Management of HPV-Related Cervical Disease: Role of p16^INK4aImmunochemistry. Review of the Literature

Abstract

This systematic review of 43 studies aims to evaluate the absolute and relative sensitivity and specificity of p16INK4a with regard to uterine cervix lesions, describing innovations and techniques for the detection of high-grade cervical dysplasia and allowing correct treatment. Studies were identified in the PubMed database up to March 2015. The keywords hrHPV, p16INK4a gene, and uterine cervical disease (MeSH terms) were used. Only English-language articles were included. We considered retrospective and prospective studies that assessed p16INK4a or p16INK4a/Ki67 staining, with or without HPV-DNA testing (HC2/PCR) as a comparator test, in cytological/histological specimens for which the diagnosis of ASCUS, LSIL or HSIL was verified with a reference standard. The primary outcome for cervical lesions was evaluation of the absolute p16INK4a immunoreactivity; the secondary outcome was evaluation of the relative p16INK4a immunoreactivity versus HPV testing in those studies where comparator tests were available. p16INK4a was more specific than HPV-DNA test (median values of 56.1% vs. 52.25% in CIN grade ≥2 lesions; 82.5% vs. 53% in negative and CIN grade ≥1 lesions). The main limitation of this study is linked to both qualitative and quantitative p16INK4a levels of expression, while the second limitation is the lack of standardized scales. p16INK4a and HPV-DNA used together increased the sensitivity and negative predictive value for CIN detection. p16INK4a can be considered a biomarker of CIN2 or CIN3, indicating a high risk of relapse or evolution to invasive carcinoma. Also p16INK4a-negative CIN should be considered and further research should be performed.

HPV-related Vulvar Diseases and Perspectives of p16INK4a Immunochemistry: A Review of the Literature

“…As in cervical cancer, p16 INK4a is a marker of HPV integration into the host genome and a useful tool to classify VIN into hrHPV-associated and hrHPV-independent vulvar lesions. The sensitivity and specificity of p16 INK4a immunostaining for detecting uVIN are close to 100%, higher than HPV DNA testing (HC2/PCR) and histological classification (11, 12).…”

Primary HPV and Molecular Cervical Cancer Screening in US Women Living With Human Immunodeficiency Virus

“…We also examined another promising screening approach, dual immunocytochemical staining for Ki-67 (a proliferation marker) and p16 (a cyclin-dependent kinase inhibitor that can accumulate when there is overexpression of the HPV oncoprotein E7). While there is increasing evidence that p16/Ki-67 testing may have a high positive predictive value (PPV) for cervical precancer/cancer, data are limited for WLWH [15,16]. The use of direct comparisons between assays in a single study (such as this) is important in order to avoid concerns regarding variations in study design, methods, and patient populations.…”

The Role of p16/Ki-67 Immunostaining, hTERC Amplification and Fibronectin in Predicting Cervical Cancer Progression: A Systematic Review

“…Viral oncogenes E6 and E7 are known to be drivers of proliferation, promoting and maintaining the malignant growth of cervical cells in the process of high-risk HPV-linked carcinogenesis [ 13 , 87 ]. p16 protein is considered a surrogate biomarker for the transforming activity of high-risk HPV and it can be detected via IHC staining of cytology or histology specimens [ 88 , 89 ]. p16-positivity is defined as strong and diffuse staining, meaning nuclear and/or nuclear plus cytoplasmic expression affecting the basal and para-basal cell layers and extending to the surface of the squamous epithelium on histological sections [ 90 ].…”