Although high-risk human papillomavirus (HPV) is essential for developing high-grade cervical intraepithelial neoplasia (CIN2 and CIN3) and has also been associated with noncervical anogenital cancers, little is known about the long-term risk for anal, vulvar, and vaginal cancer following a diagnosis of CIN2 or CIN3. To assess the long-term risk for developing these cancers, researchers in Denmark launched a large population-based cohort study and found that women with a diagnosis of CIN3 were 4.2 times more likely to develop anal cancer, 4 times more likely to develop vulvar cancer, and 17 times more likely to develop vaginal cancer than women with no history of the disease. Women with a history of CIN2 were 2.9 times more likely to develop anal cancer, 2.5 times more likely to develop vulvar cancer, and 8.1 times more likely to develop vaginal cancer compared with women with no history of the disease.
The increased risk was associated with an impaired ability to control persistent HPV infection. The study by Sand et al is published in Cancer Epidemiology, Biomarkers & Prevention.
The researchers analyzed data from 2.8 million women who were living in Denmark between 1978 and 2012, and followed some of the women for up to 34 years. The women were identified through Denmark’s system of personal identification numbers, which they linked to the Danish Cancer Registry and the Pathology Data Bank to obtain information on verified cases of CIN2 and CIN3, as well as cancer diagnoses.
Of these women, 52,135 were diagnosed with CIN2 and 104,155 had a history of CIN3.
Cox proportional hazard model was used to estimate hazard ratios (HRs) and corresponding 95% confidence interval (CI) for the association between CIN2 or CIN3 and anal, vulvar, vaginal, and rectal cancer.
The researchers found that women with a history of CIN2 or CIN3 had higher risks for subsequent anal, vulvar, and vaginal cancer than women with no such history. The relative risks were higher for CIN3 than CIN2. No excess risk was found for rectal cancer. Analyses in which time since first CIN3 was taken into account showed increased relative risks for anal (HR = 4.8; 95% confidence interval [CI] = 3.3–7.0), vulvar (HR = 3.2; 95% CI = 2.0–5.3), and vaginal (HR = 5.5; 95% CI = 2.4–12.3) cancers ≥ 25 years after CIN3 diagnosis.
“The HPV vaccine is prophylactic, and if we can prevent HPV infection from occurring in the first place, we can prevent some of these conditions that result from persistent infection,” said Susanne K. Kjaer, MD, Professor of Gynecological Cancer Epidemiology at the Danish Cancer Society Research Center in Copenhagen, Denmark, and a co-author of this study, in a statement. “We had thought that perhaps the women with CIN3 were the ones who were being treated by doctors and, therefore, receiving more examinations and consequently getting diagnosed with other cancers. But the risks persist for many years, and, therefore, our findings cannot be explained by surveillance bias.”
One of the limitations of the study, said Dr. Kjaer, is that some of the early enrollees may have had undiagnosed CIN, leading to an underestimation of the risk.
Dr. Kjaer is the corresponding author of this study.
Funding for this study was provided by the Unit of Virus, Lifestyle, and Genes at the Danish Cancer Society Research Center. The study authors’ conflicts of information disclosures are available at the end of the study.
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