use of US-guided fine-needle
aspiration.101 Criteria for the evaluation of
potentially malignant cervical nodes with
sonography also involve the assessment of
nodal size, shape, and presence of central
necrosis. Metastatic nodes are characteris-
tically round to spherical in shape and are
frequently hypoechogenic. In the presence
of extracapsular spread, loss of border def-
inition is observed. Normal lymph nodes
are frequently difficult to detect because of
their high echogenicity mimicking that of
the surrounding fatty tissue.
Positron Emission Tomography
The use of 2-18F-fluoro-2-deoxy-D-
glucose (FDG) positron emission tomog-
raphy (PET) relies on the enhanced meta-
bolic activity of tumoral tissue in the
body, of which increased glycolysis is usu-
ally the biochemical hallmark. FDG, a
radiolabeled glucose analog, is preferen-
tially taken up within tumor cells that
exhibit increased glycolysis; they can be
detected from the increased signaling in
that tissue (Figure 32-16). This study is
FIGURE 32-16 Preoperative positron emission
tomography scan demonstrates increased activity
in right tongue and right neck at levels II and III.
unique in that it represents a functional
imaging scan as opposed to a morpholog-
ic imaging scan. A prospective study by
Adams and colleagues showed a higher
sensitivity and specificity for FDG-PET
(90%, 94%) compared with CT (82%,
85%) and MRI (80%, 79%).102 Several
other studies have produced similar
results.103–105 As with ultrasound, FDG-
PET may have a unique role in the evalu-
ation of the clinically N0 neck.106 FDG-
PET has found a place in the evaluation of
an unknown primary with success rates
reported from 10 to 60% in the identifica-
tion of the index lesion.107–109
Drawbacks to the use of FDG-PET for
evaluation of the neck include the inabili-
ty to differentiate between cancerous and
reactive inflammatory lymph nodes and
the poor anatomic delineation of the pri-
mary tumor and neck nodes in relation to
surrounding structures, particularly those
of a vascular nature.
Assessment of Distant Metastasis
Final evaluation of the oral cancer patient
involves a work-up for possible distant
metastasis. Although the percentage of
individuals who present with an untreated
primary tumor who already have distant
metastasis is low, it is prudent to have
thoroughly staged the individual for opti-
mal treatment planning. Distant metastasis
from the oral cavity most frequently
involves the lung, followed by liver and
bone. Therefore, routine posterior-anterior
and lateral chest radiographs and the eval-
uation of liver function tests (LFTs) are
considered the minimum metastatic
work-up for head and neck cancer
patients. Depending on abnormalities
found in the chest radiograph or LFTs,
locoregional extent of the disease, and
degree of clinical suspicion, the surgeon
may also choose to obtain a CT of the
chest or abdomen and pelvis. Obtaining
other studies such as bone scans should be
symptom-driven. An added advantage of
an FDG-PET study in the evaluation of
distant metastatic oral cancer is its whole
body imaging of possible tumor spread.
The infrequency of distant metastasis
was recognized early by Crile.110 Studies
produced from the patient database at
Memorial Sloan-Kettering Cancer Center
have also shown relatively low rates in the
eventual development of distant metasta-
sis, ranging from 13% in individuals with
floor-of-mouth cancer to 15% in patients
with carcinoma of the tongue.57,111 As new
therapies lead to better locoregional con-
trol of disease, we can expect to see a
greater incidence of distant metastasis in
long-term follow-up.
Diagnosis
A thorough clinical examination is the
first line of defense in the detection of
oral cancer. Prognosis is directly depen-
dent on the tumor stage at diagnosis.
Nearly one-half of all oral cancers are not
detected until they are in advanced stages.
This delay may be because symptoms
may not develop until later in the disease
process or the socioeconomic group most
likely to develop oral cancer is unable to
seek treatment until it has reached an
advanced stage. Studies have shown that
only 14% of adults in the United States have
ever had an oral cancer examination.112
A study by Holmes and colleagues showed
that detection of oral and oropharyngeal
SCC during non–symptom-driven exami-
nations was associated with a lower stage
at diagnosis.113 These detections occurred
in the dental office, whether by a dentist,
dental hygienist, or oral and maxillofacial
surgeon.
Toluidine Blue
Oral cancer can have various clinical
appearances, ranging from subtle mucos-
al color or texture changes to gross ulcer-
ation or a fungating lesion. These mucos-
al alterations are particularly difficult to
assess in early cancers and dysplasia. It
was recognized in the 1960s that toluidine
blue stained malignant cells in vivo. Tolu-

idine blue is a metachromic dye that has
been used as a nuclear stain. The dye
uptake has been shown to aid in the early
recognition and diagnosis of oral SCC.114
While the dye’s exact mechanism of
action is unknown, theories have been
proposed that the dye selectively stains
cells with increased deoxyribonucleic acid
synthesis or quantitatively more nucleic
acids than other cells.115 It has also been
suggested that the dye binds to sulfated
mucopolysaccharides, found in higher
quantities in actively growing cells. Sever-
al studies have borne out toluidine blue’s
sensitivity (89 to 100%) and specificity
(62 to 90%) for oral SCC.115–117 This
specificity increases when a protocol is
followed involving a second rinse 14 days
after the initial application to allow for
resolution of any inflammatory lesions
that may be present. The sensitivity of
toluidine blue in detecting dysplastic
lesions is not as high as that for SCC. Sen-
sitivity rates have been recorded ranging
from 74 to 84.6%.115,117 These dysplastic
lesions stain inconsistently, and toluidine
blue cannot be used as reliably.
Toluidine blue is currently marketed
as a commercially available kit. Our opin-
ion is that its use should be limited to the
screening of high-risk individuals, and
assisting in directing biopsies from a large
area of abnormal-appearing tissue. In the
end, toluidine blue cannot be substituted
for a thorough oral examination and biop-
sies when clinical suspicion is high.
Biopsy
Once a clinically suspicious lesion is iden-
tified in the oral cavity, tissue diagnosis
must be obtained prior to rendering any
treatment. This biopsy can usually be done
in an office setting or rarely under general
anesthesia with panendoscopy if the lesion
is difficult to access and patient tolerance
is low. The traditional biopsy, whether
incisional or excisional (for small lesions),
is the gold standard. It should be empha-
sized that an accurate dimension of the
Oral Cancer: Classification, Staging, and Diagnosis
lesion should be acquired prior to biopsy
in order to properly stage the lesion. When
faced with a large lesion, it is best to take
several biopsies from different sites in an
attempt to decrease any sampling error
that might be read as dysplasia, necrosis,
or inflammation.
Brush cytology has gained acceptance
in the dental community as a safe, mini-
mally invasive technique for use in the
screening of clinically suspicious
lesions.118 Brush cytology differs from
exfoliate cytology in that it removes an
entire transepithelial layer for cytologic
evaluation as opposed to the sloughing
surface layer of the mucosa. Commercially
available kits exist that include a brush
biopsy instrument, glass slide, and fixative.
The suspicious lesion is sampled by rub-
bing or rotating the sampling brush
against its surface until pinpoint bleeding
at the biopsy site is obtained, indicating
sampling to the basement membrane and
an adequate specimen. This specimen is
then transferred to the slide, fixed in the
office, and sent to the corporation for eval-
uation by both a computer and oral
cytopathologist. Brush biopsy results are
classified as “negative” when no epithelial
abnormality is noted, “positive” when def-
inite cellular evidence of dysplasia or car-
cinoma is found, “atypical” when abnor-
mal epithelial changes of uncertain
diagnostic significance are observed, and
“inadequate” when an incomplete
transepithelial specimen was submitted.
The largest study of brush cytology by Sci-
ubba and colleagues found a sensitivity
and specificity of 100%.119 However, as
some authors have pointed out, a lack of
investigation with scalpel biopsy of atypi-
cal results in “innocuous-appearing”
lesions has resulted in a possible specifici-
ty exaggeration of this technique; other
studies have borne this result out with
reported sensitivities of approximately
90% but a specificity of only 3%.120
Brush biopsies’ best value may lie in
the general dentist’s hand where he or
627
she may encounter epithelial abnormali-
ties on a daily basis and is reluctant to
refer the patient for biopsy. It is our
opinion that brush cytology is only a
screening tool, and any atypical or posi-
tive results must be confirmed by an inci-
sional biopsy. The same should be said
about highly suspicious lesions read as
“negative.” If clinical suspicion remains
high despite a negative cytology result, a
biopsy should be obtained.
Conclusions
SCC of the oral cavity continues to be a
common disease worldwide including in
the United States. Despite research and
advances in surgical and adjuvant therapy,
long-term survival remains poor. It is a dis-
ease all clinicians will be faced with, and
early recognition and diagnosis of premalig-
nant and malignant disease is directly relat-
ed to outcome. Proper staging of the prima-
ry lesion and neck with a thorough clinical
examination and imaging is paramount to
designing a successful treatment plan.
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