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O Hentic Pôle des Maladies de L'appareil Digestif, Service de Pathologie, Service de Radiologie, Service de Gastroentérologie–Pancréatologie

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P Hammel Pôle des Maladies de L'appareil Digestif, Service de Pathologie, Service de Radiologie, Service de Gastroentérologie–Pancréatologie

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A Couvelard Pôle des Maladies de L'appareil Digestif, Service de Pathologie, Service de Radiologie, Service de Gastroentérologie–Pancréatologie

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V Rebours Pôle des Maladies de L'appareil Digestif, Service de Pathologie, Service de Radiologie, Service de Gastroentérologie–Pancréatologie

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M Zappa Pôle des Maladies de L'appareil Digestif, Service de Pathologie, Service de Radiologie, Service de Gastroentérologie–Pancréatologie

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M Palazzo Pôle des Maladies de L'appareil Digestif, Service de Pathologie, Service de Radiologie, Service de Gastroentérologie–Pancréatologie

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F Maire Pôle des Maladies de L'appareil Digestif, Service de Pathologie, Service de Radiologie, Service de Gastroentérologie–Pancréatologie

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G Goujon Pôle des Maladies de L'appareil Digestif, Service de Pathologie, Service de Radiologie, Service de Gastroentérologie–Pancréatologie

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A Gillet Pôle des Maladies de L'appareil Digestif, Service de Pathologie, Service de Radiologie, Service de Gastroentérologie–Pancréatologie

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P Lévy Pôle des Maladies de L'appareil Digestif, Service de Pathologie, Service de Radiologie, Service de Gastroentérologie–Pancréatologie

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P Ruszniewski Pôle des Maladies de L'appareil Digestif, Service de Pathologie, Service de Radiologie, Service de Gastroentérologie–Pancréatologie

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condition due to aggressive and diffuse disease. These tumors are characterized by aggressive histological features (high Ki-67 index, extensive necrosis, and nuclear atypia) and are classified as neuroendocrine carcinomas (NECs) grade 3 according to the new

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Andreas Venizelos K.G. Jebsen Center for Genome-Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway
Department of Oncology, Haukeland University Hospital, Bergen, Norway

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Hege Elvebakken Department of Oncology, Ålesund Hospital, Møre og Romsdal Hospital Trust, Ålesund, Norway
Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway

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Aurel Perren Institute of Pathology, University of Bern, Bern, Switzerland

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Oleksii Nikolaienko K.G. Jebsen Center for Genome-Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway
Department of Oncology, Haukeland University Hospital, Bergen, Norway

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Wei Deng K.G. Jebsen Center for Genome-Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway
Department of Oncology, Haukeland University Hospital, Bergen, Norway

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Inger Marie B Lothe Department of Pathology, Oslo University Hospital, Oslo, Norway

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Anne Couvelard Department of Pathology, Université de Paris, Bichat Hospital, AP-HP, Paris, France

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Geir Olav Hjortland Department of Oncology, Oslo University Hospital, Oslo, Norway

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Anna Sundlöv Departmentt of Oncology, Skåne University Hospital, Lund, Sweden
Department of Medical Radiation Physics, Lund University, Lund, Sweden

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Johanna Svensson Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden

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Harrish Garresori Department of Oncology, Stavanger University Hospital, Stavanger, Norway

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Christian Kersten Department of Research, Hospital of Southern Norway, Kristiansand, Norway

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Eva Hofsli Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway
Department of Oncology, St.Olavs Hospital, Trondheim, Norway

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Sönke Detlefsen Department of Pathology, Odense University Hospital, Odense, Denmark
Department of Clinical Medicine, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark

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Merete Krogh Department of Oncology, Odense University Hospital, Odense, Denmark

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Halfdan Sorbye Department of Oncology, Haukeland University Hospital, Bergen, Norway
Department of Clinical Science, University of Bergen, Bergen, Norway

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Stian Knappskog K.G. Jebsen Center for Genome-Directed Cancer Therapy, Department of Clinical Science, University of Bergen, Bergen, Norway
Department of Oncology, Haukeland University Hospital, Bergen, Norway

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-differentiated neuroendocrine tumours (NET G3) and poorly differentiated neuroendocrine carcinoma (NEC) ( WHO 2019 ). GEP-NEC have a particularly unfavourable prognosis, with median overall survival <1 year in advanced, treated cases and only 1 month if untreated ( Sorbye et

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Halfdan Sorbye Department of Oncology, Haukeland University Hospital, Bergen, Norway
Department of Clinical Sciences, University of Bergen, Bergen, Norway

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Grace Kong Department of Molecular Imaging and Therapeutic Nuclear Medicine, Peter MacCallum Cancer Centre, Melbourne, Australia
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Australia

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Simona Grozinsky-Glasberg Neuroendocrine Tumor Unit, ENETS Center of Excellence, Department of Endocrinology and Metabolism, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

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of their proliferation index (G1–G3), whereas neuroendocrine carcinoma (NEC) category is used for poorly differentiated neoplasms. The high-grade GEP NEN G3 group (Ki-67 >20%) is therefore now separated into two groups: NET G3 and NEC ( Table 1 ) and

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Jessica L Geiger Division of Hematology/Oncology, Department of Internal Medicine, University of Pittsburgh Cancer Institute, Division of Anatomic Pathology, Department of Pathology, University of Pittsburgh Medical Center, Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Pittsburgh Medical Center, Division of Molecular Genomic Pathology, Department of Pathology, University of Pittsburgh Medical Center, 5150 Centre Avenue, 5th Floor, Pittsburgh, Pennsylvania, 15232, USA

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Simion I Chiosea Division of Hematology/Oncology, Department of Internal Medicine, University of Pittsburgh Cancer Institute, Division of Anatomic Pathology, Department of Pathology, University of Pittsburgh Medical Center, Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Pittsburgh Medical Center, Division of Molecular Genomic Pathology, Department of Pathology, University of Pittsburgh Medical Center, 5150 Centre Avenue, 5th Floor, Pittsburgh, Pennsylvania, 15232, USA

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Sue M Challinor Division of Hematology/Oncology, Department of Internal Medicine, University of Pittsburgh Cancer Institute, Division of Anatomic Pathology, Department of Pathology, University of Pittsburgh Medical Center, Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Pittsburgh Medical Center, Division of Molecular Genomic Pathology, Department of Pathology, University of Pittsburgh Medical Center, 5150 Centre Avenue, 5th Floor, Pittsburgh, Pennsylvania, 15232, USA

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Marina N Nikiforova Division of Hematology/Oncology, Department of Internal Medicine, University of Pittsburgh Cancer Institute, Division of Anatomic Pathology, Department of Pathology, University of Pittsburgh Medical Center, Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Pittsburgh Medical Center, Division of Molecular Genomic Pathology, Department of Pathology, University of Pittsburgh Medical Center, 5150 Centre Avenue, 5th Floor, Pittsburgh, Pennsylvania, 15232, USA

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Julie E Bauman Division of Hematology/Oncology, Department of Internal Medicine, University of Pittsburgh Cancer Institute, Division of Anatomic Pathology, Department of Pathology, University of Pittsburgh Medical Center, Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Pittsburgh Medical Center, Division of Molecular Genomic Pathology, Department of Pathology, University of Pittsburgh Medical Center, 5150 Centre Avenue, 5th Floor, Pittsburgh, Pennsylvania, 15232, USA

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). Tumor formation occurs in the neuroendocrine organs where constitutively activated RET is expressed. Although neuroendocrine carcinoma (NEC) of the lung has been described in MEN 1 ( Farhandi et al . 1987 ), it has not been described in the MEN2

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Esben Andreas Carlsen Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet, Copenhagen, Denmark
Department of Biomedical Sciences, Cluster for Molecular Imaging, University of Copenhagen, Copenhagen, Denmark

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Nicola Fazio Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, IEO, European Institute of Oncology IRCCS, Milan, Italy

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Dan Granberg Department of Medical Sciences, Uppsala University, Uppsala, Sweden

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Simona Grozinsky-Glasberg Neuroendocrine Tumor Unit, Department of Endocrinology & Metabolism, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

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Hojjat Ahmadzadehfar Department of Nuclear Medicine, University Hospital Bonn, Bonn, Germany

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Chiara Maria Grana Division of Nuclear Medicine, IEO, European Institute of Oncology IRCCS, Milan, Italy

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Wouter T Zandee Erasmus Medical Center, Rotterdam, The Netherlands

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Jaroslaw Cwikla Medical School, University of Warmia and Mazury, Olsztyn, Poland

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Martin A Walter Department of Nuclear Medicine, University Hospital of Geneva, Geneva, Switzerland

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Peter Sandor Oturai Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet, Copenhagen, Denmark

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Anja Rinke Department of Gastroenterology, University Hospital Gießen and Marburg, Marburg, Germany

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Andrew Weaver Department of Oncology, Churchill Hospital, Oxford, UK

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Andrea Frilling Department of Surgery and Cancer, Imperial College London, London, UK

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Sara Gritti Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, IEO, European Institute of Oncology IRCCS, Milan, Italy

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Anne Kirstine Arveschoug Department of Nuclear Medicine and PET, Aarhus University Hospital, Aarhus, Denmark

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Amichay Meirovitz Department of Oncology and Radiation Therapy Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

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Ulrich Knigge Department of Biomedical Sciences, Cluster for Molecular Imaging, University of Copenhagen, Copenhagen, Denmark
Departments of Surgical Gastroenterology and Clinical Endocrinology, Rigshospitalet, Copenhagen, Denmark

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Halfdan Sorbye Department of Oncology, Haukeland University Hospital, Bergen, Norway
Department of Clinical Science, University of Bergen, Bergen, Norway

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according to the proliferation index Ki-67; ≤2% (Grade 1, G1), 3–20% (G2) and >20% (G3) ( Bosman et al . 2010 ). G1–G2 was collectively referred to as neuroendocrine tumors (NET) and G3 as neuroendocrine carcinoma (NEC). The classification is strongly

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Thomas Yang Sun Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA

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Lan Zhao Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA

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Paul Van Hummelen Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA

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Brock Martin Department of Pathology, Stanford University School of Medicine, Stanford, California, USA

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Kathleen Hornbacker Clinical Trials Office, Stanford University, Stanford, California, USA

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HoJoon Lee Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA

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Li C Xia Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
Division of Biostatistics, Department of Epidemiology and Public Health, Albert Einstein College of Medicine, Bronx, New York, USA

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Sukhmani K Padda Cedars-Sinai Medical Center, Department of Medical Oncology, Los Angeles, California, USA

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Hanlee P Ji Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California, USA
Stanford Genome Technology Center, Stanford, California, USA

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Pamela Kunz Yale School of Medicine, Smilow Cancer Hospital, Yale Cancer Center, New Haven, Connecticut, USA

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-differentiated G3 NET and poorly differentiated neuroendocrine carcinoma in the most recent version of the WHO classification system, NENs from other primary sites have not been similarly categorized ( Klimstra 2019 ). For example, the recent 2021 WHO

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Lisa D Berman-Booty Department of Cancer Biology, Kimmel Cancer Center, Departments of Urology, Radiation Oncology, Thomas Jefferson University, 233 South 10th Street, BLSB 1008, Philadelphia, Pennsylvania 19107, USA
Department of Cancer Biology, Kimmel Cancer Center, Departments of Urology, Radiation Oncology, Thomas Jefferson University, 233 South 10th Street, BLSB 1008, Philadelphia, Pennsylvania 19107, USA

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Karen E Knudsen Department of Cancer Biology, Kimmel Cancer Center, Departments of Urology, Radiation Oncology, Thomas Jefferson University, 233 South 10th Street, BLSB 1008, Philadelphia, Pennsylvania 19107, USA
Department of Cancer Biology, Kimmel Cancer Center, Departments of Urology, Radiation Oncology, Thomas Jefferson University, 233 South 10th Street, BLSB 1008, Philadelphia, Pennsylvania 19107, USA
Department of Cancer Biology, Kimmel Cancer Center, Departments of Urology, Radiation Oncology, Thomas Jefferson University, 233 South 10th Street, BLSB 1008, Philadelphia, Pennsylvania 19107, USA
Department of Cancer Biology, Kimmel Cancer Center, Departments of Urology, Radiation Oncology, Thomas Jefferson University, 233 South 10th Street, BLSB 1008, Philadelphia, Pennsylvania 19107, USA

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Introduction Prostate cancer is the second most common cancer in men worldwide ( Ferlay et al . 2010 ). With >90% of prostate cancers initially diagnosed as acinar adenocarcinomas ( Fine 2012 , Humphrey 2012 ), neuroendocrine carcinomas of the

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Maria Chiara Zatelli Department of Medical Sciences, Section of Endocrinology and Internal Medicine, University of Ferrara, Ferrara, Italy

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Elia Guadagno Department of Advanced Biomedical Sciences, Pathology Section, University of Naples Federico II, Naples, Italy

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Erika Messina Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy

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Fabio Lo Calzo Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy

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Antongiulio Faggiano Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy

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Annamaria Colao Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy

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NIKE Group
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considers neuroendocrine carcinomas (NECs) as a single category on the basis of a Ki-67 labeling index (LI) >20% ( Rindi et al. 2010 ). It has recently become apparent that the definition of NEC by the 2010 WHO classification includes a spectrum of

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A Mohamed Division of Hematology and Medical Oncology, UH Seidman Cancer Center, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA

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M Trybula Division of Hematology and Medical Oncology, UH Seidman Cancer Center, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA

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S L Asa Department of Medicine, UH Seidman Cancer Center Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA

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T R Halfdanarson Division of Medical Oncology, Department of Oncology, Mayo Clinic Comprehensive Cancer Center, Rochester, Minnesota, USA

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M B Sonbol Division of Hematology and Medical Oncology, Mayo Clinic Cancer Center, Phoenix, Arizona, USA

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classification, delineating G3-NETs as a distinct category from the poorly differentiated neuroendocrine carcinoma (NEC) ( Table 1 ) ( Velayoudom-Cephise et al. 2013 , Heetfeld et al. 2015 , Nagtegaal et al. 2020 , Elvebakken et al. 2021 , Luecke et

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Günter Klöppel Department of Pathology, Technical University of München, Ismaninger Strasse 22, 81675 München, Germany

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differentiated endocrine carcinoma/small cell carcinoma (PDEC) 2. Neuroendocrine carcinoma (NEC) G3 large cell or small cell type 4. Mixed exocrine–endocrine carcinoma (MEEC) 3. Mixed adenoneuroendocrine carcinoma (MANEC) II. Pseudotumour lesions 5. Tumour

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