Cigarette smoking and concurrent infection with high levels of human papillomavirus significantly increase risk for cervical cancer, according to an article in the November issue of Cancer Epidemiology, Biomarkers & Prevention.

Professor Anthony Gunnell, a medical biostatistician and epidemiologist and colleagues at the Karolinska Institutet in Stockholm, Sweden, reviewed the medical exams of women with non-invasive cervical cancer in situ and cancer-free women in one of the largest studies to date to examine the relationships between smoking and human papilloma. 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.

The researchers looked at Pap smear data for 105,760 Swedish women and identified 499 women with cervical cancer in situ, as well as 499 cancer-free women as controls. For these women, they compared smoking behavior with 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 invasive cervical cancer.

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

Specifically, women who smoked and had a high HPV-16 load during their first exam had a 27-fold increased risk of later cancer compared with women who smoked but did not have HPV infection. Women who were positive for HPV-16 (irrespective of viral load) and were smokers had a 14-fold increased risk over women who were HPV-16 negative and smoked. Finally, nonsmoking women with high HPV-16 loads had just a 6-fold risk compared with virus-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 virus-positive, had too few women with high viral loads for the researchers to declare both smoking and human papillomavirus, 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.

onversely, 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 human papillomavirus 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.