Predictive Value of Cytokeratin 7 Immunohistochemistry in Cervical Low-grade Squamous Intraepithelial Lesion as a Marker for Risk of Progression to a High-grade Lesion

Abstract

The squamocolumnar junction (SCJ) cell population of the uterine cervix is a discrete epithelial area and the putative source of the majority of high-grade squamous intraepithelial lesions (HSIL). The SCJ cells can be identified by immunohistochemical (IHC) stains including cytokeratin 7 (CK7). Others have theorized that an SCJ marker-positive low-grade squamous intraepithelial lesion (LSIL) has a higher risk for future HSIL compared with an SCJ marker-negative LSIL. This study has 2 aims: first, to refine the definition of a positive CK7 immunostaining pattern in cervical lesions, and, second, to test the hypothesis that CK7 positivity in LSIL indicates higher risk for future HSIL, with both questions addressed using a data set with consensus diagnoses. One hundred cases each of LSIL, moderate HSIL (CIN2), and severe HSIL (CIN3) were stained for CK7, with positivity defined as a diffuse cytoplasmic staining pattern (>5 to 6 contiguous cells); all others were considered negative. Using this model, 34% of CIN1, 45% of CIN2, and 60% of CIN3 were CK7 positive. With follow-up, CK7-positive LSILs were more likely to progress to HSIL compared with CK7-negative LSIL (32% vs. 11%, P=0.05), in concordance with the results of other researchers. This study simplifies cervical CK7 IHC grading into a reproducible system and supports the thesis that CK7 positivity in LSIL is associated with increased risk for future HSIL. Larger cohorts using consensus-diagnosed LSIL are needed to confirm these results before CK7 may be considered for clinical validation.

A clinicopathological and molecular analysis of cervical carcinomas with basaloid features

“…SCJ cells have been recognised as ‘embryonic’ cells which are thought to be uniquely susceptible to oncogenic HPV infection, and therefore to be the origin for cervical carcinoma and its precursors. SCC and HSIL invariably involve the SCJ and frequently display positive staining for CK7 while CK7 positive LSIL has a high risk for future HSIL . The ‘top‐down’ differentiation model suggests that the SCJ cells in the uterine cervix can give rise to a second population of metaplastic progeny, the subjacent basal/reserve cells, with a shift from the SCJ‐positive to ‐negative immunophenotype (negative CK7) .…”

Squamous cell carcinoma of the ascending colon: two cases

“…However, this remains an elusive association, not a cause [8,10]. Cytokeratin 7 has been used as a marker for low-grade squamous cervical lesions with high risk of progression [11]. Case 1 had benign squamous colonic tissue that resembled esophageal tissue.…”

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].…”

“…Recently, four studies analyzed the predictive value of junctional biomarkers (especially Krt7) and, interestingly, all showed that low-grade CIN arising from the SC junction have a significantly higher risk to progress to CIN2/3 compared to their counterparts observed in the transformation zone/ectocervix [12,13,14,15]. Furthermore, when compared to other risk factors, such as HPV16 infection and diffuse p16 ink4 expression, full-thickness Krt7 immunoreactivity demonstrated the highest correlation with lesion progression [14].…”