The role of misclassification in progression of cervical intraepithelial neoplasia grade 2 during active surveillance: results from a historical cohort.

Abstract

Many countries have recently implemented active surveillance for cervical intraepithelial neoplasia grade 2 as an option in younger women due to high regression rates and because excisional treatment is associated with an increased risk of preterm birth. However, the known low reproducibility of the cervical intraepithelial neoplasia grade 2 diagnosis poses a major challenge for active surveillance, suggesting that the observed risk of progression in prior studies may be due to initial misclassification of the cervical intraepithelial neoplasia grade 2 diagnosis. This study aimed to assess the association between expert-verified histological diagnoses of cervical biopsies in women undergoing active surveillance for cervical intraepithelial neoplasia grade 2 and the subsequent risk of cervical intraepithelial neoplasia grade 3 or worse. We conducted a historical cohort study on women undergoing active surveillance for cervical intraepithelial neoplasia grade 2, diagnosed at Aarhus University Hospital from 2000 to 2010. Women were identified through the Danish Pathology Data Bank and were eligible for inclusion if they were aged 23 to 40 years at the time of cervical intraepithelial neoplasia grade 2 diagnosis. Women with a prior history of cervical intraepithelial neoplasia grade 2 or worse, loop electrosurgical excision procedure, or hysterectomy were excluded. Three expert pathologists independently graded cervical lesions by reviewing hematoxylin and eosin and p16-stained tissue slides from the time of cervical intraepithelial neoplasia grade 2 diagnosis. Women were followed for 28 months, from the date of the cervical intraepithelial neoplasia grade 2 diagnosis until a record of progression, loop electrosurgical excision procedure, hysterectomy, or end of follow-up, whichever occurred first. Using modified Poisson regression analysis, we estimated the crude and adjusted relative risks of cervical intraepithelial neoplasia grade 3 or worse, including corresponding 95% confidence intervals. We adjusted for age, index cytology, and human papillomavirus genotype as potential confounders. A total of 437 women were included with a median age of 27 years. Upon expert review, 56 (12.8%) were upgraded to cervical intraepithelial neoplasia grade 3, 261 (59.7%) had cervical intraepithelial neoplasia grade 2 confirmed, and 120 (27.5%) were downgraded to cervical intraepithelial neoplasia grade 1/normal. Overall, 173 (39.6%) women had a subsequent record of cervical intraepithelial neoplasia grade 3 or worse, ranging from 22.5% in women with expert cervical intraepithelial neoplasia grade 1/normal, to 42.2% in women with expert cervical intraepithelial neoplasia grade 2, and 64.3% in women with expert cervical intraepithelial neoplasia grade 3. Thus, women with an expert-verified cervical intraepithelial neoplasia grade 3 diagnosis were more likely to have a subsequent record of cervical intraepithelial neoplasia grade 3 or worse during follow-up (adjusted relative risk, 1.37 [1.07; 1.75]) compared to those who had expert cervical intraepithelial neoplasia grade 2. This association remained significant in stratified analyses for women aged 31 to 40 years (adjusted relative risk, 1.85 [1.25; 2.76]), in women with high-grade index cytology (adjusted relative risk, 1.43 [1.04; 1.97]), and women with a nonhuman papillomavirus16 lesion (adjusted relative risk, 1.66 [1.09; 2.52]). The risk of cervical intraepithelial neoplasia grade 3 or worse remained high for women presenting with a high-grade cytology or human papillomavirus 16 positivity at baseline, irrespective of expert diagnosis. Our findings demonstrate substantial interobserver variability in the diagnosis of community-detected cervical intraepithelial neoplasia grade 2, with nearly half of the cases being reclassified upon expert review. This underscores the heterogeneity of this diagnosis and the importance of accurate diagnosis to minimize both undertreatment and overtreatment. These results highlight the need for individualized, risk-based management strategies for cervical intraepithelial neoplasia grade 2 that integrate virological and cytological factors rather than relying solely on histopathology.