MMR Deficiency is Homogeneous in Pancreatic Carcinoma and Associated with High Density of Cd8-Positive Lymphocytes
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ORIGINAL ARTICLE – TRANSLATIONAL RESEARCH AND BIOMARKERS
MMR Deficiency is Homogeneous in Pancreatic Carcinoma and Associated with High Density of Cd8-Positive Lymphocytes Christoph Fraune, MD1, Eike Burandt, MD1, Ronald Simon, PhD1, Claudia Hube-Magg, PhD1, Georgia Makrypidi-Fraune, PhD1, Martina Kluth, PhD1, Franziska Bu¨scheck, MD1, Doris Ho¨flmayer, MD1, Niclas Ch. Blessin1, Tim Mandelkow1, Wenchao Li1, Daniel Perez, MD2, Jakob R. Izbicki, MD2, Waldemar Wilczak, MD1, Guido Sauter, MD1, Jo¨rg Schrader, MD2,3, Michael Neipp, MD4, Hamid Mofid, MD5, Thies Daniels, MD6, Christoph Isbert, MD7, Till S. Clauditz, MD1, and Stefan Steurer, MD1 Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 2General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 3I. Medical Department – Gastroenterology and Hepatology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; 4General, Vascular and Visceral Surgery Clinic, Itzehoe Medical Center, Itzehoe, Germany; 5General, Visceral Thoracic and Vascular Surgery Clinic, Regio Clinic Pinneberg, Pinneberg, Germany; 6General, Visceral and Tumor Sugery Clinic, Albertinen Hospital, Hamburg, Germany; 7Department of General, Gastrointestinal and Colorectal Surgery, Amalie Sieveking Hospital, Hamburg, Germany
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ABSTRACT Background. Microsatellite instability (MSI) has emerged as a predictive biomarker for immune checkpoint inhibitor therapy. Cancer heterogeneity represents a potential obstacle for the analysis of predicitive biomarkers. MSI has been reported in pancreatic cancer, but data on the possible extent of intratumoral heterogeneity are lacking. Methods. To study MSI heterogeneity in pancreatic cancer, a tissue microarray (TMA) comprising 597 tumors was screened by immunohistochemistry with antibodies for the mismatch repair (MMR) proteins MLH1, PMS2, MSH2, and MSH6.
Christoph Fraune and Eike Burandt have equally contributed to the work described in this manuscript
Electronic supplementary material The online version of this article (https://doi.org/10.1245/s10434-020-08209-y) contains supplementary material, which is available to authorized users. Ó The Author(s) 2020 First Received: 29 October 2019 R. Simon, PhD e-mail: [email protected]
Results. In six suspicious cases, large section immunohistochemistry and microsatellite analysis (Bethesda panel) resulted in the identification of 4 (0.8%) validated MSI cases out of 480 interpretable pancreatic ductal adenocarcinomas. MSI was absent in 55 adenocarcinomas of the ampulla of Vater and 7 acinar cell carcinomas. MMR deficiency always involved MSH6 loss, in three cases with additional loss of MSH2 expression. Three cancers were MSI-high and one case with isolated MSH6 loss was MSS in PCR analysis. The analysis of 44 cancer-containing tumor blocks revealed that the loss of MMR protein expression was always homogeneous in affected tumors. Automated digital image analysis of CD8 immunostaining demonstrated markedly higher CD8 ?
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