Intraductal papillary mucinous neoplasm (IPMN)

Pancreas
Exocrine tumors / carcinomas
Intraductal papillary mucinous neoplasm (IPMN)

Author: Diana Agostini-Vulaj D.O.
Editor: Raul S. Gonzalez, M.D.

Revised: 1 August 2018, last major update July 2018

Copyright: (c) 2002-2018, PathologyOutlines.com, Inc.

PubMed Search: Intraductal papillary mucinous neoplasm[TI] pancreas[TI] free full text[sb]

Table of Contents

Cite this page: Agostini-Vulaj, D. Intraductal papillary mucinous neoplasm (IPMN). PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/pancreasipmn.html. Accessed August 15th, 2018.

Definition / general

Grossly visible noninvasive mucinous epithelial neoplasm arising from main pancreatic duct (MD IPMN) or branch ducts (BD IPMN), 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 pancreatobiliary 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-10 coding

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, 1/3 in 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 (Bosman: WHO Classification of Tumours of the Digestive System, 4th Edition, 2010)
Reported in Peutz-Jeghers syndrome and familial adenomatous polyposis (Bosman: WHO Classification of Tumours of the Digestive System, 4th Edition, 2010)

Diagrams / tables

Images hosted on PathOut server:

AFIP

Four prototypes of IPMN

Images hosted on other servers:

Proposed neoplastic pathways

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: pancreatic ductal filling defects may be seen / ductal dilation
MRCP: additional imaging option which does not produce radiation
EUS: can also allow FNA and cyst fluid analysis

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)

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) (Pancreatology 2012;12:183)

Gross description

Main duct involvement: usually diffusely dilated, tortuous and irregular, filled with mucin; usually 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 (Bosman: WHO Classification of Tumours of the Digestive System, 4th Edition, 2010)
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

Images hosted on PathOut server:

Contributed by
Dennis R. Dening, PA (ASCP)^CM

Main duct IPMN

AFIP

Main duct involvement: left sided pancreatectomy specimen

Sticky mucin

Images hosted on other servers:

Branch duct
involvement (arrows
in figure on right are
main pancreatic duct)

Main duct involvement

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)
Epithelial cells show differing differentiation and can be subclassified into: intestinal, gastric and pancreatobiliary subtypes (oncocytic lining suggests IOPN) (Bosman: WHO Classification of Tumours of the Digestive System, 4th Edition, 2010)
Associated with PanIN (Am J Surg Pathol 2004;28:1184), chronic pancreatitis
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 (Virchows Arch 2005;447:794, Bosman: WHO Classification of Tumours of the Digestive System, 4th Edition, 2010); if associated invasive carcinoma present, typically ductal (tubular) adenocarcinoma (Ann Surg 2016;263:162)
Intestinal type IPMN: cells with tall columnar epithelium (resembling intestinal villous adenomas), usually intermediate or severe dysplasia and main duct IPMN (Virchows Arch 2005;447:794, Bosman: WHO Classification of Tumours of the Digestive System, 4th Edition, 2010); if associated invasive carcinoma present, typically mucinous (colloid) carcinoma (Ann Surg 2016;263:162)
Pancreatobiliary type IPMN: complex, thin branching papillae resembling cholangiopapillary neoplasms, cuboidal cells with prominent nucleoli, usually high grade dysplasia and main duct IPMN (Virchows Arch 2005;447:794, Bosman: WHO Classification of Tumours of the Digestive System, 4th Edition, 2010); if associated invasive carcinoma present, typically ductal (tubular) adenocarcinoma (Ann Surg 2016;263:162)

Microscopic (histologic) images

Images hosted on PathOut server:

Contributed by Diana Agostini-Vulaj D.O.

IPNM intestinal 20x

IPMN gastric at 40x

IPMN gastric at 100x

MUC1

MUC2

AFIP

Branch duct

Epithelial papillary proliferations

Low grade dysplasia

Intermediate grade dysplasia:
lining epithelium of papillae is
characterized by nuclear enlargement,
stratification and crowding

High grade dysplasia and invasion (left)

High grade dysplasia:
cells have varying sized
nuclei, some show thick
nucleoli and mitoses (arrow)

High grade dysplasia:
severely atypical epithelium
forms irregular projections
without any tissue stalk

High grade dysplasia:
the atypical epithelium
shows branching and
bridging

Tall columnar mucin producing epithelium

PAS

CEA

Images hosted on other servers:

Gastric papillae

Gastric papillae top: low grade (blue arrows)
and intermediate grade dysplasia (black arrows);
bottom: high grade dysplasia (black arrows) with
cribriform formation and marked nuclear atypia

Comparison of subtypes:
gastric, intestinal,
pancreaticobiliary,
oncocytic

Intestinal papillae

Intestinal papillae (H&E and CDX2+)

Intestinal papillae:
intermediate grade
dysplasia (top) and
high grade dysplasia (bottom)

Invasive (colloid carcinoma, figure 9)

Noninvasive (figure 4)

Pancreaticobiliary papillae:
intermediate grade dysplasia
(top) and high grade
dysplasia (bottom)

Patient with both gastric and intestinal papillae

Loss of mismatch repair in patient with 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)
- Pancreatobiliary type IPMN: MUC1+, MUC6+ (focal), MUC5AC+, MUC2- (Am J Surg Pathol 2006;30:1561, Mod Pathol 2016;29:977); similar staining pattern for associated invasive ductal adenocarcinoma

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)
Pancreatobiliary 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, J Am Coll Surg 2015;220:845)
GNAS mutations more commonly associated with IPMNs with an invasive colloid carcinoma (J Am Coll Surg 2015;220:845, J Am Coll Surg 2015;220:845)
KRAS mutations more commonly associated with IPMNs with an invasive tubular (ductal) adenocarcinoma (J Am Coll Surg 2015;220:845, J Am Coll Surg 2015;220:845)
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 separate from IPMNs with ARHGAP26, ASXL1, EPHA8 and ERBB4 genetic alterations (Mod Pathol 2016;29:1058)
- MUC1+, MUC2+, MUC6+
Intraductal tubulopapillary neoplasm
- Recently recognized subtype (Am J Surg Pathol 2009;33:1164) with potential origin from peribiliary cysts
- 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
PanIN
- Only detectable microscopically, no mass lesion unlike IPMN

Board review question #1

Which subtype of IPMN is more likely to arise from a branched pancreatic duct?

Gastric
Intestinal
Pancreatobiliary
Invasive

Board review answer #1

Board review question #2

Based on the below clinical scenario which would most likely represent an 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