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H Klemen
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F M Smolle-Jüttner
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H H Popper
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ABSTRACT

Typical and atypical carcinoids are neuroendocrine epithelial lung tumours which are difficult to distinguish. Confusion has been introduced by designating atypical carcinoids as well differentiated neuroendocrine carcinomas and including some tumours which are large cell neuroendocrine carcinomas.

We therefore investigated 32 typical and 23 atypical carcinoids of the lung, and 9 combined forms of atypical carcinoid and small cell carcinoma. The following parameters were each independently correlated in a multivariate analysis with 10-year survival data: nuclear and nucleolar polymorphism, mitotic counts, vascular invasion, lymph node metastasis, structural pattern, location of the tumours, immunohistochemistry, age and sex of the patients.

Typical carcinoids were characterized by an absence of vascular invasion and lymph node metastases, and a mean mitotic rate of 0.75/10 high power fields (HPFs), while atypical carcinoids were characterized by vascular invasion and/or metastases, a mean mitotic rate of 4.25/10 HPFs and nuclear pleomorphism. Combined forms of atypical carcinoid and small cell carcinoma were characterized by vascular invasion, metastases and a mean mitotic rate of 20.7/10 HPFs. Vascular invasion, lymph node metastases, mitotic counts and nuclear pleomorphism significantly correlated with 10-year survival data, whereas location, size and structural pattern of the tumour, age and sex did not correlate with survival. All tumours were positive for cytokeratins and at least two out of three general neuroendocrine markers. However, positive reactivity for different peptides, hormones, and neurotransmitters did not correlate with one of the structural subtypes of carcinoid or with patient survival.

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Laura Moonen Department of Pathology, GROW School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands

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Jules L Derks Department of Pathology, GROW School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands
Department of Pulmonary Medicine, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands

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Lisa M Hillen Department of Pulmonary Diseases, GROW School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands

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Robert Jan van Suylen Pathology-DNA, Jeroen Bosch Hospital, s’Hertogenbosch, The Netherlands

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Michael A den Bakker Department of Pathology, Erasmus Medical Center, Rotterdam, The Netherlands

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Jan H von der Thüsen Department of Pathology, Maasstad Hospital, Rotterdam, The Netherlands

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Ronald A Damhuis Department of Research, Comprehensive Cancer Association, Utrecht, The Netherlands

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Wieneke A Buikhuisen Department of Thoracic Oncology, Netherlands Cancer Institute Amsterdam, The Netherlands

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Esther C van den Broek PALGA (Dutch Nationwide Pathology Databank), Houten, The Netherlands

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Jos Maessen Department of Cardiothoracic Surgery, Maastricht University Medical Center+, Maastricht, The Netherlands

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Alexander P W M Maat Department of Cardiothoracic Surgery, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

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Paul van Schil Department of Thoracic and Vascular Surgery, Antwerp University Hospital, Antwerp, Belgium

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Ernst J M Speel Department of Pathology, GROW School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands
Department of Pathology, Maasstad Hospital, Rotterdam, The Netherlands

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A-M C Dingemans Department of Pulmonary Diseases, GROW School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands
Department of Pulmonary Medicine, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, The Netherlands

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Introduction Pulmonary carcinoids are uncommon neuroendocrine epithelial malignancies characterised by indolent clinical behaviour. Pulmonary carcinoids can be subdivided into typical carcinoid (TC) and atypical carcinoid (AC) based on

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Luisella Righi
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Marco Volante
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Ida Rapa
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Veronica Tavaglione
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Frediano Inzani Division of Pathology, Division of Pathology, National Cancer Institute and University of Milan, Department of Clinical and Biological Sciences, University of Turin at San Luigi Hospital, Regione Gonzole 10, 10043 Orbassano, Torino, Italy

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Giuseppe Pelosi Division of Pathology, Division of Pathology, National Cancer Institute and University of Milan, Department of Clinical and Biological Sciences, University of Turin at San Luigi Hospital, Regione Gonzole 10, 10043 Orbassano, Torino, Italy

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Mauro Papotti
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choice for low-to-intermediate grade (i.e. typical carcinoids (TCs) or atypical carcinoids (ACs)) and localized tumors, while in HG and/or disseminated lesions chemotherapy is generally preferred ( Pelosi et al . 2006 , Garcia-Yuste et al . 2008

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Claire K Mulvey Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA
Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA

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Alan Paciorek Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA
Department of Epidemiology and Biostatistics, University of California, San Francisco, California, USA

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Farhana Moon Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA

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Paige Steiding Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA

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Brandon Shih Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA

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Matthew A Gubens Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA
Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA

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Li Zhang Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA
Department of Epidemiology and Biostatistics, University of California, San Francisco, California, USA

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Emily K Bergsland Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California, USA
Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA

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Iona Cheng Department of Epidemiology and Biostatistics, University of California, San Francisco, California, USA

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site after the gastrointestinal tract ( Modlin et al. 2003 ). Lung NETs have a wide spectrum of clinical behavior and a unique pathologic classification as either typical carcinoids (grade 1) or atypical carcinoids (grade 2) ( Travis et al. 2015

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E Baudin Endocrine Oncology Unit, Imaging Department, Gustave Roussy, Villejuif, France

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J Capdevila Medical Oncology Department, Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), IOB Quirón-Teknon, Barcelona, Spain

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D Hörsch ENETS Center of Excellence, Zentralklinik Bad Berka GmbH, Bad Berka, Germany

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S Singh Division of Medical Oncology, University of Toronto, Sunnybrook Odette Cancer Center, Sunnybrook HSC, Toronto, Ontario, Canada

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M E Caplin Neuroendocrine Tumour Unit, Royal Free Hospital School of Medicine, London, UK

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E M Wolin Division of Hematology and Oncology, Icahn School of Medicine at Mount Sinai, New York, New York, USA

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W Buikhuisen Department of Thorax Oncology, Netherlands Cancer Institute, Amsterdam, the Netherlands

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M Raderer Division of Oncology, Department of Medicine I, Medical University of Vienna, Vienna, Austria

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E Dansin Thoracic Oncology Unit, Centre Oscar Lambret, Lille, France

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C Grohe Department of Respiratory Diseases, Evangelische Lungenklinik, Berlin, Germany

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D Ferone Neuroendocrine Tumour Unit, Department of Internal Medicine and Medical Specialties, University of Genova, Genova, Italy

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A Houchard Data and Insights Generation and Strategy, Ipsen, Boulogne-Billancourt, France

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X-M Truong-Thanh Medical Affairs, Ipsen, Boulogne-Billancourt, France

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D Reidy-Lagunes Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical Center, New York, New York, USA

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the SPINET Study Group
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the SPINET Study Group

Introduction Bronchopulmonary (BP) neuroendocrine tumors (NETs; typical carcinoids and atypical carcinoids (TCs and ACs)) account for 20–25% of NETs and 1–2% of lung malignancies ( Öberg et al. 2012 , Filosso et al. 2018 , Baudin et al

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G Rindi
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C Klersy Institute of Anatomic Pathology, Service of Biometry and Clinical Epidemiology, Service of Pathology, Thoracic Unit, Medical Oncology Unit, Unit of Pathological Anatomy, Medical Oncology Unit of Respiratory Tract and Sarcomas, Division of Thoracic Surgery, Department of Thoracic Surgery, Division of Pathology, Division of Thoracic Surgery, Division of Pathology and Laboratory Medicine, Department of Biomedical and Clinical Sciences ‘Luigi Sacco’, Università Cattolica del Sacro Cuore – Policlinico A. Gemelli, Rome, Italy

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F Inzani
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G Fellegara Institute of Anatomic Pathology, Service of Biometry and Clinical Epidemiology, Service of Pathology, Thoracic Unit, Medical Oncology Unit, Unit of Pathological Anatomy, Medical Oncology Unit of Respiratory Tract and Sarcomas, Division of Thoracic Surgery, Department of Thoracic Surgery, Division of Pathology, Division of Thoracic Surgery, Division of Pathology and Laboratory Medicine, Department of Biomedical and Clinical Sciences ‘Luigi Sacco’, Università Cattolica del Sacro Cuore – Policlinico A. Gemelli, Rome, Italy

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L Ampollini Institute of Anatomic Pathology, Service of Biometry and Clinical Epidemiology, Service of Pathology, Thoracic Unit, Medical Oncology Unit, Unit of Pathological Anatomy, Medical Oncology Unit of Respiratory Tract and Sarcomas, Division of Thoracic Surgery, Department of Thoracic Surgery, Division of Pathology, Division of Thoracic Surgery, Division of Pathology and Laboratory Medicine, Department of Biomedical and Clinical Sciences ‘Luigi Sacco’, Università Cattolica del Sacro Cuore – Policlinico A. Gemelli, Rome, Italy

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A Ardizzoni Institute of Anatomic Pathology, Service of Biometry and Clinical Epidemiology, Service of Pathology, Thoracic Unit, Medical Oncology Unit, Unit of Pathological Anatomy, Medical Oncology Unit of Respiratory Tract and Sarcomas, Division of Thoracic Surgery, Department of Thoracic Surgery, Division of Pathology, Division of Thoracic Surgery, Division of Pathology and Laboratory Medicine, Department of Biomedical and Clinical Sciences ‘Luigi Sacco’, Università Cattolica del Sacro Cuore – Policlinico A. Gemelli, Rome, Italy

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N Campanini Institute of Anatomic Pathology, Service of Biometry and Clinical Epidemiology, Service of Pathology, Thoracic Unit, Medical Oncology Unit, Unit of Pathological Anatomy, Medical Oncology Unit of Respiratory Tract and Sarcomas, Division of Thoracic Surgery, Department of Thoracic Surgery, Division of Pathology, Division of Thoracic Surgery, Division of Pathology and Laboratory Medicine, Department of Biomedical and Clinical Sciences ‘Luigi Sacco’, Università Cattolica del Sacro Cuore – Policlinico A. Gemelli, Rome, Italy

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P Carbognani Institute of Anatomic Pathology, Service of Biometry and Clinical Epidemiology, Service of Pathology, Thoracic Unit, Medical Oncology Unit, Unit of Pathological Anatomy, Medical Oncology Unit of Respiratory Tract and Sarcomas, Division of Thoracic Surgery, Department of Thoracic Surgery, Division of Pathology, Division of Thoracic Surgery, Division of Pathology and Laboratory Medicine, Department of Biomedical and Clinical Sciences ‘Luigi Sacco’, Università Cattolica del Sacro Cuore – Policlinico A. Gemelli, Rome, Italy

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T M De Pas Institute of Anatomic Pathology, Service of Biometry and Clinical Epidemiology, Service of Pathology, Thoracic Unit, Medical Oncology Unit, Unit of Pathological Anatomy, Medical Oncology Unit of Respiratory Tract and Sarcomas, Division of Thoracic Surgery, Department of Thoracic Surgery, Division of Pathology, Division of Thoracic Surgery, Division of Pathology and Laboratory Medicine, Department of Biomedical and Clinical Sciences ‘Luigi Sacco’, Università Cattolica del Sacro Cuore – Policlinico A. Gemelli, Rome, Italy

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D Galetta Institute of Anatomic Pathology, Service of Biometry and Clinical Epidemiology, Service of Pathology, Thoracic Unit, Medical Oncology Unit, Unit of Pathological Anatomy, Medical Oncology Unit of Respiratory Tract and Sarcomas, Division of Thoracic Surgery, Department of Thoracic Surgery, Division of Pathology, Division of Thoracic Surgery, Division of Pathology and Laboratory Medicine, Department of Biomedical and Clinical Sciences ‘Luigi Sacco’, Università Cattolica del Sacro Cuore – Policlinico A. Gemelli, Rome, Italy

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P L Granone Institute of Anatomic Pathology, Service of Biometry and Clinical Epidemiology, Service of Pathology, Thoracic Unit, Medical Oncology Unit, Unit of Pathological Anatomy, Medical Oncology Unit of Respiratory Tract and Sarcomas, Division of Thoracic Surgery, Department of Thoracic Surgery, Division of Pathology, Division of Thoracic Surgery, Division of Pathology and Laboratory Medicine, Department of Biomedical and Clinical Sciences ‘Luigi Sacco’, Università Cattolica del Sacro Cuore – Policlinico A. Gemelli, Rome, Italy

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L Righi Institute of Anatomic Pathology, Service of Biometry and Clinical Epidemiology, Service of Pathology, Thoracic Unit, Medical Oncology Unit, Unit of Pathological Anatomy, Medical Oncology Unit of Respiratory Tract and Sarcomas, Division of Thoracic Surgery, Department of Thoracic Surgery, Division of Pathology, Division of Thoracic Surgery, Division of Pathology and Laboratory Medicine, Department of Biomedical and Clinical Sciences ‘Luigi Sacco’, Università Cattolica del Sacro Cuore – Policlinico A. Gemelli, Rome, Italy

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M Rusca Institute of Anatomic Pathology, Service of Biometry and Clinical Epidemiology, Service of Pathology, Thoracic Unit, Medical Oncology Unit, Unit of Pathological Anatomy, Medical Oncology Unit of Respiratory Tract and Sarcomas, Division of Thoracic Surgery, Department of Thoracic Surgery, Division of Pathology, Division of Thoracic Surgery, Division of Pathology and Laboratory Medicine, Department of Biomedical and Clinical Sciences ‘Luigi Sacco’, Università Cattolica del Sacro Cuore – Policlinico A. Gemelli, Rome, Italy

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L Spaggiari Institute of Anatomic Pathology, Service of Biometry and Clinical Epidemiology, Service of Pathology, Thoracic Unit, Medical Oncology Unit, Unit of Pathological Anatomy, Medical Oncology Unit of Respiratory Tract and Sarcomas, Division of Thoracic Surgery, Department of Thoracic Surgery, Division of Pathology, Division of Thoracic Surgery, Division of Pathology and Laboratory Medicine, Department of Biomedical and Clinical Sciences ‘Luigi Sacco’, Università Cattolica del Sacro Cuore – Policlinico A. Gemelli, Rome, Italy

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M Tiseo Institute of Anatomic Pathology, Service of Biometry and Clinical Epidemiology, Service of Pathology, Thoracic Unit, Medical Oncology Unit, Unit of Pathological Anatomy, Medical Oncology Unit of Respiratory Tract and Sarcomas, Division of Thoracic Surgery, Department of Thoracic Surgery, Division of Pathology, Division of Thoracic Surgery, Division of Pathology and Laboratory Medicine, Department of Biomedical and Clinical Sciences ‘Luigi Sacco’, Università Cattolica del Sacro Cuore – Policlinico A. Gemelli, Rome, Italy

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G Viale Institute of Anatomic Pathology, Service of Biometry and Clinical Epidemiology, Service of Pathology, Thoracic Unit, Medical Oncology Unit, Unit of Pathological Anatomy, Medical Oncology Unit of Respiratory Tract and Sarcomas, Division of Thoracic Surgery, Department of Thoracic Surgery, Division of Pathology, Division of Thoracic Surgery, Division of Pathology and Laboratory Medicine, Department of Biomedical and Clinical Sciences ‘Luigi Sacco’, Università Cattolica del Sacro Cuore – Policlinico A. Gemelli, Rome, Italy

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M Volante Institute of Anatomic Pathology, Service of Biometry and Clinical Epidemiology, Service of Pathology, Thoracic Unit, Medical Oncology Unit, Unit of Pathological Anatomy, Medical Oncology Unit of Respiratory Tract and Sarcomas, Division of Thoracic Surgery, Department of Thoracic Surgery, Division of Pathology, Division of Thoracic Surgery, Division of Pathology and Laboratory Medicine, Department of Biomedical and Clinical Sciences ‘Luigi Sacco’, Università Cattolica del Sacro Cuore – Policlinico A. Gemelli, Rome, Italy

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M Papotti Institute of Anatomic Pathology, Service of Biometry and Clinical Epidemiology, Service of Pathology, Thoracic Unit, Medical Oncology Unit, Unit of Pathological Anatomy, Medical Oncology Unit of Respiratory Tract and Sarcomas, Division of Thoracic Surgery, Department of Thoracic Surgery, Division of Pathology, Division of Thoracic Surgery, Division of Pathology and Laboratory Medicine, Department of Biomedical and Clinical Sciences ‘Luigi Sacco’, Università Cattolica del Sacro Cuore – Policlinico A. Gemelli, Rome, Italy

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G Pelosi Institute of Anatomic Pathology, Service of Biometry and Clinical Epidemiology, Service of Pathology, Thoracic Unit, Medical Oncology Unit, Unit of Pathological Anatomy, Medical Oncology Unit of Respiratory Tract and Sarcomas, Division of Thoracic Surgery, Department of Thoracic Surgery, Division of Pathology, Division of Thoracic Surgery, Division of Pathology and Laboratory Medicine, Department of Biomedical and Clinical Sciences ‘Luigi Sacco’, Università Cattolica del Sacro Cuore – Policlinico A. Gemelli, Rome, Italy
Institute of Anatomic Pathology, Service of Biometry and Clinical Epidemiology, Service of Pathology, Thoracic Unit, Medical Oncology Unit, Unit of Pathological Anatomy, Medical Oncology Unit of Respiratory Tract and Sarcomas, Division of Thoracic Surgery, Department of Thoracic Surgery, Division of Pathology, Division of Thoracic Surgery, Division of Pathology and Laboratory Medicine, Department of Biomedical and Clinical Sciences ‘Luigi Sacco’, Università Cattolica del Sacro Cuore – Policlinico A. Gemelli, Rome, Italy

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Introduction Lung neuroendocrine tumors include four different histologic subtypes, namely carcinoids (typical (TC) and atypical (AC)), large-cell neuroendocrine carcinoma (LCNEC), and small-cell lung carcinoma (SCLC), as defined by the World Health

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Luis G Perez-Rivas Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany

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Andrea Oßwald Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany

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Thomas Knösel Institute of Pathology, Ludwig-Maximilians-Universität München, Munich, Germany

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Kristin Lucia Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany
Department of Endocrinology, Max Planck Institute of Psychiatry, Munich, Germany

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Christian Schaaf Institute of Pathology, Ludwig-Maximilians-Universität München, Munich, Germany

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Michael Hristov Institute for Cardiovascular Prevention, Ludwig-Maximilians-Universität München, Munich, Germany

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Julia Fazel Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany

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Thomas Kirchner Institute of Pathology, Ludwig-Maximilians-Universität München, Munich, Germany

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Felix Beuschlein Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany

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Martin Reincke Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany

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Marily Theodoropoulou Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians-Universität München, Munich, Germany
Department of Endocrinology, Max Planck Institute of Psychiatry, Munich, Germany

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thorax was the most prevalent tumor location (11/15 patients). Six tumors were classified as typical and 2 as atypical bronchial carcinoids (according to the WHO classification of 2004; Travis et al. 2004 ), 3 were small-cell lung carcinomas (SCLC), 1

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Mei Dong Department of Gastrointestinal Medical Oncology, Unit 426, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA

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James C Yao Department of Gastrointestinal Medical Oncology, Unit 426, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030, USA

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MA Muguruza I 2007 Typical and atypical carcinoid tumours: analysis of the experience of the Spanish Multi-centric Study of Neuroendocrine Tumours of the Lung . European Journal of Cardio-Thoracic Surgery 31 192 – 197 doi:10.1016/j

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Guido Rindi Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
Università Cattolica del Sacro Cuore, Rome, Italy
ENETS Center of Excellence, Neuroendocrine Tumour (NET) Center, Rome, Italy

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Frediano Inzani Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
ENETS Center of Excellence, Neuroendocrine Tumour (NET) Center, Rome, Italy

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anterior pituitary and outlined their aggressive and malignant behavior. This was also the case for the lung, where the definitions of typical and atypical carcinoid still hold ( Travis et al. 2015 ). NEN may also display high grade malignancy. Indeed

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Bilal F Samhouri Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota, USA
Division of Pulmonary and Critical Care Medicine, Asante Health System, Medford, Oregon, USA

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Thorvardur R Halfdanarson Division of Medical Oncology, Mayo Clinic, Rochester, Minnesota, USA

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Chi Wan Koo Department of Radiology, Mayo Clinic, Rochester, Minnesota, USA

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Cormac McCarthy School of Medicine, University College Dublin, Dublin, Ireland
Department of Respiratory Medicine, St Vincent’s University Hospital, Elm Park, Dublin, Ireland

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Eunhee S Yi Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA

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Charles F Thomas Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota, USA

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Jay H Ryu Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota, USA

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neuroendocrine cells and subepithelial fibrosis in a DIPNECH case (C) hematoxylin and eosin staining; (D) MOVAT pentachrome staining; (E) synaptophysin staining; all 3× in original magnification). Carcinoid tumorlet adjacent to a bronchiole in DIPNECH case (F

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