NEWS

Recent Studies Attempt to Clarify Relationship Between Oral Cancer and Human Papillomavirus

Jeanne Erdmann

Although tobacco and alcohol are responsible for most oral cancers, physicians are reporting an increase in the disease in patients with little or no history of smoking or drinking. Some of these cancers contain the human papillomavirus (HPV), most especially HPV16, a sexually transmitted member of the papillomavirus family linked to about half of all cases of cervical cancer.



View larger version (155K):
[in this window]
[in a new window]
 
When human papillomavirus attacks the tonsil area, the cells take on a distinctive "basaloid" look. The unique shape and appearance are unlike that of oral cancer caused by tobacco or alcohol. (Source: J Natl Cancer Inst 2000;92:709–20[Abstract/Free Full Text])

 
For many years, the medical community was divided between those who were skeptical that HPV could be a risk factor for oral cancer and those who remained convinced enough to field large research projects. More than 20 years of epidemiologic and molecular work in oral cancer followed on the heels of research connecting HPV and cervical cancer. Stephen Schwartz, Ph.D., of the Fred Hutchinson Cancer Research Center, Seattle, noted that Stina Syrjänen, Ph.D., D.D.S., of the Turku-HPV group in Finland took the lead when she linked observations in cervical cancer to oral cancer and published the first evidence of that connection in 1983.



View larger version (141K):
[in this window]
[in a new window]
 
Dr. Stephen Schwartz

 
As it turns out, scientists studying HPV infections in cervical cancer worked on the easier end of the laboratory bench. Now, experts can say with confidence that HPV types collectively cause most cervical cancers. Researchers on the oral cancer-HPV side will never have that clear of a story, said Schwartz.

"The case for HPV as a risk factor will never be as strong for oral cancer as for cervical cancer. We will always feel deprived of that strong conclusion," said Schwartz. "It’s interesting to think what would have happened to the oral cancer-HPV field if there was not the cervical model to set the standard."

Oral cancers are considered rare. Virtually all are squamous-cell carcinomas that develop in epithelial cells, which are common to many tissues including the reproductive tract and the lung. Each year, roughly 30,000 new cases are diagnosed and more than 8,000 people die from the disease. The typical patient is a 60- to 65-year-old heavy drinker and heavy smoker. Some studies suggest that 15% to 25% of oropharyngeal cancer cases are associated with HPV16.

Oral cancer forms in the oral cavity, which includes the lip, tongue, and hard palate; and the oral pharynx, which includes the soft palate, base of the tongue, and tonsils. Thus far, the HPV-related cancers are found in the tonsil area. By any standard, this is a devastating disease that can be difficult to diagnose. When tumors grow at the base of the tongue, sometimes patients notice difficulty with speech or swallowing. Otherwise, tumors can grow quite large before they are detected.

Survival of oral cancer has not improved in 30 years, in part because obtaining clean surgical margins is difficult, said Bruce Haughey, M.D., of Washington University School of Medicine in St. Louis, Mo. Even after surgery, residual, undetectable disease lurks beyond that established margin, possibly in the bone marrow or circulation. The effort to get clean margins can affect everything from family life to occupation because surgeons might need to remove part of the jaw bone or tongue, affecting speech, chewing, swallowing, and airway protection.

"In a sense, oral cancer is an insidious undetectable process despite what we consider adequate treatment," said Haughey.

As with alcohol and tobacco exposure, decades pass between HPV infection and oral cancer development. Although some studies suggest that people with HPV-positive tumors develop oral cancer at a younger age, those data need to be confirmed, said Maura Gillison, M.D., Ph.D., of the of the Johns Hopkins Kimmel Cancer Center, Baltimore.

Gillison said she used to reside in the skeptic camp, but her research and that of scientists at other laboratories convinced her that HPV is a risk factor for oropharyngeal cancers. She cited several recent studies as compelling evidence—a study measuring serum levels of HPV16 in people 10 years before they developed oral cancer and an epidemiologic study finding an association between HPV16 infection and oral cancer in a small percentage of 18- to 65-year-olds, especially when combined with cigarette smoking. Gillison also pointed to additional studies showing that the HPV genome is transcribed in tonsil cancer.

In an article published in the Journal of the National Cancer Institute in 2000, Gillison and her colleagues combined epidemiology, molecular biology, and survival data to examine tumors in 253 patients ages 17 to 91 with newly diagnosed or recurring squamous cell cancers of the head and neck. They found HPV in 25% of the tumors. More than 90% of the HPV-positive tumors contained HPV16. The virus-containing tumors were found in the oropharynx of people who were less likely to smoke or drink. People with HPV-positive tumors were 59% less likely to die of their cancer compared with patients with HPV-negative tumors.

Gillison said she is uncertain why patients with HPV-positive tumors live longer, but other researchers, including scientists at the University of Michigan, Ann Arbor, have published research confirming these results.

"They don’t do better than people who have no cancer at all," said Elizabeth Sisk, M.D., of the Michigan group. "But they fare better than people with other oral cancers."

Today, Gillison is organizing a clinical trial to test an HPV16 vaccine developed at Hopkins on patients in people already diagnosed with oropharyngeal cancer. "The hope is that if you administer this vaccine to individuals who have been exposed to HPV16 and have a cancer or dysplasia caused by HPV16 that it will stimulate the body’s T lymphocytes to attack the infected cell and clear it," said Gillison. The trial is slated to begin in 2004.

The vaccine was developed by transforming mouse lung epithelial cells into tumors using three genes, two of which are oncogenes specific to HPV16. When these tumor cells are injected into mice, subsequent tumors form in the skin, lungs, and other organs.

Thus far, Gillison said, the vaccine prevents tumor development in mice vaccinated and then exposed to HPV16-positive tumors and can shrink induced tumors when these mice receive the vaccine later. Because papillomaviruses express these oncoproteins and normal tissue does not, the vaccine should generate an immune response.

Environmental agents can worsen both oral and cervical cancers. Even HPV6, a virus that does not form cancers, can turn deadly in the presence of carcinogens, such as cigarette smoke. "When you look at the incidence of cervical cancer and smoking you can draw a straight line between pack years and cancer incidence," said Thomas Carey, Ph.D., of the University of Michigan, Ann Arbor.

The line drawn between HPV16 and oral cancers is not necessarily straight for all scientists in the field, though.

Jon Sudbø, M.D., Ph.D., D.D.S., of the Norwegian Radium Hospital, Oslo, is taking a "watchful waiting" approach before he accepts HPV16 as a risk factor much less as a causative factor. He noted that most oral cancers are not associated with HPV, and almost no one with HPV will get oral cancer.

"I am just eagerly awaiting stronger evidence for HPV as a causative agent. It might be that there are subsets of oral squamous cell carcinomas with differing etiologies, and that HPV was an important factor for a subgroup," Sudbø said.

Although HPV-positive oral cancer patients might be light smokers or light drinkers, they may indeed smoke and drink more than healthy individuals, said University of Washington’s Schwartz. He cautioned that parsing oral cancers into narrow subgroups could harm research if scientists miss a possible connection among HPV, tobacco, and alcohol.

When all is said and done, Schwartz continued, the oral cancer field lags behind that of cervical cancer. Scientists still do not fully understand the natural history of the disease and the transmission routes of HPV and oral cancer. For example, HPV16 is found in pre-cancerous lesions in the cervix, but rarely in oral dysplasia, a precursor to oral cancer.

"The only way we are going to feel comfortable of a real, causal relationship is if the vaccine works in oral cancer the way it works in cervical cancer," Schwartz said.


This article has been cited by other articles in HighWire Press-hosted journals:


             
Copyright © 2003 Oxford University Press (unless otherwise stated)
Oxford University Press Privacy Policy and Legal Statement