Among young people (under the age of 45 years) with mouth cancer, up to 25 per cent appear not to have had any exposure to the major known risk factors such as tobacco, alcohol or betel. Other factors known to be involved in OSCC include solar irradiation in lip cancers. Immunodeficient patients may also develop oral potentially malignant and malignant neoplasms.
Besides these factors, infections such as poor oral hygiene, periodontal disease, chronic candidosis, and virus infections link statistically with OSCC. Human papillomavirus (HPV) infection is also increasingly implicated - particularly in oropharyngeal cancer (fig 1).
Bacteria
Many patients with OSCC have poor oral health, with carious teeth and periodontitis. The use of tobacco and alcohol are confounding factors difficult to control in epidemiological studies, but periodontal disease has been shown to increase the statistical risk for cancer. One study showed that practising no regular oral hygiene conferred a risk for oesophageal cancer when compared with those who undertook daily tooth brushing. Another large-scale casecontrol study involving 856 upper aerodigestive tract cancer cases and 2696 age- and sex-matched controls, showed that, compared with toothbrushing once per day, the adjusted odds ratio for brushing twice or more was 0.82 (95 per cent confidence interval: 0.68, 0.99) but for not brushing was 1.79 (0.79, 4.05), suggesting brushing might protect against cancer.
Specific mouth bacteria have been suggested to play a role in carcinogenesis. In the past, syphilis has been mentioned to be associated with cancer. Streptococcus anginosus and Treponema denticola have been linked with various upper gastrointestinal tract carcinomas. Several oral bacteria can metabolise alcohol to the carcinogenic product acetaldehyde - possibly explaining any association between poor oral hygiene, alcohol consumption and carcinogenesis.
Fungi
Yeasts may be causally involved in oral leukoplakia, and dysplastic changes. Candidal leukoplakias have been estimated to develop into carcinomas in up to 40 per cent of cases. Candida albicans is the most common yeast but increasing numbers of non-albicans candida albicans are seen increasingly in OSCC patients. Nitrosamine compounds can be produced by candida, and candida can also convert alcohol into acetaldehyde.
Patients with congenital chronic candidosis may also be predisposed to OSCC - but this might be because they are immunocompromised.
Viruses
Herpes simplex viruses (HSV) have been associated with lip carcinoma, and Epstein-Barr virus (EBV) has been associated with nasopharyngeal carcinomas, and lymphomas.
Human papillomavirus (HPV) infection, the most common sexually shared infection, is implicated in oropharyngeal carcinoma. HPV-6, -11, -16, -18, -31, -33, and -42 have been isolated from the mouth in various groups of patients and HPV infection may be latent in 12 per cent of subjects with clinically healthy oral mucosa.
Human papillomaviruses can be transmitted by close contact between skin and/or mucosae, and risk factors for infection include:
- early onset of sexual activity,
- unknown sexual partners,
- multiple sexual partners,
- lack of condom use.
Most sexually active adults become infected with high-risk (cancerpromoting or oncogenic) HPV types such as HPV-16 and HPV-18 at some stage - but most patients (90 per cent) clear the HPV infection spontaneously within two years. For example, in one study of 1,626 males in Brazil, Mexico, and USA, after one year:
-
4·4 per cent had acquired incident oral HPV infection, and
-
1·7 per cent acquired oral oncogenic HPV infection.
However, new oral oncogenic HPV infections were rare and most cleared spontaneously (presumably via immune defences) within one year.
Persistent HPV infection (~10 per cent) can cause cancer. HPVs play a role in some anogenital cancers, including cancers of the:
- Cervix
- Anus
- Vulva
- Vagina
- Penis
Risk factors for oropharyngeal cancer include a high lifetime number of oral-sex partners (six or more) or vaginal-sex partners (26+).
Oral cancer is also increased in:
- patients with anogenital cancer,
- patients with cervical cancer,
- partners of women with cervical cancer.
Anal, genital and skin cancers are increased in patients with OSCC. HPV of all types can be transmitted between the mouth and anogenital region, and there are associations demonstrated between oral and anogenital cancers.
HPV-16, regarded as oncogenic, is increased mainly in oropharyngeal cancer (tongue base: fauces). HPVassociated oropharyngeal cancers are associated with:
- HPV-16 (90 per cent) but also HPVs 18, 31, 33 – HPVs which are also associated with high risk anogenital cancers.
- Reduced tumour suppressor gene expression.
- Marijuana use; but they are not linked to alcohol, tobacco or betel use or poor oral health status (fig 1).
HPV-associated cancers are increasing in USA, Canada and Australia, several European countries, including Denmark and Sweden and now, 70 per cent OPSCC are caused by HPV. It has been estimated that, by 2020, OPSCCs will exceed cervical cancer. The new HPV vaccines also have a protective effect. A vaccine against HPV is now administered to young people in an effort to prevent cervical cancer and this affords protection against other HPV-related lesions but there is no hard evidence yet, as to a significant protective effect against oral cancer.
References available on request.