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Overview of Oral Cancer

Chapter · March 2012

DOI: 10.5772/30520 · Source: InTech

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 1

Overview of Oral Cancer

Kalu U. E. Ogbureke1,* and Christopher Bingham2
1Department of Oral Biology, College of Dental Medicine,
Georgia Health Sciences University, Augusta, Georgia,
2Department of Periodontology, College of Dental Medicine,

Georgia Health Sciences University, Augusta, Georgia,

USA

1. Introduction
Cancer is the second most common cause of death in the Western world, after cardiovascular
diseases (Johnson, 1991; 2001). Worldwide, an estimated cancer incidence of about 10 million
was reported for the year 2009 (Jemal et al., 2010), and 1 out of every 3 persons is estimated to
suffer from cancer by the age of 75 years (Johnson, 1991; 2001). It is also estimated that about
7.9 million people world-wide will die from cancer this year (Jemal et al., 2010), accounting for
nearly 12% of deaths worldwide (Jemal et al., 2010). In the United States alone, an estimated
569,490 deaths from cancer are projected for the 2010 (Jemal et al., 2010). Recent published
estimates of worldwide frequency of the 16 major cancers indicate that in developing countries
with a high prevalence of infectious and nutritional diseases, cancer remains a major cause of
death (Parkin, Laara and Muir, 1988). This may account partly for the current statistics
whereby more than half the global incidence of cancer is from the so-called developing
countries, since an estimated 70-80% of the global population resides in these areas (Parkin et
al., 1998). The estimated annual incidence of cancer ranges from 48 to 225 per 100,000 in
developing countries (Parkin et al., 1998).

2. Oral cancer – Epidemiologic overview

“Oral cancer” encompasses all malignancies originating in the oral cavity. Oral cancer ranks
sixth in the overall incidence for the 10 most common cancer sites worldwide and third in
the developing countries (Johnson, 2001)). There is also a marked disparity in geographic
incidence between the “high” and “low” prevalence areas of the world, suggesting major
geographic differences in risk factors (Johnson, 1991; 2001). Most of these factors have been
identified through epidemiologic studies.
For statistical purposes, oral cancer is often grouped together with cancers of the pharynx as
“oropharyngeal” cancer (Daftary et al., 1992). In the Western world, oral cancer is relatively
uncommon, and in the context of all malignant tumors, incidence in the United States and
Great Britain ranges from 2 to 3% (Batsakis, 1979; Jemal et al., 2008). Relative incidence of

* Corresponding Author
4 Oral Cancer

up to 5% however has been reported for the United States (Batsakis, 1979), and higher rates
have been reported for the so-called “high risk” areas of Europe with incidence equally
varying with different socioeconomic groups within these areas (Johnson, 1991).
Worldwide, it is estimated that about 300,000 people will be diagnosed with oral cancer in
2010 (Jemal et al., 2010). Of these, 126,000 will die from the disease (Jemal et al., 2010). In the
United States alone, an estimated 35,000 new cases of oral cancer will be diagnosed in 2009
with an estimated 7,500 resultant deaths (Jemal et al. 2008). In the Asian subcontinent of
Bangladesh, India, Pakistan, and Sri Lanka, oral cancer is the most common malignancy,
accounting for about one-third of all malignancies within the subcontinent (Daftary et al.,
1991; Jonson, 2001). About 100,000 new cases are estimated to occur annually in these
regions that include Burma, Cambodia, Malaysia, Nepal, Singapore, Thailand, and Vietnam
(Daftary et al., 1991).
The paradox in the foregoing gloomy statistics is that, although the oral cavity and
oropharynx are easily accessible to dentist and physicians for routine examinations and the
biopsy of suspicious lesions that often present with outstanding features, early diagnosis has
been painfully slow when compared with the enhanced early detection of breast, colon,
prostate cancers, and melanoma (Mashberg A, 2000). As a result, the mortality rate from oral
cancer for the past three and a half decades has remained high (over 50%) in spite of new
treatment modalities. In contrast, there has been a considerable decrease in mortality rates
for cancers of the breast, colon, prostate, and melanoma during the same period (Mashberg
A, 2000). Examination of the colonic mucosa, which requires endoscopic examination for
evaluation of colon cancer, reveals 36% of localized colon cancers among the United States
population (Mashberg A, 2000). An identical percentage of localized oral/oropharyngeal
cancers are diagnosed without endoscopy among the same population (Mashberg A, 2000).
This paradox was eloquently summed up in a four decades-old publication highlighting
“. . . the poor prognosis of a form of cancer, which presents exceptionally good opportunity
for early treatment” (Banoczy and Csiba, 1976; Wright 1994).
The impediment to early diagnosis of oral and oropharyngeal cancers, despite increased
assiduousness on the part of dentists and oral physicians in their examination of patients at
risk, stems from the persistence of archaic paradigms, and the lack of an easily available
diagnostic adjunct. In order to increase the early detection of oral cancers, and by so doing
increase the survival rates of oral cancer patients, there is therefore the need to identify
diagnostic screening modalities that identify early oral malignant lesions with precision.
About 95% of oral cancers are classified histologically as oral squamous cell carcinoma
(OSCC; Mashberg, 2000; Johnson, 2001, Sargeran et al., 2008). The remaining 5% include
such histologic variants as oral verrucous carcinoma, adenosquamous carcinoma, adenoid
squamous cell carcinoma, mucoepidermoid carcinoma, and basaloid squamous cell
carcinoma. Mucoepidermoid carcinomas are malignancies of salivary gland origin and,
within the oral cavity, arise from minor salivary glands, while adenosquamous
carcinomas are currently believed to arise from the oral mucosa with subsequent
glandular changes among the tumor cells. Basaloid squamous cell carcinoma, a relatively
newly recognized entity, is a rare histologic variant of OSCC with marked predilection for
the base of tongue in addition to the supraglottic larynx and hypopharynx. Often
included in the remainders are metastatic carcinomas from regional sites distant to the
oral cavity.
Overview of Oral Cancer 5

3. Etiologic risk factors for oral cancer

Oral cancer is a multifactorial disease. Exposure to one of three broad groups of
carcinogenic stimuli, namely, chemical, physical, and viral, is known to induce cancer in
genetically and systemically conditioned oral mucosa. Within the oral cavity, it appears that
carcinomas are caused predominantly by chemical carcinogens, although evidence
implicating viral and physical stimuli in the development of some oral cancers continues to
mount (Syrjanen, 2005; Reddout et al., 2007). The pathogenesis of oral cancer is equally
complex, and exposure to carcinogens does not inevitably result in the development of oral
cancer. This is because a number of familial, dietary, hormonal, and sex-related factors are
known to modulate neoplastic processes generally. Tobacco and alcohol have emerged as
the most important culprits contributing to the etiology of oral cancers. Other factors
frequently cited are ultraviolet light, nutritional and dietary factors, precancerous lesions,
immunosuppression, genetic, and dental factors.

3.1 Tobacco and tobacco products

An association between the use of tobacco and oral cancer can be traced to the early 18th
century, when lip cancer was observed with some frequency in tobacco users (Sawyer and
Wood, 1992). The strong association of cancers of the oral cavity and oropharynx with
tobacco use is well established (Johnson, 2001). Epidemiological studies show that the risk of
developing oral cancer is five to nine times greater for smokers than for nonsmokers, and
this risk may increase to as much as 17 times for heavy smokers of 80 or more cigarettes per
day (Neville and Day, 2002). Approximately 80 percent of oral cancer patients are smokers,
and this is two to three times greater than that of the general population (Silverman and
Griffith, 1972; Blot et al., 1988; Mashberg et al., 1993; Jovanovic et al., 1993; Andre et al., 1995,
Lewin et al., 1998). In addition, treated oral cancer patients who continue to smoke have a
two- to six- times greater risk of developing a second malignancy of the upper aerodigestive
tract than those who stop smoking (Silverman and Griffith, 1972; Silverman and Shillitoes,
1998).
Oral smokeless tobacco (snuff and chewing tobacco) have also been associated with an
increased risk for oral cancer (Brown et al., 1965). In one study of women in the southern
United States, chronic users of snuff were estimated to have a four times greater risk of
developing oral cancer (Winn et al., 1981, Johnson, 2001). In addition, a significant number
of oral cancers in smokeless tobacco users develop at the site of tobacco placement.
However, the use of smokeless tobacco appears to be associated with a much lower cancer
risk than that associated with smoked tobacco. For example, although the state of West
Virginia has the highest consumption of chewing tobacco in the United States, the incidence
of oral cancer in West Virginia is below the U.S. national average (Bouquot and Meckestroth,
1998). Recent studies from Scandinavia have suggested that the use of Swedish snuff (which
is nonfermented and has lower nitrosamine levels) is not associated with an increased risk
for oral cancer (Johnson, 2001; Neville, 2002).
The habit of oral smokeless tobacco use is evolving as “fashionable” amongst the youth in
many Western countries, and may partly account for spikes in the rate of oral cancers and
potentially malignant lesions observed in this age group in recent decades (Johnson, 1991).
The importance of teenage use of smokeless tobacco lies in the considerable length of time
6 Oral Cancer

that the oral mucosa of teenagers indulging in this habit are bathed in high concentrations of
numerous carcinogens contained in smokeless tobacco (Sawyer and Wood, 1992). In
addition to carcinogens usually associated with smoking, smokeless tobacco contains
210polonium (originating from phosphate fertilizers used to grow tobacco), 226radium, and
210lead (Main and Lacavalier, 1988). Furthermore, tobacco-specific nitrosamines present in

smokeless tobacco, and readily extracted in saliva and further enhanced in alkaline
environments, often are of higher concentrations than in cigarette smoke (Sawyer and
Wood, 1992).
In India and Southeast Asia, the chronic use of betel quid (paan) in the mouth has been
strongly associated with an increased risk for oral cancer (Murti et al., 1985; Murti et al.,
1995). The quid typically consists of a betel leaf that is wrapped around a mixture of areca
nut and slaked lime, usually with tobacco and sometimes with sweeteners and condiments.
The slaked lime results in the release of an alkaloid from the areca nut, which produces a
feeling of euphoria and well-being in the user. Betel quid chewing often results in a
progressive, scarring precancerous condition of the mouth known as oral submucous
fibrosis. In India, one study showed a malignant transformation rate of 7.6 percent for oral
submucous fibrosis (Murti et al., 1985).
Marijuana use is also considered to be a potential risk factor and may be partly responsible
for the rise in oral cancers seen among young adults (Zhang et al., 1999; Silverman, 2001;
Schantz and Yu, 2002). Marijuana smoke contains known carcinogens such as benzopyrene
and benzanthracene (aromatic hydrocarbons), and the concentration of these carcinogens is
postulated to be considerably higher than that in cigarette smoke (Sawyer and wood, 1992).
However, further epidemiological studies are necessary to confirm the purported association
of marijuana and oral cancer, particularly in younger patients.

3.2 Alcohol
The relationship between alcohol, particularly hard liquor, and squamous cell carcinoma
has been recognized for a long time (Wynder, 1971), and has been identified as a major risk
factor for cancers of the upper aerodigestive tract (Neville and Day, 2002). What presented
as a significant challenge, until recently, was the assessment of the independent role of
alcohol in oral cancers due to the difficulty in separating the effects of heavy alcohol
consumption from those of smoking and other risk factors, including nutritional (Kato and
Nomura, 1994). Most heavy consumers of alcohol beverages also are heavy smokers.
In studies controlled for smoking, moderate-to-heavy drinkers have been shown to have a
three- to nine- times greater risk of developing oral cancer (Blot et al., 1988; Mashberg et
al., 1993; Jovanovic et al., 1993; Andre et al., 1995; Lewin et al., 1998). One study from
France showed that heavy drinkers, consuming more than 100 grams of alcohol per day (a
typical serving of beer, wine, or liquor approximates 10 to 15 grams of alcohol), had a 30
times greater risk of developing oral and oropharyngeal cancer (Andre et al., 1995). Thus,
it would appear that smoking is not a necessary prerequisite for alcohol induced cancers.
Of greater significance however is the synergistic effect of alcohol and smoking; some
subsets of patients who are both heavy smokers and heavy drinkers can have over one
hundred times greater risk for developing a malignancy (Blot et al., 1988; Andre et al.,
1995).
Overview of Oral Cancer 7

While the mechanism of alcohol-induced carcinogenesis remains unclear, it is apparent that

alcohol acts primarily as a co-carcinogen or promoter. Carcinogenesis also may be related to
nutritional deficiencies associated with alcoholism. Systemically, alcohol may lead to
impaired absorption of nutrients and vitamins. It has been suggested that alcohol acts as a
solvent facilitating the entry of carcinogens into exposed cells (Sawyer and Wood, 1992). In
addition to creating a nutritional deficiency state (Harris et al., 1997; Johnson, 2001), alcohol
may alter epithelial cell metabolism, or suppress immunity (Cotran, Kumar and Robbins,
1989). There is some evidence that carcinogenic contaminants rather than ethanol may be
responsible for the increased incidence of alcohol-associated cancers (Bennie, 1976).

3.3 Human Papilloma Viruses (HPV)

The role of HPV as an etiologic agent in cancer was first recognized in the uterine cervix
(where it is present in about 99.7% of cases), and the prognostic significance of HPV-
associated cervical cancer is now well established (Clifford, Boyle and Franceschi S, 2003;
Reddout, 2007). HPV-16 and -18 are the major high-risk types and predominate in invasive
anogenital cancers (Clifford et al., 2003; Reddout, 2007). On the other hand there is as yet no
clear evidence to support a causative role for HPV in OSCCs, and any potential pathogenic
mechanism of HPV-associated OSCCs is still confounding. At best, an association between
HPV infection and oral cancer is accepted by most investigators in this field.
In oral lesions, HPV-16 is by far the most common subtype associated with OSCCs and oral
premalignant lesions (OPL) exhibiting epithelial dysplasias (Reddout, 2007). HPV-16 DNA
has been identified in primary tumors of the tonsil, hypopharynx, oral cavity, tongue, and
nasopharynx, as well as in cell-lines derived from these regions (Syrjanen, 2005; Reddout,
2007). Metastatic lymph nodes lesions have also been shown to contain DNA of the same
HPV type as in the primary tumor in 76% of the cases, supporting the involvement of HPV
in the development of OSCC (Clifford et al., 2003; Syrjanen, 2005; Reddout, 2007).
The prevalence of HPV-16 in OSCC is now considered to be as high as 50% if not more,
making it likely that every alternate OSCC patient is HPV-16 positive (Syrjanen, 2005;
Reddout, 2007). The association is strongest in the oropharynx, most notably in the tonsil
and base of tongue, which present more frequent basaloid histomorphology and less
frequent p53 mutations (Clifford et al., 2003). In addition, HPV-16 has been detected in
extremely low copy numbers (compared to copy numbers in OSCC and dysplastic OPLs) in
some human “normal” oral mucosa (NOM), suggesting that a threshold viral DNA copy
number is required for the role of oncogenic HPVs in oral carcinogenesis. HPV-18 is far less
commonly associated with oral cancers, and has been found in up to just 14 percent of cases
(Kang and Park, 2001).
It is now established that the products of two early genomic regions of high-risk HPVs, E6
and E7, are capable of forming specific complexes with vital cell cycle regulators (Kang and
Park, 2001). For example, E6 binds to p53 to induce p53 degradation, while E7 interacts with
pRb resulting in blockage of the downstream activities of pRb (Kang and Park, 2001). Both
p53 and pRb are oncosuppressors, and the overall outcome of their functional dysregulation
is an uncontrolled DNA replication and impairment of apoptosis. The combined effects of
apoptotic impairment and uncontrolled DNA replication are increased tendency towards
cellular transformation and tumorigenesis.
8 Oral Cancer

3.4 Nutritional factors

The role of metabolic and dietary deficiencies in the etiology of OSCC was long suspected
before concrete evidence began to emerge. Peterson (1919) and Kelly (1919) independently
described the symptom complex of chronic dysphagia, mucosal atrophy of the
hypopharynx, and chronic anemia in middle-aged women who also had cricoid carcinomas.
The term sideropenic dysphagia was introduced, and used to describe the disease complex
now referred to as Paterson-Kelly (or Plummer-Vinson; P-V) syndrome. P-K syndrome is
marked by diminished iron stores and the absence of stainable bone marrow iron. Other
components of the syndrome include riboflavin and other vitamin deficiencies. Subsequent
studies by Ahlbom (1936) confirmed not only the importance of P-K syndrome in the
development of pharyngeal cancers, but also showed that this applied to the buccal mucosa,
tongue, and all levels of the esophagus.
There is a high incidence of oral cancer in parts of the world where iron deficiency is endemic
(Prime, MacDonald and Rennie, 1982). Iron metabolism is essential for the overall integrity
and health of epithelia of the digestive tract, and its importance may lie in its contribution to
normal enzymes. Rennie and MacDonald (1982), and Rennie, MacDonald and Dagg (1982)
demonstrated quantitative histologic changes in the oral epithelium in human iron deficiency
anemia and in experimental iron deficiency in hamsters. The authors noted that the oral
epithelium in iron deficiency is atrophic with reduced maturation compartment, but an
increased keratinized compartment (Rennie et al., 1982). Subsequent cell kinetic studies by
Rennie and MacDonald (1984) showed increased cell proliferation, indicating that, in spite of
the atrophy, epithelial turnover is rapid. This observation suggested a possible increase in
susceptibility to chemical carcinogens due to both an increase in the population of potentially
vulnerable dividing cells and to a more permeable epithelium.
Increased cancer risks also are attributable to dietary factors, notably low intake of fruits and
vegetables (Winn et al., 1984; Winn, 1995). Increased consumption of fruits and vegetables
were said to be protective against oral cancer when controlled for demographic
characteristics, tobacco and alcohol use, relative weight, and the intake of other food items
(Winn et al., 1984). The reduction of risk is seen to be consistent with the hypothesis that
Vitamin C and/or Vitamin A and ß-carotene intake is associated with a reduced risk of oral
and pharyngeal cancers (Ibrahim, Jafarey and Zuberi, 1977). Interestingly, intervention trial
studies with ß-carotene and Vitamin A in patients with oral precancer have been shown to
result in substantial regression of the lesions (Stich et al., 1988a, 1988b).
Degenerative changes occur in riboflavin deficiency, a frequent finding in alcoholics. This
may partly explain the relationship between alcoholism and oral cancer (Wynder and Klien,
1965). It also may be that alcohol increases the risk of oral cancer by lowering nutritional
status via a substitution of non-nutritive calories for vitamins, minerals, and other elements;
alternatively, that poor nutrition allows the deleterious effects of alcohol to be manifested.

3.5 Impaired immunity

Generally, patients with malignancies have some degree of immunosuppression that tends
to worsen with the progression of their malignancy. Immunosuppression appears to
predispose some individuals to an increased risk for oral cancer. Carcinomas of the lip have
been reported in a number of kidney transplant patients receiving immunosuppressive
Overview of Oral Cancer 9

medications, and oral carcinomas have been documented in young AIDS patients (van
Zuuren, de Visscher JGAM, Bouwes Bavinck JN, 1988; Flaitz et. al., 1995; de Visscher,
Bouwes Bavinck JN and van der Waal, 1997; Flaitz and Silverman, 1998). It is however still
debated as to whether immunosuppression in malignant disease represents an effect or a
cause of the malignancy. Some studies have suggested that immunosuppressive states may
represent the effect rather than the cause of cancer (Johnson, 1991), while others have
suggested that OSCC, despite its local manifestations, is most likely a “regional” disease
process that becomes “clinically significant” only when the patient’s immunologic status is
altered (Mashberg and Samit, 1989).
It would appear however that a factor such as advanced age, which diminishes immune
competence and immune cellular surveillance, increases the risks of oral cancer. Overt
immune suppression induced by chemicals or drugs, or caused by specific viral infections
such as the human immunodeficiency virus (HIV), or Epstein Barr virus (EBV), increases the
risk of oral cancers. Barr et al. (1989); Bradford et al. (1990) variously suggested that HPV
may play an etiologic role in squamous cell carcinoma in renal allograft recipients.

3.6 Oral Premalignant Lesions

Oral premalignant lesions (OPLs) are lesions, often presenting on the oral mucosa, which
possess a higher than normal propensity for transformation to OSCC with time if untreated.
The current model for oral carcinogenesis postulates a step-wise transformation from
normal to pre-malignant to invasive carcinoma phenotype. Histologically, the transition
process involves progression from benign epithelial hyperplasia to various degrees of
epithelial dysplasia (mild, moderate, severe) to carcinoma in situ, and finally to invasive
OSCC. With respect to transition to OSCC, oral leukoplakia, oral erythroplakia, and
speckled leukoplakia are the most notable and most studied OPLs (Figure 1.1). The
transition rate of oral leukoplakia to OSCC is estimated at between 4 and 18%, while that of
OLP is to be between 1 and 4%.
Although erythroplakia is not nearly as common as leukoplakia, it is much more likely to
show dysplasia or carcinoma histologically. In a study by Shafer and Waldron (1975) of
biopsies of erythroplakic lesions from 65 patients, all cases showed some degree of epithelial
dysplasia: 51 percent showed invasive squamous cell carcinoma; 40 percent were carcinoma
in situ or severe epithelial dysplasia; and the remaining 9 percent demonstrated mild-to-
moderate dysplasia (Shafer and Waldron, 1975). Thus, true clinical erythroplakia is a much
more worrisome lesion than leukoplakia (Mashberg and Samit, 1995). Likewise, in a mixed
leukoplakia-erythroplakia (erythroleukoplakia), the erythroplakic (red component) is more
likely to demonstrate dysplastic changes than is the white component, making it imperative
that that biopsy sites be selected to ensure that the specimen incorporates the red
component. In addition, a number of studies have suggested that oral lichen planus (OLP),
especially the erosive form, may be associated with an increased cancer risk, although other
investigators have questioned the strength of this association (Silverman et al., 1991; Barnard
et al., 1993; Eisenberg, 2000).

4. Site distribution in oral cancer

Symptomatic lesions present with symptoms and signs such as intraoral pain and/or
dysfunction, extraoral swelling, and cervical lymphadenopathy. These signs and symptoms
10 Oral Cancer

alert the clinician to the need to evaluate the oral cavity for obvious primary lesions. Site
distribution in OSCC is usually described in relation to the symptomatic lesions, which are
often amenable to classification under the “T” category of the TNM classification of
malignant tumors (Neville and Day, 2002). The TNM classification allows for the clinical
staging of oral malignant tumors on the basis of the size of the primary tumor, T, the
absence or presence of corresponding regional node spread, and the absence or presence of
distant site/organ metastases (Neville and Day, 2002). In OSCC, T1 lesions are 2cm or less in
greatest dimension; T2 lesions are more than 2cm but not more than 4cm in greatest
dimension; T3 lesions are more than 4cm in greatest dimension, and T4 lesions are those that
have invaded adjacent contiguous structures such as the cortical bone, inferior alveolar
nerve, deep extrinsic muscles of the tongue, maxillary sinus, or salivary glands regardless of
their apparent visual dimension (Neville and Day, 2002).
Early asymptomatic lesions are relatively small (T1) and, not infrequently, elude clinical
diagnosis by conventional systems (Mashberg and Meyers, 1976; Neville and Day, 2002).
These early asymptomatic lesions, often presenting as erythroplastic lesions, were studied
by Mashberg and Meyers (1976) who consequently provided guidance toward enhanced
accurate designation of sites of origin of these early asymptomatic lesions (Mashberg and
Meyers, 1976). In this respect, the authors further concluded thus: “The described locations
in the literature may be points of termination or extension of the lesion rather than sites of
origin, e.g., a symptomatic lesion (T2 or T3) in the floor of mouth may have extended to and
invaded the alveolus; hence, based on clinical and x-ray evidence, it may have been reported
as a gingival or alveolar lesion” (Mashberg and Meyers (1976).
There are geographic variations in the frequency of sites of involvement, probably related
to such risk factors as occupation and lifestyle, oral habits, and certain socio-cultural
practices, such as the mode of tobacco use (Paymaster, 1962; Brown et al., 1965). For
example, presentation of intraoral cancers among the population of the high risk areas of
Southeast Asia and the Southeast United States is slightly different. Consistent with the
role of the risk factors alluded to above the most prone sites in the high risk areas of
Southeast Asia are the buccal, retromloar, and commissural mucosa (Paymaster, 1962;
Brown et al., 1965).

4.1 The lip

The World Health Organization (WHO) revision of the International Classification of
Diseases (ICD) defines cancer of the lips as malignant lesions of the vermilion area of the
upper and lower lips (Daftary et al., 1992). Cancers in these areas are not considered
intraoral cancers (Daftary et al., 1992). Over 90% of lip cancers involve the lower lip
(Neville and Day, 2002). Lip lesions are easily detectable partly because the lip is the most
visible structure of the oral cavity complex. Lip squamous cell carcinomas usually arise in
actinic cheilosis, a premalignant condition, which is a “cousin” to actinic keratosis of the
skin. Actinic cheilosis is characterized by atrophy of the vermilion border, clinically
visible as dry, scaly changes. Ulcerated foci alternating with partial healing may appear as
the lesion progresses. Not infrequently, patients mistake these recurring ulcerated lesions
for "fever blisters." Subsequently, the evolving cancer slowly becomes a crusted, non-
tender, indurated ulcer or mass (Neville et al., 2009; Silverman, Dillon and Fischbein,
1998).
Overview of Oral Cancer 11

In Romania, Hungary, Yugoslavia, and parts of Canada and the United States, the vermilion
area of the lips are the commonest sites of oral cancer (Johnson, 1991; 2001), and it has been
reported that about half of all cases of oral cancer in the Nordic countries occur on the lips
(Ringertz, 1971). The lateral aspect of the lower lip is more frequently involved than the
mid-portion (Daftary et al., 1992). Race and ethnic variations in the incidence of lip cancer
occur worldwide. Among most white population, the lip constitutes the most common site
for oral cancer (Spitzer et al., 1975; Johnson, 1991; 2001). Considerable agreement over the
association between lip cancer and occupation exists; the disease being common amongst
white males who engage in outdoor occupations, such as farming and fishing, which expose
them excessive sunlight (Spitzer et al., 1975; Johnson, 1991; 2001). On the other hand, lip
cancer is relatively rare in black males, and females of both white and black races (Bernia,
1948; Spitzer et al., 1975; Johnson, 1991; 2001).
In a 1984 study reported by Douglass and Gammon there was variation in the incidence of
lip cancer between the male non-Maori (1.7/ 100,000) and the Maori (0.2/100,000)
population of New Zealand (Douglass and Gammon, 1984). The authors similarly
highlighted ethnic differences in the incidence of lip cancer in Israel where males born in
Israel had a higher rate of lip cancer (3.5/100,000) than male immigrants from
Europe/America (2.9/100,000), or Africa/Asia (0.8/100,000).

4.2 The tongue and floor of mouth

The tongue is the most common site for intraoral carcinoma and accounts for about 40
percent of all cases in the oral cavity proper, with tumors occurring on the posterior lateral
border and ventral surfaces of the tongue (Neville and Day, 2002). The incidence of floor-of-
mouth squamous cell carcinoma closely approximates that of the tongue (Neville and Day,
2002). In the black population however the floor of mouth distinctly is the most common site
for OSCC (Batsakis, 1979). Thus, anatomically, the lateral tongue and floor of mouth
(extending to the lateral soft palate and tonsillar area) combine to form a horseshoe-shaped
region of the oral mucosa, which is at greatest risk for cancer development (Neville and Day,
2002). Two major factors may explain the high-risk status of this composite region: first,
carcinogens in saliva pool at the floor of the mouth with the tongue providing a lid; second,
this complex is covered by a thinner, non-keratinized mucosa, thus providing limited barrier
to carcinogen ingress (Jovanovic et al., 1993).

4.3 Buccal mucosa

The mucosal surface of the cheek extends from upper to lower vestibular sulci, where the
mucosa reflects itself to cover the upper and lower alveolar ridges. The buccal mucosa also
forms the commissure of the lip and covers the ramus of the mandible. A number of buccal
squamous cell carcinomas originate in the commisural areas before spreading posteriorly to
involve the mucosa along the occlusal plane of the teeth, or at the retromolar area (Batsakis,
1979). It has been suggested that, because commissural cancers have better prognoses than
buccal mucosa cancers, the former ought to be separated from the latter for purposes of site
designation (Daftary et al., 1992). However, this suggestion appears not to have gained wide
acceptance. Buccal cancers usually arise on the mucosa lying against the wisdom teeth, and
correspond to the common site of placement of tobacco-containing quid. The lesion then
grows to obscures the site of origin (Singh and von Essen, 1966; Batsakis, 1979; Daftary et al.,
12 Oral Cancer

1992). Results of some studies indicate a consistent increase in the incidence of buccal
cancers in relation to smokeless tobacco use (Brown et al., 1965; Winn et al., 1981). These
findings underscore the importance of local etiologic factors in the site distribution of
intraoral cancers.

4.4 The gingiva and alveolar ridge

Cancer of the gingivae and alveolar ridge are usually grouped together. Squamous cell
carcinomas of the gingival and alveolar ridge generally are less common than those of the
lip, tongue, and floor of mouth (McCarthy and Shklar, 1964). Similar to buccal and
commissural cancers, Daftary et al., (1992) suggested that lesions of the gingivae and
alveolar ridge be separated because of differences in prognosis. The incidence of carcinoma
of the gingivae and alveolar ridge among the rural women of the Southeast United States is
relatively high (Rosenfield and Callaway, 1963). The reported incidence of cancer of the
gingival and alveolar ridge in three Indian populations ranged from 0.6/100,000 to
1.4/100,000 per annum among women (Daftary et al., 1992). Carcinoma of the gingivae
generally arises in the premolar and molar regions and more frequently, on the lower than
on the upper arch (Cady and Catlin, 1969). These correspond to the sites of retention of
tobacco quid in those who practice the habit.

4.5 The palate

Squamous cell carcinomas of the palate are in the Western countries and the United States
(Daftary et al., (1992). Again, incidence significantly reflects different habits. In India, for
example where the habit of “reverse smoking” is prevalent among the population, the
relative frequency of squamous cell carcinoma of the palate is high (Gupta et al., 1980;
Daftary et al., 1992). The habit of reverse smoking is exemplified by the practice of placing
the glowing end of a local form of cigar called “chuttas” inside the mouth. In areas where
reverse smoking is practiced palatal cancer comprise 38 to 48 percent of all oral cancers
(Gupta et al., 1980; Daftary et al., (1992). Lesions of the hard palate may arise in the midline
or to one side close to the palatal gingivae (Batsakis, 1979).
Primary squamous cell carcinomas arising in the soft palate are uncommon, accounting for 2
percent of overall oral cancer in reverse-smoking areas (Ramulu et al., 1973), but only 0.4
percent in non-reverse smoking areas (Wahi et al., 1965). However, reports of later studies
by Mashberg and Meyers (1976) indicated a greater frequency of lesions primarily arising
from the soft palate than is ordinarily documented with the “late” symptomatic lesions. On
analyzing the site distribution of 222 cases of early asymptomatic OSCCs, the authors found
that 64 of these (28.8 percent) occurred in the “soft palate complex” comprising the soft
palate, anterior pillar of fauces, and retromolar trigone. Thus, some of the lesions designated
hard palate lesions at the time of diagnosis may have earlier arisen from the soft palate
before spreading to the hard palate at a late symptomatic stage.

5. Diagnosis and management of oral cancer

Early diagnosis of oral cancer has emerged as a priority public health objective whereby oral
health professional play leading role (Neville and Day, 2002). It is presumed that early
diagnosis of cancer should lead to less damage from interventional treatment and to a better
Overview of Oral Cancer 13

prognosis. Because most individual are seen more commonly by primary care physicians and
general dentists than by specialists, it is imperative for these clinicians to perform screening
examinations to identify potential oral and pharyngeal cancers. In addition to the need for
improved early detection by clinicians, it is also important that the patient and general public
are knowledgeable about the disease (Yellowitz and Goodman, 1995; CDC, 1998). Delays in
identification and recognition of suspicious lesions contribute to advanced stage at diagnosis
and lower survival statistics (Shafer, 1975; Hollows, McAndrew and Perini, 2000).

5.1 Diagnosis of oral cancer

A distinction has been made in the early detection of oral cancers between “screening” (test
aimed at evaluating presence of the disease in asymptomatic individuals) and “detection of
cases” (applying specific procedure to patients with a suspicious lesion; Lestón and Dios,
2010). Nevertheless, conventional visual examination accompanied by palpation of
suspicious lesions remains the gold standard screening methodology for oral precancer and
cancer, while biopsy and histopathologic examination remains the universal diagnostic
confirmatory test of choice (Lestón and Dios, 2010). Thus, in spite of the availability of
several techniques that have been advocated as aids to oral cancer diagnosis (summarized in
Table; adapted from Lestón and Dios, 2010) suspected malignant lesions must be biopsied in
order to establish a definitive diagnosis.

Toluidine blue
Light-based detection systems
Chemiluminescence (ViziLite Plus®; Microlux/DL®)
Tissue fluorescence imaging (VELscope®)
Tissue fluorescence spectroscopy
Cytology or brush biopsy (OralCDx®)
Specific analysis (, SCCAA, IAP, CYFRA, , and others)
Specific analysis (, , , CYFRA 21-1, TPS, IL-1B, DUSP 1, HA3, , , SAT, miRNA, and others)
Imaging (DPT, CT, CBCT, MRI)
Table 1. Some techniques advocated for the clinical diagnosis of OSCC supplementing
conventional oral examination, and histopathologic examination of suspicious lesions
(adapted from Lestón and Dios, 2010).
In turn, the accurate diagnosis of potentially malignant and malignant oral lesions depends
on the quality of the biopsy, selection of appropriate technique (e.g. incisional versus
excisional), the applicability of the adequate clinical information, and competent
interpretation of the biopsy results. Oral biopsy specimens can be affected by a number of
artifacts resulting from crushing, fulguration, injection, or incorrect fixation and freezing
(Trullenque-Eriksson et al., 2009). Results of cytologic examination of specimens obtained
from non-invasive procedures such as brush biopsies or comparable techniques must not
constitute the sole basis for a diagnosis of malignancy (or the absence) leading to definitive
treatments. This is because these non-invasive techniques often are fraught with several
pitfalls accounting for high rates of false-negative and false-positive results.
14 Oral Cancer

5.2 Management of oral cancer patients

While an exhaustive discussion on the management of oral cancer and precancerous lesions
is not intended in this review, it is generally recommended that leukoplakias exhibiting
degrees of epithelial dysplasia equal to, or worse than, moderate epithelial dysplasia be
removed completely when possible (Epstein et al., 2007). On the other hand, the
management guideline for mild dysplastic lesions is far less standardized with varied
schools of thought ranging from those advocating a “wait-and-see” approach to those
advocating total removal of all dysplastic lesions regardless of the degree of epithelial
dysplasia. In addition, management decisions for mild epithelial dysplasia appear to be
influenced by the size, location, and apparent etiologic factor accounting for the lesion.
Some early dysplastic lesions where an etiologic agent (e.g. smoking) is identified have been
known to regress and may reverse to normal on elimination of the etiologic factor
responsible.
Patients with invasive oral cancer are best managed by a coordinated, multidisciplinary
team of health care professionals, which may include a head and neck surgeon, oral and
maxillofacial pathologist, general pathologist, radiation oncologist, neuroradiologist,
reconstructive surgeon, medical oncologist, general dentist, oral and maxillofacial surgeon,
maxillofacial prosthodontist, dental hygienist, nurse specialist, speech pathologist,
nutritionist, and tobacco cessation counselor (Ord and Blanchaert, 2001).
Up to 15 percent of individuals with oral cancer harbor a second primary, making a
complete head and neck examination that includes the larynx imperative (Lippman and
Hong, 1989). Endoscopy of the larynx, esophagus, trachea, and lungs to rule out the
possibility of other lesions in the high-risk patient is now performed routinely. For patients
who present with a neck mass but no obvious primary site (or if the neck mass is more
amenable to biopsy than the primary tumor), a fine needle aspiration remains the diagnostic
method of choice rather than an open biopsy, because open biopsy has been reported to be
related to a lower survival rate when not accompanied by a simultaneous neck dissection
(Lefebvre et al., 1990; Kleid and Millar, 1993).
Also, imaging studies are now routines during the evaluation of primary oral tumors and
neck disease. Both contrast-enhanced computed tomographic (CT) scans and magnetic
resonance imaging (MRI) may be utilized in determining the extent of the primary tumor,
invasion, regional node status, and distant metastasis, thereby providing important staging
information (Som, Curtin and Mancuso, 1999, Robbins, 1999). Positron emission tomography
(PET) scans are also becoming an increasingly popular tool for the identification of primary,
recurrent, and metastatic diseases.
The treatment options for primary OSCCs are variable and depend on the size and location
of the tumor, lymph node status, presence or absence of distant metastases, the patient’s
ability to tolerate treatment, and the patient’s desires. Surgery and/or radiation therapy
remain the gold standards for treatment of cancers of the lip and oral cavity. Oropharyngeal
cancer may be treated with surgery and/or radiation therapy for early-stage disease. For
advanced-stage disease, surgery with adjuvant radiation therapy may be indicated,
although recent evidence suggests that the addition of chemotherapy to radiation therapy
may provide a survival advantage over radiation therapy alone in this population
(Forastiere, 1998; Calais et al., 1999). It is important to take into account disease status and
Overview of Oral Cancer 15

prevalence of occult disease in the neck when evaluating primary cancers of the lip, oral
cavity, and oropharynx (Robbins et al., 2001). Regardless of the treatment modality used,
many patients will require consideration of problems related to airway protection, enteral
feedings, xerostomia, mucositis, dysphagia, and voice change.

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