Head and neck cancer patients were once primarily older heavy smokers and drinkers. Now, the majority who are diagnosed with the disease are closer to middle age (many ages 40 to 55) and developed it not from years of tobacco or alcohol use but rather because they engaged in oral sex.

This shift has been traced to an increase in the human papillomavirus (HPV), the sexually transmitted infection that also causes cervical cancer. And oropharyngeal cancers are not the only malignancies the virus is spurring on. HPV is now likely responsible for more than 14,000 new cases of noncervical cancer in the U.S. each year.

Despite efforts to immunize more girls against HPV with the Gardasil or Cervarix vaccines—and continued debate about recommending the vaccine for boys—experts expect that number of these virus-linked cancers to continue to grow. "Based on what we have seen, in the past 10 years or so we don't see that the numbers have started to plateau," says Anil Chaturvedi, an investigator in the Division of Cancer Epidemiology and Genetics at the National Cancer Institute. "They're still on the rise."

The virus is exceedingly common. In the U.S. at least half of those who are sexually active will get HPV at some point during their lives, and most carriers manifest no obvious symptoms, so people who are infected are usually unaware that they have it—and could be transmitting it to their partners.

Most infections, including some 90 to 95 percent of cervical HPV infections, seem to clear on their own within a couple years. But for people whose infection does not go away, they face a higher risk of cancer.

Clinicians currently have no standardized way to test for other types of HPV infection outside of the cervix, and the virus's progression to cancer remains somewhat of a mystery. "We know quite a lot about the natural history of the HPV infection of the cervix," says Maura Gillison, a professor of internal medicine and epidemiology at The Ohio State University Medical Center. But, for other sites, "there's very little information."

A new anatomy of infection
Cervical cancer is still by far the most common HPV-related cancer, causing about 10,800 new cases each year for 1998 to 2003. But a 2008 U.S. Centers for Disease Control and Prevention (CDC) assessment of the U.S.'s HPV-related cancer burden found that each year the virus also likely caused about:

•    7,400 cases (some 60 percent) of oral cavity and oropharynx cancer (5,700 in men; 1,700 in women)
•    3,000 cases of anal cancer (1,100 in men; 1,900 in women)
•    2,300 cases of vulvar cancer
•    800 cases (some 40 percent) of penile cancer
•    600 cases of vaginal cancer

During the course of the study period (1998 to 2003), the CDC found that the rates of HPV-associated oral cavity and oropharynx cancer steadily rose about 3 percent annually. Although these numbers might sound small, the change has not gone unnoticed by clinicians.

Greg Hartig, a surgeon and professor of otolaryngology at the University of Wisconsin–Madison, says that in the 15 years he has worked there he has seen a significant increase in the number of patients with HPV-positive cancers. Some 60 percent of oropharyngeal squamous cell cancers now show traces of HPV.

Many researchers estimate that HPV-positive cancer rates will continue to rise for at least the next decade or two. Why? Simple societal shifts: "This increase that we are seeing could be arising from changes in sexual behaviors that have occurred over time in the United States," Chaturvedi says. People seem to be having more types of sex with more people—and starting to do so at a younger age.

Localized love
Several viruses, including hepatitis viruses and a herpesvirus, have been linked to cancers, but HPV is responsible for the highest number of virus-related malignancies. As a virus, however, it is highly unusual in that it can stick to a localized infection site, rather than spread throughout the body. "You can literally be at risk for cervical cancer and not at risk for oral cancer," Gillison explains.

This atypical infection pattern has meant specific sites in the body come under risk for cancer depending on an individual's sexual history. The virus can be spread through sexual contact and, some studies suggest, even kissing.

Thus, as Americans have expanded their sexual repertoire, as an October study from The Journal of Sexual Medicine highlighted, prevalence of HPV can sweep quickly through a population—especially one that is unprotected by a vaccine or consistent condom use.

With the increase in oropharyngeal cancer in particular, researchers have concluded that the disease stems from local infection acquired during sexual activity. "We think it's probably because of getting involved with oral sex at an earlier age than earlier generations," says Shanthi Marur, an assistant professor of oncology at Johns Hopkins Medicine's Upper Aerodigestive Cancer Program, who co-authored an August paper on the subject in The Lancet Oncology. Adults who are presenting with HPV-positive oral cancers likely contracted the virus in their teens and 20s, she notes.

Although heterosexual men seem to be at higher risk for HPV-positive oropharyngeal cancers (likely, researchers posit, because the virus tends to infect—and persist in—the genital area of female partners), men who have sex with men face an increased risk for HPV anal cancer. And for patients who have compromised immune systems, such as those with HIV or AIDS, "the risk of anal cancer is enormously high," Chaturvedi says.

And for anal, oral and other cancers, "we don't have a pap smear equivalent," Gillison says. So doctors are often left in the dark while a patient's infection turns cancerous and that cancer grows. For oral cancers, for example, she explains, "most of these cancers arise from deep within the tonsillar crypt," where visual detection is largely impossible until a sizable tumor has already formed.

Oral mystery
Despite HPV's role in increasing the number of oropharyngeal cancers, it seems to produce tumors that are much easier to treat than HPV-negative malignancies.

"The HPV status of a patient's tumor is the biggest determining factor of whether they're going to live or die from that cancer," Gillison says. Two patients that present with otherwise identical tumors could have very different outcomes if one turns out to be HPV-positive. Someone with an HPV-negative tumor who was a heavy smoker has only about a 30 percent chance of being alive five years later, she explains. On the other hand, someone who has not smoked and presents with a tumor that turns out to be HPV-positive, "that person is expected to survive," Gillison says. In fact, she says, they have about a 95 percent chance of surviving the cancer for at least five years.

Researchers are still piecing together why the two forms of cancer have such different mortality rates, but Hartig suggests that it might have something to do with the degree of genetic mutations that have been detected in cancerous cells. "The genome of these cancer cells is less abnormal as compared to cancers caused by tobacco and alcohol, where there are even more mutations present," he says.

And the susceptibility of these HPV-positive cancers to standard radiation therapy has led many researchers and clinicians to wonder "if we can dial down treatment" for this set of patients, Marur says. A reduction in harsh radiation therapy could be a big deal for many HPV-positive oral cancer patients, especially as they tend to be much younger (often in their 40s and 50s) compared with the previous majority of patients whose malignancies are linked to smoking or alcohol consumption. "Perhaps we can do less [treatment] there and give our patients better quality of life," Hartig says.

Stopping the spread
The advent of the HPV vaccine, originally developed to prevent cervical cancer, offers some promise for stemming the spread of other HPV-related cancers in the future. Most oropharyngeal cancers are caused by HPV subtype 16, which is included in the vaccine. Only about a quarter of U.S. girls, however, have received even one of the three shots in the vaccine course. And the CDC is still debating whether to recommend the vaccine for boys as well. (Gardasil is currently approved for boys, about 1 percent of whom have been vaccinated.)

The key to slowing the spread of the virus via vaccines, though, is to immunize individuals before they become sexually active. "Vaccination prior to sexual debut is definitely the best recommendation," Chaturvedi says. And that effort will likely take more education.

As more people and parents learn about the virus, how it can be spread, and its link to cancer, Gillison says, "that might open up a little bit more conversation" about sexual behaviors and getting vaccinated at an earlier age—before sexual interactions, or even kissing, start. But, as she has observed in her own practice, "most patients we talk to who have HPV-associated head and neck cancers had no idea what HPV was."

Whether the vaccine will actually work to quell cancer rates down the road, however, remains to be seen. Given current vaccination rates, Gillison says, she is not optimistic it will make much difference "even if the vaccine works." Many researchers will have their eye on other countries, such as Australia, which made the vaccine free to girls and women ages 12 to 26, and started a nationwide vaccination program in 2007. So if the next few decades bring a dip in HPV-positive cancer rates there, scientists will have good evidence that the vaccine is at least partially protective for those cancers.

In the meantime, diagnostic vigilance for these increasingly common cancers will be important in order to offer patients the best treatment options. Johns Hopkins's Marur suggests that many physicians could do for more education on the topic. "These patients present to their internists, their primary care physicians," she says. "And nobody thinks about cancer because they're so young."