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Squamous cell carcinoma  

Oral cancer is more common after the age of 50 years, and incidence increases with age. Most studies suggest that 4–6% of oral cancers occur in patients under 40 years . Observed trends in oral cancer incidence and mortality essentially reflect the underlying changes in the prevalent risk factors such as tobacco and alcohol use. Data from population-based cancer registries indicate that the incidence of oral cancer is decreasing in most regions except in some countries like Scotland (UK), Finland and Eastern European countries such as Poland, the Czech Republic, Slovenia and Hungary (figure 1). An increase in the incidence of oral cancer among young subjects has been reported recently . However, trends from various population-based cancer registries indicate that the incidence of oral cancer is on the decrease among young subjects (less than 45 years of age) (figure 2). The age-standardized incidence rates of oral cancer (ICD C02-06) in selected populations in various continents is shown in (figure 3).

Most oral cancer cases, and more particularly those in developing countries, present in advanced clinical stages, often with regional lymph node involvement. Consequently, despite advances in disease management, overall 5-year survival rates have not improved significantly. The time trends in oral cancer mortality closely reflects the trends in oral cancer incidence. In most Eastern European countries including Russia, an increasing trend in oral cancer mortality has been observed. On the other hand, the other European countries, the United States, Canada and Japan, oral cancer mortality rates are stable. In France, mortality rates increased up to the early 1980s, after which a steady decline has been observed.

Several lifestyle factors play a role in oral carcinogenesis.

Etiology:

Tobacco and alcohol are the most important risk factors and account for 75–90% of oral cancers .
The other risk factors associated with oral carcinogenesis include poor oral hygiene, chronic irritation from ill-fitting dentures or sharp teeth, viral infections, nutritional deficiencies, ultraviolet light, immunosuppression, prior exposure to radiation and genetic susceptibility.

a. Tobacco
Tobacco use in any form (chewing or smoking) is the most important risk factor for oral cancer . Both these forms of tobacco use have a dose-response relationship for daily frequency and overall duration of use in years. Age at initiation shows a strong inverse relationship to the risk of developing oral cancer, and the risk is higher for those who initiate the habit at a young age . Smoking in any form including cigar, pipe and bidi (tobacco rolled in temburni leaves) smoking, which is more common in India and other South Asian countries, is associated with an increased risk for oral cancer . The relative risk estimates for smoking reported in various studies vary from 1.2–29.4 . The risk declines rather rapidly following cessation of smoking, with relative risks compared with those in non-smokers decreasing to near unity after 10 or more years .
Chewing betel quid, with or without tobacco, a habit particularly prevalent in Southern Asia, is identified as a strong risk factor for oral cancer . Recently, areca nut chewing was classified as carcinogenic to humans .The addition of tobacco to the betel quid increased the risk significantly. In India, chewing accounts for nearly 50% of oral cancers in men and over 90% in women . The relative risk estimates for use of betel quid ranged from 2–60 in different studies . Cessation of chewing also showed a decline in the risk compared to current users, though not as evident as that for smoking cessation . Alternative chewing products like gutka and pan masala (basically a preparation of areca nut, catechu, cardamom, lime and a number of other chemicals and artificial flavouring agents with or without tobacco) have been commercially available for three decades in South Asia and recently in the USA and Europe. These products are available in small attractive sachets, which are cheap, convenient and have a long shelf-life. These products are strongly implicated in the recent increase in the incidence of OSF and invasive oral cancers, especially among younger people . A number of surveys conducted in schools and colleges in India have shown that the use of these new products is on the increase . The addictive nature of these products results in a high frequency of chewing, and the changes in the mucosa are often earlier than among betel quid chewers (2.7 +/-0.6 yr compared to 8.6+/-2.3yrs) .
Habitual chewing of pan masala/gutkha is associated with earlier presentation of oral submucous fibrosis than betel quid use. Factors that may be responsible for these differences are the tobacco content, the absence of the betel leaf and its carotenes and the much higher dry weight of pan masala/gutkha. Tobacco in the form of snuff is also found to be associated with increased risk for oral cancer .
Most chemical carcinogens in tobacco and areca nut require metabolic activation to exert the carcinogenic effect. Enzymes such as glutathione-S-transferase, N-acetyl transferases and cytochrome P450 play an important role in oral carcinogenesis, and genetic polymorphisms in these enzyme levels affect the individual risk .

b. Alcohol
Alcohol consumption is recognized as a risk factor for oral cancer . and has been implicated in oral carcinogenesis in several epidemiological studies .The exact mechanism by which alcohol exerts its carcinogenic influence is not known, though several possible mechanisms have been postulated. Firstly, alcohol is capable of increasing the penetration of carcinogens through the oral mucosa by increasing the permeability of the mucosa and by its solvent effect. Secondly, acetaldehyde, the first metabolite of alcohol, is a known carcinogen, and factors leading to accumulation of acetaldehyde, like increased conversion of alcohol to acetaldehyde and decreased metabolic transformation to acetate, may lead to the development of cancer . Similarly, accumulation of acetaldehyde is seen in the saliva of some individuals following increased oxidation of ethanol due to the activity of oral microflora, leading to increased risk from oral cancer . Acetaldehyde adducts have been demonstrated in oral tissues of patients with oral cancers and precancers . Another mechanism may be enhanced liver metabolic activity due to chronic ingestion of alcohol leading to the activation of carcinogens and also causing alteration of retinoid metabolism. Alcohol can also lead to degeneration of the autonomic innervation and fatty infiltration of the salivary glands, leading to decreased salivary flow. This may cause an accumulation of carcinogenic substances on the oral mucosal surface, thus increasing the risk for oral cancer . Finally, alcoholic beverages can contain many different carcinogenic substances derived from fermentation, contamination, and from the use of additives or flavours . The risk of carcinogenesis increases with increasing consumption of alcohol, and it is not the type of beverage but the total alcohol content in the drink that contributes to the development of cancer . Daily consumption of around 50g of alcohol increases the risk of oral, pharyngeal, laryngeal and oesophageal cancers by 2–3 times compared with the risk in non-drinkers .
The independent role of tobacco and alcohol in oral carcinogenesis is clear. However, the combined effects are often not merely additive, but greater than multiplicative .

c. Dietary factors
An association between diet and oral cancer has long been suggested . A well-established and quantifiable protective effect of a diet rich in fruits and vegetables has been shown in several studies . A meta-analysis of various studies showed 28% decreased risk per 50g of non-starchy vegetables and 24% decreased risk per 50 g of citrus fruits consumed per day with a dose–response relationship .

d. Poor oral hygiene
Several studies have identified a role of poor oral hygiene (frequency of brushing and/or poor dentition) in oral carcinogenesis even after adjustment for tobacco and alcohol consumption . An inverse relationship has been observed with frequency of brushing the teeth and oral cancer . Studies have shown higher acetaldehyde levels in the saliva of those who smoke and use alcohol with poor oral hygiene .

e. HPV infection
Numerous studies have investigated the prevalence of HPV in oral cancer tissues. HPV DNA was detected in about 25% of cancers of oral cavity . Recent studies indicate that HPV infection, particularly with high-risk oncogenic types 16 and 18, plays a role in the progression to oral cancer . The transmission of HPV to the oral cavity is poorly understood. Sexual transmission has been suggested by some authors. HPV DNA is more frequently seen in the biopsy specimens of patients with oral cancer who practiced oral sex . However, other studies have found no correlation between oral sex and oral cancer . The role of HPV infection in oral cancer is not clear.

f. Chronic trauma
Several studies have shown that the presence of a chronic sore from ill-fitting dentures or sharp teeth is a risk factor for oral cancer . This is significant even after adjustment for tobacco and alcohol.

g. Mouth wash
Chronic use of alcohol-containing mouthwash is considered a risk factor. However, not many studies support this association .

h. Mate
Mate is a tea-like beverage consumed in certain parts of South America. It is brewed from the dried leaves of the perennial tree Ilex paraguarensis. Drinking hot mate is associated with oral carcinogenesis .

i. Solar radiation
Ultraviolet radiation is an important risk factor for lip cancer. Individuals engaged in outdoor work such farming, fishing or postal delivery are at higher risk .

j. Immunosuppression
Increased incidence of oral cancer is seen in immunocompromised individuals. Carcinomas of the lip have been reported in a number of kidney transplant patients receiving immunosuppressive medications, and oral cancers have been reported in young HIV seropositive patients .

k. Genetic factors
A genetic predisposition has been suggested for oral cancer risk. Studies have found that individuals with polymorphisms in GSTM1 and CYP1A1 are at a genetically higher risk of oral cancer, particularly with a low dose of cigarette smoking . Several other genetic alterations have been seen in patients with oral cancer, including activation of proto-oncogenes such as cyclin D1, RAS, MYC, EGFR and inactivation of tumour suppressor genes .

Clinical Signs and Symptoms:

Oral cancers in early stages are often asymptomatic and may present as reddish areas, small mucosal growths or ulcerations. Sometimes, there may be some discomfort and irritation. In advanced stages patients complain of ulceration or growth in the oral cavity, loosening of teeth, pain, malodour (halitosis), excessive salivation, bleeding, difficulty in speaking and swallowing, referred pain to the ear, swelling and ulceration of the face and neck swelling. The symptoms vary depending on the site of involvement. Initially, these lesions appear as a change in a preexisting precancerous lesions with induration, ulceration or growth, or present as de-novo hard indurated nodule, ulcer or growth, or as a cauliflower-like exophytic growth or ulcero-infiltrative lesion, or as a warty verrucous growth. Any site in the oral cavity can be affected, and in chewers these lesions are more common in areas where the betel quid is kept. As the tumour advances it infiltrates into adjacent tissues such as muscle, bone or skin, to adjacent structures and spreads to regional nodes. Regional lymph node involvement worsens the prognosis. Lymphatic spread is usually to the ipsilateral nodes, except in tumours located or extending to the midline. Submandibular, submental and upper deep cervical nodes are more commonly affected. As the disease advances other cervical nodes are also affected. In the case of tumours of the tongue and the floor of mouth, lymphatic involvement can occur even with small primary lesions. Haematogenous spread is rare, with the lung and spine being the commonly affected organs. Involvement of nodes in multiple levels is the most important predictor of haematogenous spread.

Prognostic Factors:

Various factors associated with the primary tumour and regional nodes have been found to be indicators of predicting treatment outcome.

Factors related to primary tumours:

a. Tumour size
The size of primary tumour affects both the choice and outcome of treatment. Large tumour size has poor prognosis . However, recent reports indicate that the thickness of the tumour is more important than the diameter in predicting nodal metastasis, local recurrences and survival . The clinical appearance (ulcerative versus proliferative) and ratio of exo/endophytic growths are also considered to be predictors of treatment outcome .

b. Tumour site
A gradual decrease in 5-year survival has been reported for tumours located more posteriorly in the oral cavity . Nodal metastases are more common for tumours of the tongue, retromolar area and oropharynx compared to lip and buccal mucosa .

c. Bone involvement
Infiltrating type bone involvement is associated with increased risk of local recurrences and poor survival compared to an erosive type of bone involvement .

d. Skin involvement
Direct spread to the skin is an indicator of poor prognosis, and carcinoma en cuirasse, due to lymphatic involvement of the skin, is more serious, indicative of a grave prognosis .

e. Lymphovascular and perineural invasion
The presence of lymphovascular and perineural invasion in the pathological specimen are considered to be poor prognostic factors .

f. Invasive front grading
Several studies have shown a poor correlation between Broders/WHO histological grading and treatment outcome . Invasive front grading is now found to be a more reliable predictor of treatment outcome . Tumours with a non-cohesive invasive front have a poor outcome compared to those with a well-defined tumour front.

g. Status of resected margins
The post-operative status of the mucosal margin, as well as of the deeper margins, has significance in deciding adjuvant treatment and the treatment outcome . According to UK guidelines, a margin of 5mm or more is clear, 1-5mm is close and less than 1mm is considered as involved margin Positive or close margins have poor outcome compared to those with clear margins.

h. Histopathology
Verrucous carcinoma is a slow-growing type of squamous cell carcinoma with good treatment outcome, whereas prognosis is poor for adenosquamous and basaloid squamous cell carcinomas .

i. DNA ploidy status
DNA ploidy status is an important predictor of overall and relapse-free survival. The presence of DNA aneunploidy is considered to be a predictor of regional metastasis .

Factors related to regional (cervical) lympnodes:

Various factors related to the regional nodes also influence treatment policy and outcome. The presence and extent of nodal involvement, size of the metastasis within the node and extracapsular spread (ECS) are the most important predictors . Of these, ECS is the best, most simple and reliable indicator of tumour aggressiveness .

Prognostic factors related to the regional nodes :

• Presence or absence of metastasis
• Number of positive nodes
• Extracapsular spread
• Size of the metastatic deposit
• Anatomical level of involvement
• Laterality of positive nodes
• Embolisation/permeation of perinodal lymphatics
• Post-operative nodal stage

Histopathology:

More than 95% of oral cancers are squamous cell carcinomas. Squamous cell carcinoma is an invasive epithelial neoplasm showing varying degrees of squamous differentiation. Squamous differentiation, seen as keratinisation with “pearl” formation and an invasive growth is a prerequisites for the diagnosis of squamous cell carcinoma. Invasion is seen as a breach of the basement membrane and extension into the underlying stroma. These tumours are graded into well-, moderately- and poorly-differentiated squamous cell carcinoma. The well-differentiated squamous cell carcinoma resembles the normal squamous epithelium with extensive keratinisation and pearl formation. Moderately-differentiated squamous cell carcinomas show less keratinisation and more nuclear pleomorphism and mitotic activity. The poorly-differentiated ones show markedly pleomorphic cells with minimal keratinisation and prominent mitotic activity with plenty of atypical mitotic figures. Most squamous cell carcinomas are moderately differentiated. Most cases of squamous cell carcinoma present no diagnostic problems; however, sometimes a pseudoepitheliomatous hyperplasia overlying a granular cell tumour in necrotising sialometaplasia and in papillary hyperplasia of palate may cause dilemmas to the histopathologist.

Image	Caption
	Figure 1: Trends in tongue and mouth cancer incidence (ages 0-85+).
	Figure 2: Trends in tongue and mouth cancer incidence (ages 0-44).
	Figure 3: Age-standardized incidence rates of tongue and mouth cancer in selected populations in each continent, 1998-2002 (all ages).
	Figure 4: Well-differentiated squamous cell carcinoma.
	Figure 5: Moderately-differentiated squamous cell carcinoma.
	Figure 6: Poorly-differentiated squamous cell carcinoma.