Increased risk of HPV-associated genital cancers in men and women as a consequence of pre-invasive disease.

To assess the excess risk of HPV-associated cancer (HPVaC) in two at-risk groups-women with a previous diagnosis of high grade cervical intraepithelial neoplasia (CIN3) and both men and women treated for non-cervical pre-invasive anogenital disease. All CIN3 cases diagnosed in 1989-2015 in Scotland were extracted from the Scottish cancer registry (SMR06). All cases of pre-invasive penile, anal, vulval, and vaginal disease diagnosed in 1990-2015 were identified within the NHS pathology databases in the two largest NHS health boards in Scotland. Both were linked to SMR06 to extract subsequent incidence of HPVaC following the diagnosis of CIN3 or pre-invasive disease. Standardised incidence ratios were calculated for the risk of acquiring HPVaC for the two at-risk groups compared to the general Scottish population. Among 69,714 females in Scotland diagnosed with CIN3 (890,360.9 person-years), 179 developed non-cervical HPVaC. CIN3 cases were at 3.2-fold (95% CI: 2.7 to 3.7) increased risk of developing non-cervical HPVaC, compared to the general female population. Among 1,235 patients diagnosed with non-cervical pre-invasive disease (9,667.4 person-years), 47 developed HPVaC. Individuals with non-cervical pre-invasive disease had a substantially increased risk of developing HPVaC - 15.5-fold (95% CI: 11.1 to 21.1) increased risk for females and 28-fold (11.3 to 57.7) increased risk for males. We report a significant additional risk of HPV-associated cancer in those have been diagnosed with pre-invasive HPV-associated lesions including but not confined to the cervix. Uncovering the natural history of pre-invasive disease has potential for determining screening, prevention and treatment.