Pancreas - Intraductal papillary mucinous neoplasm (IPMN)

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Pancreas

Exocrine tumors

Intraductal papillary mucinous neoplasm (IPMN)

Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised:15 July 2014, last major update December 2012
Copyright: (c) 2001-2014, PathologyOutlines.com, Inc.

General
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● Proposed definition: intraductal grossly visible (1 cm or more) epithelial neoplasm of mucin producing cells, arising in main pancreatic duct or its branches; neoplastic epithelium is usually papillary; variable mucin secretion, duct dilatation (cyst formation), and dysplasia; classify based on highest degree of cytoarchitectural atypia and invasiveness as:
• IPMN with low- to intermediate-grade dysplasia; previously called intraductal papillary mucinous adenoma
• IPMN with high grade dysplasia; previously called intraductal papillary mucinous carcinoma, non invasive
• IPMN with associated invasive carcinoma (WHO)
● One of three precursor lesions of pancreatic adenocarcinoma (also PanIN, Mucinous Cystic Neoplasm)

Clinical features
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● More common in men age 60+ at head of pancreas
● Signs and symptoms include epigastric pain, weight loss, jaundice, diabetes, pancreatitis (Arch Pathol Lab Med 1996;120:981)
● Associated with Peutz-Jegher syndrome
● IPMN component may be favorable prognostic factor in invasive disease (Hum Pathol 2001;32:834)
● Resection often requires frozen sections, since most lesions are contiguous
● Patients with branch duct involvement only: associated with mild dilation of main duct; much lower risk of invasive carcinoma; management uncertain but less aggressive (Dig Liver Dis 2012;44:257, Am J Surg Pathol 2000;24:1372)

Diagnosis
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● Clinical subtypes include main duct, which is symptomatic; branch duct, which is typically asymptomatic, and mixed
● Assess dysplasia (none, low/intermediate grade dysplasia, high grade dysplasia)
● 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)
● Minimal invasion does not affect survival (Am J Surg Pathol 2008;32:243)

Patterns of papillae
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Proposed neoplastic pathways

Gastric foveolar-type papillae:
● Low-grade lesion, occurs in small branch ducts
● Resembles gastric foveola, MUC5AC+, MUC6+, MUC2- (Am J Surg Pathol 2006;30:1561)

Intestinal-type papillae:
● More common, occurs in main duct, usually intermediate to high grade dysplasia
● Resembles colonic villous adenoma, may exhibit pale apical mucin reminiscent of gastric foveolar cells, MUC1-, MUC2+, CDX2+
● Also claudin4+ (Mod Pathol 2011;24:533)
● When invasive, associated with colloid carcinoma (also MUC1-, MUC2+)

Pancreaticobiliary type papillae:
● Complex arborizing papillae with 2-5 cell layers and cuboidal cells with prominent nucleoli, less mucinous, more cytologic atypia
● MUC1+, MUC2-/focal, MUC6+ (Am J Surg Pathol 2010;34:364)
● When invasive, associated with usual ductal adenocarcinoma (also MUC1+, MUC2-)
● Associated with invasive carcinoma more often than intestinal-type

Oncocytic type papillae (Intraductal oncocytic papillary neoplasm, IOPN):
● See IOPN topic
● MUC1+, MUC2+, MUC6+

Intraductal tubulopapillary neoplasm
● Recently recognized subtype (Am J Surg Pathol 2009;33:1164)
● See ITPN topic
● Potential origin from peribiliary cysts; tubulopapillary architecture, necrotic foci, more solid growth without visible mucin, scanty cytoplasmic mucin, no KRAS2 gene mutations
● MUC1+, MUC2-, MUC6+

Notes:
● Benign and non-neoplastic pancreas is MUC1-
● PanIN and invasive ductal NOS are usually MUC2-

Case reports
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● 40 year old woman with combined MCN and IPMN (Arch Pathol Lab Med 2011;135:264)

Treatment
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● Resect entire tumor if >3cm, symptomatic with positive cytology, dilated main duct and mural nodules
● Sample extensively (> 50 blocks) to rule out invasion or atypia

Gross description
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● 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; associated with higher risk of high-grade dysplasia and invasive carcinoma than branch duct involvement; uninvoled pancreas is often pale and firm, reflecting extensive chronic obstructive pancreatitis
● Branch duct involvement: often in uncinate process; forms multicystic, grape-like structures; cystically dilated ducts are 1 to 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 (WHO)

Gross images
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Drawing

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

Main duct involvement

Main duct involvement: left-sided pancreatectomy specimen shows a markedly dilated main pancreatic duct

Main duct involvement: left-sided pancreatectomy specimen with marked cystic dilatation

Sticky mucin

Micro description
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● Multicentric
● Complex papillary fronds of mucin-producing epithelial cells with variable atypia
● Various types of papillae described above and below
● Ductal fibrosis, acinar atrophy but well preserved islets
● Associated with PanIN (Am J Surg Pathol 2004;28:1184), chronic pancreatitis
● No ovarian-type stroma

Micro images
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Branch duct

Epithelial papillary proliferations

Comparison of subtypes: gastric, intestinal, pancreaticobiliary, oncocytic

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

Intestinal papillae

Intestinal papillae (H&E and CDX2+)

Low grade dysplasia

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

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

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

High grade dysplasia and invasion (left)

Invasive (colloid carcinoma, figure 9)

Non-invasive (figure 4)

Pancreaticobiliary papillae

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

PAS

CEA

Patient with both gastric and intestinal papillae

Tall columnar mucin-producing epithelium which forms varying sized papillae

Various images

With loss of mismatch repair in patient with Lynch syndrome

Cytology images
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Various images

Positive stains
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● Varies by type of papillae (see above)
● Often S100P, MUC5AC (Hum Pathol 2010;41:824)

Molecular description
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● Associated with Kras mutations (Hum Pathol 2009;40:612)
● Cyst fluid shows mutations in KRAS2 and GNAS
● With increasing grades of dysplasia, see increased mutations in KRas, p53, p16, hypermethylation, reduced BRG1 (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)

Differential diagnosis: Mucinous cystic neoplasm (MCN)
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MCN IPMN
F >> M M > F
Age: 40-50 60-70 years
Tail Head
Grossly cystic Grossly cystic with papillae >1cm
Not in duct In duct
Ovarian type stroma No ovarian type stroma

● See also MCN topic

Differential diagnosis: other
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● IOPN
● PanIN: resembles small IPMN

End of Pancreas > Exocrine tumors > Intraductal papillary mucinous neoplasm (IPMN)

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