Intraductal Papillary Mucinous Neoplasm (IPMN) of the Pancreas: it’s Histopathologic Difference Between 2 Major Types Shinichi Ban, MD,* Yoshihisa Naitoh, MD,* Mari Mino-Kenudson, MD, Takaki Sakurai, MD, Makoto Kuroda, MD,J Isamu Koyama, MD, Gregory Y. Lauwers, MD, and Michio Shimizu, MD* Am J Surg Pathol 2006, November ;Vol. 30: 1561–1569 指導老師:方嘉郎；報告人:李俊志

Introduction IPMN is characterized by a predominantly noninvasive growth pattern with mucin production and cystic duct dilatation. The distinction between IPMN and pancreatic intraepithelial neoplasia (PanIN) ,which is the common precursor of invasive carcinomas

Introduction 1999, Yonezawa Villous dark cell type--- resembles colorectal villous; MUC2 (+); intestinal type Papillary clear cell type--- resembles gastric foveolar epi. MUC (-); gastric type gastric type have not been fully described.

Introduction Mucin profiles MUC1--- membrane-bound mucin MUC2--- secretory mucins, intestinal MUC5AC--- secretory mucins, gastric foveolar MUC6--- secretory mucins, pyloric gland.

Introduction GOALS: Evaluate the distribution of the IPMNs and their derived invasive carcinomas Refine their differences of gastric-type and intestinal-type--- regard to their histopathologic characteristics and mucin profiles Better characterize the gastric type

Materials and Methods Patients’ data--- 80 cases: M/F(49/31) Mean age(65.3y/o, 37-83y/o); From1983 to 2003; from 4 hospitals (Saitama Medical School, Japan; Kyoto University Hospital, Japan; Fujita Health University, Japan, and Massachusetts General Hospital, USA) Exclusion: IPMNs of other type (ex:pancreatobiliary,oncocytic) and IPMN-like lesions

Materials and Methods based on WHO classification on tumors of the digestive system international consensus guidelines for IPMN and mucinous cystic neoplasms (MCNs) Gastric type--- clear/lightly eosinophilic; columnar; round to ovoid nuclei; no/minimal pseudostratified Intestinal type--- dark eosinophilic; columnar; oval to spindle nuclei; pseudostratified

Materials and Methods Evaluation of 8 histologic features: distribution--- main duct or branch duct histologic grade---benign/borderline/noninvasive intraluminal nodular growth pyloric glandlike structures low-grade PanIN-like complex within the tumor, atrophy of the surrounding pancreas tissue mucous lake formation occurrence of invasive carcinoma.

B. main duct-type IPMN A. branch duct-type IPMN intraluminal nodular growth atrophy of the surrounding pancreas tissue with fibrosis mucous lakes devoid of neoplastic cells

A, benign(hyperplasia) B, borderline; C, noninvasive carcinoma (high-grade dysplasia) Benign-borderline Borderline-noninvasive

A. Pyloric glandlike: 2-3 glands lined by clear columnar epi A. Pyloric glandlike: 2-3 glands lined by clear columnar epi., located at the base of papilla B. PanIN-like complex: collection of small ducts lined by tall columnar mucinous cell

Materials and Methods Mucin profiles (Semiquantitative) Extent of staining(extent score)--- 0(no staining), 1(<1/3 positive), 2(1/3-2/3 positive), and 3(>2/3 positive) intensity of staining (intensity score)---0(no staining), 1(weak), and 2(strong). labeling score--- extent score+ intensity score

Results no significant difference between gender and age. Number GENDER: M/F MEAN AGE GASTRIC TYPE 50 31/19 65.5 (47-83) INTESTINAL TYPE 30 18/12 65.1(37-81) no significant difference between gender and age.

Results

Results

A. mucinous adenocarcinoma derived from intestinal-type IPMN; intestinal-type IPMN (upper left) and mucinous adenocarcinoma (lower right); B. invasive ductal adenocarcinoma of the conventional type (desmoplasia and infiltration)derived from gastric-type IPMN ; gastric-type IPMN (upper right); conventional-type invasive ductal adenocarcinoma (lower left)

Results

A, gastric type, MUC5AC(Foveolar); B, intestinal type, MUC5AC; C, gastric type, MUC2; (+) in scattered goblet cells D, intestinal type, MUC2;

E, gastric type, MUC6(pyloric gland); F, intestinal type, MUC6; G, gastric type, MUC1;H, intestinal type, MUC1.

Discussion Larger main duct-type (73%) + Rare (3%) (33%) high (50%) Intra-luminal nodular growth Low grade PanIN complex Pyloric gland-like structure grade atrophy and fibrosis Mucous lake invasive Intestinal type Larger main duct-type (73%) + Rare (3%) (33%) high (50%) 7/30 (23%) Gastric type Branch duct-type (98%) rare (82%) (96%) low 1/50 (2%)

Discussion Intestinal-type IPMNs MUC2(+), whereas most gastric-type IPMNs are not. MUC5AC--- Both(+) in papilla, like organoid differentiation in stomach and pancreas. MUC6, both (+) ; more frequent in pyloric glandlike structures of gastric type MUC1--- a marker for aggressiveness. both (-)--- IPMNs progress slowly

Discussion Malignant change: intestinal >gastric Mucin pools --- associated with mucinous adenocarcinoma in intestinal-type IPMNs; lead to muconodular infiltration, like occurred in invasive colorectal villous tumors; sign of invasive Gastric-type IPMNs--- conventional type

Discussion Gastric-type IPMNs V.S Low-grade PanIN Both have “pyloric gland-like structures” and “low-grade PanIN-like complex” Both are MUC5AC+/MUC2- Both have genetic alterantions associated with ductal carcinoma, ex: K-ras, p53, DPC4/Smad4, p16 (more common in Low-grade PanIN) Low-grade PanIN gastric-type IPMNs Further molecular studies still needed

Discussion Two hypothesis Gastric type, which being called “null-type” by Adsay et al, may progress to intestinal type or others Different phathogenesis between the two types --- different mode of spreading through the pancreatic ductal system Gastric type --- low-grade PanIN-like complex Intestinal type --- involving small ducts with complete atrophy of surrounding parenchyma