Intraductal Papillary Mucinous Neoplasm IPMN of the Pancreas

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

Introduction v 1. 2. v 1999, Yonezawa Villous dark cell type--- resembles colorectal villous; MUC 2 (+); intestinal type Papillary clear cell type--- resembles gastric foveolar epi. MUC (-); gastric type have not been fully described.

Introduction v 1. 2. 3. 4. Mucin profiles MUC 1 --- membrane-bound mucin MUC 2 --- secretory mucins, intestinal MUC 5 AC--- secretory mucins, gastric foveolar MUC 6 --- secretory mucins, pyloric gland.

Introduction v 1. 2. 3. 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 v 1. 2. 3. 4. 5. Patients’ data--- 80 cases: M/F(49/31) Mean age(65. 3 y/o, 37 -83 y/o); From 1983 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 v based on 1. WHO classification on tumors of the digestive system international consensus guidelines for IPMN and mucinous cystic neoplasms (MCNs) 2. v v 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 v 1. 2. 3. 4. 5. 6. 7. 8. Evaluation of 8 histologic features: distribution--- main duct or branch duct histologic grade---benign/borderline/noninvasive intraluminal nodular growth pyloric glandlike structures low-grade Pan. IN-like complex within the tumor, atrophy of the surrounding pancreas tissue mucous lake formation occurrence of invasive carcinoma.

A. branch duct-type IPMN B. main duct-type IPMN 1. intraluminal nodular growth 2. atrophy of the surrounding pancreas tissue with fibrosis 3. 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. , located at the base of papilla B. Pan. IN-like complex: collection of small ducts lined by tall columnar mucinous cell

Materials and Methods v 1. 2. 3. 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 GASTRIC TYPE INTESTINAL TYPE Number GENDER: MEAN AGE M/F 50 31/19 65. 5 (4783) 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, MUC 5 AC(Foveolar); B, intestinal type, MUC 5 AC; C, gastric type, MUC 2; (+) in scattered goblet cells D, intestinal type, MUC 2;

E, gastric type, MUC 6(pyloric gland); F, intestinal type, MUC 6; G, gastric type, MUC 1; H, intestinal type, MUC 1.

Discussion Type Intestinal Larger type main Intraluminal nodular growth Low grade Pan. IN complex Pyloric glandlike structure grade atrophy and fibrosis Mucous invasive lake + Rare (3%) + (33%) high + + (50%) + (82%) + (96%) low 7/30 (23%) duct-type (73%) Gastric type Branch rare duct-type (98%) 1/50 (2%)

Discussion v Intestinal-type IPMNs MUC 2(+), whereas most gastric-type IPMNs are not. v MUC 5 AC--- Both(+) in papilla, like organoid differentiation in stomach and pancreas. v MUC 6, both (+) ; more frequent in pyloric glandlike structures of gastric type v MUC 1 --- a marker for aggressiveness. both (-)--- IPMNs progress slowly

Discussion v 1. 2. Malignant change: intestinal >gastric Mucin pools --- associated with mucinous adenocarcinoma in intestinaltype IPMNs; lead to muconodular infiltration, like occurred in invasive colorectal villous tumors; sign of invasive Gastric-type IPMNs--- conventional type

Discussion v 1. 2. 3. 4. 5. Gastric-type IPMNs V. S Low-grade Pan. IN Both have “pyloric gland-like structures” and “low-grade Pan. IN-like complex” Both are MUC 5 AC+/MUC 2 Both have genetic alterantions associated with ductal carcinoma, ex: K-ras, p 53, DPC 4/Smad 4, p 16 (more common in Low-grade Pan. IN) Low-grade Pan. IN gastric-type IPMNs Further molecular studies still needed

Discussion v 1. 2. 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 Pan. IN-like complex Intestinal type --- involving small ducts with complete atrophy of surrounding parenchyma