Neuroendocrine Tumors of the Pancreas

Neuroendocrine Tumors of thePancreasProf. Dr. med. P. KomminothZürich, SwitzerlandProf. Dr. med. Paul KOMMINOTHInstitute of PathologyCity Hospital TriemliBirmensdorferstrasse 497CH-8063 Zürich, Switzerlandpaul.komminoth@triemli.zuerich.chwww.stadt-zuerich.ch/triemli

Layout• Intoduction• Look alikes• Two of a kind– UICC/AJCC versus ENETS TNM• Is there more ?– Molecular PathologyProf. 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)• othersProf. Dr. med. P. KomminothZürich, SwitzerlandWDHHA: watery diarrhea, hypokalemia, hypochlorhydria, alcalosis

GlucagonomapostopProf. Dr. med. P. KomminothZürich, Switzerlandnecrolytic migratory erythema

PanNEN: Distribution300250Insulinoma Non functioning253200150174100500Prof. Dr. med. P. KomminothZürich, Switzerland5124Insulinomas Glucagonomas Somatostatinomas Gastrinomas Vipomas NonfunctioningTumours804115Tumoursproducing ectopichormones

What do the clinicians want from us?• Diagnosis what is it ? WHO• Gradinghow aggressiveis it ?MiB-1• Staginghow advancedis it ?TNMProf. Dr. med. P. KomminothZürich, Switzerland

What do the clinicians want from us?• Diagnosis what is it ? WHO• Gradinghow aggressiveis it ?MiB-1• Staginghow advancedis it ?TNMProf. Dr. med. P. KomminothZürich, Switzerland

is it .....or is it not ?Prof. Dr. med. P. KomminothZürich, Switzerland

Prof. Dr. med. P. KomminothZürich, Switzerland

DD solid pancreatic tumor• Pancreatic endocrine tumor• Acinar cell carcinoma• Solid pseudopapillary tumor• PancreatoblastomaProf. Dr. med. P. KomminothZürich, Switzerland

Prof. Dr. med. P. KomminothZürich, Switzerland

Prof. Dr. med. P. KomminothZürich, SwitzerlandSyn

Prof. Dr. med. P. KomminothZürich, Switzerland

Prof. Dr. med. P. KomminothZürich, Switzerland

Prof. Dr. med. P. KomminothZürich, Switzerland

Prof. Dr. med. P. KomminothZürich, Switzerland

Prof. Dr. med. P. KomminothZürich, Switzerland

Prof. Dr. med. P. KomminothZürich, Switzerland

LipaseProf. Dr. med. P. KomminothZürich, Switzerland

Acinar cell carcinomaProf. Dr. med. P. KomminothZürich, Switzerland• 1-2 % of 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• Pancreas stone protein(< 100%)• Trypsin (> 95%)• Lipase (70%)• Amylase (30%)• 1/3 focal Syn/CgA +Prof. Dr. med. P. KomminothZürich, Switzerland

Prof. Dr. med. P. KomminothZürich, Switzerland

Prof. Dr. med. P. KomminothZürich, Switzerland

Prof. Dr. med. P. KomminothZürich, Switzerland

Prof. Dr. med. P. KomminothZürich, Switzerland

Prof. Dr. med. P. KomminothZürich, Switzerland

Solid-pseudopapillary tumor• 1-2% of exocrine pancreatic tumors• young women (8-67 yrs)• rare in men• solid, cystic, necrosis, hemorrhage• rarely malignant (5-15%)• prognosis mostly goodProf. Dr. med. P. KomminothZürich, Switzerland

Metastatic SPN4/95 (5%)Prof. Dr. med. P. KomminothZürich, Switzerland5% to 15% of SPNs metastasize or recur

Prof. Dr. med. P. KomminothZürich, Switzerland

Prof. Dr. med. P. KomminothZürich, Switzerland

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 -Prof. Dr. med. P. KomminothZürich, Switzerland

Prof. Dr. med. P. KomminothZürich, Switzerland

Prof. Dr. med. P. KomminothZürich, Switzerland

Prof. Dr. med. P. KomminothZürich, Switzerland

Pancreatoblastoma• squamoid corpuscules• acinar differentiation 90%• mesenchymal component• endocrine differentiation 2/3focal• ductal differentiation 1/2focalProf. Dr. med. P. KomminothZürich, Switzerland

Prof. Dr. med. P. KomminothZürich, Switzerland

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 +Prof. Dr. med. P. KomminothZürich, Switzerland

What do the clinicians want from us?• Diagnosis what is it ? WHO• Gradinghow aggressiveis it ?MiB-1• Staginghow advancedis it ?TNMProf. 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 of adjacent organs and/or metastasesFunctioning: gastrinoma, insulinoma, glucagonoma, VIPoma,somatostatinoma or ectopic hormonal syndromeNonfunctioning3. Poorly differentiated neuroendocrine carcinomaHigh grade malignantProf. Dr. med. P. KomminothZürich, Switzerlandvery difficult to apply in biopsies

Prof. Dr. med. P. KomminothZürich, Switzerland

WHO 2010• Categories for NEN:1. Neuroendocrine tumor NET G12. Neuroendocrine tumor NET G23. Neuroendocrine carcinoma NEC(small or large cell type)4. Mixed adeno-neuroendocrinecarcinoma MANEC5. Hyperplastic/preneoplastic lesionsProf. Dr. med. P. KomminothZürich, Switzerland

Prof. Dr. med. P. KomminothZürich, Switzerland

What do the clinicians want from us?• Diagnosis what is it ? WHO• Gradinghow aggressiveis it ?MiB-1• Staginghow advancedis it ?TNMProf. Dr. med. P. KomminothZürich, Switzerland

ENETS GradingProf. Dr. med. P. KomminothZürich, SwitzerlandRindi G et al. Virchows Arch 2006; 449: 395-401

Prof. Dr. med. P. KomminothZürich, SwitzerlandRindi et al. J Natl Cancer Inst 2012;104:764–777

Prof. Dr. med. P. KomminothZürich, Switzerland

(somatostatin)(peptide receptor radiotherapy)Öberg K. Curr Opin Oncol 2012,24:433-40Prof. Dr. med. P. KomminothZürich, Switzerland

What do the clinicians want from us?• Diagnosis what is it ? WHO• Gradinghow aggressiveis it ?MiB-1• Staginghow advancedis it ?TNMProf. Dr. med. P. KomminothZürich, Switzerland

ENETS TNM TNM UICC/AJCC 2010200620072010ENETS: European Neuroendocrine Tumor SocietyUICC: International Union Against CancerAJCC: American Joint Committee on CancerProf. Dr. med. P. KomminothZürich, Switzerland

Prof. Dr. med. P. KomminothZürich, SwitzerlandPancreatic NENs

ENETS and AJCC/UICC TNM are different forappendiceal and pancreatic NENsuse both in your reportProf. 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 of follow-up1990 to 2007Prof. Dr. med. P. KomminothZürich, Switzerland

Prof. Dr. med. P. KomminothZürich, SwitzerlandRindi et al. J Natl Cancer Inst 2012;104:764–777

Prof. Dr. med. P. KomminothZürich, Switzerland

WHOTNMTumortypeGrade&StagingBiopsiesClinically preopSurgical specimensImproved risk stratification-> therapy planingProf. Dr. med. P. KomminothZürich, Switzerland

Molecular pathology of PanNENand possible implications fordiagnosticsProf. Dr. med. P. KomminothZürich, Switzerland

Syndromic PanNENPancreatic Tumors• MEN1 11q13 20-70%• VHL 3p25 < 20%• NF1 17q11.2 < 10%• TSC1 9q34 ≈ 1%TSC2 16p13.3Prof. 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%Prof. Dr. med. P. KomminothZürich, Switzerland

many chromosomesinvolvedboth gains and losseswhole chromosomesgenetic instabilitytumor suppressorpathwayProf. Dr. med. P. KomminothZürich, Switzerland Am J Pathol 1999;155:1787

Sporadic PET: progression model4+, 4+, 7+, 7+, 21-Number ofgenomicalterationsNFVIP, GlucInsGast3-, , 6q-, , 17+, 20+6q-, , 11-, , 4+MEN1-MEN1+9q34+, 1p-, , 4-, 4 , 11q-, , XY-18q-Prof. Dr. med. P. KomminothZürich, Switzerland2cm

cDNA expression arraySpearman 3fachverändert in 4samplescontrol >1 p 2cm "uncertain behavior" WHOreduced expressionincreased expressionProf. Dr. med. P. KomminothZürich, SwitzerlandPerren et al. unpublished data

Prof. Dr. med. P. KomminothZürich, SwitzerlandJ Clin Oncol 2010;28:245-255

10 PanNEN -> genome widesequencing: 157 mutations in149 genes (8-23/Tu !!)Selection of most mutated genes-> screening of 58 additionalPanNENsProf. Dr. med. P. KomminothZürich, SwitzerlandN = 68

43%17%Prof. Dr. med. P. KomminothZürich, Switzerlandde Wilde, R. F. et al. Nat. Rev. Gastroenterol. Hepatol. 9, 199–208 (2012)

Perren et al. unpublished dataALT: alternative lengthening of telomeresProf. Dr. med. P. KomminothZürich, Switzerland

DAXX ATRX-> DAXX ATRX probably late event• only in PanNEN of MEN1 larger (>3 cm)• nearly one-quarter of the sporadicPanNEN have dual mutations in MEN1and either ATRX or DAXX• G2/M checkpoint dysfunction is neededin ALT cellsProf. Dr. med. P. KomminothZürich, Switzerland

number of samples252015105Daxx and Atrx (+)Daxx or Atrx (-)0T1 T2 T3/4T stagePerren et al. unpublished dataProf. Dr. med. P. KomminothZürich, Switzerland

Sporadic PanNEN: Progression modelNumber ofgenomicalterationsNFVIP, GlucInsGastMEN1mTOR pathway genesDAXX/ATRX?Prof. Dr. med. P. KomminothZürich, Switzerland2cm

Genes and pathways alterations in PanNENmTOR pathwayEGFRIGFRpredictive markers !IRS1ATRXPI3K* PTEN +MENINDAXXATMTargetedtherapyAktTSC1TSC2*VHL*HIF1Chromatin assembly andhistone remodellingProf. Dr. med. P. KomminothZürich, SwitzerlandGβLmTORRaptorCell proliferationHypoxiaNo targeted therapyPARP inhibitors (poly ADP ribose polymerase) ?Chk1 inhibitors (checkpoint kinase-1) ?

Prof. Dr. med. P. KomminothZürich, Switzerland

Prof. 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 therapeuticdecision making in advanced PanNET• Increasing significance of pedictiveIHC markers for therapy (mTOR pathway)

ThanksProf. Dr. med. P. KomminothZürich, SwitzerlandA. Perren and his groupP. Saremaslani, S. SchmidE.J. Speel, J. ZhaoG. Klöppel, M. AnlaufPh. U. Heitz, J. Rothmany others

Questions ?Prof. Dr. med. P. KomminothZürich, Switzerland

PanNEN: outcome• CK-19 +• COX-2 +• CD 99 -adverse outcome• p27 +• αHCG +• CT +• MAGE-1 ++/-• progesteron R -• CD44v6 -Prof. 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 PECProf. Dr. med. P. KomminothZürich, SwitzerlandSchmitt et al. Am J Surg Path 2007;31:1677-82