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. In 2012, 300,400 new cases of OSCC were diagnosed worldwide, with 12,170 deaths occurring annually (World Health Organization 2014). The highest incident rates of oral cavity cancer 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. Majority (90%) of the cases reported of oral cancer is attributed to tobacco consumption in various forms in these regions (Johnson et al., 2011) Besides smoking, alcohol consumption, smokeless tobacco use, and HPV infections are also the major risk factors for oral cavity cancer, with smoking and alcohol drinking having synergistic effects (Blot et al., 1988). Worldwide, 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) Recently, 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). However, a low 5-year survival rate of 50% is

globally seen among patients with oral cancer (Greenlee et al., 2001). Despite oral cavity being accessible for examination, individuals report to a clinician only in later stages of malignancy, thus no improvement in survival rate for oral cancer over the decades have been observed (Neville et al., 2002). The mortality rate increase in females in most European countries and in several Eastern European countries, including Hungary and Slovakia (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). A change in trend for incidence rates of 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 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

100,000 people in males. And since 2006, oral cavity squamous cell carcinoma (OSCC) had become and kept the 6th most common cancer in Taiwan and the 4th most common cancer 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 younger 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 reported in lower age at diagnosis of head and neck cancer over time. 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. 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 (Ko et al., 1995; Liao et al., 2007; Liao et al., 2008). About 50% or more of OSCC patients were found to have their tumours ranked as stage III or stage IV during their first visit to the medical center in Taiwan, leading to a low overall 5-year survival rate, despite recent advances in surgery, radiotherapy and chemotherapy (Lo et al., 2003). However, 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). Approximately, 95% of oral cancer is oral squamous cell carcinoma. OSCC is associated with chronic irritant factors such as tobacco, smoking, alcohol and betel quid (BQ) use. While cigarette smoking and alcohol drinking are the major risk factors in Western countries, Areca quid chewing independently contributes to the risk of head and neck cancer, and the estimated prevalence of areca quid chewing in Taiwanese patients (Boyle et al., 1990; Ko et al., 1995). Almost 2.5 million people are BQ users in Taiwan.

A higher rate of incidence of OSCC and its mortality were found to be associated with the increasing prevalence rate of betel chewing in this area. In south Taiwan, betel chewing has been generally accepted as a social custom or behavior. 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 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 (Ko et al., 1995; Chen et al., 1999; Liao et al., 2008).

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), Herpes simplex virus, etc.), nutrition deficiency (Plummer-Vinson Syndrome, Vitamin A deficiency, Vitamin C deficiency, etc.), family hereditary, immunodeficiency, gene mutation, environment factor, such as UV exposure (Pukkala et al., 1997) and so on.

Recent 2003 IARC monograph declared areca quid chewing or even areca nut alone, to be a Group 1 carcinogen. The 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 betel leaf, areca nut and slaked lime, and Piper betel inflorescence. Other substances, particularly spices, including tobacco, cardamom, saffron, cloves, aniseed, turmeric, mustard or sweeteners, are added according to local preferences (Yang et al., 2001; Yang et al., 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 (Shirname et al., 1983; Jeng et al., 2001). 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-induced DNA damage generated by chewing areca quid may be derived from tobacco, and reactive oxygen species may be involved in generating this DNA damage (Wu et al., 2005). Approximately 50% of patients who were betel quid chewers are also alcohol drinkers and tobacco smokers. (Kuo et al., 1994; Liu et al., 1996). 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 conditions and lesions

Many OSCCs develop from premalignant conditions of the oral cavity (Silverman 1968; 1984). The World Health Organization classifies oral precancerous/potentially malignant disorders into 2 general groups.A precancerous 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. 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.

The Taiwanese national cancer screening program began in 1985 by providing oral mucosa screening programs in oral cancer high-risk groups. At the same time, patients’ self-awareness regarding the prevention of OSCC that had been intensively propagated through the mass media in the recent years (Lo et al., 2003; Chen et al., 2012) . The results strongly suggest the importance and effective outcomes from early diagnosis and treatment of premalignant lesions (Shiau et al., 1979; Speight et al., 1992; Scully 1995; van der Waal et al., 1997) and OSCC.

Intervention should be based on histopathological features of a biopsy of the lesions. At present, 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 listed as follows:

Mild dysplasia (grade I) shows proliferation or hyperplasia of cells of the basal

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.

In moderate dysplasia (grade II) there is 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.

Severe dysplasia (grade III) demonstrates 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

Carcinoma in situ is the worse 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.

These premalignant changes and lesions of the head and neck carry a high risk to progress towards malignant transformation. Severe epithelial dysplasia has an overall malignant transformation rate of about 16% but studies show a wide range of 7% – 50%(Mincer et al., 1972; JBanoczy et al., 1976; Silverman et al., 1984; Vedtofte et al., 1987; Bouquot et al., 1988; Lumerman et al., 1995; Pindborg et al., 1997; Schepman et al., 1998; 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%).

Therefore, all oral premalignant changes and lesions should be submitted to microscopic analysis before any definite treatment. Long-term follow-up of patients with premalignant oral lesions is highly recommended (Chang et al., 2002; Lin et al., 2002).

1.1.5 Clinicopathological classification and treatment modalities of oral squamous cell carcinoma

Currently, TNM staging and pathological grade are the most prevalent and traditional prognostic indicators and basis of individualized treatment. The ‘TNM’

classification of the International Union Against cancer (UICC) relates well to the prognosis and overall survival, earlier the tumor stage, better the prognosis and less complicated is the treatment (Schroeff et al., 2009). Logistic regression analysis revealed

is a growing concern that TNM staging is insufficient to accurately map or classify OSCC, whose biological impact may be related to volume and pathological aggressiveness of disease (Kademani et al., 2005). The WHO grading system (Pindborg et al., 1997) recommends histologic features of OSCC are classified into 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 (Kademani et al., 2005). 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 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 initially considered palliative in the 1950’s, 60’s and 70’s. Nowadays, chemotherapy is also used as a component of multimodality treatment in the neoadjuvant setting, clinical trials of induction chemotherapy with Cis-platinum demonstrated that response to chemotherapy is observed in a significant number of patients (Kademani et al., 2005). In addition, intra-arterial chemotherapy, particularly superselective IA infusion of high-dose cisplatin with systemic neutralization by intravenous sodium thiosulfate(RADPLAT), is a theoretically attractive approach to the treatment of advanced head and neck cancer. intra-arterial infusion of high-dose (Akihiro et al., 2016).

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).