I. Introduction and literature review
1.1 Overview of oral squamous cell carcinoma …
1.1 Overview of oral squamous cell carcinoma
1.1.1 Epidemiology of global oral cancers
Oral cancer is the sixth most common cancer worldwide, with a high prevalence in South Asia.
An estimated 263,900 new cases and 128,000 deaths from oral cavity cancer (including lip cancer)
were reported in 2008 worldwide. Generally, the highest oral cavity cancer rates are found in
Melanesia, South-Central Asia, and Central and Eastern Europe and the lowest in Africa, Central
America, and Eastern Asia for both males and females. Smoking, alcohol consumption, smokeless
tobacco use, and HPV infections are the major risk factors for oral cavity cancer, with smoking and
alcohol drinking having synergistic effects (Blot et al., 1988; Hashibe et al., 2009). Worldwide,
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smoking accounts for 42% of deaths from cancers of the oral cavity (including the pharynx) and
heavy alcohol consumption for 16% of the deaths; the corresponding percentages in high-income
countries are about 70% and 30%, respectively (Danaei et al., 2005). The rise in the incidence rate
of oral cancer in Taiwan may have been in part due to the increased consumption of areca quid and
alcohol (Ho et al., 2002). Oral cavity cancer mortality rates among males decreased significantly in
most countries, including those of Europe and Asia, over the past decades (Garavello et al., 2010;
Mayne et al., 2006). However, rates continued to increase in several Eastern European countries,
including Hungary and Slovakia (Garavello et al., 2010). The mortality rate increase in females in
most European countries largely reflects the ongoing tobacco epidemic (Garavello et al., 2010).
This contrasts with the decreasing trends at all ages in both males and females in the United States
and United Kingdom, where the tobacco epidemic began and declined earlier (Garavello et al.,
2010). However, incidence rates for oral cancer sites related to HPV infections, such as the
oropharynx, tonsil, and base of the tongue, are increasing in young adults in the United States and in
some countries in Europe, which is hypothesized to be in part due to changes in oral sexual
behavior (D’Souza et al., 2009; Marur et al., 2010).
1.1.2 Epidemiology of oral cancers in Taiwan
With rapid aging of populations, cancer has become the first leading cause of death in Taiwan
since 1982 (Chen et al., 2002). In 1982, the incidence rate of head and neck cancer was 5.12 per
100,000 people in males and 1.54 per 100,000 people in females. In 1991, the incidence rate of head
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and neck cancer had not much changed, with the incidence rate being 6.02 and 1.51 per 100,000
people in males and females, respectively. However, in 2003, the incidence rate of head and neck
cancer significantly increased to 35.08 and 3.56 per 100,000 people in males and females, an
alarming 5.82-fold increase in men and 2.35-fold increase in woman in a decade was found (Chen
et al., 2008). In 2008, the incidence rate of head and neck cancer significantly increased to 37.57
per 100,000 people in males. In 2010, oral cavity cancer had become the 5th most common cancer
causing mortality in Taiwanese men. Similarly, the mortality rate also increased significantly, from
4.25 per 100,000 in 1995 to 9.6 per 100,000 in 2006, a 2.26-fold increase in the past decade. There
has been a trend toward lower age at diagnosis of head and neck cancer over time. From 1989 to
1993, the peak of incidence rate was for people aged 50–59 years, but this shifted to ages 40–49
years between 1993 and 2000. A similar trend was also found in the mortality rate. During the
period between 1991 and 1994, mortality rate peaked at age 50–59 years, but shifted to age 40–49
years between 1999 and 2002. These data are consistent with other regional reports from northern
and southern Taiwan. In 2006, the median age at death from head and neck cancer was 54 years
compared with 69 years in other forms of cancer. Gender differences in head and neck cancer have
been described, with a marked male predominance. A study analyzing 703 OSCC patients between
1985 and 1996 in southern Taiwan found a 51:1 male-to-female ratio (Chen et al., 1999). The
overall 5-year survival rate in patients with head and neck cancer is one of the lowest among
common malignant neoplasms and has not significantly changed during the last two decades.
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Cancer clinical stage is the major determinant of survival rate. The 5-year survival rates of oral
cavity cancer patients in stages I, II, III and IV are 72–90%, 39–85%, 27–70% and 12–50%,
respectively (Liao et al., 2008; Liao et al., 2007; Ko et al., 1995). Survival rates for head and neck
cancer are significantly influenced by tumor size, lymph node involvement, distant metastasis,
tumor differentiation and areca quid chewing (Liao et al., 2004; 2008). Areca quid chewing
independently contributes to the risk of head and neck cancer, and the estimated prevalence of areca
quid chewing in Taiwanese patients with head and neck cancer is approximately 85% (Liao et al.,
2004; 2007; 2008). Approximately 50% of patients who were areca quid chewers are also alcohol
drinkers and tobacco smokers (Liao et al., 2004; 2007; 2008). A cumulative effect from areca quid
chewing, alcohol drinking and tobacco smoking has been observed, with a 123-fold increased risk
of oral cancer when the three risk factors are present (Ko YC et al., 1995). With regard to the
anatomical location of oral cavity cancers, approximately 30–40% of all cases occur in the tongue
or in the buccal mucosa. Altogether, lesions at these sites account for approximately 70% of all oral
cavity malignancies ( Liao et al., 2008; Chen et al.,1999; Ko et al.,1995).
1.1.3 Risk factors related to oral cancers
Oral cancer was known to be associated with cigarette smoking, excessive alcohol consumption, areca quid chewing, viral or fungal infection (candida, human papilloma virus (HPV), Herpex simplex virus, etc.), nutrition deficiency (Plummer-Vinson Syndrome, Vitamin A deficiency, Vitamin C deficiency, etc.), family hereditary, immunodeficiency, gene mutation, and so on. Recent 2003 IARC monograph declared areca quid chewing, by itself, to be a Group 1 carcinogen. The
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Taiwanese chewers commonly use fresh, unripe betel fruit with slaked lime as an essential ingredient. The composition of areca quid differs geographically; the areca quid used in Taiwan contains areca nut, lime and Piper betel inflorescence (Yang et al., 2001; 2005). Piper betel inflorescence contains high concentrations of hydroxychavicol and safrole, whereas arecoline, a major areca nut alkaloid, is considered to be the most important carcinogen in the areca nut.
Arecoline has been shown to induce structural chromosomal aberration, sister chromatid exchange and micronuclei formation in different cell types (Jeng et al., 2001; Shirname et al., 1983). Studies in human oral cancer cells have shown that exposure to arecoline or areca nut extract (ANE) results in growth arrest in the late S and G2/M phases (Lee et al., 2006). Piper betel inflorescence, which contains safrole, is a unique ingredient of areca quid in Taiwan. Safrole–DNA adducts have been suggested to play an important role in oral carcinogenesis (Chen et al., 1999). A further report has provided evidence that alkaline saliva generated by chewing areca quid may play a role in cigarette-related nicotine-induced DNA damage, and reactive oxygen species may be involved in generating this DNA damage (Wu et al., 2005). These findings provide a molecular explanation for the synergistic effect of areca quid chewing and tobacco smoking in the development of head and neck cancer in Taiwan.
1.1.4 Precancerous lesions and conditions
Many OSCCs develop from premalignant conditions of the oral cavity (Silverman et al., 1984;
1968). The World Health Organization classifies oral precancerous/potentially malignant disorders
into 2 general groups.A precancerous lesion is “a morphologically altered tissue in which oral cancer is more likely to occur than its apparently normal counterpart.” These precancerous lesions
include leukoplakia, erythroplakia, and the palatal lesions of reverse smokers. A precancerous
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condition is “a generalized state associated with significantly increased risk of cancer.” The
precancerous conditions include submucous fibrosis, lichen planus, epidermolysis bullosa, and
discoid lupus erythematosus. Intervention should be based on histopathological features of a biopsy
of the lesions. In many cases, a biopsy is mandatory so that such lesions can be further evaluated.
Currently, histological criteria (presence and degree of dysplasia) represent the gold standard in
precancerous lesion risk evaluation (Blot et al., 1988). The latest WHO classification (Barnes et al.,
2005) recommends a more objective gradings. The criteria for grading of oral epithelial dysplasia
are summarized as follows:
Mild dysplasia (grade I) demonstrates proliferation or hyperplasia of cells of the basal and
parabasal layers which does not extend beyond the lower third of the epithelium. Cytological atypia
is generally slight with only mild pleomorphism of cells or nuclei. Mitoses are not prominent, and
when present are usually basally located and normal. Architectural changes are minimal.
Moderate dysplasia (grade II) demonstrates a proliferation of atypical cells extending into the
middle one-third of the epithelium. The cytological changes are more severe than in mild dysplasia
and changes such as hyperchromatism, and prominent cell and nuclear pleomorphism may be seen.
Increased and abnormal mitoses may be present, but these are usually located in the basal layers.
Architectural changes may be seen in the lower half of the epithelium where there may be loss of
basal polarity and hyperplasia leading to bulbous rete pegs. However stratification and maturation
are relatively normal, often with hyperkeratosis.
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Severe dysplasia (grade III) shows abnormal cell proliferation from the basal layer into the
upper third of the epithelium. Cytological and architectural changes can be very prominent. All the
changes seen in mild and moderate dysplasia are seen but in addition there is marked pleomorphism
often with abnormally large nuclei with prominent or even multiple nucleoli. Prominent and
suprabasal mitoses are usually evident and abnormal tripolar or star-shaped forms may be seen.
Apoptotic bodies may also be prominent. Architectural changes are severe, often with complete loss
of stratification and with deep abnormal keratinization and even formation of keratin pearls.
Abnormal forms of rete pegs are usual and bulbous rete pegs are regarded as particularly significant
in the diagnosis of severe dysplasia. Abnormal shaped rete pegs may also be seen, with lateral
extensions or small branches. These are quite abnormal and may be the earliest signs of invasion.
Occasional lesions may show prominent acantholysis with severe disruption of the architecture.
Although the epithelium may be thickened, severe dysplasia is sometimes accompanied by marked
epithelial atrophy.
Carcinoma in situ is the most severe form of epithelial dysplasia and is characterized by full
thickness cytological and architectural changes. In the oral cavity, such changes are rare, and often,
even in the presence of the most severe atypia, there is still an intact keratinized surface layer.
Carcinoma in situ is thought by some to be a premalignancy but others regard it as evidence of
actual malignant change but without invasion. Severe epithelial dysplasia has an overall malignant
transformation rate of about 16% but studies show a wide range of 7% – 50% (Silverman et al.,
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1984; Schepman et al., 1998; Gupta et al., 1990; Bouquot et al., 1988; JBanoczy et al., 1976;
Amagasa et al., 1985; Vedtofte et al., 1987; Mincer et al., 1972; Pindborg et al., 1977; Lumerman et
al., 1995; Jaber et al., 2003). Moderate dysplasia has a malignant transformation potential of 3% –
15%, whereas mild epithelial dysplasia shows a very low risk (less than 5%). It is always assumed,
however, that there is a temporal progression of disease, analogous to multistage carcinogenesis,
and that mild dysplasia will progress to severe dysplasia and then to carcinoma.
1.1.5 Clinicopathological classification and treatment modalities of oral squamous cell
carcinoma
The WHO grading system (Pindborg et al., 1997) recommends 3 categories: well-differentiated,
moderately-differentiated and poorly-differentiated. This usually depends on the subjective
assessment of the degree of keratinization, cellular and nuclear pleomorphism, and mitotic activity
(Woolgar, 2006). The influence of histologic grading as a prognostic factor in OSCC was assessed
in 215 patients and was found to be a significant predictor of locoregional failure and tumour
recurrence (Kademani et al., 2005).
Surgery is the most well-established mode of initial definitive treatment for a majority of oral
cancers, with a longstanding history of being the accepted method of treatment for oral cancers over
a century. Introduction of ionizing radiation, following the discovery of radium, became an
important means of non-surgical treatment of oral carcinoma. However, in the majority of patients
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with advanced cancer, radiotherapy is employed in conjunction with surgery, most often offered as
post-operative treatment. Chemotherapy in the management of oral carcinoma was considered palliative in the 1950’s, 60’s and 70’s. However with the introduction of Cis-platinum, clinical trials
of induction chemotherapy demonstrated that response to chemotherapy is observed in a significant
number of patients (Shah et al., 2009). For patients with advanced-staged disease, the current
preference for the sequence of combined modality treatment program is surgical resection with
immediate appropriate reconstruction followed by post-operative radiation therapy or post-operative
concurrent chemoradiotherapy. The observations from two prospective randomized trials of
adjuvant chemoradiotherapy have shown that patients who have extracapsular extension of disease
in metastatic cervical lymph nodes and those who have positive margins have a significant
improvement in local regional control and disease free survival by addition of chemotherapy to
postoperative radiation therapy compared to post-operative radiation therapy alone (Bernier et al.,
2005). Targeted therapies with epidermal growth factor receptor (EGFR) inhibitors are an active
area of investigation at this time. Immunotherapy and gene therapy are also areas of research where
further work needs to be done (Shah et al., 2009).