Expression Status of p16 Protein Is Associated with Human Papillomavirus Oncogenic Potential in Cervical and Genital Lesions

Abstract

The p16 protein (p16) is a cyclin-dependent kinase (CDK) inhibitor that decelerates the cell cycle by in-Many studies have shown that human papillomavirus (HPV) infection plays an important role in cervical carcinogenesis.1 In fact, HPV infection has been detected in almost all preneoplastic and neoplastic lesions of the cervix. Recent extensive studies have revealed the existence of more than 70 subtypes of HPV, of which approximately 20 can infect the cervical epithelium and give rise to various lesions of the cervix.1-3 Moreover, each HPV subtype has been shown to be associated with a different risk of neoplastic transformation by cervical epithelial cells, and the HPV subtypes have been classified into three categories according to the risk: high, intermediate, and low.2,3 HPV-16 and -18 are representative of highrisk HPVs and are the most clinically important HPV subtypes, because infection by these viruses has a marked influence on outcome. HPV-31, -33, -35, -51, -52, and -58 are associated with intermediate risk for development of cervical cancer and high-grade squamous intraepithelial lesions (HSILs), whereas HPV-6 and -11 are classified as low-risk HPVs and are usually associated with benign hyperplastic lesions such as condylomata acuminata and low-grade squamous intraepithelial lesions (LSILs).

HPV infection and immunochemical detection of cell-cycle markers in verrucous carcinoma of the penis

“…45 However, in tumours with HPV infection, accumulation of p16 INK4A is a well-known event in response to RB inactivation by viral E7 protein. 46 We detected a lack of p16 INK4A nuclear and cytoplasmic expression in our penile verrucous carcinoma series in 93% (14/15) and 87% (13/15) of cases, respectively. Ferreux et al 47 found at least three alternative mechanisms targeting the p16 INK4A /cyclin D/RB pathway in penile carcinoma.…”

Usefulness of liquid-based cytology specimens for the immunocytochemical study of p16 expression and human papillomavirus testing

“…Several studies using p16 have corroborated the above results and confirmed that nearly all high-grade CIN lesions and invasive carcinomas immunohistochemically express very high levels of p16, whereas normal and hyperplastic cervical epithelia usually do not express p16. 21,30,31 Moreover, these findings also have been confirmed in cytologic specimens using liquid-based Pap smears. However, to our knowledge, there are no systematic reports published to date examining immunohistochemical p16 expression and HPV status in both cytology and tissue samples obtained simultaneously from the same patient.…”

“…In 1998, Sano et al clearly demonstrated the overexpression of p16 in CIN lesions and nearly all cervical carcinomas. 16,30 Moreover, because p16 overexpression is observed in many CIN lesions with highrisk and intermediate-risk HPV infections, p16 is be- lieved to be a suitable biomarker for screening CIN lesions and cervical carcinoma during routine pathologic diagnosis. Several studies using p16 have corroborated the above results and confirmed that nearly all high-grade CIN lesions and invasive carcinomas immunohistochemically express very high levels of p16, whereas normal and hyperplastic cervical epithelia usually do not express p16.…”

“…A previous immunohistochemical study of p16 using ThinPrep smears (Cytyc Corporation, Boxborough, MA) has revealed that p16 marks dysplastic squamous and glandular cells of the cervix with a sensitivity of 99.9% and a specificity of 100%, values that are far beyond those of HPV. 30 Even in adenocarcinoma of the cervix, it has been reported that p16 diffuse expression is correlated with high-risk HPV infection. 31 In LSIL cases, the frequency of p16 expression was found to be relatively low in the current study compared with previously published data.…”

P16INK4A immunostaining is a strong indicator for high‐risk‐HPV‐associated oropharyngeal carcinomas and dysplasias, but is unreliable to predict low‐risk‐HPV‐infection in head and neck papillomas and laryngeal dysplasias

“…2,7,37 The upregulation of p16 INK4A results from inactivation of pRb by the HPV-E7 oncoprotein, or alternatively through E7-mediated epigenetic induction of KDM6B, subsequently leading to activation of the p16 INK4A gene. 6,16 Although several studies have reported a high interobserver conformity in the evaluation of p16 INK4A immunostaining patterns, 4,14,18,19,42 others have indicated limitations in this procedure. The immunohistochemical p16 INK4A staining procedure is subject to variations in the protocol and to difficulties in the interpretation of the staining patterns as a result of different scoring criteria.…”