Immunohistochemical Evaluation of a Panel of Tumor Cell Markers During Malignant Progression in Barrett Esophagus

Abstract

Histopathologic grading of dysplasia in Barrett esophagus (BE) shows substantial interobserver and intraobserver variation. We used immunohistochemical analysis with a set of tumor cell markers, ie, epidermal growth factor receptor (EGFR), ERBB2 (HER2/neu), MYC, CDKN2A (p16), SMAD4, MET, CCND1 (cyclin D1), CTNNB1 (beta-catenin), and TP53 (p53), in histologic sections of endoscopic biopsies of 86 patients with BE in various stages of neoplastic progression. The markers, except SMAD4, were scored as 0 (<1% of cells stained), 1 (1%-25%), 2 (26%-50%), or 3 (>50%). All markers, except EGFR, showed a significant trend for immunohistochemical protein overexpression during malignant progression in BE (P <.01). When the successive stages along the metaplasia-low-grade dysplasia (LGD)-high-grade dysplasia (HGD)-adenocarcinoma axis were compared, protein overexpression of beta-catenin separated LGD from metaplasia, whereas protein overexpression of cyclin D1 and p53 discriminated HGD from LGD (all P <.001). beta-Catenin can be helpful for a diagnosis of LGD in BE, although it stains positively in a subset only, whereas p53 remains an appropriate marker to define HGD. In case of doubt, cyclin D1 can be added to separate LGD from HGD in BE.

Gene expression alterations in formalin-fixed, paraffin-embedded Barrett esophagus and esophageal adenocarcinoma tissues.

“…46 β-catenin, which was reduced at the mRNA level in this study, has a pattern of progressive loss of membranous protein expression with, in some studies, an increase in nuclear accumulation. [47][48][49][50][51][52] Variable findings have been reported for EGFR (epidermal growth factor receptor) expression 53 or amplification, 54 but the progressive reduction in EGFR expression in this study, together with the failure to identify significant differences in EGFR protein expression in normal, BE and EAC tissues in another study, 47 raise doubts regarding the applicability of EGFR-targeted therapy for this cancer type. 55 Another monoclonal antibody target, HER-2/erbB-2, was the most stably expressed gene in this study, with very similar mRNA levels in normal, BE and EAC tissues.…”

American Gastroenterological Association Technical Review on the Management of Barrett's Esophagus

“…108 Immunostaining for α-methylacyl-CoA racemase (AMACR) and for a panel of biomarkers that includes β-catenin, cyclin D1, and p53 also has shown promise in preliminary studies for distinguishing dysplasia from reactive changes and for distinguishing among grades of dysplasia. 109–111 In contrast to those promising reports, a study that attempted to correlate grades of dysplasia with messenger RNA expression levels for a panel of 10 genes believed to contribute to carcinogenesis in Barrett's esophagus found that the utility of the panel was severely limited by significant interpatient and intrapatient variations in gene expression levels. 112 At this time, data supporting the use of biomarkers to confirm the histologic diagnosis of dysplasia must be considered preliminary, and biomarkers cannot yet be recommended for this purpose for routine clinical practice.…”

Barrett’s Esophagus: Emerging Knowledge and Management Strategies

“…Immunohistochemistry for p53 and Ki67 has also been reported to correlate with the severity of dysplasia in assessing Barrett's biopsies [133, 134]. In another study of 86 biopsies, protein overexpression of β -catenin helped diagnose LGD, whereas overexpression of cyclin D1 and p53 discriminated HGD from LGD [135]. However, most pathologists rely on routine stains and morphology to diagnose and grade dysplasia and immunohistochemistry is rarely, if ever, used in routine day-to-day practice in most centers.…”