Neuroendocrine Tumors of the Pancreas
Neuroendocrine Tumors of the Pancreas
Neuroendocrine Tumors of the Pancreas
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<strong>Neuroendocrine</strong> <strong>Tumors</strong> <strong>of</strong> <strong>the</strong><strong>Pancreas</strong>Pr<strong>of</strong>. Dr. med. P. KomminothZürich, SwitzerlandPr<strong>of</strong>. Dr. med. Paul KOMMINOTHInstitute <strong>of</strong> PathologyCity Hospital TriemliBirmensdorferstrasse 497CH-8063 Zürich, Switzerlandpaul.komminoth@triemli.zuerich.chwww.stadt-zuerich.ch/triemli
Layout• Intoduction• Look alikes• Two <strong>of</strong> a kind– UICC/AJCC versus ENETS TNM• Is <strong>the</strong>re more ?– Molecular PathologyPr<strong>of</strong>. Dr. med. P. KomminothZürich, Switzerland
PanNEN: Clinical classification•Functioning (active, syndromic)• Insulinoma• Gastrinoma• Glucagonoma• VIPoma• SomatostatinomaHypoglycemiaZollinger-Ellison syndromeDiabetes, dermatitis etc.WDHHA- or Verner-Morrison synd.Diabetes, gallbladder disease•Non-functioning (inactive, clinically silent)• PPoma (pancreatic polypeptide)• o<strong>the</strong>rsPr<strong>of</strong>. Dr. med. P. KomminothZürich, SwitzerlandWDHHA: watery diarrhea, hypokalemia, hypochlorhydria, alcalosis
GlucagonomapostopPr<strong>of</strong>. Dr. med. P. KomminothZürich, Switzerlandnecrolytic migratory ery<strong>the</strong>ma
PanNEN: Distribution300250Insulinoma Non functioning253200150174100500Pr<strong>of</strong>. Dr. med. P. KomminothZürich, Switzerland5124Insulinomas Glucagonomas Somatostatinomas Gastrinomas Vipomas NonfunctioningTumours804115Tumoursproducing ectopichormones
What do <strong>the</strong> clinicians want from us?• Diagnosis what is it ? WHO• Gradinghow aggressiveis it ?MiB-1• Staginghow advancedis it ?TNMPr<strong>of</strong>. Dr. med. P. KomminothZürich, Switzerland
What do <strong>the</strong> clinicians want from us?• Diagnosis what is it ? WHO• Gradinghow aggressiveis it ?MiB-1• Staginghow advancedis it ?TNMPr<strong>of</strong>. Dr. med. P. KomminothZürich, Switzerland
is it .....or is it not ?Pr<strong>of</strong>. Dr. med. P. KomminothZürich, Switzerland
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DD solid pancreatic tumor• Pancreatic endocrine tumor• Acinar cell carcinoma• Solid pseudopapillary tumor• PancreatoblastomaPr<strong>of</strong>. Dr. med. P. KomminothZürich, Switzerland
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LipasePr<strong>of</strong>. Dr. med. P. KomminothZürich, Switzerland
Acinar cell carcinomaPr<strong>of</strong>. Dr. med. P. KomminothZürich, Switzerland• 1-2 % <strong>of</strong> exocrine pancreatic Tu• 10-15 % lipase hypersecretion• 50% have mets at diagnosis• 5 years survival < 10 %• staging like PDAC; no grading system• mixed types: acinar-endocrine; acinarductal;acinar-endocrine-ductal(> 1/3 component)
Acinar cell carcinoma• <strong>Pancreas</strong> stone protein(< 100%)• Trypsin (> 95%)• Lipase (70%)• Amylase (30%)• 1/3 focal Syn/CgA +Pr<strong>of</strong>. Dr. med. P. KomminothZürich, Switzerland
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Solid-pseudopapillary tumor• 1-2% <strong>of</strong> exocrine pancreatic tumors• young women (8-67 yrs)• rare in men• solid, cystic, necrosis, hemorrhage• rarely malignant (5-15%)• prognosis mostly goodPr<strong>of</strong>. Dr. med. P. KomminothZürich, Switzerland
Metastatic SPN4/95 (5%)Pr<strong>of</strong>. Dr. med. P. KomminothZürich, Switzerland5% to 15% <strong>of</strong> SPNs metastasize or recur
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Solid-pseudopapillary tumor• CK (focal; weak)• NSE, CD56 (diffuse; weak)• Syn (focal/ single cells)• CgA -• Progesteronreceptor+• CD10 +• ß catenin +• Alpha-1-AT (focal; strong)• Vim +• CEA -• AFP -Pr<strong>of</strong>. Dr. med. P. KomminothZürich, Switzerland
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Pancreatoblastoma• squamoid corpuscules• acinar differentiation 90%• mesenchymal component• endocrine differentiation 2/3focal• ductal differentiation 1/2focalPr<strong>of</strong>. Dr. med. P. KomminothZürich, Switzerland
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Pancreatoblastoma• CK + (but not corpuscules !)• alpha-1-AT may be +• lipase, trypsin, (amylase) + (90%)• endocrine markers focal + (2/3)Syn, CgA• ductal markers focal + (1/2)CEA• AFP may be focally +Pr<strong>of</strong>. Dr. med. P. KomminothZürich, Switzerland
What do <strong>the</strong> clinicians want from us?• Diagnosis what is it ? WHO• Gradinghow aggressiveis it ?MiB-1• Staginghow advancedis it ?TNMPr<strong>of</strong>. Dr. med. P. KomminothZürich, Switzerland
PanNEN: WHO 20041. Well-differentiated neuroendocrine tumorBenign: confined to pancreas, < 2 cm in size, nonangioinvasive,= 2 mitoses/10HPF and = 2% Ki-67-positive cellsFunctioning: insulinomaNonfunctioningBenign or low grade malignant (uncertain malignant potential):confined to pancreas, = 2 cm in size, > 2 mitoses/10HPF,> 2% Ki-67-positive cells, or angioinvasiveFunctioning: gastrinoma, insulinoma, VIPoma, glucagonoma,somatostatinoma or ectopic hormonal syndromeNonfunctioning2. Well-differentiated neuroendocrine carcinomaLow grade malignant: invasion <strong>of</strong> adjacent organs and/or metastasesFunctioning: gastrinoma, insulinoma, glucagonoma, VIPoma,somatostatinoma or ectopic hormonal syndromeNonfunctioning3. Poorly differentiated neuroendocrine carcinomaHigh grade malignantPr<strong>of</strong>. Dr. med. P. KomminothZürich, Switzerlandvery difficult to apply in biopsies
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WHO 2010• Categories for NEN:1. <strong>Neuroendocrine</strong> tumor NET G12. <strong>Neuroendocrine</strong> tumor NET G23. <strong>Neuroendocrine</strong> carcinoma NEC(small or large cell type)4. Mixed adeno-neuroendocrinecarcinoma MANEC5. Hyperplastic/preneoplastic lesionsPr<strong>of</strong>. Dr. med. P. KomminothZürich, Switzerland
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What do <strong>the</strong> clinicians want from us?• Diagnosis what is it ? WHO• Gradinghow aggressiveis it ?MiB-1• Staginghow advancedis it ?TNMPr<strong>of</strong>. Dr. med. P. KomminothZürich, Switzerland
ENETS GradingPr<strong>of</strong>. Dr. med. P. KomminothZürich, SwitzerlandRindi G et al. Virchows Arch 2006; 449: 395-401
Pr<strong>of</strong>. Dr. med. P. KomminothZürich, SwitzerlandRindi et al. J Natl Cancer Inst 2012;104:764–777
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(somatostatin)(peptide receptor radio<strong>the</strong>rapy)Öberg K. Curr Opin Oncol 2012,24:433-40Pr<strong>of</strong>. Dr. med. P. KomminothZürich, Switzerland
What do <strong>the</strong> clinicians want from us?• Diagnosis what is it ? WHO• Gradinghow aggressiveis it ?MiB-1• Staginghow advancedis it ?TNMPr<strong>of</strong>. Dr. med. P. KomminothZürich, Switzerland
ENETS TNM TNM UICC/AJCC 2010200620072010ENETS: European <strong>Neuroendocrine</strong> Tumor SocietyUICC: International Union Against CancerAJCC: American Joint Committee on CancerPr<strong>of</strong>. Dr. med. P. KomminothZürich, Switzerland
Pr<strong>of</strong>. Dr. med. P. KomminothZürich, SwitzerlandPancreatic NENs
ENETS and AJCC/UICC TNM are different forappendiceal and pancreatic NENsuse both in your reportPr<strong>of</strong>. Dr. med. P. KomminothZürich, Switzerland
1072 patients8 European cancer centersVerona-Roma (365) (12), Berlin-Charité (170)Varese-Milano San Raffaele-Pavia (144)Heidelberg (118), Zurich (114), Clichy (111)London-UCL (32), Erasmus-Rotterdam (18)at least 2 years <strong>of</strong> follow-up1990 to 2007Pr<strong>of</strong>. Dr. med. P. KomminothZürich, Switzerland
Pr<strong>of</strong>. Dr. med. P. KomminothZürich, SwitzerlandRindi et al. J Natl Cancer Inst 2012;104:764–777
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WHOTNMTumortypeGrade&StagingBiopsiesClinically preopSurgical specimensImproved risk stratification-> <strong>the</strong>rapy planingPr<strong>of</strong>. Dr. med. P. KomminothZürich, Switzerland
Molecular pathology <strong>of</strong> PanNENand possible implications fordiagnosticsPr<strong>of</strong>. Dr. med. P. KomminothZürich, Switzerland
Syndromic PanNENPancreatic <strong>Tumors</strong>• MEN1 11q13 20-70%• VHL 3p25 < 20%• NF1 17q11.2 < 10%• TSC1 9q34 ≈ 1%TSC2 16p13.3Pr<strong>of</strong>. Dr. med. P. KomminothZürich, Switzerland
MEN1 in sporadic PanNENMutationsAllelic deletions• Insulinomas 7.7% 39%• Non-functioning 8% 75%• Gastrinomas 37% 90%• Glucagonomas 67% 75%• VIPomas 44% 80%• All 21% 68%Pr<strong>of</strong>. Dr. med. P. KomminothZürich, Switzerland
many chromosomesinvolvedboth gains and losseswhole chromosomesgenetic instabilitytumor suppressorpathwayPr<strong>of</strong>. Dr. med. P. KomminothZürich, Switzerland Am J Pathol 1999;155:1787
Sporadic PET: progression model4+, 4+, 7+, 7+, 21-Number <strong>of</strong>genomicalterationsNFVIP, GlucInsGast3-, , 6q-, , 17+, 20+6q-, , 11-, , 4+MEN1-MEN1+9q34+, 1p-, , 4-, 4 , 11q-, , XY-18q-Pr<strong>of</strong>. Dr. med. P. KomminothZürich, Switzerland2cm
cDNA expression arraySpearman 3fachverändert in 4samplescontrol >1 p 2cm "uncertain behavior" WHOreduced expressionincreased expressionPr<strong>of</strong>. Dr. med. P. KomminothZürich, SwitzerlandPerren et al. unpublished data
Pr<strong>of</strong>. Dr. med. P. KomminothZürich, SwitzerlandJ Clin Oncol 2010;28:245-255
10 PanNEN -> genome widesequencing: 157 mutations in149 genes (8-23/Tu !!)Selection <strong>of</strong> most mutated genes-> screening <strong>of</strong> 58 additionalPanNENsPr<strong>of</strong>. Dr. med. P. KomminothZürich, SwitzerlandN = 68
43%17%Pr<strong>of</strong>. Dr. med. P. KomminothZürich, Switzerlandde Wilde, R. F. et al. Nat. Rev. Gastroenterol. Hepatol. 9, 199–208 (2012)
Perren et al. unpublished dataALT: alternative leng<strong>the</strong>ning <strong>of</strong> telomeresPr<strong>of</strong>. Dr. med. P. KomminothZürich, Switzerland
DAXX ATRX-> DAXX ATRX probably late event• only in PanNEN <strong>of</strong> MEN1 larger (>3 cm)• nearly one-quarter <strong>of</strong> <strong>the</strong> sporadicPanNEN have dual mutations in MEN1and ei<strong>the</strong>r ATRX or DAXX• G2/M checkpoint dysfunction is neededin ALT cellsPr<strong>of</strong>. Dr. med. P. KomminothZürich, Switzerland
number <strong>of</strong> samples252015105Daxx and Atrx (+)Daxx or Atrx (-)0T1 T2 T3/4T stagePerren et al. unpublished dataPr<strong>of</strong>. Dr. med. P. KomminothZürich, Switzerland
Sporadic PanNEN: Progression modelNumber <strong>of</strong>genomicalterationsNFVIP, GlucInsGastMEN1mTOR pathway genesDAXX/ATRX?Pr<strong>of</strong>. Dr. med. P. KomminothZürich, Switzerland2cm
Genes and pathways alterations in PanNENmTOR pathwayEGFRIGFRpredictive markers !IRS1ATRXPI3K* PTEN +MENINDAXXATMTargeted<strong>the</strong>rapyAktTSC1TSC2*VHL*HIF1Chromatin assembly andhistone remodellingPr<strong>of</strong>. Dr. med. P. KomminothZürich, SwitzerlandGβLmTORRaptorCell proliferationHypoxiaNo targeted <strong>the</strong>rapyPARP inhibitors (poly ADP ribose polymerase) ?Chk1 inhibitors (checkpoint kinase-1) ?
Pr<strong>of</strong>. Dr. med. P. KomminothZürich, Switzerland
Pr<strong>of</strong>. Dr. med. P. KomminothZürich, SwitzerlandSummary• PanNEN diagnosis may be challenging inFNA´s and biopsy cylinders• Rule out acinar cell carcinoma and solidpseudopapillarytumor• New WHO and TNM will help tostandardize diagnostics and treatment• Grading (MiB1) crucial for <strong>the</strong>rapeuticdecision making in advanced PanNET• Increasing significance <strong>of</strong> pedictiveIHC markers for <strong>the</strong>rapy (mTOR pathway)
ThanksPr<strong>of</strong>. Dr. med. P. KomminothZürich, SwitzerlandA. Perren and his groupP. Saremaslani, S. SchmidE.J. Speel, J. ZhaoG. Klöppel, M. AnlaufPh. U. Heitz, J. Rothmany o<strong>the</strong>rs
Questions ?Pr<strong>of</strong>. Dr. med. P. KomminothZürich, Switzerland
PanNEN: outcome• CK-19 +• COX-2 +• CD 99 -adverse outcome• p27 +• αHCG +• CT +• MAGE-1 ++/-• progesteron R -• CD44v6 -Pr<strong>of</strong>. Dr. med. P. KomminothZürich, Switzerland
WHO 2004 + CK19Tumor Percent specific survival survival100 PET CK19-806040201a1b00 60 120 180 240 300 360follow up (months)23PET CK19+PET ub CK19-PET ub CK19+wd PEC CK19-wd PEC CK19+pd PECPr<strong>of</strong>. Dr. med. P. KomminothZürich, SwitzerlandSchmitt et al. Am J Surg Path 2007;31:1677-82