Epidemic in Sex-Related Oral Cancer Highlights Need for Guidelines

Human papilloma virus

Over the past few decades, the annual incidence of oropharyngeal squamous cell carcinoma (OPSCC) has increased sharply in several countries, including in the United States.^1,2A closer look at the data shows that the rise in human papilloma virus (HPV)—positive OPSCC accounts for most of the increase.²

The Role of Oral Human Papilloma Virus in OPSCC

“The proportion of HPV-positive oropharyngeal cancers has increased over the past 20 to 30 years in the US,” said Anil K. Chaturvedi, PhD, an investigator in the Infections and Immunoepidemiology branch of the National Cancer Institute (NCI), who has conducted extensive research into the prevalence and natural history of HPV-related OPSCC. Chaturvedi said the proportion of HPV-positive OPSCC was only 16% during the 1980s but climbed to 72% during the 2000s. He and several colleagues have predicted that in 20 years HPV-positive OPSCC will be the predominant head and neck cancer in the US.²Maura L. Gillison, MD, PhD, is a professor of internal medicine and the Jeg Coughlin Chair of Cancer Research, division of medical oncology, at The Ohio State University, and one of the first clinicians to discover the link between oral HPV and oral cancer. It was 1996, and HPV was already recognized as the primary cause of cervical cancer and a driver of other anogenital cancers.

“My thesis mentor, Keerti V. Shah, MD, PhD, at John Hopkins School of Public Health, was intrigued by a single case report that found HPV DNA in a cell line derived from an oral cancer. He and I decided to investigate the association further to determine if this was just a one-time rare occurrence or indicative of a more frequent event than was appreciated at the time,” Gillison explained.

Since then, Gillison has conducted numerous studies and published several articles on the link between oral HPV and OPSCC. Not surprisingly, the increase in HPV-positive OPSCC coincides with an increase in the prevalence of oral HPV.

&ldquo;Data through 2009 from the Centers for Disease Control and Prevention (CDC) and the NCI indicate an ongoing increase in the rate of oral HPV to that time,&rdquo;³Gillison said. Her research shows that 7% of US men and women 14 to 69 years of age are infected with oral HPV.³The rate of oral HPV is significantly greater among men than among women (10.1% vs 3.6%, respectively;P<.001), and Gillison said she and her colleagues will soon publish a paper that shows men are more susceptible than are women to HPV-positive oral cancer.

Age is also a significant risk factor for oral HPV infection, with higher rates in people 30 to 34 years of age (7.3%; 95% confidence interval [CI], 4.6%-11.4%) and in those 60 to 64 years of age (11.4%; 95% CI, 8.5%-15.1%). Gillison and colleagues found no racial differences in prevalence of oral HPV infection. However, a recent study reported lower rates of HPV-positive OPSCC in black people than in white or Hispanic people or in Asian Pacific Islanders.⁴More studies are needed to explain these racial differences.

In a study by Gillison et al,³the prevalence of oral HPV infection was 8 times greater in individuals who had experienced sexual intercourse than in people who had not, and having a higher number of partners was associated with a higher likelihood of having oral HPV infection. Approximately 20% of people who reported having had more than 20 sexual partners had oral HPV.

Testing for Oral HPV Infection in OPSCC

&ldquo;Just like genital HPV, oral HPV seems to be a sexually transmittable disease, and cultural changes in sexual practices over time are certainly having an effect,&rdquo; said William H. Westra, MD, Johns Hopkins. Although oral-to-anogenital contact is strongly believed to be the primary transmission route for oral HPV, the risk of contracting oral HPV this way or through kissing is unclear; the few studies investigating the subject report conflicting results.⁵More than 200 types of HPV have been identified.6 With most types, the body is able to fight off the infection. However, type 16 and type 18 are highly carcinogenic and responsible for most cervical cancers.¹

&ldquo;Probably around 95% of HPV-positive OPSCC is due to HPV-16,&rdquo; Westra said, who recommends testing patients with OPSCC for oral HPV infection.

&ldquo;Even if you just tested for HPV-16, you would pick up the vast majority of HPV-related tumors,&rdquo; he explained.

Pathologists at Johns Hopkins automatically test biopsy specimens from suspected oropharyngeal cancer for HPV.

&ldquo;HPV status probably represents the most powerful prognostic indicator for patients with HPV-positive tumors,&rdquo; Westra said, explaining that HPV-negative OPSCC is associated with worse outcomes than HPV-positive disease. Another reason to test OPSCC cancer for HPV is that it may be used to guide therapy in the near future, according to Westra.

&ldquo;Clinical studies right now are looking at de-intensification therapy for patients with HPV-positive tumors, which would minimize the side effects of therapy,&rdquo; he explained.

Although current guidelines do not call for routine HPV testing in patients with OPSCC, oncology consensus groups are moving in that direction, according to Westra.

Preventing HPV-Positive OPSCC

&ldquo;I&rsquo;m currently working with the College of American Pathologists, and we hope to put out our recommendations within the next year or two,&rdquo; said Westra. He recently published a review on the different modalities available for HPV testing and said the many options make it easy to accurately determine the HPV status of almost all OPSCC tumors.⁷Although some physicians test all head and neck cancers for HPV, Westra said the published data do not support this.No medical treatment is available for oral HPV. Many people manage to fight off HPV infection or clear the disease, but without being able to predict who those individuals are, prevention of oral HPV is essential for reducing the risk of OPSCC. Although studies have not specifically tested whether or not HVP vaccination prevents OPSCC, Chaturvedi said, &ldquo;A recent analysis from the NCI-sponsored Costa Rica HPV Vaccine Trial indicated that current vaccines had high efficacy against the presence of HPV in the mouth 4 years after vaccination.&rdquo;⁸

He added: &ldquo;Because vaccination is currently done at younger ages (9 to 26 years), it will take several decades to observe declines in oropharyngeal cancer rates.&rdquo;

Without clear data on how oral HPV is transmitted, physicians may struggle with how to advise their patients on how to prevent oral HVP infection.

&ldquo;For other sexually transmitted infections transmitted through oral sex, such as oral gonorrhea, use of condoms or other barrier methods has been shown to reduce transmission,&rdquo; said Gillison.

Clinical Pearls

• Over the past few decades, incidence OPSCC increased sharply worldwide.
• HPV-positive OPSCC was 16% during 1980s but 72% during 2000s.
• Prevalence of oral HPV was 8 times greater in individuals who had sexual intercourse than in people who had not.
• HPV type 16 and type 18 are highly carcinogenic and responsible for most cervical cancers.
• HPV status represents prognostic indicator for patients with HPV-positive tumors.
• Current guidelines do not call for routine HPV testing in patients with OPSCC, but oncology consensus groups are moving in that direction.
• Recent analysis indicated that current vaccines have high efficacy against the presence of HPV in the mouth 4 years after vaccination.
• Several clinical trials in patients with HPV-positive OPSCC are ongoing.

Gillison and others have identified smoking as a risk factor for oral HPV, which offers patients another reason to quit. She said it is not clear whether smoking increases the risk of HPV-positive OPSCC but that, &ldquo;preliminary studies suggest smoking mediates the effect of oral HPV infection by promoting persistence of the infection.&rdquo;

What this means, said Gillison, is that, &ldquo;If a person has acquired an oral HPV infection through sexual behavior and they also happen to smoke, their immune system may not clear the infection as effectively as someone who does not smoke.&rdquo;

Several clinical trials in patients with HPV-positive OPSCC are ongoing, and results are expected to be available in the next few years. Oncologists looking for treatment alternatives for their patients with HPV-positive oral cancer can search for an open trial at ClinicalTrials.gov.

References

1. Chaturvedi AK, Anderson WF, Lortet-Tieulent J, et al. Worldwide trends in incidence rates for oral cavity and oropharyngeal cancers.J Clin Oncol. 2013;31:4550-4559.
2. Chaturvedi AK, Engels EA, Pfeiffer RM, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States.J Clin Oncol. 2011;29:4294-4301.
3. Gillison ML, Broutian T, Pickard RKL, et al. Prevalence of oral HPV infection in the United States, 2009-2010.JAMA. 2012;307:693-703.
4. Steinau M, Saraiya M, Goodman MT, et al. Human papillomavirus prevalence in oropharyngeal cancer before vaccine introduction, United States.Emerg Infect Dis. 2014;20:822-828.
5. Centers for Disease Control and Prevention. Human papillomavirus (HPV) and oropharyngeal cancer—fact sheet. http://www.cdc.gov/std/hpv/STDFact-HPVandoropharyngealcancer.htm. Updated November 22, 2013. Accessed January 22, 2015.
6. Oral Cancer Foundation. The HPV connection. http://www.oralcancerfoundation.org/hpv. Accessed January 22, 2015.
7. Westra WH. Detection of human papillomavirus (HPV) in clinical samples: evolving methods and strategies for the accurate determination of HPV status of head and neck carcinomas.Oral Oncol. 2014;50:771-779.
8. Herrero R, Quint W, Hildensheim A, et al. Reduced prevalence of oral human papillomavirus (HPV) 4 years after bivalent HVP vaccination in a randomized clinical trial in Costa Rica.PLoS One. 2013;8:e68329.

<<<

Back to the Head & Neck Cancers Special Report