The impact of epithelial biomarkers, local immune response and human papillomavirus genotype in the regression of cervical intraepithelial neoplasia grades 2-3

Background and aims 15-30% of cases of cervical intraepithelial neoplasia grades 2-3 (CIN2-3) detected in punch biopsies regress spontaneously (ie, show CIN1 or less in the follow-up cone). Epithelial retinoblastoma protein (pRb), tumour suppressor protein (p53), HPV genotype and immunoreactive cells have been reported to be helpful in predicting regression but their interaction in regression prediction is unknown. Material and methods 55 cases of CIN2-3 in cervical biopsies with subsequent cervical cones were studied retrospectively to assess how epithelial biomarkers, immunoreactive cells (with immunohistochemistry) and high-risk (hr) HPV genotypes (by the AMPLICOR and linear array tests) prognostically interact with epithelial pRb and p53. Results 18% of CIN2-3s regressed (median biopsy-cone interval of 12.0 weeks, range 5.0-34.1 weeks). CIN2-3s that regressed had higher epithelial pRb and p53, lower stromal CD25(+) and CD138(+), and higher CD8 cells than persistent lesions. They also had higher ratios of CD4(+)/CD25(+) and CD8(+)/CD25 in stroma and epithelium. HPV16 correlated with low pRb and low CD8(+). With multivariate analysis a combined high ratio of CD8(+)/CD25(+) in the stroma, high epithelial pRb and p53 expression had independent value to predict the regression. Conclusions CIN2-3 lesions with a non-hrHPV16 infection, high ratios of stromal CD8(+)/CD25(+) and high epithelial expression of pRb or p53 are associated with spontaneous regression.