Incidence and mortality from cervical cancer and other malignancies after treatment of cervical intraepithelial neoplasia: a systematic review and meta-analysis of the literature

Abstract

Background Although local treatments for cervical intraepithelial neoplasia (CIN) are highly effective, it has been reported that treated women remain at increased risk of cervical and other cancers. Our aim is to explore the risk of developing or dying from cervical cancer and other human papillomavirus (HPV)- and non-HPV-related malignancies after CIN treatment and infer its magnitude compared with the general population. Materials and methods Design: Systematic review and meta-analysis. Eligibility criteria: Studies with registry-based follow-up reporting cancer incidence or mortality after CIN treatment. Data synthesis: Summary effects were estimated using random-effects models. Outcomes Incidence rate of cervical cancer among women treated for CIN (per 100 000 woman-years). Relative risk (RR) of cervical cancer, other HPV-related anogenital tract cancer (vagina, vulva, anus), any cancer, and mortality, for women treated for CIN versus the general population. Results Twenty-seven studies were eligible. The incidence rate for cervical cancer after CIN treatment was 39 per 100 000 woman-years (95% confidence interval 22–69). The RR of cervical cancer was elevated compared with the general population (3.30, 2.57–4.24; P < 0.001). The RR was higher for women more than 50 years old and remained elevated for at least 20 years after treatment. The RR of vaginal (10.84, 5.58–21.10; P < 0.001), vulvar (3.34, 2.39–4.67; P < 0.001), and anal cancer (5.11, 2.73–9.55; P < 0.001) was also higher. Mortality from cervical/vaginal cancer was elevated, but our estimate was more uncertain (RR 5.04, 0.69–36.94; P = 0.073). Conclusions Women treated for CIN have a considerably higher risk to be later diagnosed with cervical and other HPV-related cancers compared with the general population. The higher risk of cervical cancer lasts for at least 20 years after treatment and is higher for women more than 50 years of age. Prolonged follow-up beyond the last screening round may be warranted for previously treated women.

Risk of HPV-related extra-cervical cancers in women treated for cervical intraepithelial neoplasia

“…The correlation between anogenital tumour or pretumour lesions and HPV infection has been well described [18]. There is general consensus in stating that patients treated for high grade CIN or cervical cancer are at increased risk of invasive neoplasia and our study confirms this trend [5][6][7][8][9][10][11][12][13][14]16].…”

“…All studies use SIR or Relative Risk (RR) to estimate the correlation between primary cervical lesions and SPCs. Surgical removal (LLETZ) of CIN does not mean removal of HPV infection and HPV DNA can be present in surrounding, clinical normal tissues and this viral persistence can rise the subsequent precancer/cancer risk [7].…”

“…Despite CIN treatment has a high impact in reducing cancer risk (from 95 to 99%), treated women are still considered at higher risk of cervical malignancies compared to the general population and at risk of HPVrelated malignancies in other body sites [6,7]. Many studies demonstrated that women with history of diagnosis and treatment for high-grade CIN are at increased risk for HPV subsequent primary cancers (SPCs) [6][7][8][9][10][11][12][13][14][15][16]. An HPV-SPC is defined as a metachronous invasive primary solid tumour, which develops at least 2 months after the diagnosis of a primary HPV-related tumour [17].…”

The Vaginal Microbiota and Innate Immunity After Local Excisional Treatment for Cervical Intraepithelial Neoplasia

“…This may be a factor that predisposes these women to acquisition of oncogenic HPV infections, persistence and ultimately cervical oncogenesis. Consistent with this notion, clinical epidemiological studies have consistently reported higher CIN recurrence rates and increased incidence of invasive cervical and other HPV-related cancers in women treated with conisation for CIN [54][55][56]. Although this increased incidence may be partly explained by residual infection/disease [55] and/or poor compliance with follow-up [54], it is also possible that these high-risk women are highly sensitive to infection by HPV and as a results are more susceptible to the development of persistent infection, precancer and ultimately cancer.…”

Cervical Pathology Following HPV Vaccination in Greece: A 10-year HeCPA Observational Cohort Study

“…The role of HPV vaccination in unvaccinated women undergoing CIN treatment is not clear due to lack of evidence from randomised studies, but observational studies have shown that it decreases the risk of preinvasive recurrence (26,27). A recent systematic review and meta-analysis showed that women previously treated for CIN are at increased longterm risk of invasive cervical and other HPV-related cancers (28), thus HPV vaccination after CIN treatment could also reduce the incidence of these HPV-related cancers in this population.…”