Accurate histological grading of cervical intraepithelial neoplasia (CIN) is essential for clinical management. However, CIN grading has a moderate inter- and intra-observer agreement. We investigated the reproducibility of the performance of a score system based solely on the cumulative score value of the biomarkers Ki-67 and p16ink4a (immune-score), and compared the results to consensus pathologist CIN grading based on slides stained for H&E, Ki-67 and p16ink4a.
Three expert gynaeco-pathologists received H&E slides of 115 randomly selected cervical tissue specimens, selected the most abnormal area and rendered a diagnosis (diagnosis 1). At a later time point, the individual pathologists independently scored corresponding Ki-67 and p16ink4a immunostainings by a three-tiered immune-score system. Next, a diagnosis was made based on both the H&E and immunostainings (diagnosis 2). The consensus diagnosis 2 was used as the Gold Standard. Consistency of diagnosis 1, 2 and immune-score was determined by Spearman Correlation coefficients, Kappa values and absolute agreement between pathologists. Validity of the diagnosis 1, 2 and immune-score was determined by sensitivity and specificity for CIN2+ and CIN3+ graded by the Gold Standard diagnosis.
Gold Standard diagnoses revealed 35 specimens without dysplasia, 20 CIN1, 17 CIN2, 22 CIN3 and 21 specimens with SCC. The highest consistency between pathologists was found for the immune-score, with a Spearman correlation coefficient of 0.907, and a maximum Kappa of 0.829 and absolute agreement of 92%. Immune-score showed a higher sensitivity for Gold Standard CIN2+ and CIN3+ than diagnosis 1 and 2, with a sensitivity for marker scores 3 to 6 being higher than 97.0% and an increase in specificity from 70.0% to 85.9%, respectively.
CIN grading based on a simple three-tiered Ki-67 and p16ink4a immune-score has a higher reproducibility and accuracy in terms of consistency and validity than classical histological and immunohistochemical CIN grading. Moreover, this immune-score defines more accurately where on the trajectory of development of cervical cancer via CIN1 to CIN3 the cervical lesion is situated. This is important for the clinician to decide on cervical treatment or a wait and see policy.