"Like investigators elsewhere, we're seeing an increased incidence of oropharyngeal cancer," says Dr. John Deeken, a medical oncologist at Georgetown's Lombardi Cancer Center. Cancer-causing HPV strains tend to infect immune cells at the base of the tongue and tonsils, Deeken explains. "This may be why we're seeing the virus in tumors in those parts of the oropharynx, while the incidence of lip, larynx, and vocal cord cancers is not going up." If the cancer were simply caused by infection with HPV upon sexual transmission there would be more cases in women, he considers.

"The epidemiology is perplexing," he says. "The assumption, when we noticed the trend eight or nine years ago, was that this was a sexually transmitted disease due to more oral sex," he says. "But at least at Georgetown, we have patients in their 80s with this kind of cancer," he notes. "That raises questions about the sexual habits of Americans who are older, or about HPV."

The latency period between initial HPV infection and cancer can last decades, confirms Dr. Maura L. Gillison, an oncologist and professor at Ohio State who has published seminal findings on HPV and cancer. Her group carried out a case control study, reported in the New England Journal of Medicine, revealing that individuals who've had more vaginal and oral sex partners in their lifetime have a higher risk of developing oropharyngeal cancer, and that HPV-16 infection correlates with this cancer type.

Human papillomavirus was one of the first viruses identified in human cancers. Approximately 40 subtypes spread sexually. Two types, HPV-16 and HPV-18, account for most cases of cervical cancer in the U.S. Most women with HPV are asymptomatic and don't get cervical cancer; when and if malignancy develops, it's usually 20, 30 years or longer after initial infection. Most often, oropharyngeal cancers are caused by the HPV-16 subtype.

"The mechanisms by which HPV causes cancer are pretty well-established," Gillison says. Two viral genes, called E6 and E7, are implicated. The virus itself contains only a few genes; it can't propagate apart from human cells. But once HPV has infected squamous cells like those lining the cervix, anus, or pharynx, E6 and E7 take over critical machinery that control processes like DNA repair, cell cycle, and maturation, she explains. Because the virus interferes with signals that normally regulate cell growth, HPV-infected cells tend to survive and replicate.

The E6 and E7 proteins, encoded by the genes, are necessary but not sufficient for cancer formation, Gillison considers. As is the case for HPV infection in the genitals, most individuals infected with HPV in the mouth don't develop tumors. The key question is what other factors -- like damage to the oral cavity from nicotine or other toxins, immune changes, or possibly a genetic disposition -- lead to oropharyngeal tumors in some people, typically years after the initial infection.