Cover Story
A Cancer Gone Viral
A rise in the incidence of oropharyngeal cancer in younger people has been linked to the human papillomavirus.
By Jeanne Mettner
Nearly 20 years ago, dentists and otolaryngologists began noticing an intriguing phenomenon: squamous cell carcinomas of the tonsil area and at the base of the tongue showing up in populations of patients that had never before been affected by the disease. Typically, oropharyngeal cancers were seen in older patients who had a history of smoking and heavy alcohol use. This time, however, the disease was showing up in 30- to 40-year-olds, some of whom had never had a strong cocktail or cigarette in their life.
Something was amiss.
By the late 1990s, scientists were homing in on a possible culprit: the human papillomavirus (HPV). In 2000, researchers from Johns Hopkins University in Baltimore published findings in the Journal of the National Cancer Institute that demonstrated the presence of the virus—specifically HPV16, a strain known to be sexually transmitted and cause cervical cancers—in some of the oropharyngeal cancers they tested. By the late 2000s, investigators from several other institutions had substantiated these findings, and in 2007, the World Health Organization’s International Agency for Research Against Cancer formally recognized HPV as a risk factor for oropharyngeal cancer.
The HPV Vaccine Preventive Tool or Shot in the Dark?
In many countries, including the United States, vaccines against some types of the human papilloma virus (HPV) are being administered to girls and young women to protect them against HPV-related cervical cancer. Most HPVrelated oropharyngeal cancer is linked to one strain of the virus, HPV16, which is targeted by the vaccines Gardasil and Cervarix.
Until last month, no organizations were formally recommending the HPV vaccine for boys. In late October, however, a Centers for Disease Control and Prevention (CDC) advisory committee recommended that boys and young men be vaccinated against HPV to protect against anal and throat cancers that can result from sexual activity. The recommendations are subject to approval by the CDC.
Clinicians who work with patients who are getting HPV-related cancers have long advocated for such a move. “I can’t speak for all in my specialty, but I would support vaccination for both males and females,” says Nelson Rhodus, M.D., director of oral medicine/diagnosis at the University of Minnesota School of Dentistry and a faculty member in the department of otolaryngology.
Before the CDC committee announced its decision, Bevan Yueh, M.D., professor and chair of the University of Minnesota’s department of otolaryngology/ head and neck surgery, stated: “If we are going to make inroads with prevention of HPV-related oropharyngeal cancer, we are going to need to start vaccinating young males as well as females.”—J.M.
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Since then, the evidence for HPV being the cause of the cancers showing up in these patients has become even more compelling. An article published in the October 3, 2011, Journal of Clinical Oncology reported that 16.3 percent of oropharyngeal cancer tumor samples collected between 1984 and 1989 tested positive for HPV, compared with 71.7 percent of samples collected between 2000 and 2004. The Ohio State University researchers who conducted the study found that the incidence rate of HPV-associated oropharyngeal cancers had increased from about 0.8 cancers per 100,000 population in the late 1980s to 2.6 per 100,000 in 2004.
What’s behind this phenomenon?
Although there have been no formal studies looking into why the incidence rate of HPV-associated oropharyngeal cancer is increasing, the speculation within the medical community is that it may be associated with an increase in oral sex practices. According to Eric Moore, M.D., a head and neck surgeon at Mayo Clinic, the cervix of the vaginal opening and the back of the oral cavity have similarities that may make them welcoming environments for HPV. “HPV does not have a role in vaginal cancer or uterine cancer,” he notes, “but there is a real predilection for cervical cancer and HPV.” And the same thing is happening with HPV and oropharyngeal cancer. Says Moore: “The HPV-related cancers are not happening in the gums or the front part of the tongue, the major salivary glands, or the floor of mouth; they’re happening in the tongue base and tonsils.”
One Name, Two Diseases
Some, including the authors of the Journal of Clinical Oncology article, now suspect that oropharyngeal cancer may actually be two different diseases—one caused by exposure to tobacco and alcohol and the other caused by the sexually transmitted virus. A number of things suggest this. One is the age difference between those who get HPV-related cancer and those who get the cancer caused by tobacco and alcohol exposure, which tends to affect people in their 60s, 70s, and even their 80s. “There is this really long latency period between the time someone is exposed to smoking and the time the smoking-associated cancer develops—the end result being that it takes a number of hits for affected cells to become cancerous,” says John Soler, senior epidemiologist with the Minnesota Department of Health’s Minnesota Cancer Surveillance System. That system tracked a dramatic increase in the age-adjusted rates of HPV-associated cancer in certain parts of the oropharynx among 20- to 44-year-olds between the 1988 and late 2008 and a decrease in the age-adjusted rates of non-HPV-related cancers of the oral cavity among older people during the same period. Human papillomavirus-associated oropharyngeal cancer is believed to affect people at a younger age because HPV-associated cancer cells mutate faster than non-HPV cancer cells. “So being able to calculate the incidence of oropharyngeal cancers in these younger populations tends to be a ‘purer’ measure of the HPV-oropharyngeal cancer connection because less time elapses between exposure and development of the disease,” Soler says.
Another indication that HPV-related and non-HPV-related oropharyngeal cancers may be two diseases is the fact that patients with tobacco-associated disease present with symptoms that are different from those of HPV-associated cancer. “The patients who were older tended to come in with a sore throat, painful swallowing, and referred pain in the ears. You would do an exam and see signs of tonsillar cancer,” says Ronald Hanson, M.D., an otolaryngologist with St. Cloud Ear, Nose, and Throat—Head and Neck Clinic, who spoke on the topic at a recent meeting of the Minnesota Cancer Registrars Association. Patients with HPV-associated cancers tend to present with swelling or a lump in the neck, which may be discovered during a routine dental exam. “In the course of our evaluations, we may find a very small lesion in their tonsil that ends up being HPV-related tonsillar cancer,” Hanson says.
Scientists now can implicate HPV in an oropharyngeal cancer case by isolating DNA from the tumor specimen and then testing for the presence of HPV within that tumor-specific DNA. “If the patient is not a smoker or drinker, we see HPV in the biopsy almost 100 percent of the time,” Moore says.
Same Treatment, Better Response
If there is good news to be had, it’s that most patients with HPV-associated cancer have a good prognosis. The Johns Hopkins researchers who published findings on HPV-related oropharyngeal cancer also found that patients with HPV-positive tumors had significantly better survival rates than those with HPV-negative lesions—even after adjusting for age, lymph node status, and alcohol use.
“Ten years ago, we would prescribe treatment for the patient who was a heavy smoker and drinker who had tonsil cancer with positive lymph nodes in their neck and know that there was a 50 percent chance that it would recur,” Moore says. “With HPV tumors, we see patients at the same advanced stage, and they have about a 90 percent chance of being cured.”
Most clinicians are using the same therapeutic regimen for both types of cancer; it involves surgery to remove the tumor, then radiation concomitant with chemotherapy. In a recent study involving more than 100 patients at Mayo Clinic with HPV-positive oropharyngeal cancer, Moore and his team found a 92 percent cure rate, which they defined as having no evidence of carcinoma two years after completing treatment.
Studies are underway to determine why HPV-positive patients respond better to treatment than those whose tumors are negative for HPV. Investigators are looking at a number of theories. One is that because those patients are younger, they tend to have better health, a better host immune response to the HPV-positive form of cancer, better resistance to the spread of cancer, and better tolerance of treatment. Another is that the patient’s immune response to HPV helps promote an aggressive response to the tumor. Yet another is that HPV-associated tumors may spread less aggressively and cause less DNA damage than tumors not associated with the virus.
In addition, researchers are looking at the absence of what could be considered the “genetic programming” of cancer in these patients. “Most people who have [non-HPV] oral cancers have altered gene mutations or polymorphisms that make them susceptible,” says Nelson Rhodus, D.M.D., M.P.H., director of oral medicine/diagnosis at the University of Minnesota School of Dentistry and a faculty member in the university’s department of otolaryngology. With HPV-associated oropharyngeal cancer, the development of lesions is more directly related to the virus, which may mean that the chemotherapy or radiation therapy kills the virus as well as the cancer cells. “So the person’s overall systemic susceptibility to the cancer isn’t as strong molecularly or immunologically,” he says. “Simply speaking, people who have HPV-related oropharyngeal cancer may not be as genetically programmed to continue having it as those with other types of oral cancer.”
Researchers are also beginning to look at whether patients with HPV-related cancers need to be treated the same as patients with other oral cancers. According to Bevan Yueh, M.D., professor and chair of the University of Minnesota’s department of otolaryngology/head and neck surgery, the current chemotherapy regimen, which involves three agents instead of one, presents risks that HPV-positive patients may not need to face. “We’re dealing with toxicity now that we didn’t have 15 or 20 years ago, and with a significant portion of the oropharyngeal cancer population having HPV, some of us have begun to wonder whether we have to subject these patients to the same amount of toxicity that we need to give for the smoking-related cancers,” he says. This month, Yueh will attend a National Cancer Institute meeting to address these concerns and work on plans for multi-institutional trials of less-toxic treatments.
Prevention and Screening
As more research unfolds to determine the best protocols for treating HPV-related oropharyngeal cancer, otolaryngologists and dentists are continuing to push for early screening and prevention. Yueh and his colleagues conduct inservices to increase providers’ awareness of oropharyngeal cancers including those linked to HPV. Rhodus makes dozens of presentations annually across the country, educating dentists and primary care providers about how to check for HPV-associated oropharyngeal tumors (palpate the neck and look for swelling or a firm, marble-like nodule). “The increased awareness of what can put these patients at risk could lead to heightened surveillance,” he says.
In the meantime, Rhodus and his team are investigating new ways to screen for the disease. Currently, they are exploring whether a saliva test might detect its presence. Until such a test becomes available, educating patients about HPV-related cancer and how to prevent it and educating physicians about how to detect it is the key to keeping it from taking lives. MM
Jeanne Mettner is a freelance writer in Minneapolis and a frequent contributor to Minnesota Medicine.