Stepwise overexpression of p63, p53, and cytokeratin 14 during progression of esophageal squamous intraepithelial neoplasia: useful immunohistochemical markers for differential diagnosis

Abstract

Background Esophageal squamous intraepithelial neoplasia (ESIN) as a precursor for invasive carcinoma is classified into low-grade IN (LIN) and high-grade IN (HIN), the latter including carcinoma in situ (CIS). Increasing grades of ESIN are associated with increasing risk of invasive carcinoma, but differentiation among LIN, HIN, and CIS is subjective and challenging. As p63, a member of the p53 family, is known to regulate differentiation and proliferation in epithelial progenitor cells, its expression, along with that of cytokeratin (CK) 14 (basal squamous marker) and Ki-67 (proliferation marker), might be of diagnostic assistance. Methods Immunohistochemical staining was performed on endoscopically resected specimens from 69 patients (73 lesions) with ESIN between 2008 and 2010. Specimens having no atypical cells distant from ESIN were defined as negative for IN (NIN). Results There were 13 LIN, 29 HIN, and 31 CIS lesions. The size of CIS (mean 20.1 mm) was significantly larger than that of HIN (14.3 mm) or LIN (10.0 mm). Immunolabeling scores (ILS) for p63, p53, CK14, and Ki-67 showed stepwise increase with ESIN progression (NIN vs. LIN and LIN vs. HIN, P \ 0.05-0.0001; HIN vs. CIS, P \ 0.05-0.001). Mean total ILSs of all four markers were 2.0 for NIN, 4.3 for LIN, 7.4 for HIN, and 9.1 for CIS (P \ 0.0001). A cutoff value for total ILS of B5 versus C6 demonstrated highest sensitivity (96.0%) and specificity (85.7%) in distinguishing HIN from LIN.Conclusions This study suggests that p63 and p53 are coordinately upregulated in esophageal squamous carcinogenesis, and assessment of their expression might provide a useful adjunct tool for differential diagnosis of ESIN.

Novel Insight of Cytokeratin 14 as a Biomarker in Diagnosing Bladder Cancer

“…Contrast to these findings, Nakayama et al (2011) reported increased expression of CK14 as squamous intraepithelial neoplasia progressed with the greatest expression observed in CIS [54]. Similar results were identified in other studies about invasive salivary adenoid cystic carcinoma and breast cancer [55], [56].…”