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: 9 December 2012, last major update December 2012
Copyright: (c) 2001-2012, 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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This drawing shows historical prototypes of IPMN:
Upper left, diffuse papillary tumor growth within the entire pancreatic duct system
Lower left, focal papillary growth in the main pancreatic duct
Upper right, diffuse involvement of the entire pancreatic duct system by mucin hypersecreting tumor
Lower right, focal involvement of the pancreatic duct system by a mucin hypersecreting tumor

Main duct involvement

Main duct involvement: left-sided pancreatectomy specimen with marked cystic dilatation of main duct in tail due to mucin hypersecretion; macroscopically, the duct wall shows no papillary projections

Main duct involvement: left-sided pancreatectomy specimen shows a markedly dilated main pancreatic duct filled with tumor tissue (arrows); surrounding pancreatic tissue is severely fibrotic

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

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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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+)

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

Pancreaticobiliary papillae

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

Comparison of subtypes: gastric, intestinal, pancreaticobiliary, oncocytic

Patient with both gastric and intestinal papillae

Various images

IPMN with loss of mismatch repair in patient with Lynch syndrome

Non-invasive (figure 4)

Invasive (colloid carcinoma, figure 9)

Cross section through main pancreatic duct shows epithelial papillary proliferations

Wall of main pancreatic duct is lined by tall columnar mucin-producing epithelium which forms varying sized papillae; tips of papillae are sectioned tangentially and appear to be free floating in mucin

PAS stain of mucin-producing tumor epithelium shows that neoplastic epithelium extends into secondary duct

Low grade dysplasia: wall of duct is lined by tall columnar epithelium which forms plump papillae; epithelial cells show apical mucin accumulation, minimal pleomorphism, and regular oval nuclei; note the goblet-like appearance of some columnar cells

Intermediate grade dysplasia: wall of duct is lined by columnar epithelium which forms irregularly shaped papillae with small fibrovascular stalks; epithelium shows focal cellular stratification and nuclear crowding

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

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

High grade dysplasia and invasion: upper part shows secondary duct lined by severely dysplastic epithelium; surrounding pancreatic tissue is fibrotic and contains only some islets; lower part shows atypical ductal structures (arrows) characterizing the invasive component

Branch duct: lining by neoplastic columnar epithelium; surrounding tissue displays chronic obstructive pancreatitis with remnant of a lobulus containing an islet

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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