1. Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) An update of epidemiological data NET MASTERCLASS – 5th July 2014 George Kanakis Consultant Endocrinologist Athens Naval & VA Hospital

2. Definition • heterogeneous group of tumors • several NE cells of the GI tract • putative common precursor cell • ability to produce peptides / amines • cause distinct hormonal syndromes • variable biological behaviour • neuroendocrine cell of origin • anatomic site Vinik, Woltering, Neuroendocrine Tumors, 2006

3. Nomenclature • Oberndorfer in 1907 first introduced the term “karzinoide” or cancer-like tumor • it does not convey the malignant potential of tumors • since then several names to describe the same tumor: apudoma / carcinoid / enterchromaffin cell tumor • lately the term “neuroendocrine neoplasm” has been widely accepted Modlin et al (2008) The Lancet

4. Classification

5. Data Sources • Autopsy Data for ALL NETs (Malmö– Sweden 1958-1969) • IR for ALL NETs about 8.4 per 100,000 • Surveillance Epidemiology and End Results (SEER) database • 7 262 696 cancer patients • 49,012 NETs - 25.531 GEP-NETs • National cancer registries of European Countries & Japan • Not Population Based National Registries: • Germany, France, Spain, Korea • Regional registries in Europe and in the USA • One prospective study in Austria in which: • all diagnoses of NETs in 1 yr (2004-2005) in the country recorded • the 2000 WHO classification was used • One systematic review: • IRs between 1958 and 2007 in different parts of the world • 33 papers included M Fraenkel et al. ERC (2014)21, R153–R163

6. Incidence Rates M Fraenkel et al. ERC (2014)21, R153–R163

7. Temporal Trends • GEP-NETs IR has increased steadily over the past four decades • 3.65-fold in the USA • 3.8 to 4.8-fold in the UK • The greatest increase • gastric and rectal NETs • The smallest increase • small intestine NETs • Annual Percent Change: 4.4% • exceeds that of any other malignancy Lawrenceet al. (2011) Endocr. & Metab. Clin. of N. America, 401–18

8. Organ distribution

9. Presentation Male : Female 1,08–1,5 : 1 Peak age at Dx: 50 – 70 y.o Gastric 60-64 Pancreas ~60 SINET 59-65 Colon 63-68 Rectal 52-57 Appendix 31-49 generally more indolent than carcinomas occasionally associated with a very aggressive clinical course Presentation symptoms related to tumor burden 46% Endocrine syndrome 23% Incidental diagnosis 29% Faggiano A et al (2012) J Endocrinol Invest.Oct;35(9):817-23

10. Staging - Grading Niederle et al, Endocrine-Related Cancer(2010)17: 909–918

11. Behavior vs origin ERC 2010; 17:909

12. Survival 5 yr Survival rates: 45 – 82% SEER 2007: 64% Disease specific: 87% USA vs Europe

13. Survival R A SI S C P Lawrenceet al. (2011) Endocr. & Metab. Clin. of N. America, 401–18

14. Secondary Malignancies • SEER: “A higher incidence of further primary cancers compared to the general population (SIR: 1.15)” • German registry: “about 20% of GEP-NET patients developed one or more second malignancies” • More common in: • functional NETs • local / locoregional tumors Sherübl et al, World J Gastroenterol. 2013

15. Specific Remarks I • Gastric Neuroendocrine Tumors • up to 23% of GEP-NETs • Type I tumors 75–80% • IRs now tend to be similar in males and females • Duodenal Neuroendocrine Tumors • 1.8- 3,8% of GEP-NETs • 40–60% have lymph node metastases • 15% associated with a functional syndrome • 10% ZES • 4% Carcinoid Syndrome

16. Specific Remarks II • SI-NETs • the most common GEP-NETs in the Western world for years • low APC - recently surpassed by R-NETs in the USA • usually not approached with endoscopic techniques • male predominance • Appendiceal NETs • Goblet cell tumor was inconsistently included • often incidental finding @ appendicectomies (1,13%) • frequency is higher in females

17. Specific Remarks III • Colon Tumours • predominance of right-sided NETs • 30–40% metastatic at the time of diagnosis • a low 5-year survival rate of about 43–50% • Rectal Tumours • IR increased 10X in 40 yrs • distant metastases occur in only 2.3% • an excellent five-year survival reaching about 90%

18. Specific Remarks IV • Gastrinomas: • IR 0.5–2/ million population / year • Liver metastases much more frequent with pancreatic tumors • Insulinomas • IR 1–3/ million population / year • Less than 10% are malignant • Pancreatic Non-Functioning Tumors • 60–90% of PNETs • an increase in the incidental detection of NF-NETs • PFS is much greater for incidental NF-pNETs

19. Key points • IR of GEP-NET has increased steadily over past 40 yrs • largest increases found in Gastric & Rectal NETs • Rectal NETs are the most common: • in east Asia • recently in the US SEER database • SI NET: still the most common in most European series • Appendiceal NETs: more common in young females • Pancreatic NETs: IR in registries dedicated to NETs • Five-year survival rates are: • highest in rectal and appendiceal NET • lowest in small intestinal and pancreatic NETs

20. (Un)answered questions • Inconsistency in the nomenclature and classification of NETs • recent WHO classification criteria unify classification suggestions • Older cancer registries included only ‘malignant carcinoids’ • new ICD coding includes ‘benign’ NETs. This may explain some of the increase in the incidence of GEP-NETs • Registries document malignant diseases on the basis of clinical reports • recent prospective studies rely on strict histolological criteria • Data are still lacking in many parts of the world (Asia and Africa) • Population-based studies, ideally of whole countries • standardized collection of pathology reports • a uniform classification system, preferably the most updated WHO

21. Thank you! geokan@endo.gr