HPV and Head & Neck Cancers

Human Papillomavirus (HPV) is one of most common sexually transmitted infections in Australia. It is highly contagious, and although most commonly associated with infection in genital areas, can infect both the mouth and throat. HPV found in the mouth and throat is called ‘oral HPV’.

Few studies have examined specifically how people contract oral HPV, but a clear link has been established with oral sex and possibly open-mouthed kissing. There are numerous subtypes of HPV; with 15 classified as ‘high risk’ subtypes of which 2 (HPV16 and HPV18) are the most common. These high-risk strains can cause cancers in the Head and Neck region, most commonly in the oral cavity and oropharynx.

Studies continue to demonstrate the compelling association between HPV and an increasing proportion of Head and Neck cancers. Such cancers are approximately 3 times more common in men than in women. A recent, paradigm shifting discovery is that patients with Head and Neck cancer are 15 times more likely to be infected with HPV in their mouths or throats than those without. In this way, the epidemeology of Head and Neck cancer is being actively changed by the prevalence of oral HPV.

Oral Cavity and Oropharyngeal Cancers

Each year, oral cavity and oropharyngeal cancer kills hundreds of people; HPV is responsible for between 45 and 90 percent of all oropharyngeal cancers so an understanding of the virus is pivotal.

HPV-positive oropharyngeal malignancies have increased 225 percent from 1988 to 2004, possibly due to changing sexual practices. However, there are many factors at play; until recently there was no widespread clinical awareness of the link between HPV and oral malignancies. This meant it was not routinely looked for or tested.

HPV subtype 16 has become the major player in oral malignancies; it represents over 90 percent of the viruses isolated in HPV-positive Head and Neck cancers. Tumours with HPV 16 status have been shown to be the strongest independent prognostic factor for tumour control and survival in oropharyngeal cancers.

Etiological Factors of HPV-positive Head & Neck Cancers

The etiological factors of HPV-positive cancers of the oral cavity and oropharynx are altogether different to those of their HPV-negative counterparts. Most significantly, this cancer has been strongly linked to sexual activity, specifically having many oral sex partners.

Unlike HPV-negative Head and Neck cancer, there is no statistical association with excess drinking and smoking. A strong clinical suspicion remains that smoking and drinking potentiates the carcinogenic affects of HPV, but increasing evidence suggests this is not the case.

There is emerging information that in the subset of people who have HPV related oral malignancies, there is an increased prevalence of marijuana smoking; how that interplays as a potentiating factor has as yet not been elucidated.

Diagnostic Factors of HPV-positive Head & Neck Cancers

Determining whether oral cavity or oropharyngeal cancer is HPV-positive is important in determining a prognosis for patients, and to some extent, their most appropriate treatment regimes. HPV-positive head and neck cancer is usually diagnosed at a more advanced stage than HPV-negative cancer; upon physical examination, there is often involvement of the cervical lymph nodes.

There is no standardized HPV testing mechanism in Head and Neck cancer; both in situ hybridization and PCR are commonly used. The PCR-based approaches are often linked to a specific genotyping system. There are also methods based on DNA hybridization with specifically labeled probes that can be applied to detect HPV on histological sections.

In general, it is recommended that at least two recognised methods should be used to confirm the diagnosis of clinically relevant HPV-positive Head and Neck cancer.

Another approach for detecting clinically relevant HPV infection is by a combination of p16 immunohistochemistry and GP5+/6+ PCR.

HPV in saliva and oral exfoliated cells has been detected in some recent studies, but the sensitivity and specificity for HPV-related head and neck cancers is too low and the role of HPV detection in saliva and oral exfoliated cells seems uncertain.

It is always important to advise patients that there is no simple blood testing or antibody assay that can at this stage determine whether a tumour is HPV positive.

Prognostic Factors of HPV-positive Head & Neck Cancers

Numerous studies have confirmed that HPV positive tumours of the Head and Neck region have a significantly better prognosis than those that are HPV negative. Lessen’s research demonstrates that their 5 year survival rate is 62 percent compared to 26 percent for non-HPV malignancies. This improved prognosis is regardless of treatment given; it includes even those patients treated exclusively with surgery. Importantly, HPV-positive patients are 58 percent less likely to die within 3 years of treatment compared to their HPV- negative counterparts.

Patients with HPV-positive tumours respond better to chemotherapy and radiation. One study found the 3 year overall survival rate to be 82. 4 percent, compared to 57.1 percent where tumours were HPV-negative. If tumours tested HPV-positive, median survival was nearly 11 years versus 1.6 years for HPV- negative tumours.

HPV positive cancers silence protein 53 (p53) but the gene itself remains intact. This may prove crucial in explaining why people with HPV-positive oropharyngeal cancers respond better to treatment.

Other considerations include that people with the disease are generally healthier than their HPV-negative counterparts, are younger (by 3 to 5 years), don’t smoke and are more likely to comply with treatment regimes. Another possibility is that HPV-negative tumours are more heterogenous than HPV- positive tumours. Vu et al study suggests the underlying mechanism behind the better prognosis of HPV-positive tumours may be enhanced immune response following radiotherapy.

Treatment for HPV-positive Cancers

The treatment of choice for HPV-positive malignancies is either chemotherapy/radiation up front, or surgery followed by radiation therapy with the possible addition of chemotherapy.

Radiation therapy delivers high levels of radiation to kill cancerous cells or stop them from growing. Chemotherapy refers to the use of drugs that kill cancer cells directly. In the treatment of oropharyngeal tumours, chemotherapy is believed to boost the effectiveness of radiation; one meta-analysis found the combination approach increased 5 year overall survival by 8.1 percent.

The demographic of HPV-positive oropharyngeal tumour patients is significantly younger than that of non-HPV patients. As a result of the often debilitating long- term side effects of surgery, chemo and radiation therapies; there is a growing consensus amongst medical professionals that there needs to be a focus on less invasive forms of treatment that deliver the same positive prognosis for HPV positive patients.

Current studies are investigating whether a de-escalation of treatment can reduce toxicity without compromising the strong outcomes for patients. Ongoing phase 3 randomized trials are underway that aim to identify strategies to safely and effectively deescalate treatment. These include TROG 12.01 conducted in Australia, which will assess the substitution of high dose Cisplatin with Cetuximab in chemotherapy. One stage 3 trial will assess whether Erbitux works as well in HPV-positive patients as long standing Cisplatin based chemotherapy regimens. A further trial is examining whether IMRT regimen can be shortened from 6 to 5 weeks; therefore delivering a lower dose of radiation to HPV-positive patients.

Alternative surgical techniques, such as TransOral Robotic Surgery that uses tiny robotic cameras to remove difficult to reach tumours through a patient’s mouth, can also be employed. Operation times are longer and the cost per operation is significantly higher, but doctors can often avoid incisions associated with conventional surgery and the need to split the jaw. There is, at this stage, no evidence that this affords any improvement in results or a lower complication rate than conventional surgical techniques.

HPV Cancer Prevention

Researchers have found that antibodies against HPV may help identify those who are at a significantly higher risk of contracting these oral malignancies. In the study, at least 1 in 3 individuals with oropharyngeal cancer compared to less than 1 in 100 individuals without the cancer were found to have antibodies. When these antibodies were present, they were detectable many years before the onset of the disease. This discovery could mean that in the future a blood test could be used to identify patients with this type of cancer.

The two vaccines approved to prevent cervical cancer (Gardasil and Cervarix) both protect against HPV-16; the cause of 90 percent of HPV related oral malignancies. A clinical trial of 5840 women showed that Cervarix is 93 percent effective at preventing oral HPV infection in both women with pre-existing cervical cancer and those without.

The value and cost benefit of vaccinating boys with Cervarix and Gardasil is under discussion in many countries. Further research needs to be conducted to prove the efficacy of these HPV-16 vaccinations in guarding against HPV-positive head and neck cancers. Currently HPV vaccines are prescribed only to people under 26, although there is evidence they could help prevent Head and Neck cancer in all adults.

HPV in Cancers of the Head and Neck

Background Notes: Transmission of HPV

Like all sexually transmitted infections, HPV is transmitted through sexual contact, specifically genital contact occurring most often during vaginal and anal sex. It can also be passed on during oral sex and genital-to-genital contact.

It is possible to transmit HPV to the mouth during oral sex. Infection may occur after direct contact with a visible wart or contact with genital skin where the virus is present. HPV can be transmitted between both heterosexual and same- sex partners—even when the infected person has no signs or symptoms. Most people infected by HPV do not realize they are infected, or that they are passing HPV onto a sex partner. The majority will never develop symptoms or health problems and 90 percent of infections go away of their own accord within 2 years. A person can still have HPV even if years have passed since he or she has had sexual contact with an infected person. It is also possible to get more than one subtype of HPV.

A recent study concluded that if one person in a heterosexual couple has HPV, there is a 20 percent chance that his or her partner will pick up the virus within six months. The study found no difference between male-to-female and female- to-male transmission rates.

A link has been established between the number of sexual partners in a person’s history and their chances of contracting HPV from a current partner (a significantly increased risk in those with over 5 partners).