Expression of KOC, S100P, mesothelin and MUC1 in pancreatico-biliary adenocarcinomas: development and utility of a potential diagnostic immunohistochemistry panel

Abstract

BackgroundPancreatico-biliary adenocarcinomas (PBA) have a poor prognosis. Diagnosis is usually achieved by imaging and/or endoscopy with confirmatory cytology. Cytological interpretation can be difficult especially in the setting of chronic pancreatitis/cholangitis. Immunohistochemistry (IHC) biomarkers could act as an adjunct to cytology to improve the diagnosis. Thus, we performed a meta-analysis and selected KOC, S100P, mesothelin and MUC1 for further validation in PBA resection specimens.MethodsTissue microarrays containing tumour and normal cores in a ratio of 3:2, from 99 surgically resected PBA patients, were used for IHC. IHC was performed on an automated platform using antibodies against KOC, S100P, mesothelin and MUC1. Tissue cores were scored for staining intensity and proportion of tissue stained using a Histoscore method (range, 0–300). Sensitivity and specificity for individual biomarkers, as well as biomarker panels, were determined with different cut-offs for positivity and compared by summary receiver operating characteristic (ROC) curve.ResultsThe expression of all four biomarkers was high in PBA versus normal ducts, with a mean Histoscore of 150 vs. 0.4 for KOC, 165 vs. 0.3 for S100P, 115 vs. 0.5 for mesothelin and 200 vs. 14 for MUC1 (p < .0001 for all comparisons). Five cut-offs were carefully chosen for sensitivity/specificity analysis. Four of these cut-offs, namely 5%, 10% or 20% positive cells and Histoscore 20 were identified using ROC curve analysis and the fifth cut-off was moderate-strong staining intensity. Using 20% positive cells as a cut-off achieved higher sensitivity/specificity values: KOC 84%/100%; S100P 83%/100%; mesothelin 88%/92%; and MUC1 89%/63%. Analysis of a panel of KOC, S100P and mesothelin achieved 100% sensitivity and 99% specificity if at least 2 biomarkers were positive for 10% cut-off; and 100% sensitivity and specificity for 20% cut-off.ConclusionA biomarker panel of KOC, S100P and mesothelin with at least 2 biomarkers positive was found to be an optimum panel with both 10% and 20% cut-offs in resection specimens from patients with PBA.

Investigating Various Thresholds as Immunohistochemistry Cutoffs for Observer Agreement

“…These cores have previously been studied for diagnostic utility 23 . These cores were carefully selected for each biomarker based on a variable range of staining intensity and proportion of positive cells.…”

“…We selected three cut-offs for investigation based on our diagnostic IHC work 23 and the wider IHC literature. These cut-offs are 10% positive epithelial cells (10% hereafter), 20% positive epithelial cells (20% hereafter) and moderate to strong staining intensity with any proportion of positive cells (+2/+3 hereafter) 8,14,17,[23][24][25][26][27] .…”

“…These cut-offs are 10% positive epithelial cells (10% hereafter), 20% positive epithelial cells (20% hereafter) and moderate to strong staining intensity with any proportion of positive cells (+2/+3 hereafter) 8,14,17,[23][24][25][26][27] . These cut-offs are clinically relevant and we postulated that they are easily interpretable and reproducible amongst pathologists.…”

Mesothelin Expression in Advanced Gastroesophageal Cancer Represents a Novel Target for Immunotherapy

“…The final score represents a combination of all labeling patterns and an average of the tumor cores. Cases were considered mesothelin or E-cadherin positive if at least moderate cytoplasmic, membranous or luminal labeling was present in 10% or more of the tumors cells (Figure 1) (20-22). Labeling for c-met was considered positive if at least 50% of the tumor cells exhibited moderate and/or strong membranous staining similar to scoring criteria proposed for non-small cell lung carcinomas(23, 24).…”

Prognostic value of several biomarkers for the patients with malignant pleural mesothelioma

“…Mesothelin, a membrane-bound peptide, is consistently present in normal mesothelial cells and overexpressed in many malignancies including mesothelioma, ovarian, colon, gastric, lung, triple-negative breast cancer, and pancreatico-biliary adenocarcinomas [5][6][7][8][9][10][11]. The mesothelin gene encodes a 69-71-kDa polypeptide anchored to the cell membrane by a glycosyl-phosphatidyl-inositol (GPI) linkage that can be processed to yield mesothelin, which remains attached to cell membrane, and another protein called MPF secreted into the blood [12][13][14].…”