Когда он начинал практиковать в 1994 году, специалист по раку головы и шеи Вендел Yarbrough, то знал какога типа пациенты будут проходить через двери его клиники. Они были, как правило, 50 или 60-ти лет, и в большинстве случаев они объясняли рак свого горла и миндалин годами курения табака и злоупотреблением алкоголя. Yarbrough 's список пациентов из Вандербильт-Ingram ракового центра в Нэшвилле, штат Теннесси, в настоящее время рассказывает иную историю: ткперь нет ничего необычного, что пациентами становятся в возрасте 20 или 30 лет, говорит он, и лишь некоторые из пациентов курят.

Nationally, while the total number of oropharyngeal cancers? affecting the area from the base of the tongue through the tonsils? is in decline, the rate among Americans younger than age 50 is creeping upward. According to surveillance data from the National Cancer Institute (NCI), rates of oropharyngeal cancer in the 20 to 49 age group more than doubled from 1975 to 2005.

A search for the cause has led to a famil- iar suspect: the human papilloma viruses? specifically HPV 16 and to a lesser extent HPV 18, the same strains that cause 70% of cervical cancers in the United States. Sev- eral papers in recent years have documented active HPV DNA in tumor samples from oral cancer patients. In November, an epi- demiological analysis from the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, linked up to 60% of oropharyngeal cancer cases from 1998 and 2003 to HPV. The link is as solid as it is for cervical cancer, says pathologist Lubomir Turek of the University of Iowa in Iowa City.

How significant HPV infection is as a risk factor? and what behaviors put someone at risk for cancer? remain unclear. But the realization that HPV is behind a subset of head and neck cancers is prompting researchers and clinicians to reevaluate how they diagnose and treat oral cancer, which strikes about 34,000 Americans each year. And it's adding another facet to the picture of the health threat of HPV as public health officials weigh expanding vaccination pro- grams. This year, Merck is seeking to get its anti-HPV vaccine Gardasil, which was approved for women in 2006, approved for use in men.

High-risk group? The U.S. rate of oropharyngeal cancer among people aged 20 to 49 rose sharply between 1975 and 2005.

One of the first to publish suspicions that HPV might cause oral cancer is dentist- turned-researcher Stina Syrjanen of the University of Turku in Finland. She and her colleagues started to examine oral cancer tumors for HPV after virologist Harald zur Hausen began isolating HPV DNA in cervi- cal cancer lesions in the early 1980s. The Syrjanen group' s initial surveys and immunochemistry staining of 40 lesions published in 1983 turned up nearly a quarter that were shaped like HPV lesions in cervi- cal cancer. But there wasn' t much interest in this at the time, Syrjanen says.

Papers from other European labs trickled in documenting the presence of HPV anti- bodies in some oral cancer tumors. One published in 1995 by R. D. Steenbergen and colleagues at the Free University Hospital in Amsterdam showed that HPV 16 was integrated and its onco proteins were expressed in an oral cancer tumor cell line.

Those findings had a big impact on Maura Gillison, then a postdoc at Johns Hopkins University in Baltimore, Mary- land. ? I was pretty convinced from this one case? that the link between the virus and this oral cancer was real, she says. Gillison, now a chair of cancer research at Ohio State University, Columbus, began looking for more evidence that the virus actually was triggering oral cancers. Using PCR, sequencing, Southern blot assays, and in situ hybridization, Gillison and colleagues at Johns Hopkins examined 253 head and neck tumors and identified HPV in 62 of them, as they reported in the 3 May 2000 Journal of the National Cancer Institute.

Recent research on HPV and cervical cancer suggests how the process works. Two specific HPV genes, E6 and E7, turn off proteins in cervical cells that suppress tumor growth. In their 2000 study, Gillison and colleagues examined these tumor sup- pressor proteins in head and neck cancer samples. Previous work revealed that the tumor suppressor proteins of HPV-negative oral cancers often show mutations, likely caused by long-term exposure to carcino- gens and alcohol. But the researchers found few such mutations in the HPV-positive samples, so they argued that the onco-proteins were disarming the cell' s tumor suppressors, just as they do in cervical cancer. Over the next several years, labs in the United States and in Europe confirmed the findings. At the 2007 American Society for Clinical Oncology (ASCO) meeting in Chicago, Illinois, Yale University researcher Amanda Psyrri reported that suppressing E6 and E7 RNA in HPV-positive oral cancer cells reactivated the cells' natural tumor sup- pression genes.

The molecular and pathological evi- dence that HPV, particularly HPV 16, can cause oral cancer is convincing, researchers say. ? HPV-related head and neck cancer represents a new entity that is now well- defined,? Dana-Farber Cancer Institute oncologist Robert I. Haddad wrote to the Oral Cancer Foundation after the 2007 ASCO meeting.

Gillison and colleagues at Johns Hop- kins and NCI have been building up an epi- demiological picture of HPV-positive oral cancer. A May 2007 paper in The New Eng- land Journal of Medicine (NEJM) exam- ined 100 cases of oropharyngeal cancer and found that HPV infection could be a risk factor independent of smoking or drinking history. In February 2008, the researchers reported in the Journal of Clinical Oncol- ogy that U.S. National Institutes of Health records show that rates of HPV-related oral cancers significantly increased between 1973 and 2004 while rates of non-HPV oral cancers declined.

When the researchers interviewed patients about their health behaviors, they reported in the 19 March 2008 Journal of the National Cancer Institute, two different profiles emerged. Risk factors for HPV- negative tumors included several decades of pack-a-day smoking, years of heavy drink- ing, and losing teeth? but not having more sex partners. In contrast, having more oral sex partners significantly increased the risk of developing HPV-positive cancer. Unex- pectedly, a history of heavy marijuana usage also seemed to increase risk for HPV- negative tumors in these patients.

Gillison says she has concluded that HPV-positive oral cancer isn' t just a subset of oral cancer but a completely independent disease: ? If the risk factors are that differ- ent, what other evidence do you need??

What you need, Turek and Syrjanen say, are more confirmatory studies. They agree that Gillison' s team is on the right track in doing the larger, case-control studies of the past 2 years. But questions remain. As Turek and Syrjanen have noted, Gillison' s group used the anatomic site of some tumors (around the tonsils, where HPV-positive tumors overwhelmingly occur) as a proxy for evidence of HPV' s presence. Gillison says her team is now doing a molecular analysis of these tumor samples and expects results this year.

Large epidemiological studies could help clinch the risk-factor profile. Stephen Schwartz, an epidemiologist at the Univer- sity of Washington, Seattle, who studies HPV-related cancers, says he's skeptical of a proposed link between HPV-positive oral cancer and marijuana usage, because only one study has demonstrated it so far. But the evidence that disease risk increases with more sexual partners seems stronger, hav- ing been suggested in several studies by independent researchers, he says.

One question all the researchers agree remains unresolved is the natural history of HPV-positive oral cancer. Researchers know it can take 20 to 30 years after HPV infection for cervical cancer to develop in an otherwise healthy woman. They don' t know how long it takes oral cancer to develop or how much of the virus must be present in oral cells to trig- ger cancer, Turek says. A single study of 292 HPV-positive oral cancer patients published in 2001 in NEJM suggests it might take only a decade, but researchers agree that studies are needed to confirm that finding and explain why oral cancer might develop so much faster than cervical cancer.

Gillison argues that researchers don' t need to wait for all questions to be resolved before reassessing how they diag- nose and treat HPV-positive oral cancer patients. In November, Gillison pressed her case to more than 80 head and neck cancer experts at a closed meeting at NCI in Bethesda, Maryland. She and other researchers, including Turek, believe the standard treatment protocol for oral cancer? chemotherapy and radiation, fol- lowed by possible surgery? may be too aggressive for patients with HPV-positive tumors. Researchers and clinicians say they have noticed that these patients tend to respond much better to treatment, specifically radiation: About 85% of patients with HPV-positive tumors are still alive within 5 years of their cancer diagno- sis, compared with about 45% of those with non-HPV tumors. So radiation alone might be enough to treat some of these patients, Gillison argues.

Public health officials, meanwhile, are asking what can be done to prevent the dis- ease. CDC has approved four vaccines against HPV for use in young women to prevent cervical cancer; now the question is whether to expand the recommendations to include young men. Preliminary results from a Merck-funded study found that Gar- dasil effectively prevented HPV infection in the genitals of men, says study leader Joel Palefsky of the University of California, San Francisco. Full results are expected some time this spring, he says. NCI epi- demiologists are also conducting clinical trials to assess whether the vaccine can pre- vent oral HPV infection. It may be years before those results come in, says study leader Aimee Kreimer.

Well before that, CDC's Advisory Com- mittee on Immunization Practices (ACIP) hopes to give its own recommendations on whether men should get vaccinated for HPV and if so, at what age, says CDC medical epi- demiologist Lauri Markowitz. She says ACIP is currently reviewing data from the Merck trials, along with studies on HPV and oral cancer. Schwartz says he thinks the vac- cine will be approved for use in men soon, before researchers fill in the lingering gaps in knowledge about HPV and oral cancer or how effectively vaccination programs might prevent disease. That means taking a bit on faith, he says: I don't have any real reason to think it won't work, but we have to acknowl- edge we're just taking more of a leap here.