1. 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

2. 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

3. 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.

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

5. 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

6. 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

7. 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

8. 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.

9. 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

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

11. 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

12. 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

13. 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.

14. Results

15. Results

16. 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)

17. Results

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

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

20. 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%)

21. 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

22. 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

23. 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

24. 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