Cytokeratin7 and cytokeratin19 expression in high grade cervical intraepithelial neoplasm and squamous cell carcinoma and their possible association in cervical carcinogenesis

Abstract

BackgroundHigh risk human papillomavirus (HR HPV) infects cells at the squamocolumnar junction (SCJ) of the cervix, causing cancer. Cytokeratin (CK)7 is an SCJ marker, and stains cervical neoplasia. CK19 is a binding partner of CK7 and expressed in cervical cancer. Despite this possible association between CK7/CK19 and cervical cancer, not much is known about the mechanism of CK7/CK19 involvement in HR HPV-mediated cervical carcinogenesis.MethodsWe analyzed the expression pattern of CK7, CK19, and p16 by using immunohistochemistry and HPV infection by in situ hybridization in 25 cases of high grade cervical intraepithelial neoplasia (CIN3) and in 30 cases of squamous cell carcinoma (SCC).ResultsCK19, p16, and HPV expression was positive in all CIN3 and SCC cases. CK7 expression was positive in all CIN3 cases and in 20/30 (66%) SCCs. Each protein showed diffuse or patchy staining with topographic distinction. Patchy staining of CK7 and episomal HPV DNA overlapped in the upper layer of CIN3 and central portion of an invasive nest in the SCC, whereas patchy CK19 staining and integrated HPV DNA were usually noted in the lower layer of CIN3 and the periphery of the SCC nest. The p16 staining pattern coincided with that of CK19 in a subset of SCC.ConclusionThese results suggest that CK7 may be more related with viral episomal replication and CK19 with viral integration, contributing to viral replication and malignant transformation in HR HPV infected cells. In addition, coordinate CK7/CK19 staining may be used as a valuable marker for predicting physical status of HR HPV and E7 oncoprotein level in cervical tumor.Electronic supplementary materialThe online version of this article (doi:10.1186/s13000-017-0609-4) contains supplementary material, which is available to authorized users.

CK7/CK19 index: A potential prognostic factor for postoperative intrahepatic cholangiocarcinoma patients

“…Previously, the majority of studies investigated the prognostic or diagnostic significance of individual CK7 or CK19 in various kinds of cancers, with the ignorance of combined CK7 and CK19. Recently, Lee et al reported that CK7 was a binding partner of CK19 in cervical cancer, and both were involved in HPV‐mediated cervical carcinogenesis. Although CK7 and CK19 mainly expressed in the bile duct epitheliums, several studies also asserted that CK7 and CK19 could be expressed in HCC and affecting prognosis of HCC patients .…”

Cytokeratin7 expression in histologic and cytologic specimens of cystic neck metastasis from HPV positive squamous cell carcinoma of the tonsil: A case report

“…Tonsillar and uterine cervical SCCs share some histopathological and immunohistochemical features. They both arise in CK7 and CK19 positive squamocolumnar junctional cells infected by HR HPV and frequently accompany intratumoral cystic changes . In an earlier study, we observed cystic change in a subset of uterine cervical SCC and topological differences between the expressions of CK7, CK19, and p16 .…”

“…They both arise in CK7 and CK19 positive squamocolumnar junctional cells infected by HR HPV and frequently accompany intratumoral cystic changes. 4,5,7,9 In an earlier study, we observed cystic change in a subset of uterine cervical SCC and topological differences between the expressions of CK7, CK19, and p16. 9 The present case exhibited a staining pattern similar to that of uterine cervical SCC, that is, patchy CK7 staining in the inner portions of cystic tumor nests, diffuse CK19 staining in cystic and solid tumor nests, and strong p16 staining in solid tumor component.…”

“…Immunohistochemical staining was carried out for CK7 (Dako, Carpinteria, CA, 1:100), CK19 (Dako, 1:100), and p16 (Dako p16INK4a kit) using Dako Autostainer (DakoCytomation, Carpinteria, CA) . Immunohistochemistry revealed diffuse and strong p16 staining in both primary and metastatic tumors, but its absence in cystic spaces within the metastatic tumor nest (Figures B, B, and B).…”

Deciphering the Multifactorial Susceptibility of Mucosal Junction Cells to HPV Infection and Related Carcinogenesis

“…In addition to being actively involved in adult adaptive processes (metaplasia, hyperplasia) [10], SC junction cells exhibit intriguing phenotypic similarities with approximately 90% of cervical SCC and high-grade precursors [9,12]. These findings underlying the instrumental role of junctional cells in cervical carcinogenesis were recently confirmed by several immunohistochemical and/or transcriptional studies analyzing the expression of SC junction-overexpressed biomarkers (i.e., cytokeratin 7 (Krt7), anterior gradient protein 2 (AGR2) or cystic fibrosis transmembrane conductance regulator (CFTR)) in large cohorts of cervical (pre)neoplastic lesions [13,14,15,16,17]. Moreover, the evidence that normal-appearing SC junction cells harbor both HPV transcripts (E6*I/II) and early viral proteins (HPV E2) was reported and sustains the possibility that these cuboidal cells could serve as a reservoir for latent infections and subsequent CIN development in asymptomatic HPV-positive patients [18].…”