Abstract
Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel-Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10-75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2cm; P<0.001) and tumor volume doubling time (TVDT) was faster (22 vs 126 months; P=0.001). All metastatic tumors were ≥2.8cm. Codons 161 and 167 were hotspots for VHL germline mutations with enhanced risk for metastatic PanNETs. Multivariate prediction modeling disclosed maximum tumor diameter and TVDT as significant predictors for metastatic disease (positive and negative predictive values of 51% and 100% for diameter cut-off ≥2.8cm, 44% and 91% for TVDT cut-off of ≤24 months). In 117 of 273 patients, PanNETs >1.5cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs <2.8cm vs ≥2.8cm (94% vs 85% by 10 years; P=0.020; 80% vs 50% at 10 years; P=0.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs.
| Original language | English |
|---|---|
| Journal | Endocrine-Related Cancer |
| Volume | 25 |
| Issue number | 9 |
| Pages (from-to) | 783-793 |
| Number of pages | 11 |
| ISSN | 1351-0088 |
| DOIs | |
| Publication status | Published - 01.09.2018 |
Funding
1Department of Radiology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany 2Familial Cancer Clinic and Oncoendocrinology, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy 3Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands 4Department of Surgery, University of Luebeck, Luebeck, Germany 5Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, USA 6Institute of Endocrinology and Metabolism, NAMS of Ukraine, Kiev, Ukraine 7Central Services, Servicio de Salud de Castilla-La Mancha (SESCAM), Toledo, Spain 8Department of Surgery, Endocrinology Research Center, Moscow, Russia 9Department of Surgery, Bakhrushin Brothers Moscow City Hospital, Moscow, Russia 10Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada 11Department of Medicine IV, Faculty of Medicine, Albert-Ludwigs-University, Freiburg, Germany 12Department of Endocrinology, KEM Hospital, Mumbai, India 13Interdisciplinary Center of Metabolism: Endocrinology, Diabetes and Metabolism, Charité-University Medicine Berlin, Campus Virchow-Klinikum, Berlin, Germany 14Department of Endocrine Oncology, Uppsala University Hospital, Uppsala, Sweden 15Endocrinology, Abdominal Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland 16Department of Clinical and Experimental Medicine, Department of Surgery, University of Linköping, Linköping, Sweden 17Department of Endocrinology, University Medical Center, Ljubljana, Slovenia 18Cancer Genetics Service, Division of Medical Oncology, National Cancer Center Singapore and Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore 19Department of Endocrine Oncology and Nuclear Medicine, Center of Oncology, MSC Memorial Institute, Gliwice, Poland 20Centro de Investigaciones Endocrinológicas “Dr Cesar Bergada” (CEDIE), Hospital de Niños Ricardo Gutiérrez, CABA, Buenos Aires, Argentina 21Department of Oncologic and Urologic Surgery, the 117th PLA Hospital, Wenzhou Medical University, Hangzhou, Peoples Republic of China 22Department of General Surgery, Breast and Endocrine Surgery Unit, Marmara University School of Medicine, Istanbul, Turkey 23Endocrine Section, Hospital del Salvador, Santiago de Chile, Chile 24Department of Medicine, Endocrine Section, Hospital del Salvador, University of Chile, Santiago de Chile, Chile 25Department of Hypertension, Institute of Cardiology, Warsaw, Poland 263rd Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany 27Serviço de Endocrinologia, Hospital das Clínicas (HCFMUSP) and Instituto do Cancer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil 28Serviço de Endocrinologia, Hospital das Clinicas (HCFMUSP), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil 29Department of Internal Medicine-Endocrinology, Faculty of medicine-Hospital Universitario Clementino Fraga Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil 30Department of Physiology and Pharmacology, Drug Research and Development Center (NPDM), Faculty of Medicine, Federal University of Ceará (UFC), Fortaleza, Brazil 31Department of Urology, 2nd Hospital of Zhejiang University, School of Medicine, Hangzhou, China 32Hospital Universitari de Girona, Gerencia Territorial Girona, Institut Català de la Salut, Girona, Spain 33Unidad de Tumores Digestivos, Servicio de Oncología Médica, Hospital Universitario 12 de Octubre, Madrid, Spain 34Division of Endocrinology and metabolism, Siriraj Hospital, Mahidol University, Bangkok, Thailand 35Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 36Neuroendocrine Tumor Division, Endocrinology & Metabolism Service, Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel 37Department of Endocrinology, Heinrich-Heine-University, Düsseldorf, Germany 38Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua, Italy 39Department of Cardiology and Angiology I, Heart Center Freiburg University, Faculty of Medicine, University of Freiburg, Freiburg, Germany 40Department of Nuclear Medicine, Faculty of Medicine, Albert-Ludwigs-University, Freiburg, Germany 41Department of Radiology, Campus Virchow-Klinikum, Charité – Universitätsmedizin Berlin, Berlin, Germany 42Department of Surgery, Asklepios-Paulinen Klinik, Wiesbaden, Germany 43Section of Endocrine Surgery, Reinbek Hospital, Academic Teaching Hospital University of Hamburg, Reinbek, Germany 44Department of Clinical Nuclear Medicine, Charité – Universitätsmedizin Berlin, Berlin, Germany 45Department of General Surgery, Division of Endocrine Surgery, Izmir, Turkey 462nd Department of Medicine and Molecular Medicine Research Group, Hungarian Academy of Sciences, Semmelweis-University, Budapest, Hungary 47Department of Surgery, Huyssens Foundation Clinics, Essen, Germany 48Department of Medicine II, Faculty of Medicine, Medical Center – University of Freiburg, University of Freiburg, Freiburg, Germany 49Department of Surgical Sciences, Uppsala University, University Hospital, Uppsala, Sweden 50Department of Medicine, University of Toronto, University Healthy Network & Mount Sinai Hospital, The Fred A Litwin Family Center in Genetic Medicine, Toronto, Ontario, Canada 51Department of Clinical Genetics and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden 52Department of Endocrinology, Ludwigs-Maximilians-University of Munich, Munich, Germany 53Scientific Direction, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy 54Genomic Medicine Institute, Lerner Research Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA 55Section for Preventive Medicine, Faculty of Medicine, Albert-Ludwigs-University, Freiburg, Germany
Research Areas and Centers
- Research Area: Luebeck Integrated Oncology Network (LION)
