Clinical and Pathological Heterogeneity of Cervical Intraepithelial Neoplasia Grade 3

Abstract

ObjectiveCervical intraepithelial neoplasia grade 3 (CIN3), the immediate cervical cancer precursor, is a target of cervical cancer prevention. However, less than half of CIN3s will progress to cancer. Routine treatment of all CIN3s and the majority of CIN2s may lead to overtreatment of many lesions that would not progress. To improve our understanding of CIN3 natural history, we performed a detailed characterization of CIN3 heterogeneity in a large referral population in the US.MethodsWe examined 309 CIN3 cases in the SUCCEED, a large population-based study of women with abnormal cervical cancer screening results. Histology information for 12 individual loop electrosurgical excision procedure (LEEP) segments was evaluated for each woman. We performed case-case comparisons of CIN3s to analyze determinants of heterogeneity and screening test performance.ResultsCIN3 cases varied substantially by size (1–10 LEEP segments) and by presentation with concomitant CIN2 and CIN1. All grades of CINs were equally distributed over the cervical surface. In half of the women, CIN3 lesions were found as multiple distinct lesions on the cervix. Women with large and solitary CIN3 lesions were more likely to be older, have longer sexual activity span, and have fewer multiple high risk HPV infections. Screening frequency, but not HPV16 positivity, was an important predictor of CIN3 size. Large CIN3 lesions were also characterized by high-grade clinical test results.ConclusionsWe demonstrate substantial heterogeneity in clinical and pathological presentation of CIN3 in a US population. Time since sexual debut and participation in screening were predictors of CIN3 size. We did not observe a preferential site of CIN3 on the cervical surface that could serve as a target for cervical biopsy. Cervical cancer screening procedures were more likely to detect larger CIN3s, suggesting that CIN3s detected by multiple independent diagnostic tests may represent cases with increased risk of invasion.

The role of co-factors in the progression from human papillomavirus infection to cervical cancer

“…Furthermore, these risk factors were more strongly associated with progression to CIN3 compared to invasion. This observation is consistent with a previous study of the heterogeneity of CIN3, which showed factors such as parity, OC use, and smoking were not associated with the size of CIN3 lesions, suggesting that they may not play a major role in the later stages of the natural history of cervical cancer [30]. …”

CADM1andMALpromoter methylation levels in hrHPV-positive cervical scrapes increase proportional to degree and duration of underlying cervical disease

“…More advanced and larger lesions are likely to exfoliate more aberrant cells, facilitating the detection of promoter methylation in cervical scrapes. Accordingly, Wentzensen et al 26 and Yang et al 27 recently demonstrated that high-grade squamous intraepithelial lesion cytology and CIN3 colposcopy and biopsy results indicate larger CIN3. The observation that scrapes of women with CIN2/3 and a short-term (<5 years) PHI revealed lower methylation levels compared to lesions with long-term infections indicates that part of the scrapes of women with a short-term hrHPV infection may be scored as 'methylationnegative' when choosing certain thresholds of the respective qMSPs for scoring methylation.…”

“…Accordingly, Wentzensen et al . and Yang et al . recently demonstrated that high‐grade squamous intraepithelial lesion cytology and CIN3 colposcopy and biopsy results indicate larger CIN3.…”

The increased detection of cervical intraepithelial neoplasia when using a second biopsy at colposcopy

“…However, it remains to be elucidated how clinically relevant the earlier detection of CIN2 and also CIN3 lesions is because small lesions that are not easy to detect with one biopsy are more likely to regress spontaneously than evident lesions [25]. From our data it appears that women who are most likely to benefit from a second directed biopsy are women with HSIL cytology and HSIL cytology is associated with larger CIN2+ lesions than ASCUS or LSIL cytology [23,26,27]. Another approach to look at clinical relevance of earlier detection of disease is that with multiple biopsies it is possible to identify women who have CIN2+ but also women without significant disease.…”