High c-Met expression in stage I-II pancreatic adenocarcinoma: proposal for an immunostaining scoring method and correlation with poor prognosis

• Published in: Histopathology Vol. 67; no. 5; pp. 664 - 676
• Main Authors: Neuzillet, Cindy, Couvelard, Anne, Tijeras-Raballand, Annemilaï, de Mestier, Louis, de Gramont, Armand, Bédossa, Pierre, Paradis, Valérie, Sauvanet, Alain, Bachet, Jean-Baptiste, Ruszniewski, Philippe, Raymond, Eric, Hammel, Pascal, Cros, Jérôme
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01-11-2015; Wiley Subscription Services, Inc
• Subjects: Adult; Aged; biomarker; Biomarkers, Tumor - analysis; Carcinoma, Pancreatic Ductal - mortality; Carcinoma, Pancreatic Ductal - pathology; Disease-Free Survival; Female; Humans; immunochemistry; Immunohistochemistry - methods; invasion; Kaplan-Meier Estimate; Male; Medical prognosis; Middle Aged; Multivariate analysis; Neoplasm Staging; pancreatic cancer; Pancreatic Neoplasms - mortality; Pancreatic Neoplasms - pathology; Prognosis; Proportional Hazards Models; Proto-Oncogene Proteins c-met - biosynthesis; Reproducibility of Results; survival; Tissue Array Analysis; pancreatic cancer; invasion; biomarker; immunochemistry; survival
• ISSN: 0309-0167; 1365-2559
• DOI: 10.1111/his.12691

Aims
c‐Met is an emerging biomarker in pancreatic ductal adenocarcinoma (PDAC); there is no consensus regarding the immunostaining scoring method for this marker. We aimed to assess the prognostic value of c‐Met overexpression in resected PDAC, and to elaborate a robust and reproducible scoring method for c‐Met immunostaining in this setting.
Methods and results
c‐Met immunostaining was graded according to the validated MetMab score, a classic visual scale combining surface and intensity (SI score), or a simplified score (high c‐Met: ≥20% of tumour cells with strong membranous staining), in stage I–II PDAC. A computer‐assisted classification method (Aperio software) was developed. Clinicopathological parameters were correlated with disease‐free survival (DFS) and overall survival(OS). One hundred and forty‐nine patients were analysed retrospectively in a two‐step process. Thirty‐seven samples (whole slides) were analysed as a pre‐run test. Reproducibility values were optimal with the simplified score (kappa = 0.773); high c‐Met expression (7/37) was associated with shorter DFS [hazard ratio (HR) 3.456, P = 0.0036] and OS (HR 4.257, P = 0.0004). c‐Met expression was concordant on whole slides and tissue microarrays in 87.9% of samples, and quantifiable with a specific computer‐assisted algorithm. In the whole cohort (n = 131), patients with c‐Methigh tumours (36/131) had significantly shorter DFS (9.3 versus 20.0 months, HR 2.165, P = 0.0005) and OS (18.2 versus 35.0 months, HR 1.832, P = 0.0098) in univariate and multivariate analysis.
Conclusions
Simplified c‐Met expression is an independent prognostic marker in stage I–II PDAC that may help to identify patients with a high risk of tumour relapse and poor survival.