Disclosure Select problems in cystic pancreatic lesions Five Prime Therapeutics shareholder Adicet Bio shareholder Bristol-Meyer Squibb advisory board grace.kim@ucsf.edu Pancreatic cystic lesions Intraductal papillary mucinous neoplasm 1. Injury-related and inflammation-related cysts (30%) Pseudocyst, paraduodenal pancreatitis, hydatid cyst 2. Miscellaneous /congenital cyst (<5%) Epidermoid, lymphoepithelial, or duplication cysts 3. Neoplastic cysts (60%) Pancreatic intraepithelial neoplasia, retention cyst, simple mucinous cyst Intraductal papillary mucinous neoplasm, including oncocytic variant, intraductal tubulopapillary neoplasm Mucinous cystic neoplasm Serous cystic neoplasm, acinar cystadenoma, lymphangioma Solid pseudopapillary neoplasm Solid neoplasms with cystic change or intraductal spread of invasive carcinoma: pancreatic ductal adenocarcinoma, neuroendocrine neoplasm, acinar cell carcinoma, pancreatoblastoma Arch Pathol Lab Med. 2009 Mar;133(3):423-438. 1
Mucinous cystic neoplasm Pancreatic neuroendocrine tumor Outline Assessing and reporting margin status Utility of molecular markers Uncommon cystic lesions Clinical History - case 1 60 year old man with a mass in the pancreatic head Surgeon sends Whipple resection specimen Requests intraoperative diagnosis of pancreatic neck resection margin 2
Question 1. Is the pancreatic neck margin: a. malignant? Invasive adenocarcinoma b. preneoplastic? Pancreatic intraepithelial neoplasia (PanIN) Intraductal papillary mucinous neoplasm (IPMN) c. benign? Chronic pancreatitis Normal Question 2. Surgical management impact of diagnosis? Not infiltrative 3
Lobulocentric Mucinous epithelium without cytologic atypia Baltimore Consensus Meeting From three-tiered to two-tiered classification system for Pancreatic intraepithelial neoplasia (PanIN) Intraductal papillary mucinous neoplasm (IPMN) Mucinous cystic neoplasm (MCN) Clinically relevant diagnostic options Low-grade or high-grade PanIN IPMN, low-grade or high-grade MCN, low-grade or high-grade Not all IPMN cysts have tall finger-like papillae Am J Surg Pathol. 2015 Dec;39(12):1730-41. 4
Grossly identifiable >1 cm cyst PanIN-2 PanIN-1a PanIN-3 Normal Low-grade PanIN Consequence of PanIN or IPMN at margin? If patient has invasive cancer Only PanIN at margin, regardless of grade, does not affect survival If patient does not have invasive cancer High-grade PanIN at margin may warrant additional surgery IPMN less clear All patients require careful clinical follow-up after resection High-grade PanIN Normal 5
Pancreatic neck margin diagnosis case 1 Low-grade mucinous epithelium (low-grade PanIN or low-grade IPMN) Pancreatic adenocarcinoma with cystic degeneration Alternatively No invasive carcinoma or high grade dysplasia Dilated and partially denuded main duct with low grade mucinous epithelium IPMN or PanIN? Pancreatic duct diameter >1 cm 6
Level 1 Atypical glands adjacent to muscular blood vessel Level 3 - Large dilated glands 7
Invasive carcinoma in IPMN Attempt to document relationship Distinguish derived from (arising in area of) IPMN versus concomitant (not contiguous with) IPMN Sample entire lesion Liberally sample uninvolved pancreas Verify continuity or discontinuity Measure size of invasive component independent of non-invasive component Ann Surg. 2015 Jan; 263(1):162-177. Invasive adenocarcinoma and concomitant IPMN Cystic mass Adjacent pancreas Adenocarcinoma arising in MCN 8
AJCC 8 th edition cancer staging manual Pancreas exocrine TX T0 Tis T1 T1a T1b T1c T2 T3 T4 Criteria Primary tumor cannot be assessed No evidence of primary tumor High grade dysplasia 2 cm 0.5 cm > 0.5 cm and < 1 cm 1-2 cm > 2 cm and 4 cm > 4 cm Tumor involves celiac axis, superior mesenteric artery and/or common hepatic artery, irrespective of size If multifocal invasive adenocarcinoma (1.5 cm, 1.1 cm, and 0.5 cm) derived from IPMN, how do you report the pt stage? A. pt1c (m) based on largest focus of 1.5 cm B. pt2 (m) based on sum (3.1 cm) C. pt3 (m) based on entire span of tumor (4.3 cm) p T 1 c ( m ) b a s e d o n l a r g e s t... 83% p T 2 ( m ) b a s e d o n s u m ( 3.... 4% p T 3 ( m ) b a s e d o n e n t i r e... 13% Grossing practice alteration To determine invasive tumor size Take a full cross-section of largest dimension of the grossly identifiable tumor flanked by nontumorous pancreatic parenchyma Verify by histologic examination Clinical History - case 2 60 year old man with pancreatic head mass Whipple resection specimen Gross examination reveals a 1.4 cm unilocular cyst 9
Two questions: 1. Any helpful tools? 2. Clinical impact? Molecular markers of pancreatic cysts IPMN (n=96) KRAS (78%), GNAS (58%), RNF43(38%), TP53 (9%) CTNNB1 (6%) MCN (n=12) KRAS (50%), RNF43 (8%) SCA (n=12) VHL (42%) SPN (n=10) CTNNB1 (100%), PIK3CA (20%), TP53 (10%) * Nearly all PanIN have KRAS mutation Cysts with mucinous lining Gross Size GNAS mutations PanIN Microscopic < 0.5 cm Rarely 0.5-1 cm IPMN Macroscopic > 1 cm Typical Diagnostic options: a. Incipient IPMN, if long finger-like papillae, villous intestinal or oncocytic differentiation, or GNAS mutation b. Intraductal neoplasm, 0.7 cm, lined by low-grade gastric type epithelium; see comment Gastroenterology. 2015 Nov;149(6):1501-10. Pancreas 2005;31:344-349 10
Simple mucinous cyst Clinical History - case 3 Other terms Mucinous non-neoplastic cyst, cystic mucinous duct lesion KRAS mutations (55%) High-grade dysplasia (8%) Features Macroscopic cyst (> 1 cm) Communication to ductal system (8%) No ovarian stroma Non-papillary gastric-type mucinous epithelium (MUC5AC and/or MUC6 positive) Pathogenesis and natural course is unknown; still needs to be studied 55 year old woman with solid/cystic mass in the pancreatic head Whipple resection specimen Am J Surg Pathol. 2017 Jan;41(1):121-127. 11
What one diagnostic stain do you perform? A. Synaptophysin B. Cytokeratin 7 C. Trypsin D. Beta-catenin E. GLUT-1 45% Rare cystic variant acinar cell carcinoma Acinar cell cystadenocarcinoma 12% 17% 21% 5% S y n a p t o p h y s i n C y t o k e r a t i n 7 T r y p s i n B e t a - c a t e n i n G L U T - 1 12
Intraductal tubulopapillary neoplasm Intraductal growth Circumscribed nodules of back-to-back tubular glands Cuboidal cells with minimal to moderate eosinophilic to amphophilic cytoplasm and moderate to marked nuclear atypia Immunoreactive for CK7 (100%), MUC1 (88%), MUC6 (68%), and focal/rarely lineage markers Genetics Absence of KRAS and BRAF mutations Am J Surg Pathol 2017;41:313-325. 13
Am J Surg Pathol. 2017 Mar;41(3):313-325. Arch Pathol Lab Med. 2016 Oct;140(10):1068-73. Images from above articles Distinguishing features Architecture Cytology Stain IPMN IPMN (oncocytic subtype) ITPN Papillary Solid or tubular Tubular or cribriform Can have intracytoplasmic mucin Abundant granular eosinophilic cytoplasm Cuboidal cells; minimal to moderate eosinophilic to amphophilic cytoplasm Acinar cell carcinoma Solid with acinar structures Trypsin and/or chymotrypsin positive Am J Surg Pathol. 2017 Mar;41(3):313-325. 14
Take home points Knowledge of primary cystic pancreatic lesions is still evolving Clinically relevant and more splitting to enhance further studies From 3 to 2 tier classification Derived vs concomitant pt stage based on size Less common cystic entities Simple mucinous cyst Acinar cell carcinoma Intraductal tubulopapillary neoplasm 15