Risk Stratification By p16 Immunostaining of CIN1 Biopsies

Abstract

Previous studies of p16 immunohistochemistry (IHC) on CIN1 have suggested the likely utility of p16 in stratification of women at risk for subsequent CIN2/3. But those studies had limitations in statistical power, histologic diagnosis, and disease ascertainment. We conducted a retrospective study of p16 IHC on adjudicated CIN1 tissue diagnosed in young women participating in the placebo arm of the quadrivalent human papillomavirus (HPV) vaccine trials. Tissue sections were stained with p16 IHC and hematoxylin and eosin. p16 IHC was scored using LAST criteria, and hematoxylin and eosin-stained sections were reviewed for concordance with the adjudicated diagnosis. p16 IHC, antecedent high-grade cytology, review diagnosis, and HPV16 detection were assessed as independent risk factors for subsequent CIN2/3. Five hundred twenty-four patients with CIN1 biopsies and complete data were identified, 63 (12.0%) of whom developed CIN2/3 in follow-up. p16 positivity (P=0.06), review diagnosis of CIN2/3 (P=0.04), HPV16 positivity (P=0.01), and antecedent high-grade cytology (P=0.02) were (marginally) associated with CIN2/3. In a logistic regression model, the associations with CIN2/3 (vs. other), expressed as odds ratios (95% confidence intervals), were 1.6 (0.91-2.8) for p16, 2.0 (1.0-3.7) for HPV16, and 2.2 (1.1-2.4) for antecedent high-grade cytology. The mean risks for CIN2/3 estimated from the model ranged from 7.6% for negative for all markers to 36.3% for positive for all 3 markers. p16 IHC does not risk stratify CIN1 patients in a manner that would alter recommended management for CIN1. This reinforces the LAST recommendations that p16 should only be used selectively for problematic scenarios, such as CIN2 because of its inherent lack of reproducibility, cases in which one is struggling between CIN1 and CIN2, and benign mimics of CIN3.

The role of p16 as putative biomarker for cervical neoplasia: A controversial issue?

“…Moreover, it is still unclear whether p16 is suitable as a prognostic marker for low-grade lesions. 17 Mills et al 22 recommend that p16 should only be used selectively for problematic scenarios, such as CIN 2 because of its inherent lack of reproducibility, especially in cases in which CIN 1 and CIN 2 are benign mimics of CIN3. Tsoumpou et al 12 considered the reproducibility assays for p16 is still limited due to insufficient standardization and interpretation of the different immunoreactive stain.…”

“…They suggested that cases with a p16/HPV ratio within the high-risk range should not be considered to have clinical value, because the mere presence of high risk HPV is a poor predictor of CIN 1. However, Mills et al 22 demonstrated that women with the diagnosis of CIN 1 with positive p16 that exhibited diffuse pattern had a higher risk of lesion progression after two years of diagnosis of CIN 1.…”

Distribution of cervical lesions in high-risk HPV (hr-HPV) positive women with ASC-US: A retrospective single-center study in China

“…(3) The previous researches found that CIN1 and a subset CIN2 lesions are clinical manifestations of the result of productive hr-HPV infection [32] , which can regularly regress within 1-2 years spontaneously and have a low risk to progress to invasive carcinoma [33] .…”

“…Distribution of oncogenic hr-HPV types and histological results among hr-HPV-positive/ASC-US women. = single hr-HPV infection except HPV16, 18, 33, 39, 51, 52, 53, 56, 58 and 66 †= double infections with hr-HPV ‡= triple infections =4 or more than kinds hr-HPV infections ‖= infection(s) with a pool of 12 other hr-HPV types (includingHPV 31,33,35,39,45,51,52,56,58,59,66 and 68) that did not know the specific type of HPV (from Cobas 4800 HPV test) ¶= hr-HPV infection that did not know the specific type of HPVfrom Cervista HPV HR (Hologic) or Hybrid Capture 2 testTable 3. Distribution of histological results among viral load groups in ASC-US women Distribution of histological results among viral load groups in ASC-US women.…”

Prognostic value of human papillomavirus 16/18 genotyping in low-grade cervical lesions preceded by mildly abnormal cytology

“…Previous studies have explored the values of immunohistochemical markers (such as p16 INK4A and cytokeratin 7) in predicting the behavior of LSIL/ CIN1. However, microscopically interpretive variability confounded such studies, and results have been inconsistent (Liao et al, 2014;Mills et al, 2015;Huang et al, 2016;Paquette et al, 2016;Sagasta et al, 2016).…”