Long-Lasting Increased Risk of Human Papillomavirus–Related Carcinomas and Premalignancies After Cervical Intraepithelial Neoplasia Grade 3: A Population-Based Cohort Study

Abstract

Purpose The aim of this study was to determine the risk of human papillomavirus (HPV)-related carcinomas and premalignancies in women diagnosed with cervical intraepithelial neoplasia grade 3 (CIN3). Knowledge of this risk is important to preventing the development and progression of other HPV-related premalignancies and carcinomas, by considering prophylactic HPV vaccination and/or by paying increased attention to other HPV-related carcinomas and premalignancies when CIN3 is identified. Methods Women diagnosed with a CIN3 between 1990 and 2010 were identified from the Dutch nationwide registry of histopathology and cytopathology (PALGA) and matched with a control group of women without CIN3. Subsequently, all cases of high-risk (hr) HPV-associated high-grade lesions and carcinomas in the anogenital region and oropharynx between 1990 and 2015 were extracted. Incidence rate ratios were estimated for carcinomas and premalignancies of the vulva, vagina, anus, and oropharynx. Results A total of 178,036 women were identified: 89,018 with a previous diagnosis of CIN3 and 89,018 matched control subjects without a history of CIN3. Women with a history of CIN3 showed increased risk of HPV-related carcinomas and premalignancies, with incidence rate ratios of 3.85 (95% CI, 2.32 to 6.37) for anal cancer, 6.68 (95% CI, 3.64 to 12.25) for anal intraepithelial neoplasia grade 3, 4.97 (95% CI, 3.26 to 7.57) for vulvar cancer, 13.66 (93% CI, 9.69 to 19.25) for vulvar intraepithelial neoplasia grade 3, 86.08 (95% CI, 11.98 to 618.08) for vaginal cancer, 25.65 (95% CI, 10.50 to 62.69) for vaginal intraepithelial neoplasia grade 3, and 5.51 (95% CI, 1.22 to 24.84) for oropharyngeal cancer. This risk remained significantly increased, even after long-term follow-up of up to 20 years. Conclusion This population-based study shows a long-lasting increased risk for HPV-related carcinomas and premalignancies of the anogenital and oropharyngeal region after a CIN3 diagnosis. Studies that investigate methods to prevent this increased risk in this group of patients, such as intensified screening or vaccination, are warranted.

Human papillomavirus‐related anogenital premalignancies and cancer in renal transplant recipients: A Danish nationwide, registry‐based cohort study

“…With respect to vulvar, vaginal, anal and penile premalignancies, screening of these sites is not recommended or routinely performed in Denmark. However, since it is well-established that individuals with HPV-related disease at one site are at increased risk of HPV-related disease at other sites, 49 clinicians may be more likely to examine for anogenital premalignancies in individuals with prior HPVrelated disease, and this could cause surveillance bias in RTRs vs. non-RTRs. However, given the very high estimated E-values for noncervical IN2/3 (>20 for all sites), we believe it is unlikely that the observed HRs are fully explained by surveillance bias.…”

Risk of vaginal cancer among hysterectomised women with cervical intraepithelial neoplasia: a population‐based national cohort study

“…Unlike cervical cancer, the incidence of which has decreased substantially as a result of the introduction of population‐based screening in Sweden, the age‐standardised incidence of vaginal cancer in Sweden has undergone only minor changes. History of cervical intraepithelial neoplasia (CIN), vaginal intraepithelial neoplasia or cervical cancer are known risk factors . Albeit to a lower extent than cervical cancer, vaginal cancer has a strong association with human papillomavirus (HPV) infection .…”

“…History of cervical intraepithelial neoplasia (CIN), vaginal intraepithelial neoplasia or cervical cancer are known risk factors. [2][3][4][5][6][7][8][9] Albeit to a lower extent than cervical cancer, vaginal cancer has a strong association with human papillomavirus (HPV) infection. 10 The incidence of vaginal cancer is highly age-related 4 and a history of CIN3 further increased the age-specific incidence in one large study.…”

Epidemiologic associations of HPV‐positive oropharyngeal cancer and (pre)cancerous cervical lesions

“…2,[20][21][22] Chaturvedi et al, using data from 104,760 1-year survivors of cervical cancer calculated standardized incidence ratios (SIRs) for second primary cancers. 2,[20][21][22] Chaturvedi et al, using data from 104,760 1-year survivors of cervical cancer calculated standardized incidence ratios (SIRs) for second primary cancers.…”