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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 Llewellyn CD, Johnson NW, Warnakulasuriya KA (2001). Risk factors for squamous cell carcinoma of the oral cavity in young people--a comprehensive literature review. Oral Oncol 37: 401-418.. 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 Llewellyn CD, Johnson NW, Warnakulasuriya KA (2001). Risk factors for squamous cell carcinoma of the oral cavity in young people--a comprehensive literature review. Oral Oncol 37: 401-418.Gupta PC (1999). Mouth cancer in India: a new epidemic? J Indian Med Assoc 97: 370-373.. 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 (figure 4). 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 (figure 4).

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 WHO meeting, (1984). Control of oral cancer in developing countries. A WHO meeting. Bull World Health Organ 62: 817-830.IARC Monographs (2004). Betal -quid and Areca nut Chewing and some Areca nut-derived Nitrosamines (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans), Lyon, IARC Press.IARC Monographs, (2004). Tobacco Smoke and Involuntary Smoking (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans), Lyon, France, IARC Press.Baan R, Straif K, Grosse Y, Secretan B, El Ghissassi F, Bouvard V, Altieri A, Cogliano V; Carcinogenicity of alcoholic beverages. WHO International Agency for Research on Cancer Monograph Working Group. Lancet Oncol. 2007 Apr;8(4):292-3. .
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 IARC Monographs (2004). Betal -quid and Areca nut Chewing and some Areca nut-derived Nitrosamines (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans), Lyon, IARC Press.Llewellyn CD, Johnson NW, Warnakulasuriya KA (2001). Risk factors for squamous cell carcinoma of the oral cavity in young people--a comprehensive literature review. Oral Oncol 37: 401-418.IARC Monographs, (2004). Tobacco Smoke and Involuntary Smoking (IARC Monographs on the Evaluation of Carcinogenic Risks to Humans), Lyon, France, IARC Press.Muwonge R, Ramadas K, Sankila R, Thara S, Thomas G, Vinoda J, Sankaranarayanan R (2007). Role of tobacco smoking, chewing and alcohol drinking in the risk of oral cancer in Trivandrum, India: A nested case-control design using incident cancer cases. Oral Oncol . 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 IARC Working Group, (2004). Tobacco Smoke and Involuntary Smoking (IARC Working Group on the Evaluation of Carcinogenic Risks to Humans), Lyon, France, IARC Press.Franceschi S, Talamini R, Barra S, Baron AE, Negri E, Bidoli E, Serraino D, La VC (1990). Smoking and drinking in relation to cancers of the oral cavity, pharynx, larynx, and esophagus in northern Italy. Cancer Res 50: 6502-6507. . 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  IARC Working Group, (2004). Tobacco Smoke and Involuntary Smoking (IARC Working Group on the Evaluation of Carcinogenic Risks to Humans), Lyon, France, IARC Press.Muwonge R, Ramadas K, Sankila R, Thara S, Thomas G, Vinoda J, Sankaranarayanan R (2007). Role of tobacco smoking, chewing and alcohol drinking in the risk of oral cancer in Trivandrum, India: A nested case-control design using incident cancer cases. Oral Oncol Znaor A, Brennan P, Gajalakshmi V, Mathew A, Shanta V, Varghese C, Boffetta P (2003). Independent and combined effects of tobacco smoking, chewing and alcohol drinking on the risk of oral, pharyngeal and esophageal cancers in Indian men. Int J Cancer 105: 681-686.Balaram P, Sridhar H, Rajkumar T, Vaccarella S, Herrero R, Nandakumar A, Ravichandran K, Ramdas K, Sankaranarayanan R, Gajalakshmi V, Munoz N, Franceschi S (2002). Oral cancer in southern India: the influence of smoking, drinking, paan-chewing and oral hygiene. Int J Cancer 98: 440-445.Sankaranarayanan R, Duffy SW, Day NE, Nair MK, Padmakumary G (1989). A case-control investigation of cancer of the oral tongue and the floor of the mouth in southern India. Int J Cancer 44: 617-621.. The relative risk estimates for smoking reported in various studies vary from 1.2–29.4  IARC Working Group, (2004). Tobacco Smoke and Involuntary Smoking (IARC Working Group on the Evaluation of Carcinogenic Risks to Humans), Lyon, France, IARC Press.. 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  IARC Working Group, (2004). Tobacco Smoke and Involuntary Smoking (IARC Working Group on the Evaluation of Carcinogenic Risks to Humans), Lyon, France, IARC Press. .
Chewing betel quid, with or without tobacco, a habit particularly prevalent in Southern Asia, is identified as a strong risk factor for oral cancer  IARC Working Group (2004). Betal -quid and Areca nut Chewing and some Areca nut-derived Nitrosamines (IARC Working Group on the Evaluation of Carcinogenic Risks to Humans), Lyon, IARC Press.Llewellyn CD, Johnson NW, Warnakulasuriya KA (2001). Risk factors for squamous cell carcinoma of the oral cavity in young people--a comprehensive literature review. Oral Oncol 37: 401-418.Muwonge R, Ramadas K, Sankila R, Thara S, Thomas G, Vinoda J, Sankaranarayanan R (2007). Role of tobacco smoking, chewing and alcohol drinking in the risk of oral cancer in Trivandrum, India: A nested case-control design using incident cancer cases. Oral Oncol Sankaranarayanan R, Duffy SW, Day NE, Nair MK, Padmakumary G (1989). A case-control investigation of cancer of the oral tongue and the floor of the mouth in southern India. Int J Cancer 44: 617-621.Thomas S, Wilson A (1993). A quantitative evaluation of the aetiological role of betel quid in oral carcinogenesis. Eur J Cancer B Oral Oncol 29B: 265-271.Nandakumar A, Thimmasetty KT, Sreeramareddy NM, Venugopal TC, Rajanna, Vinutha AT, Srinivas, Bhargava MK (1990). A population-based case-control investigation on cancers of the oral cavity in Bangalore, India. Br J Cancer 62: 847-851.. Recently, areca nut chewing was classified as carcinogenic to humans  IARC Working Group (2004). Betal -quid and Areca-nut Chewing and some Areca-nut-derived Nitrosamines (IARC Working Group on the Evaluation of Carcinogenic Risks to Humans), Lyon, IARC Press..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 Balaram P, Sridhar H, Rajkumar T, Vaccarella S, Herrero R, Nandakumar A, Ravichandran K, Ramdas K, Sankaranarayanan R, Gajalakshmi V, Munoz N, Franceschi S (2002). Oral cancer in southern India: the influence of smoking, drinking, paan-chewing and oral hygiene. Int J Cancer 98: 440-445.. The relative risk estimates for use of betel quid ranged from 2–60 in different studies  IARC Working Group (2004). Betal -quid and Areca-nut Chewing and some Areca-nut-derived Nitrosamines (IARC Working Group on the Evaluation of Carcinogenic Risks to Humans), Lyon, IARC Press.Balaram P, Sridhar H, Rajkumar T, Vaccarella S, Herrero R, Nandakumar A, Ravichandran K, Ramdas K, Sankaranarayanan R, Gajalakshmi V, Munoz N, Franceschi S (2002). Oral cancer in southern India: the influence of smoking, drinking, paan-chewing and oral hygiene. Int J Cancer 98: 440-445.Sankaranarayanan R, Duffy SW, Day NE, Nair MK, Padmakumary G (1989). A case-control investigation of cancer of the oral tongue and the floor of the mouth in southern India. Int J Cancer 44: 617-621.. Cessation of chewing also showed a decline in the risk compared to current users, though not as evident as that for smoking cessation Znaor A, Brennan P, Gajalakshmi V, Mathew A, Shanta V, Varghese C, Boffetta P (2003). Independent and combined effects of tobacco smoking, chewing and alcohol drinking on the risk of oral, pharyngeal and esophageal cancers in Indian men. Int J Cancer 105: 681-686.. 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 Gupta PC, Sinor PN, Bhonsle RB, Pawar VS, Mehta HC (1998). Oral submucous fibrosis in India: a new epidemic? Natl Med J India 11: 113-116.Gupta PC, Ray CS (2003). Epidemiology of betel quid usage. Ann Acad Med Singapore. 2004 Jul; 33(4 Suppl):31-6.. A number of surveys conducted in schools and colleges in India have shown that the use of these new products is on the increase Gupta PC, Ray CS (2004). Epidemiology of betel quid usage. Ann Acad Med Singapore 33: 31-36.. 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) Babu S, Bhat RV, Kumar PU, Sesikaran B, Rao KV, Aruna P, Reddy PR (1996). A comparative clinico-pathological study of oral submucous fibrosis in habitual chewers of pan masala and betelquid. J Toxicol Clin Toxicol 34: 317-322..
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 Winn DM, Blot WJ, Shy CM, Pickle LW, Toledo A, Fraumeni JF, Jr. (1981). Snuff dipping and oral cancer among women in the southern United States. N Engl J Med 304: 745-749..
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 Sreelekha TT, Ramadas K, Pandey M, Thomas G, Nalinakumari KR, Pillai MR (2001). Genetic polymorphism of CYP1A1, GSTM1 and GSTT1 genes in Indian oral cancer. Oral Oncol 37: 593-598.Anantharaman D, Chaubal PM, Kannan S, Bhisey RA, Mahimkar MB (2007). Susceptibility to oral cancer by genetic polymorphisms at CYP1A1, GSTM1 and GSTT1 loci among Indians: tobacco exposure as a risk modulator. Carcinogenesis 28: 1455-1462..

b. Alcohol
Alcohol consumption is recognized as a risk factor for oral cancer Baan R, Straif K, Grosse Y, Secretan B, El Ghissassi F, Bouvard V, Altieri A, Cogliano V; Carcinogenicity of alcoholic beverages. WHO International Agency for Research on Cancer Monograph Working Group. Lancet Oncol. 2007 Apr;8(4):292-3. . and has been implicated in oral carcinogenesis in several epidemiological studies Muwonge R, Ramadas K, Sankila R, Thara S, Thomas G, Vinoda J, Sankaranarayanan R (2007). Role of tobacco smoking, chewing and alcohol drinking in the risk of oral cancer in Trivandrum, India: A nested case-control design using incident cancer cases. Oral Oncol Macfarlane GJ, Zheng T, Marshall JR, Boffetta P, Niu S, Brasure J, Merletti F, Boyle P (1995). Alcohol, tobacco, diet and the risk of oral cancer: a pooled analysis of three case-control studies. Eur J Cancer B Oral Oncol 31B: 181-187.La Vecchia C., Tavani A, Franceschi S, Levi F, Corrao G, Negri E (1997). Epidemiology and prevention of oral cancer. Oral Oncol 33: 302-312.Figuero RE, Carretero Pelaez MA, Cerero LR, Esparza GG, Moreno Lopez LA (2004). Effects of the consumption of alcohol in the oral cavity: relationship with oral cancer. Med Oral 9: 14-23..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 Matsuo K, Hamajima N, Shinoda M, Hatooka S, Inoue M, Takezaki T, Tajima K (2001). Gene-environment interaction between an aldehyde dehydrogenase-2 (ALDH2) polymorphism and alcohol consumption for the risk of esophageal cancer. Carcinogenesis 22: 913-916.. 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 Homann N, Jousimies-Somer H, Jokelainen K, Heine R, Salaspuro M (1997). High acetaldehyde levels in saliva after ethanol consumption: methodological aspects and pathogenetic implications. Carcinogenesis 18: 1739-1743.Homann N, Seitz HK, Wang XD, Yokoyama A, Singletary KW, Ishii H (2005). Mechanisms in alcohol-associated carcinogenesis. Alcohol Clin Exp Res 29: 1317-1320.. Acetaldehyde adducts have been demonstrated in oral tissues of patients with oral cancers and precancers Warnakulasuriya S, Parkkila S, Nagao T, Preedy VR, Pasanen M, Koivisto H and Niemela O, (2008). Demonstration of ethanol-induced protein adducts in oral leukoplakia (pre-cancer) and cancer, J. Oral Pathol. Med., vol. 37, no. 3, pp. 157-165.. 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 Maier H, Dietz A, Gewelke U, Seitz HK, Heller WD (1990). [Tobacco- and alcohol-associated cancer risk of the upper respiratory and digestive tract]. Laryngorhinootologie 69: 505-511.Simanowski UA, Suter P, Stickel F, Maier H, Waldherr R, Smith D, Russell RM, Seitz HK (1993). Esophageal epithelial hyperproliferation following long-term alcohol consumption in rats: effects of age and salivary gland function. J Natl Cancer Inst 85: 2030-2033.. Finally, alcoholic beverages can contain many different carcinogenic substances derived from fermentation, contamination, and from the use of additives or flavours Baan R, Straif K, Grosse Y, Secretan B, El Ghissassi F, Bouvard V, Altieri A, Cogliano V; Carcinogenicity of alcoholic beverages. WHO International Agency for Research on Cancer Monograph Working Group. Lancet Oncol. 2007 Apr;8(4):292-3. . 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 La Vecchia C., Tavani A, Franceschi S, Levi F, Corrao G, Negri E (1997). Epidemiology and prevention of oral cancer. Oral Oncol 33: 302-312.. 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 Baan R, Straif K, Grosse Y, Secretan B, El Ghissassi F, Bouvard V, Altieri A, Cogliano V; Carcinogenicity of alcoholic beverages. WHO International Agency for Research on Cancer Monograph Working Group. Lancet Oncol. 2007 Apr;8(4):292-3. .
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 Franceschi S, Talamini R, Barra S, Baron AE, Negri E, Bidoli E, Serraino D, La VC (1990). Smoking and drinking in relation to cancers of the oral cavity, pharynx, larynx, and esophagus in northern Italy. Cancer Res 50: 6502-6507. Znaor A, Brennan P, Gajalakshmi V, Mathew A, Shanta V, Varghese C, Boffetta P (2003). Independent and combined effects of tobacco smoking, chewing and alcohol drinking on the risk of oral, pharyngeal and esophageal cancers in Indian men. Int J Cancer 105: 681-686.Baan R, Straif K, Grosse Y, Secretan B, El Ghissassi F, Bouvard V, Altieri A, Cogliano V; Carcinogenicity of alcoholic beverages. WHO International Agency for Research on Cancer Monograph Working Group. Lancet Oncol. 2007 Apr;8(4):292-3. .

c. Dietary factors
An association between diet and oral cancer has long been suggested Steinmetz KA, Potter JD (1991). Vegetables, fruit, and cancer. I. Epidemiology. Cancer Causes Control 2: 325-357.World Cancer Research Fund (WCRF)/American Institute for Cancer Research (AICR), (2007). Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective, Washington DC.. A well-established and quantifiable protective effect of a diet rich in fruits and vegetables has been shown in several studies Steinmetz KA, Potter JD (1991). Vegetables, fruit, and cancer. I. Epidemiology. Cancer Causes Control 2: 325-357.World Cancer Research Fund (WCRF)/American Institute for Cancer Research (AICR), (2007). Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective, Washington DC.Boeing H, Dietrich T, Hoffmann K, Pischon T, Ferrari P, Lahmann PH, Boutron-Ruault MC, Clavel-Chapelon F, Allen N, Key T, Skeie G, Lund E, Olsen A, Tjonneland A, Overvad K, Jensen MK, Rohrmann S, Linseisen J, Trichopoulou A, Bamia C, Psaltopoulou T, Weinehall L, Johansson I, Sanchez MJ, Jakszyn P, Ardanaz E, Amiano P, Chirlaque MD, Quiros JR, Wirfalt E, Berglund G, Peeters PH, van Gils CH, Bueno-de-Mesquita HB, Buchner FL, Berrino F, Palli D, Sacerdote C, Tumino R, Panico S, Bingham S, Khaw KT, Slimani N, Norat T, Jenab M, Riboli E (2006). Intake of fruits and vegetables and risk of cancer of the upper aero-digestive tract: the prospective EPIC-study. Cancer Causes Control 17: 957-969.. 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 World Cancer Research Fund (WCRF)/American Institute for Cancer Research (AICR), (2007). Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective, Washington DC..

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 Balaram P, Sridhar H, Rajkumar T, Vaccarella S, Herrero R, Nandakumar A, Ravichandran K, Ramdas K, Sankaranarayanan R, Gajalakshmi V, Munoz N, Franceschi S (2002). Oral cancer in southern India: the influence of smoking, drinking, paan-chewing and oral hygiene. Int J Cancer 98: 440-445.La Vecchia C., Tavani A, Franceschi S, Levi F, Corrao G, Negri E (1997). Epidemiology and prevention of oral cancer. Oral Oncol 33: 302-312.Bundgaard T, Wildt J, Frydenberg M, Elbrond O, Nielsen JE (1995). Case-control study of squamous cell cancer of the oral cavity in Denmark. Cancer Causes Control 6: 57-67.. An inverse relationship has been observed with frequency of brushing the teeth and oral cancer Velly AM, Franco EL, Schlecht N, Pintos J, Kowalski LP, Oliveira BV, Curado MP (1998). Relationship between dental factors and risk of upper aerodigestive tract cancer. Oral Oncol 34: 284-291.Moreno-Lopez LA, Esparza-Gomez GC, Gonzalez-Navarro A, Cerero-Lapiedra R, Gonzalez-Hernandez MJ, Dominguez-Rojas V (2000). Risk of oral cancer associated with tobacco smoking, alcohol consumption and oral hygiene: a case-control study in Madrid, Spain. Oral Oncol 36: 170-174.. Studies have shown higher acetaldehyde levels in the saliva of those who smoke and use alcohol with poor oral hygiene Homann N, Jousimies-Somer H, Jokelainen K, Heine R, Salaspuro M (1997). High acetaldehyde levels in saliva after ethanol consumption: methodological aspects and pathogenetic implications. Carcinogenesis 18: 1739-1743.Moreno-Lopez LA, Esparza-Gomez GC, Gonzalez-Navarro A, Cerero-Lapiedra R, Gonzalez-Hernandez MJ, Dominguez-Rojas V (2000). Risk of oral cancer associated with tobacco smoking, alcohol consumption and oral hygiene: a case-control study in Madrid, Spain. Oral Oncol 36: 170-174..

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 IARC Monographs, (2007). Human Papillomaviruses. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, Lyon, IARC Press.. Recent studies indicate that HPV infection, particularly with high-risk oncogenic types 16 and 18, plays a role in the progression to oral cancer  Luo CW, Roan CH, Liu CJ (2007). Human papillomaviruses in oral squamous cell carcinoma and pre-cancerous lesions detected by PCR-based gene-chip array. Int J Oral Maxillofac Surg 36: 153-158.La Vecchia C., Tavani A, Franceschi S, Levi F, Corrao G, Negri E (1997). Epidemiology and prevention of oral cancer. Oral Oncol 33: 302-312.. 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 Herrero R, Castellsague X, Pawlita M, Lissowska J, Kee F, Balaram P, Rajkumar T, Sridhar H, Rose B, Pintos J, Fernandez L, Idris A, Sanchez MJ, Nieto A, Talamini R, Tavani A, Bosch FX, Reidel U, Snijders PJ, Meijer CJ, Viscidi R, Munoz N, Franceschi S (2003). Human papillomavirus and oral cancer: the International Agency for Research on Cancer multicenter study. J Natl Cancer Inst 95: 1772-1783.. However, other studies have found no correlation between oral sex and oral cancer Garrote LF, Herrero R, Reyes RM, Vaccarella S, Anta JL, Ferbeye L, Munoz N, Franceschi S (2001). Risk factors for cancer of the oral cavity and oro-pharynx in Cuba. Br J Cancer 85: 46-54.Lissowska J, Pilarska A, Pilarski P, Samolczyk-Wanyura D, Piekarczyk J, Bardin-Mikollajczak A, Zatonski W, Herrero R, Munoz N, Franceschi S (2003). Smoking, alcohol, diet, dentition and sexual practices in the epidemiology of oral cancer in Poland. Eur J Cancer Prev 12: 25-33.. 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 Velly AM, Franco EL, Schlecht N, Pintos J, Kowalski LP, Oliveira BV, Curado MP (1998). Relationship between dental factors and risk of upper aerodigestive tract cancer. Oral Oncol 34: 284-291.Lockhart PB, Norris CM, Jr., Pulliam C (1998). Dental factors in the genesis of squamous cell carcinoma of the oral cavity. Oral Oncol 34: 133-139.Rosenquist K, Wennerberg J, Schildt EB, Bladstrom A, Goran HB, Andersson G (2005). Oral status, oral infections and some lifestyle factors as risk factors for oral and oropharyngeal squamous cell carcinoma. A population-based case-control study in southern Sweden. Acta Otolaryngol 125: 1327-1336.Perez MA, Raimondi AR, Itoiz ME (2005). An experimental model to demonstrate the carcinogenic action of oral chronic traumatic ulcer. J Oral Pathol Med 34: 17-22.. 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 Carretero Pelaez MA, Esparza Gomez GC, Figuero RE, Cerero LR (2004). Alcohol-containing mouthwashes and oral cancer. Critical analysis of literature. Med Oral 9: 120.Elmore JG, Horwitz RI (1995). Oral cancer and mouthwash use: evaluation of the epidemiologic evidence. Otolaryngol Head Neck Surg 113: 253-261. .

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 IARC Monographs, (1991). Coffee, Tea, Mate, Methylxanthines and Methylglyoxal. (IARC Monographs on the Evaluation of Carcinogenic Risks to Human (VOL 51)), Lyon, IARC Press.Goldenberg D (2002). Mate: a risk factor for oral and oropharyngeal cancer. Oral Oncol 38: 646-649. .

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  Pindborg JJ, Reichart PA, Smith CJ, van der Waal I, (1997). World Health Organisation International Histological Classification of Tumours.Histological Typing of Cancer and Precancer of the Oral Mucosa. 2 ed. Berlin: Springer.Perea-Milla LE, Minarro-Del Moral RM, Martinez-Garcia C, Zanetti R, Rosso S, Serrano S, Aneiros JF, Jimenez-Puente A, Redondo M (2003). Lifestyles, environmental and phenotypic factors associated with lip cancer: a case-control study in southern Spain. Br J Cancer 88: 1702-1707..

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 de Visscher JG, Bouwes Bavinck JN, van dW, I (1997). Squamous cell carcinoma of the lower lip in renal-transplant recipients. Report of six cases. Int J Oral Maxillofac Surg 26: 120-123.Flaitz CM, Nichols CM, dler-Storthz K, Hicks MJ (1995). Intraoral squamous cell carcinoma in human immunodeficiency virus infection. A clinicopathologic study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 80: 55-62. .

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 Sreelekha TT, Ramadas K, Pandey M, Thomas G, Nalinakumari KR, Pillai MR (2001). Genetic polymorphism of CYP1A1, GSTM1 and GSTT1 genes in Indian oral cancer. Oral Oncol 37: 593-598.Katoh T, Kaneko S, Kohshi K, Munaka M, Kitagawa K, Kunugita N, Ikemura K, Kawamoto T (1999). Genetic polymorphisms of tobacco- and alcohol-related metabolizing enzymes and oral cavity cancer. Int J Cancer 83: 606-609. . 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 Stewart BW, Kleihues P, eds, (2003). Head and Neck Cancer. In:.  World Cancer Report, Lyon, IARC Press, 232-236..

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 Maddox WA (1984). Hayes Martin lecture. Vicissitudes of head and neck cancer. Am J Surg 148: 428-432.Crissman JD, Liu WY, Gluckman JL, Cummings G (1984). Prognostic value of histopathologic parameters in squamous cell carcinoma of the oropharynx. Cancer 54: 2995-3001.. However, recent reports indicate that the thickness of the tumour is more important than the diameter in predicting nodal metastasis, local recurrences and survival Po Wing YA, Lam KY, Lam LK, Ho CM, Wong A, Chow TL, Yuen WF, Wei WI (2002). Prognostic factors of clinically stage I and II oral tongue carcinoma-A comparative study of stage, thickness, shape, growth pattern, invasive front malignancy grading, Martinez-Gimeno score, and pathologic features. Head Neck 24: 513-520.charoenrat P, Pillai G, Patel S, Fisher C, Archer D, Eccles S, Rhys-Evans P (2003). Tumour thickness predicts cervical nodal metastases and survival in early oral tongue cancer. Oral Oncol 39: 386-390.Woolgar JA, Scott J (1995). Prediction of cervical lymph node metastasis in squamous cell carcinoma of the tongue/floor of mouth. Head Neck 17: 463-472. . The clinical appearance (ulcerative versus proliferative) and ratio of exo/endophytic growths are also considered to be predictors of treatment outcome Po Wing YA, Lam KY, Lam LK, Ho CM, Wong A, Chow TL, Yuen WF, Wei WI (2002). Prognostic factors of clinically stage I and II oral tongue carcinoma-A comparative study of stage, thickness, shape, growth pattern, invasive front malignancy grading, Martinez-Gimeno score, and pathologic features. Head Neck 24: 513-520..

b. Tumour site
A gradual decrease in 5-year survival has been reported for tumours located more posteriorly in the oral cavity Arthur K, Farr HW (1972). Prognostic significance of histologic grade in epidermoid carcinoma of the mouth and pharynx. Am J Surg 124: 489-492.Farr HW, Goldfarb PM, Farr CM (1980). Epidermoid carcinoma of the mouth and pharynx at Memorial Sloan-Kettering Cancer Center, 1965 to 1969. Am J Surg 140: 563-567.. Nodal metastases are more common for tumours of the tongue, retromolar area and oropharynx compared to lip and buccal mucosa Woolgar JA (2006). Histopathological prognosticators in oral and oropharyngeal squamous cell carcinoma. Oral Oncol 42: 229-239..

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 Shaw RJ, Brown JS, Woolgar JA, Lowe D, Rogers SN, Vaughan ED (2004). The influence of the pattern of mandibular invasion on recurrence and survival in oral squamous cell carcinoma. Head Neck 26: 861-869..

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 Cole RD, McGuirt WF (1995). Prognostic significance of skin involvement from mucosal tumors of the head and neck. Arch Otolaryngol Head Neck Surg 121: 1246-1248..

e. Lymphovascular and perineural invasion
The presence of lymphovascular and perineural invasion in the pathological specimen are considered to be poor prognostic factors Woolgar JA (2006). Histopathological prognosticators in oral and oropharyngeal squamous cell carcinoma. Oral Oncol 42: 229-239.Woolgar JA, Rogers S, West CR, Errington RD, Brown JS, Vaughan ED (1999). Survival and patterns of recurrence in 200 oral cancer patients treated by radical surgery and neck dissection. Oral Oncol 35: 257-265.Sutton DN, Brown JS, Rogers SN, Vaughan ED, Woolgar JA (2003). The prognostic implications of the surgical margin in oral squamous cell carcinoma. Int J Oral Maxillofac Surg 32: 30-34..

f. Invasive front grading
Several studies have shown a poor correlation between Broders/WHO histological grading and treatment outcome  Pindborg JJ, Reichart PA, Smith CJ, van der Waal I, (1997). World Health Organisation International Histological Classification of Tumours. Histological Typing of Cancer and Precancer of the Oral Mucosa. 2 ed. Berlin: Springer.Po Wing YA, Lam KY, Lam LK, Ho CM, Wong A, Chow TL, Yuen WF, Wei WI (2002). Prognostic factors of clinically stage I and II oral tongue carcinoma-A comparative study of stage, thickness, shape, growth pattern, invasive front malignancy grading, Martinez-Gimeno score, and pathologic features. Head Neck 24: 513-520.charoenrat P, Pillai G, Patel S, Fisher C, Archer D, Eccles S, Rhys-Evans P (2003). Tumour thickness predicts cervical nodal metastases and survival in early oral tongue cancer. Oral Oncol 39: 386-390.. Invasive front grading is now found to be a more reliable predictor of treatment outcome Woolgar JA, Scott J (1995). Prediction of cervical lymph node metastasis in squamous cell carcinoma of the tongue/floor of mouth. Head Neck 17: 463-472.Woolgar JA, Rogers S, West CR, Errington RD, Brown JS, Vaughan ED (1999). Survival and patterns of recurrence in 200 oral cancer patients treated by radical surgery and neck dissection. Oral Oncol 35: 257-265.Martinez-Gimeno C, Rodriguez EM, Vila CN, Varela CL (1995). Squamous cell carcinoma of the oral cavity: a clinicopathologic scoring system for evaluating risk of cervical lymph node metastasis. Laryngoscope 105: 728-733.. 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 Woolgar JA (2006). Histopathological prognosticators in oral and oropharyngeal squamous cell carcinoma. Oral Oncol 42: 229-239.Shaw RJ, Brown JS, Woolgar JA, Lowe D, Rogers SN, Vaughan ED (2004). The influence of the pattern of mandibular invasion on recurrence and survival in oral squamous cell carcinoma. Head Neck 26: 861-869.Sutton DN, Brown JS, Rogers SN, Vaughan ED, Woolgar JA (2003). The prognostic implications of the surgical margin in oral squamous cell carcinoma. Int J Oral Maxillofac Surg 32: 30-34.. 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 Helliwell T, Woolgar JA, (1988). Standards and minimum datasets for reporting common cancers. Minimum dataset for head and neck carcinoma histopathology reports., London, The Royal College of Pathologists. 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  Pindborg JJ, Reichart PA, Smith CJ, van der Waal I, (1997). World Health Organisation International Histological Classification of Tumours.Histological Typing of Cancer and Precancer of the Oral Mucosa. 2 ed. Berlin: Springer.Helliwell T, Woolgar JA, (1988). Standards and minimum datasets for reporting common cancers. Minimum dataset for head and neck carcinoma histopathology reports., London, The Royal College of Pathologists. Wieneke JA, Thompson LD, Wenig BM (1999). Basaloid squamous cell carcinoma of the sinonasal tract. Cancer 85: 841-854..

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 Van Heerden WF, Dreyer L, Swart TJ, Van Heerden MB and Boy SC, (2002). The suitability of paraffin-embedded material to predict metastatic potential of oral squamous cell carcinoma, Anticancer Res., vol. 22, no. 6C, pp. 4147-4150.Hemmer J, Nagel E and Kraft K, (1999). DNA aneuploidy by flow cytometry is an independent prognostic factor in squamous cell carcinoma of the oral cavity. Anticancer Res., vol. 19, no. 2B, pp. 1419-1422..

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 Woolgar JA, Scott J (1995). Prediction of cervical lymph node metastasis in squamous cell carcinoma of the tongue/floor of mouth. Head Neck 17: 463-472. Calhoun KH, Fulmer P, Weiss R, Hokanson JA (1994). Distant metastases from head and neck squamous cell carcinomas. Laryngoscope 104: 1199-1205. Kowalski LP, Bagietto R, Lara JR, Santos RL, Silva JF, Jr., Magrin J (2000). Prognostic significance of the distribution of neck node metastasis from oral carcinoma. Head Neck 22: 207-214.Greenberg JS, Fowler R, Gomez J, Mo V, Roberts D, El Naggar AK, Myers JN (2003). Extent of extracapsular spread: a critical prognosticator in oral tongue cancer. Cancer 97: 1464-1470.. Of these, ECS is the best, most simple and reliable indicator of tumour aggressiveness Woolgar JA, Scott J (1995). Prediction of cervical lymph node metastasis in squamous cell carcinoma of the tongue/floor of mouth. Head Neck 17: 463-472..

Prognostic factors related to the regional nodes Woolgar JA, Scott J (1995). Prediction of cervical lymph node metastasis in squamous cell carcinoma of the tongue/floor of mouth. Head Neck 17: 463-472.:

  • 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.


ImageLegend
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.
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