718

Experimental Oncology 30, 259–264, 2008 (December) 259

The term “oral cancer” (OC) includes a diverse group of tumors arising from the oral cavity. Usually in-cluded are cancers of the lip, tongue, pharynx, and oral cavity. The World Health Organization (WHO) reported oral cancer as having one of the highest mortality ratios amongst all malignancies [1]. Although OC is rare and attracts little attention, it is more common than Hodg-kin’s disease or tumours of brain, liver, bone, thyroid gland, stomach, ovaries, or cancer of the cervix. It ranks 12th among all cancers [2]. The vast majority of malignant neoplasms in the mouth are squamous cell carcinomas (SCC). The aetiology of OC is multi-factorial. Genetic, environment, social and behavioral effects may all be implicated [3]. It is well known that alcohol and tobacco are two of the most important risk factors for development of OC. The consumption of alcohol and tobacco is closely associated not only with the development of OC, but also with the course of the disease and this consumption is associated with a poor prognosis [4]. Thus, environmental insults such as alcohol, ultraviolet light, and/or tobacco products presumably increase DNA damage, reduce murine double minute (MDM2), increase p53 expression, and thereby activate clusters of genes associated with cell growth, and/or cell death [5]. Many studies reported that, up to three-quarters of OC could be prevented by avoiding environmental factors, notably the consumption of tobacco and excess alcohol [6, 7]. The lack of public awareness of the signs, symptoms and risk factors associated with oral cancer has been reported [8]. Unfortunately, most oral cancers lack early signs [9], and despite improvements in diagnostic and therapeutic modalities, the prognosis of patients with oral malignancies has remained poor. In essence,

this poor outcome is related to the majority of patients presenting at an already advanced stage of disease at the time of diagnosis [10]. Since, biopsy is a diagnostic method with limited sensitivity. Recently, a number of molecular-based diagnostic markers have been used to detect OC. Therefore, the purpose of present review was undertaken in an attempt to the incidence, mor-tality, risk factors, prevention, and current diagnostic markers of OC.

INCIDENCE AND MORTALITY OC incidence and mortality rates vary widely across

the world. Mortality rate is an important tool that pro-vides implicit information about incidence, diagnosis stage, solving capacity of health services, available technology and health programs to be applied, among others. Although globally oral cancer represents an incidence of 3% (males) and 2% (females) of all ma-lignant neoplasms, it has one of the lowest survival rates — 50 percent, within a five-year period [11]. There has been a nearly five-fold increase in incidence in oral cancer patients under age 40, many with no known risk factors [12,13]. Study shows that one American dies from oral cancer every hour [14]. OC incidence in men is higher in the Bas Rhin in France, in the south of India, where is the most common cancer, in some areas in the center and east of Europe, and in some regions of Latin America [15,16]. The highest incidence was registered in India in women with a moderate rise in mortality, in the Central and Eastern Europe in the 1980’s and 1990’s [17]. Cohort studies show that OC incidence has risen in all the age groups throughout the world in the last decades [16], especially in young men in Eastern European countries, such as, Estonia, Hungary, Ukraine, and Russia [17,18]. In Australia, the incidence of OC in New South Wales increased by 27% in men and 3% in women the periods 1973–1977 and 1988–1992 [19], and most of the increase occurred in the early 1980’s in parallel with similar trends in Europe and the United States [20]. The risk of dying from OC in Australia is low and more than 75% occurred in people aged 60 years or older [19]. The prevalence of oral cancer in India is up to four times higher than in other countries [16]. Overall, comparisons are difficult

ORAL CANCER: RISK FACTORS, PREVENTION AND DIAGNOSTICJ. Khalili

Department of Therapeutic Stomatology, National Medical Academy of Postgraduate Education, 01004 Kiev, Ukraine

Although oral cancer is rare and attracts little attention, it ranks 12th among all cancers and constitutes the most life threatening of all dental conditions. The aetiology of oral cancer is multi-factorial and like other types of cancer, the key to decreasing the suffering of patients and increasing their survival rate is early detection. The global increase in frequency and mortality of oral cancer has intensified current research efforts in the field of prevention and early detection of this disease. Therefore, scientists have been searching for alternative approaches to biopsy. A number of molecular-based diagnostic markers have been used to detect the presence of oral cancer with varying degrees of sensitivity and specificity. In this paper, incidence, mortality, risk factors, prevention, and diagnostic of oral cancer have been reviewed.Key Words: oral cancer, incidence and mortality, risk factors, prevention, diagnostic.

Received: September 8, 2008. Correspondence: Fax: +38 (044) 501-39-18 E-mail: [email protected] Abbreviations used: COX-2 — cyclooxygenase-2; ET-1 — endothe-lin-1; HPV — human papilloma viruses; HSV — herpes simplex viruses; iNOS — inducible nitric oxide synthase; LOH — loss of heterogeneity; OC — oral cancer; OSCC — oral squamous cell car-cinomas; ROS — reactive oxygen species; RNS — reactive nitro-gen species; NO — nitric oxide; 4-NQO — 4-nitroquinoline 1-oxide; SCC — squamous cell carcinomas.

Exp Oncol 200830, 4, 259–264

REVIEw

260 Experimental Oncology 30, 259–264, 2008 (December)

considering that OC mortality rate and incidence data are not published using the same format [16].

THE RISK FACTORS Tobacco. All forms of tobacco — cigarettes, pipes,

cigars, and smokeless tobacco have been implicated in the development of OC [21]. While tobacco confers the highest risk for OC of the floor of the mouth [22] also, it is associated with an increased risk for all sites of OC. Tobacco use is responsible for 90% of OC deaths in males [23].

Alcohol. Alcohol use is a second independent ma-jor risk factor for the development of OC [24, 25]. For non-smokers it is the most important risk factor. Above 30 grams of alcohol per day, risk increases linearly with amount of alcohol consumed [26].

Chewing tobacco. In addition to tobacco use, the use of chewing products such as betel nuts, paan, chaalia, gutka, naswar, and areca increases the risk for OC; these products are socially acceptable in South-east Asia, the South Pacific Islands, and India [27].

Shammah. Shammah, a traditional smokeless to-bacco habit in the Arabian Peninsula, has a significant association between the prevalence of leukoplakia and the daily duration of shammah application — in a dose-dependent manner [28].

Marijuana. The carcinogenic properties of marijuana smoke are similar to those of tobacco. Marijuana use may interact with mutagen sensitivity and other risk factors to increase the risk of head and neck cancer [29].

Poor nutrition. Dietary deficiencies, particularly of vitamin A, vitamin C, vitamin E, iron, selenium, folate and other trace elements have been linked to increased risk of OC [30, 31]. Intervention studies where diets have been supplemented have shown some beneficial effect on pre-malignant conditions and reducing the risk OC, but further work into diet and the role of chemopreven-tion in oral cancers is needed [32, 33].

Ultraviolet light. Solar irradiation is a major risk fac-tor for cancer of the lip. The vast majority of lip cancer occur on the lower lip and many patients have outdoor occupations where sun exposure is increased. Lip can-cer is three times more common in men than women which may be an effect of occupation, smoking and sun-exposure [34].

Irritation. Although it has been suggested that chronic irritation to the lining of the mouth from poorly fitting or defective complete dentures may be a risk factor for OC, the majority of studies have shown no correlation [35].

Dental plaque. Polymicrobial supragingival dental plaque is a possible independent risk factor, as it pos-sesses a relevant mutagenic interaction with saliva, and thus oral health may be a co-factor in the develop-ment of OC [36].

Mouth rinses. Ethyl alcohol is added to mouth rinses as a solvent for other ingredients and as a pre-servative. Study shows that cancer was not statistically associated with mouthwash use in alcohol or tobacco users [37]. Currently, there is insufficient clinical evi-

dence to suggest a relationship between ethyl alcohol found in mouth rinses and OC [38].

Candidiasis. Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy an autosomal re-cessive disease associated with a limited T lymphocyte defect, and exceptionally common in Finland, seems to favour the growth of Candida albicans and predis-pose to chronic mucositis and OC [39].

Diabetes. The molecular basis for the putative association of diabetes mellitus with oral squamous cell carcinomas (OSCC) from epidemiological stu dies, may involve insulin receptor substrate-1 and focal adhesion kinase [40].

Free radicals. Free radicals such as reactive oxygen species (ROS) and reactive nitrogen species (RNS) can function both as initiators and promoters in carcinogenesis, while antioxidants provide protection against the cellular and molecular damage caused by reactive oxygen species and reactive nitrogen species [41]. The increase in ROS and RNS may have been the event that led to the consumption and reduction of salivary antioxidant systems, thus explaining the oxidative damage to the DNA and proteins, and pos-sibly the promotion of OC [42].

Viruses. The role of viruses remains unclear. Evi-dence is perhaps strongest for infection with high-risk human papilloma viruses (HPV) [43–45]. Studies show an increased risk of OC in women with cervical cancer suggesting a common risk factor other than smoking, such as HPV infection: transmission of HPV via oral sex is one possibility. A recent multicentre case control study reported that infection with HPV-16 increased the risk of cancer of the oral cavity and particularly oropha rynx [46, 47]. The role of infection with Epstein-Barr virus and herpes simplex viruses (HSV) remains uncertain [48]. The role of herpes simplex viruses, HSV-1 and HSV-2, as co-factors in association with tobacco, alcohol, or HPV-16 infection has also been ex-amined [49]. Heavy use of tobacco, alcohol and HPV-16 infection was associated with an increased risk of OSCC but, after adjusting for age, tobacco, alcohol use, and number of sexual partners, the risk of cancer was not significantly increased in those with HSV-1 or HSV-2, though seropositivity to HSV-1 and HSV-2, may modify the risk associated with exposure to tobacco, alcohol, or HPV [49]. In a study using a fuzzy logic technique, HPV infection showed an association with OC [50].

Family History. Family history of OC is a risk factor. Head and neck cancer patients show an increased sus-ceptibility to chromosome damage by mutagens [51]. Study used cDNA array and identified genes such as keratin 17 and 19, laminin-5, connexin-26 and vascular endothelial growth factor (VEGF) as being differentially expressed in head and neck SCC tissues, with respect to normal tissue [52].

PREVENTION OF ORAL CANCER Primary prevention. Primary prevention has been

estimated to be the most cost-effective method of pre-venting OC [53]. Previous study has shown poor public


awareness of OC [54]. Up to three-quarters of OC could be prevented by avoiding environmental factor, notably the consumption of tobacco and excess alcohol [55].

Secondary prevention. Intervention and excision of leukoplakis and erythroplakias combined with elimi-nation of risk factors associated with their develop-ment, reduces the incidence of OC [56]. Opportunistic screening for OC can be carried out during patients’ regular visits. Patient with positive finding should be referred to a specialist for a definitive diagnosis, biopsy and further management.

CURRENT EXPERIMENTAL MODELSSeveral animal models have been used for in-

vestigation of carcinogenesis and development of diagnostic [57]. The most commonly used model is 7,12 dimethylbenz(a)anthracene (DMBA)-induced

hamster cheek pouch carcinogenesis model [58]. Treatment by the administration of 4-nitroquinoline 1-oxide (4-NQO) in drinking water can induce tumors in oral cavities mice [59], and 4-NQO-induced rat tongue carcinogenesis [60]. Also, nitric oxide (NO) plays an important role in both carcinogenesis and tumor progression [61]. A significantly higher expres-sion level of inducible nitric oxide synthase (iNOS) was found in rat tongue cancer induced by 4-NQO [62].

CURRENT ORAL CANCER DIAGNOSTICClinical examination and histopathological studies

of biopsied material are the classical and the most accep ted diagnostic methods used for precancer-ous and cancerous oral lesions. While conventional oral examination may be useful in the discovery of some oral lesions, it does not identify all potentially premalignant and/or malignant lesions. On the other hand, biopsy is a technique with surgical implications, technique limitations for some professionals, and psychological implications for some patients. Since most OCs arise as asymptomatic small lesions, formal diagnosis procedures begin only when the clinician or patient notices abnormal tissues [63]. Furthermore, microscopic investigation of the progressive cancer is often conducted too late for successful intervention [64]. Also, it is impractical to use imaging techniques for cancer screening, since they are time-consuming and expensive. These techniques are typically used for confirmation due to their insensitivity for small lesions [65]. With this in mind, scientists have been searching for alternative approaches. In this regard, cytokeratin expression profile provides useful information on cell differentiation status [66], but its potential for early diagnosis of OC is limited [67]. Furthermore, certain cytokeratins, such as K8 and K19 [68], are useful if not definitive indicators of malignancy, particularly if their presence is interpreted in conjunction with other infor-mation, such as DNA profile [69]. Mutation of the tumour suppressor gene p53 is another frequent genomic change in human cancers [70]. According to most stud-ies, p53 is not present in normal oral mucosa [71, 72], but it is detectable by immunohistochemical methods in SCCs and potentially malignant lesions of the oral

mucosa [73]. Likewise, p53 has been detected in cells of malignant tumours obtained by exfoliative cytology [74]. In addition, p53 mutations are present in only about 50% of squamous cell carcinomas of the oral cavity, and only seen at advanced stages of carcinogenesis [75]. Therefore, early diagnosis of OCs on the basis of p53 detection in oral mucosa smears is not a useful option, since exfoliative cytology does not obtain basal epithe-lial cells [76]. A dramatic switch from histopathological to molecular methods of disease diagnosis [77], and exfoliative cytology has gained importance as a rapid and simple method for obtaining DNA samples. Loss of heterogeneity (LOH) and other molecular changes indicative of oral carcinogenesis can be readily identi-fied in exfoliated cells [78]. Polymerase chain reaction (PCR) techniques to amplify DNA from exfoliation samples from oral carcinomas, for analysis of restric-tion-fragment length polymorphisms (RFLPs) have been used [79]. They found that 66% of the tumours studied showed LOH at one position in the p53 sequence, while 55% showed LOH at some other location. Leukoplakia is a marker of an increased risk of OC, but there are no

reliable clinical or histological features that can be used to predict whether the lesion will regress spontaneously or progress to cancer. Microsatellite analyses have been used to identify novel molecular targets (e. g., p16, p53, and cyclin D1) for chemopreventive drugs that could be useful in the treatment of oral leukoplakia [80]. NO could stimulate tumor growth and metastasis by promoting the migratory, invasive and angiogenic abilities of tumor cells, which may also be triggered by the activation of cy-clooxygenase-2 (COX-2) [81]. Recently, much attention has been paid to the role of COX-2 in carcinogenesis. It’s also extensively expressed in OC and oral premalignant lesions and seems to be enhanced specifically in high-risk oral lesions [82]. A significantly higher expression level of iNOS was found in the human OSCC [83]. As a result, iNOS generating NO, and might be able to play an important role in OC progression. It is well known that saliva is a wonderful marker of early disease detection that leads to more effective treatment, risk assessment for future oral and systemic disease and a simple, non-invasive alternative to blood and urine tests. The study of salivary endothelin-1 (ET-1) levels in patients diagnosed with OSCC prior to treatment showed significantly raised salivary ET-1 levels in the OC, relative to controls, suggesting a potential utility of salivary analysis for ET-1 levels for monitoring patients at risk for OC [84]. In addition, detection of antioxidant enzymes may be a useful future marker in the molecular diagnosis of the OC [85].

CONCLUSIONSOC constitutes the most life threatening of all dental

condition. Unfortunately, most malignant oral tumors are not detected until they are in advanced stages. In essence, this poor outcome is related to the majority of patients presenting at an already advanced stage of disease at the time of diagnosis. Even though the biopsy study is fundamental, it is a diagnostic method


with limited sensitivity where one of the most important features is the subjectivity of the pathologist. In the last few years the interest in new diagnostic and prognostic methodology and also for monitoring patients in oral precancer and cancer has re-emerged. Furthermore, a number of molecular-based diagnostic markers have been used to detect the presence of OC with varying degrees of sensitivity and specificity. But, still lack of specific tumoral markers present in all malignant le-sions of the oral cavity.

REFERENCES1. Parkin DM, Bray F, Ferlay J, Pisani P. Estimating the world

cancer burden: Globocan 2000. Int J Cancer 2001; 94: 153–6.2. Jemal A, Thomas A, Murray T, Thun M. Cancer statis-

tics, 2002. CA Cancer J Clin 2002; 52: 23–47.3. Wake M. The urban/rural divide in head and neck can-

cer — the effect of atmospheric pollution. Clin Otolaryngol Allied Sci 1993; 18: 298–302.

4. Bundgaard T, Bentzen SM, Wildt J. The prognostic effect of tobacco and alcohol consumption in intra-oral squamous cell carcinoma. Eur J Cancer B Oral Oncol 1994; 30B: 323–8.

5. Slavkin HC. The human genome, implications for oral health and diseases, and dental education. J Dental Education 2001; 65: 463–79.

6. Blot WJ, McLaughlin JK, Winn DM, et al. Smoking and drinking in relation to oral and pharyngeal cancer. Cancer Res 1988; 48: 3282–7.

7. Negri E, La Vecchia C, Franceschi S, Tavani A. Attribu-table risk for oral cancer in northern Italy. Cancer Epidemiol Biomarkers Prev 1993; 2: 189–93.

8. Horowitz AM, Goodman HS, Yellowitz JA, Nourjah PA. The need for health promotion in oral cancer prevention and early detection. J Public Health Dent 1996; 56: 319–30.

9. Dolan RW, Vaughan CW, Fuleihan N. Symptoms in early head and neck cancer: an inadequate indicator. Otolaryngol Head Neck Surg 1998; 119: 463–7.

10. Ellison MD, Campbell BH. Screening for cancer of the head and neck: addressing the problem. Surg Oncol Clin N Am 1999; 8: 725–34.

11. Greenlee RT, Hill-Harmon MB, Murray T, Thun M. Cancer statistics, 2001. CA Cancer J Clin 2001; 51: 15–36.

12. Dahlstrom KR, Little JA, Zafereo ME, et al. Squamous cell carcinoma of the head and neck in never smoker-never drinkers: a descriptive epidemiologic study. Head Neck 2008; 30: 75–84.

13. Llewellyn CD, Johnson NW, Warnakulasuriya KA. Risk factors for squamous cell carcinoma of the oral cavity in young people–a comprehensive literature review. Oral Oncol 2001; 37: 401–18.

14. Kademani D. Oral cancer. Mayo Clin Proc 2007; 82: 878–87.

15. Franceschi S, Bidoli E, Herrero R, Muñoz N. Com-parison of cancers of the oral cavity and pharynx worldwide: etiological clues. Oral Oncol 2000; 36: 106–15.

16. Moore SR, Johnson NW, Pierce AM, Wilson DF. The epidemiology of mouth cancer: a review of global incidence. Oral Dis 2000; 6: 65–74.

17. La Vecchia C, Lucchini F, Negri E, Levi F. Trends in oral cancer mortality in Europe. Oral Oncol 2004; 40: 433–9.

18. La Vecchia C, Tavani A, Franceschi S, et al. Epidemiology and prevention of oral cancer. Oral Oncol 1997; 33: 302–12.

19. McCredie M, Coates MS, Day P, Bell JC. Changes in cancer incidence and mortality in New South Wales. Med J Aust 1995; 163: 520–3.

20. Macfarlane GJ, McCredie M, Coates M. Patterns of oral and pharyngeal cancer: Incidence in New South Wales, Australia. J Oral Pathol Med 1994; 23: 241–5.

21. Spitz MR, Newell GR. Descriptive epidemiology of squamous cell carcinoma of the upper aerodigestive tract. Cancer Bull 1987; 39: 79–81.

22. Macfarlane GJ, Zheng T, Marshall JR, et al. Alcohol, tobacco, diet and the risk of oral cancer: a pooled analysis of three case-control studies. Eur J Cancer B Oral Oncol 1995; 31B: 181–7.

23. Cinciripini PM, McClure JB. Smoking cessation: re-cent developments in behavioral and pharmacologic interven-tions. Oncology (Williston Park) 1998; 12: 249–56.

24. Altieri A, Bosetti C, Gallus S, et al. Wine, beer and spi-rits and risk of oral and pharyngeal cancer: a case-control study from Italy and Switzerland. Oral Oncol 2004; 40: 904–9.

25. Franceschi S, Levi F, Dal Maso L, et al. Cessation of alcohol drinking and risk of cancer of the oral cavity and pharynx. Int J Cancer 2000; 85: 787–90.

26. Rodriguez T, Altieri A, Chatenoud L, et al. Risk factors for oral and pharyngeal cancer in young adults. Oral Oncol 2004; 40: 207–13.

27. Chen PC, Pan CC, Kuo C, Lin CP. Risk of oral nonma-lignant lesions associated with human papillomavirus infec-tion, betal quid chewing, and cigarette smoking in Taiwan: an integrated molecular and epidemiologic study. Arch Pathol Lab Med 2006; 130: 57–61.

28. Scheifele C, Nassar A, Reichart PA. Prevalence of oral cancer and potentially malignant lesions among shammah users in Yemen. Oral Oncol 2007; 43: 42–50.

29. Zhang ZF, Morgenstern H, Spitz MR, et al. Marijuana use and increased risk of squamous cell carcinoma of the head and neck. Cancer Epidemiol Biomarkers Prev 1999; 8: 1071–8.

30. Taghavi N, Yazdi I. Type of food and risk of oral cancer. Arch Iran Med 2007; 10: 227–32.

31. Pelucchi C, Talamini R, Negri E, et al. Folate intake and risk of oral and pharyngeal cancer. Ann Oncol 2003; 14: 1677–81.

32. Pavia M, Pileggi C, Nobile CG, Angelillo IF. Associa-tion between fruit and vegetable consumption and oral cancer: a meta-analysis of observations studies. Am J Clinical Nutr 2006; 83: 1126–34.

33. Hunter KD, Parkinson EK, Harrison PR. Profiling early head and neck cancer. Nat Rev Cancer 2005; 5: 127–35.

34. Perea-Milla López E, Miñarro-Del Moral RM, Martínez-García C, et al. Lifestyles, environmental and phe-notypic factors associated with lip cancer: a case-control study in southern Spain. Br J Cancer 2003; 88: 1702–7.

35. Rosenquist K, Wennerberg J, Schildt EB, et al. Oral status, oral infections and some lifestyle factors as risk fac-tors for oral and oropharyngeal squamous cell carcinoma: a population-based case-control study in southern Sweden. Acta Otolaryngol 2005; 125: 1327–36.

36. Bloching M, Reich W, Schubert J, et al. The influence of oral hygiene on salivary quality in the Ames Test, as a marker for genotoxic effects. Oral Oncol 2007; 43: 933–9.

37. Mashberg A, Barsa P, Grossman ML. A study of the relationship between mouthwash use and oral and pharyngeal cancer. J Am Dent Assoc 1985; 110: 731–4.

38. Carretero Pelaez MA, Esparza Gomez GC, Figuero Ruiz E, Cerero Lapiedra R. Alcohol-containing mouthwashes and oral cancer: critical analysis of literature. Med Oral 2004; 9: 116–20.

39. Rautemaa R, Hietanen J, Niissalo S, et al. Oral and oesophageal squamous cell carcinoma-a complication or compo-nent of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, APS-I). Oral Oncol 2007; 43: 607–13.


40. Goutzanis L, Vairaktaris E, Yapijakis C, et al. Diabetes may increase risk for oral cancer through the insulin receptor substrate-1 and focal adhesion kinase pathway. Oral Oncol 2007; 43: 165–73.

41. Rasheed MH, Beevi SS, Geetha A. Enhanced lipid per-oxidation and nitric oxide products with deranged antioxidant status in patients with head and neck squamous cell carcinoma. Oral Oncol 2007; 43: 333–8.

42. Bahar G, Feinmesser R, Shpitzer T, et al. Salivary analysis in oral cancer patients: DNA and protein oxidation, reactive nitro-gen species, and antioxidant profile. Cancer 2007; 109: 54–9.

43. Herrero R, Castellsagué X, Pawlita M, et al. Human papillomavirus and oral cancer: the International Agency for Research on Cancer multicenter study. J Natl Cancer Inst 2003; 95: 1772–83.

44. Smith EM, Ritchie JM, Summersqill KF, et al. Human papillomavirus in oral exfoliated cells and risk of head and neck cancer. J Natl Cancer Inst 2004; 96: 449–55.

45. Kreimer AR, Clifford GM, Boyle P, Franceschi S. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev 2005; 14: 467–75.

46. D’Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med 2007; 356: 1944–56.

47. Llewellyn CD, Johnson NW, Warnakulasuriya KA. Risk factors for oral cancer in newly diagnosed patients aged 45 years and younger: a case-control study in Southern England. J Oral Pathol Med 2004; 33: 525–32.

48. Mork J, Lie AK, Glattre E, et al. Human papilloma-virus infection as a risk factor for squamous-cell carcinoma of the head and neck. N Engl J Med 2001; 344: 1125–31.

49. Parker TM, Smith EM, Ritchie JM, et al. Head and neck cancer associated with herpes simplex virus 1 and 2 and other risk factors. Oral Oncol 2006; 42: 288–96.

50. Campisi G, Giovannelli L, Calvino F, et al. HPV infec-tion in relation to OSCC histological grading and TNM stage. Evaluation by traditional statistics and fuzzy logic model. Oral Oncol 2006; 42: 638–45.

51. Spitz MR, Fueger JJ, Beddingfield NA, et al. Chro-mosome sensitivity to bleomycin induced mutagenesis an independent risk factor for upper aerodigestive tract cancer. Cancer Res 1989; 49: 4626–8.

52. Villaret DB, Wang T, Dillon D, et al. Identification of genes over expressed in head and neck squamous cell carci-noma using a combination of complementary DNA subtraction and microarray analysis. Laryngoscope 2000; 110: 374–81.

53. Petti S, Scully C. Oral cancer knowledge and aware-ness: primary and secondary effects of an information leaflet. Oral Oncol 2007; 43: 408–15.

54. Pitchers M, Martin C. Delay in referral of oropharyn-geal squamous cell carcinoma to secondary care correlates with a more advanced stage at presentation, and is associated with poorer survival. Br J Cancer 2006; 94: 955–8.

55. Franceschi S, Talamini R, Barra S, et al. Smoking and drinking in relation to cancers of oral cavity, pharynx, larynx and esophagus in Northern Italy. Cancer Res 1990; 50: 6502–7.

56. Holmstrup P, Vedtofte P, Reibel J, Stoltze K. Oral premalignant lesions: is a biopsy reliable? J Oral Pathol Med 2007; 36: 262–6.

57. Mognetti B, Di Carlo F, Berta GN. Animal models in oral cancer research. Oral Oncol 2006; 42: 448–60.

58. Gimenez-Conti IB, Slaga TJ. The hamster cheek pouch model of carcinogenesis and chemoprevention. Adv Exp Med Biol 1992; 320: 63–7.

59. Tang XH, Knudsen B, Bemis D, et al. Oral cavity and esophageal carcinogenesis modeled in carcinogen-treated mice. Clin Cancer Res 2004; 10: 301–13.

60. Ogawa K, Tanuma J, Hirano M, et al. Selective loss of re-sistant alleles at p15INK4B and p16INK4A genes in chemically-induced rat tongue cancers. Oral Oncol 2006; 42: 710–7.

61. Takahashi M, Wakabayashi K. Gene mutations and altered gene expression in azoxymethane-induced colon car-cinogenesis in rodents. Cancer Sci 2004; 95: 475–80.

62. Tanaka T, Kohno H, Nomura E, et al. A novel gerany-lated derivative, ethyl 3-(4’-geranyloxy-3’-methoxyphenyl)-2-propenoate, synthesized from ferulic acid suppresses car-cinogenesis and inducible nitric oxide synthase in rat tongue. Oncology 2003; 64: 166–75.

63. Epstein JB, Zhang L, Rosin M. Advances in the diag-nosis of oral premalignant and malignant lesions. J Can Dent Assoc 2002; 68: 617–21.

64. Just T, Stave J, Kreutzer HJ, et al. Confocal micro-scopic evaluation of epithelia of the larynx. Laryngorhinooto-logie 2007; 86: 644–8 [In German].

65. Myers L, Wax MK. Positron emission tomography in the evaluation of the negative neck in patients with oral cavity cancer. J Otolaryngol 1998; 27: 342–7.

66. Lane EB, Alexander CM. Use of keratin antibodies in tumour diagnosis. Semin Cancer Biol 1990; 1: 165–79.

67. Ogden GR, Chisholm DM, Adi M, Lane EB. Cyto-keratin expression in oral cancer and its relationship to tumour differentiation. J Oral Pathol Med 1993; 22: 82–6.

68. Ogden GR, McQueen S, Chisholm DM, Lane EB. Keratin profiles of normal and malignant oral mucosa using exfoliative cytology. J Clin Pathol 1993; 46: 352–6.

69. Ogden GR, Cowpe JG, Chisholm DM, Lane EB. DNA and keratin analysis of oral exfoliative cytology in the detection of oral cancer. Eur J Cancer B Oral Oncol 1994; 30B: 405–8.

70. Burstein HJ, Schwartz RS. Molecular origins of cancer. N Engl J Med 2008; 358: 527.

71. Warnakulasuriya KA, Johnson NW. Expression of p53 mutant nuclear phosphoprotein in oral carcinoma and potentially malignant oral lesions. J Oral Pathol Med 1992; 21: 404–8.

72. Kaur J, Srivastava A, Ralhan R. Overexpression of p53 protein in betel- and tobacco-related human oral dysplasia and squamous-cell carcinoma in India. Int J Cancer 1994; 58: 340–5.

73. Raybaud-Diogene H, Tetu B, Morency R, et al. p53 over-expression in head and neck squamous cell carcinoma: review of the literature. Eur J Cancer B Oral Oncol 1996; 32B: 143–9.

74. Lopez-Martínez M, Anzola M, Cuevas N, et al. Clinical applications of the diagnosis of p53 alterations in squamous cell carcinoma of the head and neck. Med Oral 2002; 7: 108–20.

75. Ogden GR, Kiddie RA, Lunny DP, Lane DP. Assess-ment of p53 protein expresion in normal, benign and malignant oral mucosa. J Pathol 1992; 166: 389–94.

76. Ogden GR, Leigh I, Chisholm DM, et al. Exfoliative cytology of normal oral mucosa-assessing basal cell keratin phenotype. Acta Cytol 1996; 40: 933–6.

77. Ogden GR. The future role for oral exfoliative cytolo-gy-bleak or bright? Oral Oncol 1997; 33: 2–4.

78. Partridge M, Pateromichelakis S, Phillips E, et al. A case-control study confirms that microsatellite assay can identify patients at risk of developing squamous cell carcinoma within a field of cancerization. Cancer Res 2000; 60: 3893–8.

79. Huang MF, Chang YC, Liao PS, et al. Loss of heterozy-gosity of p53 gene of oral cancer detected by exfoliative cytolo-gy. Oral Oncol 1999; 35: 296–301.


80. Rosin MP, Cheng X, Poh C, et al. Use of allelic loss to predict malignant risk for low-grade oral epithelial dysplasia. Clin Cancer Res 2000; 6: 357–62.

81. Lala PK, Chakraborty C. Role of nitric oxide in carcinogene-sis and tumour progression. Lancet Oncol 2001; 2: 149–56.

82. Wang Z. The Role of COX-2 in Oral Cancer Develop-ment, and Chemoprevention / Treatment of Oral Cancer by Se-lective COX-2 Inhibitors. Curr Pharm Des 2005; 11: 1771–7.

83. Chen YK, Hsue SS, Lin LM. Increased expression of inducible nitric oxide synthase for human buccal squamous-

cell carcinomas: immunohistochemical, reverse transcription-polymerase chain reaction (RT–PCR) and in situ RT–PCR studies. Head Neck 2002; 24: 925–32.

84. Pickering V, Jordan RC, Schmidt BL. Elevated salivary endothelin levels in oral cancer patients — a pilot study. Oral Oncol 2007; 43: 37–41.

85. Yang J, Lam EW, Hammad HM, et al. Antioxidant enzyme levels in oral squamous cell carcinoma and normal human oral epithelium. J Oral Pathol Med 2002; 31: 71–7.

РАК РОТОВОЙ ПОЛОСТИ: ФАКТОРЫ РИСКА, ПРОФИЛАКТИКА И ДИАГНОСТИКА

Рак ротовой полости — редкое заболевание, не привлекавшее до недавнего времени особого интереса у исследователей. Указанная патология находится на 12-м месте среди других форм рака по частоте возникновения и относится к наиболее опасным заболе-ваниям ротовой полости. Этиология рака ротовой полости обусловлена многими факторами. Как при других злокачественных заболеваниях, ранняя диагностика способствует повышению уровня выживаемости и облегчению страданий больных. Повышение частоты заболеваемости и смертности от рака ротовой полости во всем мире привело к повышению интереса к исследованиям в области профилактики и ранней диагностики данной патологии. Таким образом, начался поиск новых подходов, которые могли бы стать альтернативой биопсии. Для выявления рака был использован ряд молекулярно-биологических маркеров с разной сте-пенью чувствительности и специфичности. В данном обзоре рассмотрены современные представления о частоте возникновения, показателях смертности, поиске факторов риска, профилактике и диагностике рака ротовой полости.Ключевые слова: рак ротовой полости, частота возникновения, смертность, факторы риска, профилактика, диагностика.

Copyright © Experimental Oncology, 2008

Documents

718