Intraductal papillary mucinous neoplasm

Pancreas

Exocrine tumors / carcinomas

Author: Diana Agostini-Vulaj, D.O.

Editorial Board Member: Raul S. Gonzalez, M.D.

Editor-in-Chief: Debra Zynger, M.D.

Topic Completed: 1 July 2018

Minor changes: 13 July 2020

Copyright: 2002-2020, PathologyOutlines.com, Inc.

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Table of Contents

Cite this page: Agostini-Vulaj D. Intraductal papillary mucinous neoplasm. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/pancreasipmn.html. Accessed August 7th, 2020.

Definition / general

Grossly visible noninvasive mucinous epithelial neoplasm arising from main pancreatic duct or branch ducts, usually > 1 cm, composed of various cell types with various cytologic and architectural atypia (Virchows Arch 2005;447:794)
- Further classified as:
  - Low grade (encompasses low or intermediate grade dysplasia) (Am J Surg Pathol 2015;39:1730)
  - High grade (Am J Surg Pathol 2015;39:1730)
  - With an associated invasive carcinoma (Bosman: WHO Classification of Tumours of the Digestive System, 4th Edition, 2010)
One of three precursor lesions of pancreatic adenocarcinoma (see also mucinous cystic neoplasm)

Essential features

Grossly visible (> 1 cm) cystic pancreatic neoplasm usually in head of pancreas
> 90% 5 year survival with complete resection
Roughly 1/3 of cases have an associated invasive carcinoma
Further subtyped into gastric, intestinal and pancreaticobiliary types based on epithelium (note: intraductal oncocytic papillary neoplasm (IOPN) is now considered a distinct and separate entity)

Terminology

Low grade to intermediate grade dysplasia previously termed: intraductal papillary mucinous adenoma
High grade dysplasia previously termed: intraductal papillary mucinous carcinoma, noninvasive
With an associated invasive carcinoma previously termed: intraductal papillary mucinous carcinoma, invasive
Other previous terms include: mucin producing tumor, mucinous duct ectasia, ductectatic mucinous cystadenoma / cystadenocarcinoma, villous adenoma or papillary adenoma / carcinoma (Bosman: WHO Classification of Tumours of the Digestive System, 4th Edition, 2010)

ICD coding

ICD-10: D13.6 - benign neoplasm of pancreas

Epidemiology

Rising incidence likely secondary to better characterization of this entity along with use of radiologic imaging studies (Clin Gastroenterol Hepatol 2010;8:213)

Sites

Main duct IPMN mostly involves head of pancreas, 1/3 in body and tail (Hum Pathol 2012;43:1)
Branch duct IPMN mostly involves head of pancreas or uncinate process, with multiple distinct lesions seen in ~1/3 of cases (Hum Pathol 2012;43:1)

Etiology

No well established factors; cigarette smoking implicated in one series (Adv Anat Pathol 1999;6:65)
Reported in Peutz-Jeghers syndrome and familial adenomatous polyposis (Gut 2002;51:446, Am J Pathol 1999;154:1835)

Diagrams / tables

Images hosted on other servers:

Clinical management

Clinical features

More common in men, usually between ages 60 - 70 years (Hum Pathol 2012;43:1)
Clinically divided into main duct IPMN, branch duct IPMN and mixed IPMN (most mixed type IPMN presents and behaves as main duct IPMN) (Hum Pathol 2012;43:1)
Main duct IPMN tends to be symptomatic, with symptoms related to duct obstruction (pancreatitis) (Hum Pathol 2012;43:1)
- Signs and symptoms include epigastric pain, weight loss, jaundice, diabetes, pancreatitis (Arch Pathol Lab Med 1996;120:981)
Branch duct IPMN tends to be asymptomatic and discovered incidentally on imaging (Hum Pathol 2012;43:1)
Peutz-Jeghers syndrome (autosomal dominant inherited syndrome, mutations in STK11 / LKB1I) is also associated with IPMN (Hum Pathol 2012;43:1)

Diagnosis

Radiographic / endoscopic findings
Surgical specimen

Laboratory

Pancreatic cyst fluid analysis can assist in determining type of cyst (Am J Gastroenterol 2008;103:2871, Gastrointest Endosc 2009;69:1095, Gastrointest Endosc 2016;83:140)

Radiology description

CT:
- Main duct IPMN causes distention of main pancreatic duct
- Branch duct IPMN produces multilocular grape-like cystic appearance
ERCP (endoscopic retrograde cholangiopancreatography): pancreatic ductal filling defects may be seen / ductal dilation
MRCP (magnetic resonance cholangiopancreatography): additional imaging option which does not produce radiation
EUS (endoscopic ultrasound):: can also allow FNA and cyst fluid analysis

Radiology images

Images hosted on other servers:

MRCP

Enhanced CT

Cysts in isthmus

IPMN and MCN

MRCP

CT and MRCP

MRCP

Prognostic factors

Without an invasive carcinoma has > 90% 5 year survival; those associated with an invasive carcinoma carry a worse prognosis (about half die of disease) (Ann Surg 2016;263:162)
Main duct IPMN: 60% have high grade dysplasia and 45% are associated with an invasive carcinoma (Hum Pathol 2012;43:1)
Branch duct IPMN: most are low grade, 25% have high grade dysplasia and 20% are associated with an invasive carcinoma (Hum Pathol 2012;43:1)
Invasive carcinoma associated with IPMN includes:
- Tubular (ductal) adenocarcinoma: seen in about half of cases, with slightly better prognosis than non IPMN associated pancreatic ductal adenocarcinoma
- Colloid carcinoma: seen in half of cases, with much better prognosis than pancreatic ductal adenocarcinoma (Ann Surg 2016;263:162)

Case reports

52 year old man with recurrent upper abdominal pain (Int J Clin Exp Med 2015;8:3332)
53 year old man with multiple pancreatic cystic lesions (World J Gastroenterol 2013;19:3358)
55 year old woman with abdominal pain and anemia, pancreatic masses are found on CT (World J Surg Oncol 2018;16:83)
68 year old man with cystic pancreatic mass with mural nodule (Int J Surg Case Rep 2017;40:69)
74 year old man with cystic pancreatic lesion on ultrasound (Intern Med 2018;57:1093)

Treatment

Main duct IPMN: surgical resection for all cases
Branch duct IPMN: indications for resection include symptomatic, association with mural nodule, dilated main duct and positive cytology (if size > 3 cm without any of the prior characteristics, can be observed with close interval surveillance imaging) (Pancreatology 2012;12:183)

Gross description

Main duct involvement:
- Usually diffusely dilated, tortuous and irregular, filled with mucin
- Typically arises in head and progresses along path of main duct, may involve entire pancreas; may involve major or minor papillae leading to mucin extrusion from ampulla
- Uninvolved pancreas is often pale and firm, reflecting extensive chronic obstructive pancreatitis (Bosman: WHO Classification of Tumours of the Digestive System, 4th Edition, 2010)
Branch duct involvement:
- Often in uncinate process
- Forms multicystic, grape-like structures; cystically dilated ducts are 1 - 10 cm, filled with tenacious mucin; cyst walls are usually thin with flat or papillary lining
- Cysts separated by normal pancreas, suggesting that cysts are separate on cut sections (Bosman: WHO Classification of Tumours of the Digestive System, 4th Edition, 2010)
Multicentricity seen in up to 40% of cases (Am J Gastroenterol 2007;102:1759)
Extensive sampling / complete submission of cyst for microscopic evaluation important to rule out an associated invasive carcinoma (Am J Surg Pathol 2014;38:480, Ann Surg 2016;263:162)

Gross images

Contributed by Dennis R. Dening, PA (ASCP)

Main duct IPMN

Images hosted on other servers:

Main duct IPMN

Microscopic (histologic) description

Mucin producing epithelial cells with varied degrees of dysplasia (low, intermediate and high) and varied architecture ranging from flat to papillae that may be simple, complex or branching (Bosman: WHO Classification of Tumours of the Digestive System, 4th Edition, 2010)
- Low grade dysplasia is characterized by a flat epithelial lining with basal located nuclei without significant pleomorphism, while intermediate dysplasia has features between those of low and high grade dysplasia; note low and intermediate dysplasia are now both grouped as low grade dysplasia (Am J Surg Pathol 2015;39:1730)
- High grade dysplasia is characterized by complex architectural features (ie. irregular branching, cribiforming) with loss of nuclear polarity along with increased nuclear hyperchromasia and nuclear irregularities (Am J Surg Pathol 2015;39:1730)
Epithelial cells show variable differentiation and can be subclassified into: intestinal, gastric and pancreaticobiliary subtypes (oncocytic lining suggests intraductal oncocytic papillary neoplasm (IOPN)) (Bosman: WHO Classification of Tumours of the Digestive System, 4th Edition, 2010)
Associated with pancreatic intraepithelial neoplasia (PanIN), chronic pancreatitis (Am J Surg Pathol 2004;28:1184)
No ovarian type stroma
Assess presence or absence of invasive carcinoma (most important prognostic factor) (Hum Pathol 2012;43:1)
Type of invasion is associated with MUC1 / MUC2 pattern, see below (Mod Pathol 2002;15:1087)
Gastric type IPMN: cells resemble gastric foveolae, intestinal metaplasia may be seen, usually with low grade dysplasia and branch duct IPMN; if associated invasive carcinoma present, typically ductal (tubular) adenocarcinoma (Ann Surg 2016;263:162, Virchows Arch 2005;447:794, Bosman: WHO Classification of Tumours of the Digestive System, 4th Edition, 2010)
Intestinal type IPMN: cells with tall columnar epithelium (resembling intestinal villous adenomas), usually low or high grade dysplasia and main duct IPMN ; if associated invasive carcinoma present, typically mucinous (colloid) carcinoma
Pancreaticobiliary type IPMN: complex, thin branching papillae resembling cholangiopapillary neoplasms, cuboidal cells with prominent nucleoli, usually high grade dysplasia and main duct IPMN; if associated invasive carcinoma present, typically ductal (tubular) adenocarcinoma

Microscopic (histologic) images

Contributed by Diana Agostini-Vulaj D.O.

IPMN intestinal subtype with low grade dysplasia

IPMN gastric subtype with low grade dysplasia

MUC1

MUC2

AFIP

Low grade dysplasia

Intermediate grade dysplasia

High grade dysplasia

Images hosted on other servers:

Comparison of subtypes

Intestinal papillae (H&E and CDX2+)

Intermediate (top) and high (bottom) grade dysplasia

Loss of mismatch repair in Lynch syndrome

Positive stains

General ductal markers are positive, including CK7 and CK19, CA 19-9, B72.3 and CEA (Bosman: WHO Classification of Tumours of the Digestive System, 4th Edition, 2010)
Subtypes show various mucin glycoprotein (MUC) expression (as below):
- Gastric type IPMN: MUC5AC+, MUC6+ (Am J Surg Pathol 2006;30:1561, Mod Pathol 2016;29:977)
- Intestinal type IPMN: MUC2+, CDX2+, MUC5AC+, similar staining pattern for associated invasive colloid carcinoma (Mod Pathol 2016;29:977)
- Pancreaticobiliarytype IPMN: MUC1+, MUC6+ (focal), MUC5AC+; similar staining pattern for associated invasive ductal adenocarcinoma (Am J Surg Pathol 2006;30:1561, Mod Pathol 2016;29:977)

Negative stains

Gastric type IPMN: MUC1-, MUC2- (Am J Surg Pathol 2006;30:1561, Mod Pathol 2016;29:977)
Intestinal type IPMN: MUC1-; similar staining pattern for associated invasive colloid carcinoma (Mod Pathol 2016;29:977)
Pancreaticobiliary type IPMN: MUC2- (Am J Surg Pathol 2010;34:364, Mod Pathol 2016;29:977); similar staining pattern for associated invasive ductal adenocarcinoma

Molecular / cytogenetics description

KRAS, GNAS and RNF43 mutations seen in decreasing frequency in noninvasive IPMNs as well as IPMNs with an associated invasive carcinoma (J Am Coll Surg 2015;220:845)
GNAS mutations more commonly associated with IPMNs which harbor an invasive colloid carcinoma
KRAS mutations more commonly associated with IPMNs which harbor an invasive tubular (ductal) adenocarcinoma
With increasing grades of dysplasia, increased mutations in KRAS, TP53, CDKN2A (p16); also hypermethylation and reduced BRG1 protein (Hum Pathol 2012;43:585)
Loss of programmed cell death 4 (PDCD4) and CD24 expression associated with tumor progression and proliferation (Hum Pathol 2010;41:1507, Hum Pathol 2010;41:1466)
Cyst fluid shows mutations in KRAS2 and GNAS

Differential diagnosis

Intraductal oncocytic papillary neoplasm (IOPN)
- Lined by oncocytic cells with complex growth patterns and arborizing papillae
- Distinct molecular pathway with ARHGAP26, ASXL1, EPHA8 and ERBB4 genetic alterations (Mod Pathol 2016;29:1058)
- MUC1+, MUC2+, MUC6+
Intraductal tubulopapillary neoplasm
- Recently recognized subtype with potential origin from peribiliary cysts (Am J Surg Pathol 2009;33:1164)
- Confluent epithelial cells with tubular and papillary architectural patterns and usually high grade dysplasia
- Also tubulopapillary architecture, necrotic foci, more solid growth without visible mucin, scanty cytoplasmic mucin, no KRAS2 gene mutations
- MUC1+, MUC2-, MUC6+
Mucinous cystic neoplasm (MCN)
- Epithelial mucinous lining with ovarian type stroma and no communication to pancreatic ductal system
Pancreatic intraepithelial neoplasia (PanIN)
- Only detectable microscopically, no mass lesion unlike IPMN

Board review style question #1

Which subtype of intraductal papillary mucinous neoplasm (IPMN) is more likely to arise from a branched pancreatic duct?

Gastric
Intestinal
Pancreaticobiliary
Invasive

Board review answer #1

A. Gastric

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Board review style question #2

Based on the below clinical scenario which would most likely represent an intraductal papillary mucinous neoplasm (IPMN)?

29 year old woman with 8 cm solid and cystic pancreatic tail mass
45 year old woman with 3 cm cystic pancreatic tail mass
58 year old man with 3 cm solid pancreatic head mass
66 year old man with 2 cm cystic pancreatic head mass
None of the above

Board review answer #2

D. 66 year old man with 2 cm cystic pancreatic head mass

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