Oropharyngeal cancer

Human papillomavirus (HPV; odds ratio >200), smoking (odds ratio 6.82) and alcohol (odds ratio 2.43) exposure are the strongest risk factors for developing oropharyngeal carcinoma.[8][13] Often, HPV, tobacco, and/or alcohol are additive risk factors in these patients.[13]

HPV is the most common sexually transmitted disease worldwide, and is spread through sexual contact. Patients with more sexual partners, more oral sexual partners, younger age of exposure, and higher intensity of sexual exposure are at greater risk for HPV-associated oropharyngeal carcinoma.[17][18] There is a large difference in the proportion of HPV positive tumour status among oropharyngeal cancers depending on geographic location; for example, the attributable fraction in Europe is 41.9% and that in Asia is 34.6%.[19] One study found that the risk of HPV-associated second primary cancers (HPV-SPCs) among survivors of HPV-associated cancers is significant, implying that persistent HPV infection at multiple sites may be associated with HPV-SPCs.[20]

Human papillomavirus-induced carcinogenesis is due to binding and suppressing of tumour suppressor genes p53 and pRb, by early viral proteins E6 and E7.[21]

Cigarette smoke contains about 50 carcinogens and pro-carcinogens. The most prominent pro-carcinogens are polycyclic aromatic hydrocarbons and aromatic amines.[22] Most carcinogens and pro-carcinogens require activation by metabolising enzymes such as cytochrome P450.

Alcohol-induced carcinogenesis is mediated through acetaldehyde.[23] Anatomical sites that are directly exposed to alcohol (such as the oral cavity, oropharynx, and hypopharynx) are at risk of cancerisation. People who smoke and drink are at risk of secondary malignancies in their upper aerodigestive tract because of field cancerisation.

Enzymes help detoxify carcinogens such as glutathione-S-transferase (aromatic hydrocarbons and aromatic amines) and alcohol dehydrogenase (acetaldehyde). Individual susceptibility to these carcinogens and pro-carcinogens is believed secondary to genetic polymorphism of these enzymes.[24]

Nitrosamines are the main carcinogens associated with smokeless tobacco.[25]

Arecoline is the main carcinogen associated with betel nuts.[26]

WHO classification of tumours of oropharynx[1][3][4]

Oropharyngeal squamous cell carcinomas have been classified by human papillomavirus (HPV) status into HPV-associated and HPV-independent. WHO recommends this classification only for oropharyngeal cancers, as the association of HPV with cancers of non-oropharyngeal sites is less common and does not appear to affect prognosis.

HPV-associated oropharyngeal cancer (HPV-positive)

Caused by high-risk (oncogenic) HPV; type 16 accounts for most cases.[5] Diffuse expression of p16 immunohistochemical staining (nuclear and cytoplasmic) is seen, and is used as a surrogate marker for HPV positivity. Most patients present with small primary tumours that have metastasised to upper and mid-jugular chain lymph nodes. Painless cervical lymphadenopathy is the most common presentation.[6] Primary tumours are more commonly enhancing and exophytic with well-defined margins. Compared with HPV-independent tumours, HPV-associated oropharyngeal cancers tend to be more indolent and treatment responsive, with a markedly improved prognosis.[7]

HPV-independent oropharyngeal cancers (HPV-negative)

Characterised by the absence of high-risk HPV protein expression. Patients typically present with pain/sore throat, dysphagia, and/or a neck mass. Primary tumours are larger, and nodal disease burden is lower than that for HPV-positive cancers. p16 is typically not overexpressed but can be positive in a small subset of patients.

Pathophysiology

Classification

WHO classification of tumours of oropharynx[1][3][4]