Patient History. A 58 year old man presents with a 16 mm cyst in the pancreatic tail. The cyst is unilocular with a thick wall and no mural nodule.

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1 Case 1 Martha Bishop Pitman, MD Director of Cytopathology Massachusetts General Hospital Associate Professor of Pathology Harvard Medical School Boston, MA

2 Patient History A 58 year old man presents with a 16 mm cyst in the pancreatic tail. The cyst is unilocular with a thick wall and no mural nodule.

3 EUS Findings An anechoic lesion suggestive of a cyst/pseudocyst was identified in the pancreatic tail. The lesion measured 16 mm by 13 mm in maximal cross sectional diameter. There was a single compartment without septae. The outer wall of the lesion was thick. There was no associated mass. There was no internal debris within the fluid filled cavity. Diagnostic needle aspiration for fluid was performed. One pass was made with the 22 gauge needle using a transgastric approach. A stylet was used. The amount of fluid collected was 3 cc. The fluid was clear

4 Branch duct IPMN MCN Pseudocyst Imaging Impression

5 No-ROSE Cysts Direct smears If fluid thick enough Fresh undiluted cyst fluid CEA; Amylase Molecular Cytology Cytospin Cellblock Cytological Preparations MASSACHUSETTS GENERAL PHYSICIANS ORGANIZATION HARVARD MEDICAL SCHOOL

6 Fresh Pancreatic Cyst Fluid <0.5cc 0.5 cc ~0.3cc ~0.3cc vortex Centrifuge residual 0.3cc Molecular 2. Molecular 1. CEA supernatant cells ~0.3cc ~0.3cc ~0.3cc 1. CEA 2. Amylase 3. Banking Cytospin(s) Cytology (+/- mucin stains) MASSACHUSETTS GENERAL PHYSICIANS ORGANIZATION HARVARD MEDICAL SCHOOL

7 1) Is the cyst mucinous or nonmucinous? Two basic questions for Cyst analysis 2) Is the cyst low grade or high grade?

8 Case 1: Cytospin

9 Gross Cyst Fluid Characteristics 3 cc Thin Clear

10 Biochemical Analysis Amylase 1493 U/L CEA 2 ng/ml Gastroenterology 2004 May;126(5):1330 6

11 CFA cut off levels lab and study dependent (van der Waaij, et. al. Cystfluid analysis in the differential diagnosis of pancreatic cystic lesions: a pooled analysis. Gastrointes Endosc. 2005; 62:383) CEA >800ng/ml CEA <5ng/ml Amylase <250 U/L Neoplastic mucinous cysts Serous cystadenoma Pseudocyst Not a pseudocyst

12 CEA and Amylase: Key Points Elevated CEA ( 192 ng/ml) supports a mucinous cyst Does not distinguish IPMN from MCN Level does not correlate with malignancy Rare FP: PCT, GI duplication cyst, LEC Amylase levels Elevated in the 1000 s for most PCT Low amylase level tends to exclude a PCT Level does not distinguish IPMN from MCN MASSACHUSETTS GENERAL PHYSICIANS ORGANIZATION HARVARD MEDICAL SCHOOL

13 Molecular Analysis Patient: Case 1 KRAS WT GNAS WT KRAS Mutation(s) support a neoplastic mucinous cyst Does not distinguish IPMN and MCN Does not correlate with grade GNAS Mutation supports IPMN over MCN Does not correlate with grade RNF43 Mutation supports a mucinous cyst Does not distinguish IPMN and MCN 3p deletions 3p25, VHL gene, supports SCA Other 3p deletions also noted in SCA CTNNB1 (beta catenin) deletion Mutation(s) support SPN

14 Cyst Fluid Characteristics of Pancreatic Cysts IPMN MCN SCA cpannet PCT Viscosity High High Low Low Low CEA High (low) (>192 ng/ ml)* High (low) ( >192 ng/ ml)* Low Low Low Amylase High Low/high Low Low Very high Molecular (NGS) KRAS/GNAS KRAS VHL None None

15 Case 1

16 Case 1

17 Cytological Criteria of High Grade Epithelial Atypia in the Cyst Fluid of Pancreatic Intraductal Papillary Mucinous Neoplasms Martha B. Pitman, MD, Barbara A. Centeno, MD, Ebubekir S. Daglilar, MD, William R. Brugge, MD, and Mari Mino Kenudson, MD Cancer Cytopathol Jan;122(1): Reference duodenal enterocyte Low-grade High-grade HGA is most accurately identified in mucinous cyst fluids by: 1. an increased N/C ratio, 2. an abnormal chromatin pattern 3. background necrosis

18 High grade atypia High grade dysplasia in IPMN Case 1

19 Case 1

20 Cytology Cells with high N/C ratio No cytoplasmic mucin Coarse stippled chromatin Prominent nucleoli

21 Summary of Findings Demographics 58 year old male No history of pancreatitis given Imaging Small cyst (< 2cm) Thick walled, unilocular, tail Gross Thin, clear, fluid Ancillary Tests Low CEA and amylase; KRAS/GNAS WT Cytology High grade atypia

22 DIAGNOSIS?

23 DIAGNOSIS: CYSTIC NEUROENDOCRINE TUMOR

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26 Cystic Neuroendocrine Tumors Johns Hopkins Series 53/491 surgically resected NETS (~10%) y.o. (mean 52 yrs) M=F Size similar to solid NETs, avg. 3.3 cm Most in the pancreatic tail Unilocular with clear to straw colored fluid No association with MEN I and multifocal disease like solid NETs All were well differentiated with low ki 67 [2 11%; mean 1.8%] Compared to solid NETs, cystic NETs demonstrated less Tumor necrosis (6%, p= 0.04) Perineural invasion (8%, p <0.001) Vascular invasion (4%, p< 0.001) Regional lymph node metastases (13%, p<0.001) Synchronous distant metastases (4%, p = 0.015) Singhi AD, Chu LC, Tatsas AD, Shi C, Ellison TA, Fishman EK, Kawamoto S,Schulick RD, Wolfgang CL, Hruban RH, Edil BH. Cystic pancreatic neuroendocrine tumors: a clinicopathologic study. Am J Surg Pathol Nov;36(11):

27 Endoscopy. 2013;45(3):

28 Endoscopy. 2013;45(3):

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30 Cancer Cytopathol. 2014; 122:

31 Cystic PanNETs Take Home Points < 10% of pancreatic cysts ~10 of resected PanNETs Thick cyst wall is a clue Also solid cystic mass CEA and amylase are low KRAS/GNAS are WT Cytology is the diagnostic test