Oral sex with multiple partners and oral infection with human papilloma virus are the strongest risk factors for cancers of the mouth and throat, far outweighing the contribution of alcohol and tobacco, researchers from the Johns Hopkins University Kimmel Cancer Center report in the May 10th issue of the New England Journal of Medicine.
"It’s the virus that drives the cancer," said lead researcher Dr Maura Gillison, an assistant professor of oncology and epidemiology at Johns Hopkins. "Since HPV has already disrupted the cell enough to steer its change to cancer, then tobacco and alcohol use may have no further impact."
Oral cancers have in the past been blamed on heavy smoking and drinking, and an infectious cause has been debated.
Cervical and anal cancers, also caused by human papilloma virus (HPV), have been on the rise among HIV-positive people over the past ten years despite the success of antiretroviral therapy, and the Johns Hopkins findings will alert physicians to the need to be more vigilant to the emergence of cancers of the mouth and throat in HIV-positive people. One large study showed a slightly elevated rate of certain mouth and throat cancers in HIV-positive people, particularly women, in New York state between 1981 and 1994.
The newly published study compared risk factors in 100 HIV-negative patients newly diagnosed with an oropharyngeal cancer (mainly of the tongue or tonsil) and 200 control patients who did not have cancer matched for sex and age. HPV antibody testing of blood took place, and tumours and oral fluid were also examined for the presence of HPV DNA.
Oral cancer was strongly associated with human papilloma virus type 16 infection (odds ratio 44.8, confidence interval 5.9 – 338.5) and with oral HPV-16 infection (OR 43.7, CI 4.2 – 452.7 in patients with no history of heavy tobacco or alcohol use, and a 19-fold increased risk among those who did drink or smoke heavily. HPV 16 is one of the two types of human papilloma virus to be associated with cervical, vaginal and anal cancers, along with HPV 18.
The association dwarfs the connection between high cholesterol and heart attacks, say the researchers.
HPV 16 was present in the tumors of 72% of oropharyngeal cancer patients enrolled in the study, a figure that dwarfs the connection between high cholesterol and heart attacks. The researchers also were able to find higher risk in patients with traces of HPV in oral rinses, a first step to developing a "swish-and-spit" screening method for at-risk individuals.
However HPV-16 was not the only type of human papilloma virus to be associated with an increased risk of oral and throat cancers. Any type of HPV was associated with an elevated risk (OR 12.3).
Study participants who reported having more than six oral sex partners in their lifetime were 8.6 times more likely to develop the HPV-linked cancer (confidence interval 2.2 – 34, p<0.001), while individuals with more than 26 lifetime vaginal sex partners were 4.2 times more likely to be diagnosed with an oral or throat cancer (CI 1.8-9.4, p=0.001). However there was no increased risk associated with sex with same-sex partners.
Dr Gillison said that "people should be reassured that oropharyngeal cancer is relatively uncommon, and the overwhelming majority of people with an oral HPV infection probably will not get throat cancer."
"It is important for health care providers to know that people without the traditional risk factors of tobacco and alcohol use can nevertheless be at risk for oropharyngeal cancer," said Gypsyamber D’Souza, a co-author and assistant scientist at the Johns Hopkins Bloomberg School of Public Health.
Oral sex, including both fellatio and cunnilingus, is the main route of transmission for oral HPV infection, the investigators say, although mouth-to-mouth transmission remains possible and was not ruled out by the current study.
Human papilloma virus can also be transmitted by skin contact and is found in the mucous of the genital tract, and in saliva, urine, and semen. Both men and women contract the ubiquitous virus in equal numbers, which is believed to have infected a large proportion of people worldwide at some point in their lives. Most HPV infections clear with little or no symptoms, but a small percentage of men and women who acquire cancer-causing strains, such as HPV 16, may develop a cancer.
As for an oral rinse screening test, its feasibility still remains unproven. For this study, Gillison and her colleagues spent two years refining methods to detect HPV in oral samples. She also is working with manufacturers of the new FDA-approved vaccine for HPV to determine its potential in curbing oral cancers.
HPV-linked oral cancers have been on the rise since at least 1973, and Dr Gillison expects the trend to continue to a point when HPV-associated cancers will far outpace those caused by tobacco and alcohol use. They currently account for 60 percent of oropharyngeal cancers and about a third of all oral cavity and pharynx cancers in the United States, totalling more than 11,000 individuals.
D'Souza G et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med 356: 1944-1956, 2007.