Cigarette smoking and concurrent infection with high levels of the virus associated with cervical cancer can increase cancer risk by as much as 27 times, according to a study published in the November 2006 issue of Cancer Epidemiology, Biomarkers & Prevention.

Anthony Gunnell, a medical biostatistician and epidemiologist and colleagues at the Karolinska Institutet in Stockholm reviewed the medical exams of women with non-invasive cervical cancer in situ (the most common type) and cancer-free women in one of the largest studies to date to examine the relationships between smoking and the human papilloma virus (HPV). The virus and smoking behavior have long been associated with the disease, but not enough evidence has come forth to determine how either may cause the disease.

Gunnell’s study, in fact, suggests that both may create a biochemical synergy that propels the disease. The researchers looked at “Pap” smear examination data from 105,760 Swedish women and identified 499 women with cervical cancer in situ, along with 499 cancer-free women as controls. For these women, they compared their smoking behavior with concentrations (known as viral load) of HPV-16, the viral strain most associated with cervical cancer. The researchers found that a combination of high viral loads and smoking during the time they were initially examined resulted in very high risk of later cervical cancer.

“We were surprised to see this dramatically increased risk among women with high viral loads who smoked,” Gunnell said.

Among their findings:
• Women who smoked and had a high HPV-16 load during their first exam had a 27-fold increased risk of later cancer than women who smoked but did not have an HPV infection.
• Women who were positive for HPV-16 (irrespective of amount of viral load) and were smokers had a 14-fold increased risk over women who were HPV-16 negative and smoked.
• Nonsmoking women with high HPV-16 loads had just a 6-fold risk compared to HPV-negative nonsmokers.

“Our initial analyses centered on whether smoking was an independent risk factor for cervical cancer,” said Gunnell. “Clearly, both exposures need to be present at the same time for there to be interaction.

“Our study would imply a synergistic action between HPV and smoking that would greatly increase the likelihood of women developing cervical cancer if they are HPV-positive smokers. This would put them in a risk group worthy of careful monitoring.”

The study, which also may partly explain why some women may not get cervical cancer despite smoking behavior or being HPV-positive, had too few women with high viral loads for the researchers to declare both smoking and HPV, by themselves, caused the disease. But since it was one of the largest studies to examine this relationship, it strongly suggests directions that future research should take to explore a causative effect.

The researchers also found a relationship between smoking duration and cancer. “We found a statistically significant multiplicative interaction between the duration of smoking and HPV presence causing cervical cancer,” Gunnell said. “One explanation for this interaction could involve the influence of smoking on persistence of HPV infection, probably due to localized immune suppression. Conversely, it could be related to the progression of neoplastic growth, since HPV and smoking appear to alter the levels of certain cytokines, which are involved in controlling abnormal cell growth. More likely, the combination of both mechanisms are contributory factors.

In any event, confirmation of an interaction between cigarette smoking and HPV in cervical cancer development is of vital importance to public health, considering the widespread exposure to the virus and cigarette smoking in young women at risk for the disease, he said.

Cervical cancer is one of the leading causes of cancer deaths worldwide, and death rates are particularly high in developing countries. Although rates of incidence and mortality have dropped by 50 percent in the past 20 years, out of the 9,700 women diagnosed just in the United States this year, 3,700 will die. Early diagnosis and treatments have helped curb mortality rates, but the disease still remains one of the world’s deadliest. In addition, it remains more common among Hispanic and African-American women.

Gunnell’s colleagues in the study included Trung Tran, Anna Torrang, Paul Dickman, Par Sparen and Nathalie Ylitalo, of the Karolinska Institutet. Juni Palmgren also is a faculty member at Stockholm University. Their work was supported by grants from the U.S. National Institutes of Health, the Swedish Cancer Society and the Danish National Research Foundation.