HPV-RELATED DISEASE IN THE HEAD AND NECK

Oropharyngeal cancer

Epidemiology

In common with other head and neck cancers, SCC of the oropharynx has traditionally been associated with smoking and alcohol consumption. However, in the last 30 years the incidence of smoking-related head and neck cancer has declined in most countries. In contrast, the incidence of oropharyngeal cancer has been steadily increasing in many countries, including New Zealand. This has coincided with an increasing incidence of HPV as the aetiological factor in these cancers.(101,102) HPV, along with other viruses and bacteria, preferentially accumulates in the lymphoid tissue of the palatine and lingual tonsils. Because of this, hrHPV is more likely to cause SCC in these locations than at other sites in the upper aerodigestive tract. In the tonsils and base of the tongue, up to 93% of SCC is now attributable to HPV, with significant international geographic variation.(103-106) A recent New Zealand study found that 75% of oropharyngeal cancers were attributable to HPV.(107) HPV remains an uncommon factor in cancers of the oral cavity, hypopharynx and larynx.

Risk factors

It has been noted that HPV-related oropharyngeal cancers are approximately four times more common in men than in women.(101,104) In the United States, the rate of oropharyngeal cancer in men is now higher than the rate of cervical cancer in women.(101) The exact reason for this gender predilection is not clear; putative reasons are a greater viral load in the female genital tract and a greater immune response in females than in males.(108) The average age at diagnosis is lower in HPV-associated oropharyngeal cancer than in smoking-related cancer, although the latency after HPV infection is typically at least 10 years, and can be several decades.

The HPV subtypes implicated in oropharyngeal SCC are similar to those involved in cervical cancer. HPV 16 fulfils epidemiological criteria for being high-risk in the oropharynx, and is implicated in up to 90% of HPV cases. HPV types 18, 31, 33, 35 and 52 have not been studied as thoroughly, and are classified as potentially high-risk.(106,109) A strong correlation is seen between higher numbers of oral sexual partners and the development of oropharyngeal SCC, particularly with six or more lifetime sexual partners.(110,111) Other features of sexual behaviour which are less strongly associated with head and neck cancer include younger age at sexual debut, history of genital warts or sexually transmitted infections, rare or non-use of condoms and oral-anal sex.(110) Similarly, the prevalence of HPV positivity in oral samples is greater in individuals with a higher number of lifetime sexual partners.(104) As a result of these observations, oral sex is believed to be the mode of transmission of HPV to the oropharynx in most cases.

Clinical presentation

Oropharyngeal SCC can present with throat symptoms and an ulcerated or non-ulcerated mass visible on oral examination. However, many patients have lateral cervical lymph node metastases at the time of diagnosis, and not infrequently a neck mass is the only clinical finding at diagnosis. Therefore, HPV-related oropharyngeal SCC should be considered in any patient, particularly a man, presenting with a painless lateral neck mass.

Treatment and prognosis

In recent decades, in most centres the preferred treatment for oropharyngeal SCC has been concurrent chemoradiation therapy. It has been noted that the prognosis for patients with HPV-related oropharyngeal cancer is much better than for those with HPV negative, smoking-related oropharyngeal cancers. Tumours which are HPV positive occurring in smokers have an intermediate prognosis.(112,113) As a result of the observed better outcome in patients with HPV-related disease, many oncologists have felt that it may be possible to reduce the treatment intensity in some way, thereby reducing the not insignificant side effects of treatment while still maintaining a good prognosis. Such de-intensification may include omitting chemotherapy from the treatment, reducing the radiation therapy dose, and reintroducing surgery as the primary treatment modality. The latter has become more attractive with the development of trans-oral robotic surgery. However, it is generally accepted that, for the present, de-intensification of treatment should only be adopted in the context of a formal clinical trial. Many such trials are currently underway, with results expected in the next few years.(114)

Counselling patients

In common with anogenital HPV-related disease, a viral aetiology for oropharyngeal cancer raises questions for the patient, their partner and health practitioners. Common concerns are how the virus is acquired, whether there have been sexual partners outside of the couple and how to manage an ongoing sexual relationship. It is important to emphasise that a diagnosis of HPV-related cancer does not necessarily imply multiple sexual partners or other partners outside the relationship. There is no need to alter sexual activity with a stable partner, as sharing of HPV would have occurred long before the clinical appearance of the cancer. Female partners are not known to be at higher risk of developing cancer (at any site) themselves, but should follow standard cervical screening guidelines. A useful guide to discussing these issues includes a printable patient information sheet.(115) At the time of writing there is no clear evidence for transmission of HPV through kissing.

Prevention

In contrast to cervical cancer, no clinically apparent premalignant condition exists in the vast majority of patients. Similarly, there is no reliable laboratory screening test. Therefore, there is currently no indication for population screening for HPV-related head and neck disease.(116) However, this is an increasingly prevalent disease, and increased awareness of the disease among health professionals and the general population is to be encouraged. Limiting the number of sexual partners, delaying the onset of sexual activity and using barriers such as condoms and latex dams while performing oral sex, may be expected to minimise the risk of developing HPV-related

oropharyngeal cancer.

As with anogenital HPV-related disease, HPV vaccination holds great promise as a mechanism for preventing the development of benign and malignant head and neck HPV-related disease. Vaccination of both boys and girls prior to the onset of sexual activity is strongly recommended.(116)

Recurrent respiratory papillomatosis

Recurrent respiratory papillomatosis (RRP) is a benign condition characterised by papillomatous growths in the respiratory tract. The larynx is the most commonly affected site, and patients can present with hoarseness or airway symptoms. This condition has a bimodal incidence, occurring in young children and in adults. It is an uncommon condition, affecting approximately four per 100,000 children and four per 100,000 adults.(117) It is related to HPV subtypes 6 and 11 in particular.

In children, transmission is thought to be vertical via an infected birth canal in the majority of cases, although intrauterine infection appears to occur in some cases. Vaginal delivery, prolonged labour and being the first-born child of a young mother (<20 years) are associated with an increased risk of developing RRP.(91) Juvenile onset RRP is estimated to be over 200 times more common in mothers with a history of genital warts during pregnancy than in mothers without clinical warts. Despite this, only one in a few hundred children of mothers with a history of genital warts will develop RRP.(118,119)

Caesarean section has been considered as an option for preventing RRP, however it is not completely protective against RRP and is associated with higher maternal morbidity and mortality and a greater economic cost than vaginal delivery. As a result, caesarean section is not recommended for all pregnant women with genital warts. There may be some benefit in managing genital warts during pregnancy, as long as it does not result in an increased risk of miscarriage.(120)

In adult patients, development of RRP is associated with male gender, increased numbers of lifetime sexual partners and frequency of performing oral sex.(91,121) In patients with adult onset RRP the virus may have been acquired later in life than patients with juvenile onset RRP, or the development of disease may represent reactivation of a latent infection acquired at birth.(120)

The mainstay of treatment in both adults and children is surgical debridement of the papillomas. This requires specialist referral. Immunisation with a vaccine including HPV types 6 and 11 has the potential to significantly reduce the incidence of RRP. There is some evidence from Australia that this may already be occurring.(122)