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Pancreatic Neoplasms: HELP
Articles by Björn Konukiewitz
Based on 17 articles published since 2010
(Why 17 articles?)
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Between 2010 and 2020, B. Konukiewitz wrote the following 17 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Pathology of pancreatic ductal adenocarcinoma: facts, challenges and future developments. 2014

Esposito, Irene / Konukiewitz, Björn / Schlitter, Anna Melissa / Klöppel, Günter. ·Irene Esposito, Björn Konukiewitz, Anna Melissa Schlitter, Günter Klöppel, Institute of Pathology, Technische Universität München, 81675 Munich, Germany. ·World J Gastroenterol · Pubmed #25320520.

ABSTRACT: Despite major improvements concerning its diagnosis and treatment, pancreatic ductal adenocarcinoma (PDAC) remains an aggressive disease with an extremely poor prognosis. Pathology, as interface discipline between basic and clinical medicine, has substantially contributed to the recent developments and has laid the basis for further progress. The definition and classification of precursor lesions of PDAC and their molecular characterization is a fundamental step for the potential identification of biomarkers and the development of imaging methods for early detection. In addition, by integrating findings in humans with the knowledge acquired through the investigation of transgenic mouse models for PDAC, a new model for pancreatic carcinogenesis has been proposed and partially validated in individuals with genetic predisposition for PDAC. The introduction and validation of a standardized system for pathology reporting based on the axial slicing technique has shown that most pancreatic cancer resections are R1 resections and that this is due to inherent anatomical and biological properties of PDAC. This standardized assessment of prognostic relevant parameters represents the basis for the successful conduction of multicentric studies and for the interpretation of their results. Finally, recent studies have shown that distinct molecular subtypes of PDAC exist and are associated with different prognosis and therapy response. The prospective validation of these results and the integration of molecular analyses in a comprehensive pathology report in the context of individualised cancer therapy represent a major challenge for the future.

2 Review Intraductal neoplasms of the pancreas. 2014

Klöppel, Günter / Basturk, Olca / Schlitter, Anna Melissa / Konukiewitz, Björn / Esposito, Irene. ·Institute of Pathology, Technische Universität München, Munich, Germany. Electronic address: guenter.kloeppel@lrz.tum.de. · Memorial Sloan-Kettering Cancer Center, New York, New York. · Institute of Pathology, Technische Universität München, Munich, Germany. ·Semin Diagn Pathol · Pubmed #25282472.

ABSTRACT: There are three types of pancreatic neoplasms that predominantly have an intraductal growth pattern: the common, usually cystic, intraductal papillary mucinous neoplasms (IPMNs); the rare, usually solid intraductal tubulopapillary neoplasms (ITPNs); and the rare intraductal tubular pyloric gland-type adenoma. In addition to these three tumor types, pancreatic neoplasms with a usually solid growth pattern such as acinar cell carcinomas, neuroendocrine tumors, and undifferentiated carcinomas may present, though very rarely, as predominantly intraductally growing neoplasms. IPMNs can be subclassified into main duct and branch duct tumors; into low- and high-grade dysplasia groups; and into tumors with intestinal, pancreatobiliary, oncocytic, or gastric cellular differentiation. The intestinal-, pancreatobiliary-, and oncocytic-type IPMNs occur predominantly in the main duct of the head of the pancreas and more commonly progress to invasive adenocarcinomas. The gastric-type IPMNs are frequently multifocal, occur predominantly in the branch ducts of the uncinate process, and have a low risk of progressing to invasive carcinoma. The prognosis for patients with an IPMN depends largely on the subtype and the presence and the stage of an invasive carcinoma. ITPNs are nodular tumors, often in the pancreatic head, and composed of densely packed tubular glands. Molecular genetics reveal KRAS, GNAS, and RNF43 as the most frequently mutated genes in IPMNs, while ITPNs show wild-type KRAS. Recent progress in genetic sequencing of pancreatic neoplasms and the identification of specific genetic mutations also holds promise for the future development of novel gene-based diagnostic tests in intraductal neoplasms of the pancreas that might even be used in preoperative conditions.

3 Review [New insights into the origin of pancreatic cancer. Role of atypical flat lesions in pancreatic carcinogenesis]. 2012

Esposito, I / Konukiewitz, B / Schlitter, A M / Klöppel, G. ·Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Trogerstr. 18, 81675 München. Esposito@lrz.tum.de ·Pathologe · Pubmed #23011021.

ABSTRACT: The identification and characterization of precursor lesions is fundamental to develop screening programs for early diagnosis and treatment, aiming at reducing cancer-related mortality. Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease that becomes clinical apparent only in advanced stages. In order to enable screening procedures for early detection of PDAC, an exact characterization of precursor lesions is of utmost importance. Pancreatic intraepithelial neoplasias (PanIN) are the most frequent and best characterized precursors of PDAC and are lesions with a ductal phenotype thus indicating a ductal cell origin of PDAC. However, evidence from genetically engineered mouse models suggests that tubular complexes (TC) originating through a process of acinar-ductal metaplasia (ADM) form atypical flat lesions (AFL) that may represent an alternative pathway of pancreatic carcinogenesis. Based on a thorough morphological and genetic analysis of murine TC, AFL and PanIN and their human counterparts, a new dual model of pancreatic carcinogenesis is proposed taking into account the role of AFL as possible new precursors of PDAC.

4 Article Pancreatic neuroendocrine carcinomas reveal a closer relationship to ductal adenocarcinomas than to neuroendocrine tumors G3. 2018

Konukiewitz, Björn / Jesinghaus, Moritz / Steiger, Katja / Schlitter, Anna Melissa / Kasajima, Atsuko / Sipos, Bence / Zamboni, Giuseppe / Weichert, Wilko / Pfarr, Nicole / Klöppel, Günter. ·Institute of Pathology, Technical University of Munich, 81675 Munich, Germany. Electronic address: b.konukiewitz@tum.de. · Institute of Pathology, Technical University of Munich, 81675 Munich, Germany. Electronic address: moritz.jesinghaus@tum.de. · Institute of Pathology, Technical University of Munich, 81675 Munich, Germany. Electronic address: katja.steiger@tum.de. · Institute of Pathology, Technical University of Munich, 81675 Munich, Germany. Electronic address: melissa.schlitter@web.de. · Institute of Pathology, Technical University of Munich, 81675 Munich, Germany. Electronic address: atsuko.kasajima@tum.de. · Institute of Pathology, University Hospital of Tuebingen, 72076 Tuebingen, Germany. Electronic address: Bence.Sipos@med.uni-tuebingen.de. · Institute of Pathology, Sacro Cuore Don Calabria Hospital, 37024 Negrar, Verona, Italy. Electronic address: giuseppe.zamboni@sacrocuore.it. · Institute of Pathology, Technical University of Munich, 81675 Munich, Germany. Electronic address: wilko.weichert@tum.de. · Institute of Pathology, Technical University of Munich, 81675 Munich, Germany. Electronic address: nicole.pfarr@tum.de. · Institute of Pathology, Technical University of Munich, 81675 Munich, Germany. Electronic address: guenter.kloeppel@alumni.uni-kiel.de. ·Hum Pathol · Pubmed #29596894.

ABSTRACT: Pancreatic neuroendocrine carcinoma is a rare aggressive tumor commonly harboring TP53 and RB1 alterations and lacking neuroendocrine-related genetic changes such as mutations in MEN1 and ATRX/DAXX. Little is known about its genetic profile with regard to that of pancreatic ductal adenocarcinoma. We therefore conducted a detailed genetic study in 12 pancreatic neuroendocrine carcinomas of large cell (n = 9) and small cell type (n = 3) using massive parallel sequencing applying a 409-gene panel on an Ion Torrent system. The genetic data were compared with known data of pancreatic ductal adenocarcinoma and correlated with exocrine lineage marker expression. A similar analysis was performed in 11 pancreatic neuroendocrine tumors G3. Neuroendocrine carcinomas harbored 63 somatic mutations in 45 different genes, affecting most commonly TP53 (8/12 cases), KRAS (5/12 cases), and RB1 (loss of expression with or without deletion in 4/12 cases). Five carcinomas had both TP53 and KRAS mutations. Neuroendocrine tumors G3 only shared singular mutations in 5 different genes with neuroendocrine carcinomas, including TP53, CDKN2A, ARID1A, LRP1B, and APC, affecting 5 different cases. Most KRAS-positive neuroendocrine carcinomas also expressed MUC1 (4/5) and carcinoembryonic antigen (3/5) as markers of ductal differentiation. Our data indicate that almost half of the pancreatic neuroendocrine carcinomas are genetically and phenotypically related to pancreatic ductal adenocarcinoma, and might therefore respond to chemotherapies targeting the latter carcinomas.

5 Article Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes. 2018

Mueller, Sebastian / Engleitner, Thomas / Maresch, Roman / Zukowska, Magdalena / Lange, Sebastian / Kaltenbacher, Thorsten / Konukiewitz, Björn / Öllinger, Rupert / Zwiebel, Maximilian / Strong, Alex / Yen, Hsi-Yu / Banerjee, Ruby / Louzada, Sandra / Fu, Beiyuan / Seidler, Barbara / Götzfried, Juliana / Schuck, Kathleen / Hassan, Zonera / Arbeiter, Andreas / Schönhuber, Nina / Klein, Sabine / Veltkamp, Christian / Friedrich, Mathias / Rad, Lena / Barenboim, Maxim / Ziegenhain, Christoph / Hess, Julia / Dovey, Oliver M / Eser, Stefan / Parekh, Swati / Constantino-Casas, Fernando / de la Rosa, Jorge / Sierra, Marta I / Fraga, Mario / Mayerle, Julia / Klöppel, Günter / Cadiñanos, Juan / Liu, Pentao / Vassiliou, George / Weichert, Wilko / Steiger, Katja / Enard, Wolfgang / Schmid, Roland M / Yang, Fengtang / Unger, Kristian / Schneider, Günter / Varela, Ignacio / Bradley, Allan / Saur, Dieter / Rad, Roland. ·Center for Translational Cancer Research (TranslaTUM), Technische Universität München, 81675 Munich, Germany. · Department of Medicine II, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany. · German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. · Institute of Pathology, Technische Universität München, 81675 Munich, Germany. · The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge CB10 1SA, UK. · Comparative Experimental Pathology, Technische Universität München, 81675 Munich, Germany. · Anthropology & Human Genomics, Department of Biology II, Ludwig-Maximilians Universität, 82152 Martinsried, Germany. · Helmholtz Zentrum München, Research Unit Radiation Cytogenetics, 85764 Neuherberg, Germany. · Department of Veterinary Medicine, University of Cambridge, Cambridge CB3 0ES, UK. · Instituto de Medicina Oncológica y Molecular de Asturias (IMOMA), 33193 Oviedo, Spain. · Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, 33006 Oviedo, Spain. · Institute of Oncology of Asturias (IUOPA), HUCA, Universidad de Oviedo, 33011 Oviedo, Spain. · Nanomaterials and Nanotechnology Research Center (CINN-CSIC), Universidad de Oviedo, 33940 El Entrego, Spain. · Medizinische Klinik und Poliklinik II, Klinikum der LMU München-Grosshadern, 81377 Munich, Germany. · Instituto de Biomedicina y Biotecnología de Cantabria (UC-CSIC), 39012 Santander, Spain. ·Nature · Pubmed #29364867.

ABSTRACT: The poor correlation of mutational landscapes with phenotypes limits our understanding of the pathogenesis and metastasis of pancreatic ductal adenocarcinoma (PDAC). Here we show that oncogenic dosage-variation has a critical role in PDAC biology and phenotypic diversification. We find an increase in gene dosage of mutant KRAS in human PDAC precursors, which drives both early tumorigenesis and metastasis and thus rationalizes early PDAC dissemination. To overcome the limitations posed to gene dosage studies by the stromal richness of PDAC, we have developed large cell culture resources of metastatic mouse PDAC. Integration of cell culture genomes, transcriptomes and tumour phenotypes with functional studies and human data reveals additional widespread effects of oncogenic dosage variation on cell morphology and plasticity, histopathology and clinical outcome, with the highest Kras

6 Article None 2018

Iacovazzo, Donato / Flanagan, Sarah E / Walker, Emily / Quezado, Rosana / de Sousa Barros, Fernando Antonio / Caswell, Richard / Johnson, Matthew B / Wakeling, Matthew / Brändle, Michael / Guo, Min / Dang, Mary N / Gabrovska, Plamena / Niederle, Bruno / Christ, Emanuel / Jenni, Stefan / Sipos, Bence / Nieser, Maike / Frilling, Andrea / Dhatariya, Ketan / Chanson, Philippe / de Herder, Wouter W / Konukiewitz, Björn / Klöppel, Günter / Stein, Roland / Korbonits, Márta / Ellard, Sian. ·Centre for Endocrinology, Barts and The London School of Medicine, Queen Mary University of London, EC1M 6BQ London, United Kingdom. · Institute of Biomedical and Clinical Science, University of Exeter Medical School, EX2 5DW Exeter, United Kingdom. · Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232. · Serviço de Endocrinologia e Diabetes, Hospital Universitário Walter Cantídio, Universidade Federal do Ceará, 60430-372 Fortaleza, Brazil. · Division of Endocrinology and Diabetes, Department of Internal Medicine, Kantonsspital St. Gallen, CH-9007 St. Gallen, Switzerland. · Section of Endocrine Surgery, Division of General Surgery, Department of Surgery, University of Vienna, A-1090 Vienna, Austria. · Division of Diabetes, Endocrinology and Metabolism, University Hospital of Basel, CH-4031 Basel, Switzerland. · Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital of Bern, Inselspital, CH-3010 Bern, Switzerland. · Department of Pathology, University of Tübingen, 72076 Tübingen, Germany. · Department of Surgery and Cancer, Imperial College London, W12 0HS London, United Kingdom. · Elsie Bertram Diabetes Centre, Norfolk and Norwich University Hospitals NHS Foundation Trust, NR4 7UY Norwich, United Kingdom. · Service d'Endocrinologie et des Maladies de la Reproduction, Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, F-94275 Le Kremlin-Bicêtre, France. · INSERM 1185, Faculté de Médicine Paris Sud, Université Paris-Saclay, F-94276 Le Kremlin-Bicêtre, France. · Department of Internal Medicine, Sector of Endocrinology, ENETS Centre of Excellence for Neuroendocrine Tumors, Erasmus MC, 3015 Rotterdam, The Netherlands. · Department of Pathology, Consultation Center for Pancreatic and Endocrine Tumors, Technical University of Munich, 81675 Munich, Germany. · Centre for Endocrinology, Barts and The London School of Medicine, Queen Mary University of London, EC1M 6BQ London, United Kingdom; m.korbonits@qmul.ac.uk. ·Proc Natl Acad Sci U S A · Pubmed #29339498.

ABSTRACT: The β-cell-enriched MAFA transcription factor plays a central role in regulating glucose-stimulated insulin secretion while also demonstrating oncogenic transformation potential in vitro. No disease-causing

7 Article Pancreatic Ductal Adenocarcinoma Subtyping Using the Biomarkers Hepatocyte Nuclear Factor-1A and Cytokeratin-81 Correlates with Outcome and Treatment Response. 2018

Muckenhuber, Alexander / Berger, Anne Katrin / Schlitter, Anna Melissa / Steiger, Katja / Konukiewitz, Björn / Trumpp, Andreas / Eils, Roland / Werner, Jens / Friess, Helmut / Esposito, Irene / Klöppel, Günter / Ceyhan, Güralp O / Jesinghaus, Moritz / Denkert, Carsten / Bahra, Marcus / Stenzinger, Albrecht / Sprick, Martin R / Jäger, Dirk / Springfeld, Christoph / Weichert, Wilko. ·Institute of Pathology, Technical University Munich and German Cancer Consortium (DKTK; partner site Munich), Munich, Germany. · Department of Medical Oncology, Heidelberg University Hospital and National Center for Tumor Diseases, Heidelberg, Germany. · Division of Stem Cells and Cancer, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany. · Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM GmbH, Heidelberg, Germany. · German Cancer Consortium (DKTK), Heidelberg, Germany. · Division of Theoretical Bioinformatics and Heidelberg Center for Personalised Oncology (DKFZ-HIPO), German Cancer Research Center (DKFZ), Heidelberg, Germany. · Department for Bioinformatics and Functional Genomics, Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, Heidelberg University, Heidelberg, Germany. · Department of Surgery, University Hospital of the Ludwig-Maximilian University, Munich, Germany. · Department of Surgery, University Hospital of the Technical University Munich, Munich, Germany. · Institute of Pathology, University Hospital Düsseldorf, Düsseldorf, Germany. · Institute of Pathology, Charité University Medicine Berlin and German Cancer Consortium (DKTK; partner site Berlin), Berlin, Germany. · Department of Surgery, Charité University Medicine Berlin, Berlin, Germany. · Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany. · Institute of Pathology, Technical University Munich and German Cancer Consortium (DKTK; partner site Munich), Munich, Germany. wilko.weichert@tum.de. ·Clin Cancer Res · Pubmed #29101303.

ABSTRACT:

8 Article R0 Versus R1 Resection Matters after Pancreaticoduodenectomy, and Less after Distal or Total Pancreatectomy for Pancreatic Cancer. 2018

Demir, Ihsan Ekin / Jäger, Carsten / Schlitter, A Melissa / Konukiewitz, Björn / Stecher, Lynne / Schorn, Stephan / Tieftrunk, Elke / Scheufele, Florian / Calavrezos, Lenika / Schirren, Rebekka / Esposito, Irene / Weichert, Wilko / Friess, Helmut / Ceyhan, Güralp O. ·Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. · Institute for Pathology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. · Institute for Medical Statistics and Epidemiology, Technical University of Munich, Munich, Germany. · Institute of Pathology, Heinrich Heine University, Düsseldorf, Germany. ·Ann Surg · Pubmed #28692477.

ABSTRACT: OBJECTIVE: The aim of this study was to decipher the true importance of R0 versus R1 resection for survival in pancreatic ductal adenocarcinoma (PDAC). SUMMARY OF BACKGROUND DATA: PDAC is characterized by poor survival, even after curative resection. In many studies, R0 versus R1 does not result in different prognosis and does not affect the postoperative management. METHODS: Pubmed, Embase, and Cochrane databases were screened for prognostic studies on the association between resection status and survival. Hazard ratios (HRs) were pooled in a meta-analysis. Furthermore, our prospective database was retrospectively screened for curative PDAC resections according to inclusion criteria (n = 254 patients) between July 2007 and October 2014. RESULTS: In the meta-analysis, R1 was associated with a decreased overall survival [HR 1.45 (95% confidence interval, 95% CI 1.37-1.52)] and disease-free survival [HR 1.44 (1.30-1.59)] in PDAC when compared with R0. Importantly, this effect held true only for pancreatic head resection both in the meta-analysis [R0 ≥0 mm: HR 1.21 (1.05-1.39) vs R0 ≥1 mm: HR 1.66 (1.46-1.89)] and in our cohort (R0 ≥0 mm: 31.8 vs 14.5 months, P < 0.001; R0 ≥1 mm, 41.2 vs 16.8 months; P < 0.001). Moreover, R1 resections were associated with advanced tumor disease, that is, larger tumor size, lymph node metastases, and extended resections. Multivariable Cox proportional hazard model suggested G3, pN1, tumor size, and R1 (0 mm/1 mm) as independent predictors of overall survival. CONCLUSION: Resection margin is not a valid prognostic marker in publications before 2010 due to heterogeneity of cohorts and lack of standardized histopathological examination. Within standardized pathology protocols, R-status' prognostic validity may be primarily confined to pancreatic head cancers.

9 Article pT but not pN stage of the 8th TNM classification significantly improves prognostication in pancreatic ductal adenocarcinoma. 2017

Schlitter, Anna Melissa / Jesinghaus, Moritz / Jäger, Carsten / Konukiewitz, Björn / Muckenhuber, Alexander / Demir, Ihsan Ekin / Bahra, Marcus / Denkert, Carsten / Friess, Helmut / Kloeppel, Günter / Ceyhan, Güralp O / Weichert, Wilko. ·Institute of Pathology, Technical University Munich, Munich, Germany. Electronic address: melissa.schlitter@tum.de. · Institute of Pathology, Technical University Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich, Germany. · Department of Surgery, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany. · Institute of Pathology, Technical University Munich, Munich, Germany. · Department of Surgery, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany; German Cancer Consortium (DKTK), Partner Site Munich, Germany. · Department of Surgery, Charité University Hospital, Berlin, Germany. · Institute of Pathology, Charité University Hospital, Berlin, Germany; German Cancer Consortium (DKTK), Partner Site Berlin, Germany. ·Eur J Cancer · Pubmed #28802189.

ABSTRACT: The UICC TNM (tumour-node-metastasis) staging system for pancreatic ductal adenocarcinoma (PDAC) has been a matter of debate over decades because survival prediction based on T stages was weak and unreliable. To improve staging, the recently published 8th TNM edition (2016) introduced a conceptually completely changed strictly size-based T staging system and a refined N stage for PDAC. To investigate the clinical value of the novel TNM classification, we compared the prognostic impact of pT and pN stage between the 7th and 8th edition in two well-characterised independent German PDAC cohorts from different decades, including a total number of 523 patients. Former UICC T staging (7th edition 2009) resulted in a clustering of pT3 cases (72% and 85% of cases per cohort, respectively) and failed to show significant prognostic differences between the four stages in one of the investigated cohorts (p = 0.074). Application of the novel size-based T stage system resulted in a more equal distribution of cases between the four T categories with a predominance of pT2 tumours (65% and 60% of cases). The novel pT staging algorithm showed greatly improved discriminative power with highly significant overall differences between the four pT stages in both investigated cohorts in univariate and multivariate analyses (p < 0.001, each). In contrast, no prognostic differences were observed between the recently introduced pN1 and pN2 categories in both cohorts (p = 0.970 and p = 0.061). pT stage of resected PDAC patients according to the novel UICC staging protocol (8th edition) significantly improves patient stratification, whereas introduction of an extended N stage protocol does not demonstrate high clinical relevance in our cohorts.

10 Article Molecular, morphological and survival analysis of 177 resected pancreatic ductal adenocarcinomas (PDACs): Identification of prognostic subtypes. 2017

Schlitter, Anna Melissa / Segler, Angela / Steiger, Katja / Michalski, Christoph W / Jäger, Carsten / Konukiewitz, Björn / Pfarr, Nicole / Endris, Volker / Bettstetter, Markus / Kong, Bo / Regel, Ivonne / Kleeff, Jörg / Klöppel, Günter / Esposito, Irene. ·Institute of Pathology, Technische Universität München, Munich, Germany. · Department of Surgery, University Hospital Heidelberg, Germany. · Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany. · Institute of Pathology, University Hospital of Heidelberg, Heidelberg, Germany. · Molecular Pathology South-Bavaria, Munich, Germany. · Institute of Pathology, Heinrich-Heine-University, Düsseldorf, Germany. · The Royal Liverpool and Broadgreen University Hospitals, Prescot Street, Liverpool L7 8XP, United Kingdom. · Department of General-, Visceral- and Pediatric Surgery, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Germany. ·Sci Rep · Pubmed #28145465.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) has generally a poor prognosis, but recent data suggest that there are molecular subtypes differing in clinical outcome. This study examines the association between histopathologic heterogeneity, genetic profile, and survival. Tumor histology from 177 resected PDAC patients with follow-up data was subclassified according to predominant growth pattern, and four key genes were analyzed. PDACs were classified as conventional (51%), combined with a predominant component (41%), variants and special carcinomas (8%). Patients with combined PDACs and a dominant cribriform component survived longer than patients with conventional or other combined PDACs. Genetic alterations in at least two out of four genes were found in 95% of the patients (KRAS 93%, TP53 79%, CDKN2A/p16 75%, SMAD4 37%). Patients with less than four mutations survived significantly longer (p = 0.04) than those with alterations in all four genes. Patients with either wildtype KRAS or CDKN2A/p16 lived significantly longer than those with alterations in these genes (p = 0.018 and p = 0.006, respectively). Our data suggest that the number of altered genes, the mutational status of KRAS and certain morphological subtypes correlate with the outcome of patients with PDAC. Future pathology reporting of PDAC should therefore include the KRAS status and a detailed morphological description.

11 Article Somatostatin receptor expression related to TP53 and RB1 alterations in pancreatic and extrapancreatic neuroendocrine neoplasms with a Ki67-index above 20. 2017

Konukiewitz, Björn / Schlitter, Anna Melissa / Jesinghaus, Moritz / Pfister, Dominik / Steiger, Katja / Segler, Angela / Agaimy, Abbas / Sipos, Bence / Zamboni, Giuseppe / Weichert, Wilko / Esposito, Irene / Pfarr, Nicole / Klöppel, Günter. ·Institute of Pathology, Technical University of Munich, Munich, Germany. · Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Institute of Pathology, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital, Erlangen, Germany. · Institute of Pathology, University Hospital of Tuebingen, Tuebingen, Germany. · Institute of Pathology, Sacro Cuore Hospital of Negrar, Verona, Italy. · Institute of Pathology, Heinrich-Heine-University, Düsseldorf, Germany. ·Mod Pathol · Pubmed #28059098.

ABSTRACT: Somatostatin receptor 2A expression is a feature of well-differentiated neuroendocrine neoplasms and is important for their diagnosis and therapy. Little is known about somatostatin receptor 2A expression in poorly differentiated neuroendocrine neoplasms in relation to TP53 and RB1 status and how these features may contribute to the separation of well from poorly differentiated neuroendocrine neoplasms with a proliferation index above 20%. This study investigates the expression of somatostatin receptors, p53 and Rb1, and TP53 alterations in pancreatic and extrapancreatic well and poorly differentiated neuroendocrine neoplasms (Ki67-index >20%). Thirty-seven poorly differentiated neuroendocrine neoplasms of pancreatic (n=12) and extrapancreatic origin (n=25) as well as 10 well-differentiated neuroendocrine neoplasms of the pancreas (n=9) and rectum (n=1) with a Ki67-index >20% were immunostained for synaptophysin, chromogranin A, Ki67, CD56, p53, Rb1, ATRX, DAXX, progesterone receptor, somatostatin receptor 2A, somatostatin receptor 5, and cytokeratin 20, and sequenced for TP53, exons 5-9. Somatostatin receptor 2A was positive in 6/37 of poorly differentiated and in 8/10 of well-differentiated neuroendocrine neoplasms. One well-differentiated and two poorly differentiated neuroendocrine neoplasms expressed somatostatin receptor 5. Abnormal nuclear p53 and Rb1 staining was found in 29/37 and 22/37 poorly differentiated neuroendocrine neoplasms, respectively, whereas all well-differentiated neuroendocrine neoplasms showed normal p53 and Rb1 expression. TP53 gene alterations were restricted to poorly differentiated neuroendocrine neoplasms (24/34) and correlated well with p53 expression. All cases were progesterone receptor negative. Somatostatin receptor 2A expression is not limited to well-differentiated neuroendocrine neoplasms but also occurs in 16% of poorly differentiated neuroendocrine neoplasms from various sites. Most poorly differentiated neuroendocrine neoplasms are characterized by TP53 alterations and Rb1 loss, usually in the absence of somatostatin receptor 2A expression. In the pancreas, these criteria contribute to separate well-differentiated neuroendocrine neoplasms with a Ki67-index above 20% from poorly differentiated neuroendocrine neoplasms.

12 Article Aberrant Menin expression is an early event in pancreatic neuroendocrine tumorigenesis. 2016

Hackeng, Wenzel M / Brosens, Lodewijk A A / Poruk, Katherine E / Noë, Michaël / Hosoda, Waki / Poling, Justin S / Rizzo, Anthony / Campbell-Thompson, Martha / Atkinson, Mark A / Konukiewitz, Björn / Klöppel, Günter / Heaphy, Christopher M / Meeker, Alan K / Wood, Laura D. ·Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Pathology, University Medical Center Utrecht, Utrecht 3584, CX, the Netherlands. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. · Department of Pathology, College of Medicine, University of Florida, Gainesville, FL 32610-0275, USA. · Department of Pathology, College of Medicine, University of Florida, Gainesville, FL 32610-0275, USA; Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL 32610-0275, USA. · Department of Pathology, Technical University Munich, 81675 Munich, Germany. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA; Department of Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. Electronic address: ldwood@jhmi.edu. ·Hum Pathol · Pubmed #27342911.

ABSTRACT: Pancreatic neuroendocrine tumors (PanNETs) are the second most common pancreatic malignancy and cause significant morbidity and mortality. Neuroendocrine microadenomas have been proposed as a potential precursor lesion for sporadic PanNETs. In this study, we applied telomere-specific fluorescent in situ hybridization (FISH) to a series of well-characterized sporadic neuroendocrine microadenomas and investigated the prevalence of alterations in known PanNET driver genes (MEN1 and ATRX/DAXX) in these same tumors using immunohistochemistry for the encoded proteins. We identified aberrant Menin expression in 14 of 19 (74%) microadenomas, suggesting that alterations in Menin, at least a subset of which was likely due to somatic mutation, are early events in pancreatic neuroendocrine tumorigenesis. In contrast, none of the microadenomas met criteria for the alternative lengthening of telomeres phenotype (ALT) based on telomere FISH, a phenotype that is strongly correlated to ATRX or DAXX mutations. Two of 13 microadenomas (15%) were noted to have very rare abnormal bright telomere foci on FISH, suggestive of early ALT, but these lesions did not show loss of ATRX or DAXX protein expression by immunohistochemistry. Overall, these data suggest that loss of Menin is an early event in pancreatic neuroendocrine tumorigenesis and that ATRX/DAXX loss and ALT are relatively late events.

13 Article [Recurrent duodenal ulcer bleeding as the first manifestation of a solid pseudopapillary neoplasm of the pancreas with hepatic metastases]. 2013

Schlitter, A M / Konukiewitz, B / Kleeff, J / Klöppel, G / Esposito, I. ·Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München. ·Dtsch Med Wochenschr · Pubmed #23670260.

ABSTRACT: HISTORY AND ADMISSION FINDINGS: In a 17-year-old girl recurrent duodenal ulcer bleeding had led to severe anemia. INVESTIGATIONS: Sonography and computed tomography revealed a partially cystic tumour of the pancreatic head and suspicious hepatic lesions. TREATMENT AND PATHOLOGICAL DIAGNOSIS: A partial duodenopancreatectomy was performed and two liver metastases were resected. Histological examination of the resected pancreatic specimen revealed a solid pseudopapillary neoplasm of the pancreas (SPN) with hepatic metastases. CLINICAL COURSE AND PROGNOSIS: The seven remaining liver metastases were removed in a second procedure (right hepatectomy). One year later two new liver metastases were treated by radiofrequency ablation. Two years after the initial operation, the patient is well and tumor-free. CONCLUSION: SPN is a rare cystic tumor that is mainly found in young women. Direct tumor infiltration of stomach or duodenum can cause gastrointestinal bleedings in rare cases. Resection of the primary tumor and surgical or interventional removal of metastases are the treatment of choice.

14 Article ISL1 expression is not restricted to pancreatic well-differentiated neuroendocrine neoplasms, but is also commonly found in well and poorly differentiated neuroendocrine neoplasms of extrapancreatic origin. 2013

Agaimy, Abbas / Erlenbach-Wünsch, Katharina / Konukiewitz, Björn / Schmitt, Anja M / Rieker, Ralf J / Vieth, Michael / Kiesewetter, Franklin / Hartmann, Arndt / Zamboni, Giuseppe / Perren, Aurel / Klöppel, Günter. ·Institute of Pathology, University Hospital, Erlangen, Germany. abbas.agaimy@uk-erlangen.de ·Mod Pathol · Pubmed #23503646.

ABSTRACT: The human insulin gene enhancer-binding protein islet-1 (ISL1) is a transcription factor involved in the differentiation of the neuroendocrine pancreatic cells. Recent studies identified ISL1 as a marker for pancreatic well-differentiated neuroendocrine neoplasms. However, little is known about ISL1 expression in pancreatic poorly differentiated and in extrapancreatic well and poorly differentiated neuroendocrine neoplasms. We studied the immunohistochemical expression of ISL1 in 124 neuroendocrine neoplasms. Among pancreatic neuroendocrine neoplasms, 12/13 with poor differentiation were negative, whereas 5/7 with good differentiation but a Ki67 >20% were positive. In extrapancreatic neuroendocrine neoplasms, strong positivity was found in Merkel cell carcinomas (25/25), pulmonary small cell neuroendocrine carcinomas (21/23), medullary thyroid carcinomas (9/9), paragangliomas/pheochromocytomas (6/6), adrenal neuroblastomas (8/8) and head and neck neuroendocrine carcinomas (4/5), whereas no or only weak staining was recorded in pulmonary carcinoids (3/15), olfactory neuroblastomas (1/4) and basaloid head and neck squamous cell carcinomas (0/15). ISL1 stained the neuroendocrine carcinoma component of 5/8 composite carcinomas and also normal neuroendocrine cells in the thyroid, adrenal medulla, stomach and colorectum. Poorly differentiated neuroendocrine neoplasms, regardless of their ISL1 expression, were usually TP53 positive. Our results show the almost ubiquitous expression of ISL1 in extrapancreatic poorly differentiated neuroendocrine neoplasms and neuroblastic malignancies and its common loss in pancreatic poorly differentiated neuroendocrine neoplasms. These findings modify the role of ISL1 as a marker for pancreatic neuroendocrine neoplasms and suggest that ISL1 has a broader involvement in differentiation and growth of neuroendocrine neoplasms than has so far been assumed.

15 Article Serotonin expression in pancreatic neuroendocrine tumors correlates with a trabecular histologic pattern and large duct involvement. 2012

McCall, Chad M / Shi, Chanjuan / Klein, Alison P / Konukiewitz, Björn / Edil, Barish H / Ellison, Trevor A / Wolfgang, Christopher L / Schulick, Richard D / Klöppel, Günter / Hruban, Ralph H. ·Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. ·Hum Pathol · Pubmed #22221702.

ABSTRACT: Pancreatic neuroendocrine tumors with prominent stromal fibrosis are often clinically, radiographically, and grossly indistinguishable from ductal adenocarcinoma. We recently described a small series of fibrotic pancreatic neuroendocrine tumors that express serotonin. To understand better the relationship between histopathologic patterns and serotonin expression, we reviewed 361 pancreatic neuroendocrine tumors to identify those with prominent stromal fibrosis exceeding 30% of total tumor area. We identified 52 cases and immunolabeled these neoplasms with antibodies to serotonin and Ki-67. Two predominant histologic subtypes were identified: 14 (26.9%) of 52 had a trabecular or trabecular-glandular cellular pattern with interspersed fibrosis, whereas 38 (73.1%) of 52 had solid architecture. Of the 52, 14 (26.9%) pancreatic neuroendocrine tumors showed at least focal serotonin immunoreactivity. Tumors with predominantly trabecular architecture were significantly more likely to express serotonin than those with solid architecture (P < .01). Only 2 of 34 pancreatic neuroendocrine tumors with fibrosis less than 30% of total tumor area expressed serotonin. The 14 serotonin-expressing tumors were less likely to have lymph node metastases (P = .016) and more likely to involve large pancreatic ducts (P < .01) than were the 38 serotonin-negative tumors. The serotonin-expressing tumors were also found in a younger patient population (P < .01). There was no significant association of serotonin immunoreactivity with Ki-67 proliferation index, tumor size, or distant metastases. Our data demonstrate a strong correlation between trabecular architecture and serotonin immunoreactivity in pancreatic neuroendocrine tumors with stromal fibrosis. Serotonin-expressing tumors are also less likely to have lymph node metastases and more likely to involve large pancreatic ducts.

16 Article Hormonally defined pancreatic and duodenal neuroendocrine tumors differ in their transcription factor signatures: expression of ISL1, PDX1, NGN3, and CDX2. 2011

Hermann, Gratiana / Konukiewitz, Björn / Schmitt, Anja / Perren, Aurel / Klöppel, Günter. ·Department of Pathology, Assaf Harofeh Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. ·Virchows Arch · Pubmed #21739268.

ABSTRACT: We recently identified the transcription factor (TF) islet 1 gene product (ISL1) as a marker for well-differentiated pancreatic neuroendocrine tumors (P-NETs). In order to better understand the expression of the four TFs, ISL1, pancreatico-duodenal homeobox 1 gene product (PDX1), neurogenin 3 gene product (NGN3), and CDX-2 homeobox gene product (CDX2), that mainly govern the development and differentiation of the pancreas and duodenum, we studied their expression in hormonally defined P-NETs and duodenal (D-) NETs. Thirty-six P-NETs and 14 D-NETs were immunostained with antibodies against the four pancreatic hormones, gastrin, serotonin, calcitonin, ISL1, PDX1, NGN3, and CDX2. The TF expression pattern of each case was correlated with the tumor's hormonal profile. Insulin-positive NETs expressed only ISL1 (10/10) and PDX1 (9/10). Glucagon-positive tumors expressed ISL1 (7/7) and were almost negative for the other TFs. Gastrin-positive NETs, whether of duodenal or pancreatic origin, frequently expressed PDX1 (17/18), ISL1 (14/18), and NGN3 (14/18). CDX2 was mainly found in the gastrin-positive P-NETs (5/8) and rarely in the D-NETs (1/10). Somatostatin-positive NETs, whether duodenal or pancreatic in origin, expressed ISL1 (9/9), PDX1 (3/9), and NGN3 (3/9). The remaining tumors showed labeling for ISL1 in addition to NGN3. There was no association between a particular TF pattern and NET features such as grade, size, location, presence of metastases, and functional activity. We conclude from our data that there is a correlation between TF expression patterns and certain hormonally defined P-NET and D-NET types, suggesting that most of the tumor types originate from embryologically determined precursor cells. The observed TF signatures do not allow us to distinguish P-NETs from D-NETs.

17 Article Glucagon expression in cystic pancreatic neuroendocrine neoplasms: an immunohistochemical analysis. 2011

Konukiewitz, Björn / Enosawa, Tetsuji / Klöppel, Günter. ·Department of Pathology, University of Kiel, Kiel, Germany. ·Virchows Arch · Pubmed #20922407.

ABSTRACT: Pancreatic neuroendocrine neoplasms (P-NENs) are usually solid and only rarely cystic. Glucagon expression and the association with multiple endocrine neoplasia type 1 (MEN1) seem to be common in cystic P-NENs. In this study, we analyzed 404 P-NENs to gain information about the relative frequency of grossly cystic P-NENs and their association with glucagon production by the tumor cells. Three hundred forty-six solitary P-NENs and 58 P-NENs (>1 cm in diameter) from 35 patients with an MEN1 syndrome were studied. Immunostaining was performed for the four pancreatic hormones; 5.5% (19/346) of the sporadic P-NENs showed unilocular or multilocular cystic changes that were macroscopically detectable. Sixty-three percent of the solitary cystic P-NENs (versus 7% of the solitary non-cystic P-NENs) expressed predominantly glucagon. In MEN1-associated P-NENs, the relative frequency of cystic tumors was 10.3%, and all of them expressed glucagon. None of the glucagon-positive cystic P-NENs were associated with a glucagonoma syndrome. Solitary non-MEN1-associated and MEN1-associated cystic P-NENs are predominantly non-syndromic glucagon-expressing tumors. However, cystic insulinomas may also occur. Cyst formation seems to be related to hormone production.