Günter Klöppel Dept. of Pathology Consultation Center for Pancreatic and Endocrine tumors Technische Universität München
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1 Günter Klöppel Dept. of Pathology Consultation Center for Pancreatic and Endocrine tumors Technische Universität München
2 Incidental 1.5 cm tumor in a 45-year old man: Most probable diagnosis - Pan NEN. What should be done?
3 Incidental 1.5 cm tumor in a 45-year old man: Most probable diagnosis - Pan NEN. What should be done? - Remove at once - Watch and wait (how long?) and then remove
4 Survival in surgically treated patients with Pan NENs - Overall 5-year: 45 % year survival: 20 %
5 P e r c e n t s u r v iv a l Survival in surgically treated patients with Pan NENs < 2 cm ( T1 accord. To UICC/ENETS) Resected T1 PanNENs 43% 32% 100 T T2 T3 T D F S ( m o n t h s ) Schmitt, AJSP 2007 Fischer, Br. J. Surg 2008
6 Incidental tumor 1.5 cm in a 45-year old man: Pan NEN The tumor should be removed, but there is no hurry
7 SYN -NEN positive for SYN and CG -WHO classification 2010: NET G2 (6%) -UICC/ENETS TNM classification: pt1 N0 M0 G2 MIB1 6%
8 Standardized approach towards the diagnosis of GEP-NEN ENETS mandatory -expression of the neuroendocrine markers synaptophysin and chromogranin A (both or only syn) -histopathology (H&E) : well or poorly differentiated -proliferative activity (Ki67/MIB1): G1 G3 -stage: ptnm ENETS 2007 and UICC 2009 Klöppel et al Neuroendocrinology 2009
9 Risk of malignant behavior in neuroendocrine neoplasms of the pancreas -Very low risk of malignant behavior: Well differentiated, functioning (e.g. insulinoma) and non-functioning, nonangioinvasive, G1 (Ki-67< 2%) neoplasm, <2 cm in size. -Low risk of malignant behavior: Well differentiated, functioning and non-functioning, non-angioinvasive or angioinvasive, G2 (Ki % ) neoplasm, 2-4 cm in size. -Low-grade malignant behavior: Well-differentiated, functioning and non-functioning neoplasm with gross local invasion and/or metastases, angioinvasive, G2 (Ki-67 >5 20 % ) -High-grade malignant behavior: Poorly differentiated neoplasm of small or large cell type, usually nonfunctioning, G3 (Ki-67 >20%)
10 The Neuroendocrine Neoplasms of the gastroenteropancreatic system: The WHO classification: the problems NET G1 < 2% or < 5%? NET G2 > 5% to 20% or >5 10%? >10 20%? - Is there a NET G3 or are all NENs >20% neuroendocrine carcinomas NEC G3 >20%?
11 NET: well differentiated NEN G1 <2% or G2-2% - 20%
12 NEC: poorly differentiated NEN -small cell type G3 > 20%
13 NEC: poorly differentiated NEN -large cell type G3 > 20 %
14 poorly differentiated NEN - NEC -fast growth -bad prognosis -no hormonal syndromes -genetics: mutations of basic genes such as p53 -related to smoking well differentiated NEN - NET -slow growth -favorable prognosis -hormonal syndro. possible -hereditary syndromes -genetics differ from NEC -unrelated to smoking
15 Stem cell origin of GEP-NENs Intestinal stem cell NGN3 Isl1? endocrineprecursor cell duodenum NGN3 Somatostatin cell Gastrin cell CDX2 MATH1 Poorly differentiated - NEC Stem cell P53 Isl- MEN1 Isl1 + PDX1 Well differentiated - NET Pancreas stem cell Isl1 NGN3 endocrineprecursor cell pancreas Isl1 Isl1 Isl1 Isl1 Isl1, PDX1 Gastrin cell Somatostatin cell PP cell Glucagon cell Insulin cell
16 25 % Well diff NEN - NET Agaimy Modern Pathol 2013
17 Well diff NEN - NET Poorly diff NEN NEC Yachida AJSP 2012
18 NET G3 NEC G3
19 Natural history of Pan NENs Tumor Size - cm metastases 3 cm 2 cm NET G3 1 cm NEC G3 NET G Time course - years
20 Natural history of Pan NENs Tumor Size - cm metastases 3 cm 2 cm 1 cm Time course - years
21 icroadenoma in the MEN1 and normal pancreas GLU
22 Frequency / Incidence of Pan NENs - Frequency of microadenomas (o.5 cm) in p.m. pancreata 10% ,000 / Incidence of PanNENs in the population /
23 Gastrin Glucagon Insulin PP Somatostatin Unclassified Lk Metastasen Endokrine Tumore > 5 mm < 5 mm - 1 mm < 1 mm - 0.5mm endokrine Hyperplasie sstr2 + < 0.5 mm Anlauf et al. AJSP 2008
24 Development of MEN1 tumors in the pancreas Adenoma Islet Glucagoncell hyperplasia M+/LOH 13q - Islet + microadenoma Glucagoncell tumor M+/LOH 13q + Perren et al JCEM 2007 M+/LOH 13q + M+ : MEN1 germ cell mutation
25 Glucagon cell adenomatosis Tobias Henopp, Martin Anlauf, Anja Schmitt, Nele Garbrecht, Attila Zalatnai, Anne Couvelard, Philippe Ruszniewski, Oliver Gimm, Henning Dralle, Andreas Raffel, Wolfram T. Knoefel, Philipp U. Heitz, Paul Komminoth, Aurel Perren, Günter Klöppel J Endocrinol Metab 94, , 2009
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