Pancreas

Cystic and intraductal lesions

Intraductal papillary mucinous neoplasm

Editorial Board Member: Monika Vyas, M.D.

Deputy Editor-in-Chief: Catherine E. Hagen, M.D.

Topic Completed: 14 September 2021

Minor changes: 14 September 2021

Copyright: 2002-2021, PathologyOutlines.com, Inc.

PubMed Search: Intraductal papillary mucinous neoplasm[title] pancreas[title] review[ptyp]

Page views in 2020: 13,651

Page views in 2021 to date: 12,051

Table of Contents

Cite this page: Agostini-Vulaj D. Intraductal papillary mucinous neoplasm. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/pancreasipmn.html. Accessed September 19th, 2021.

Definition / general

Grossly visible noninvasive mucinous epithelial neoplasm arising from main pancreatic duct or branch ducts, usually > 5 mm, composed of various cell types with various cytologic and architectural atypia (Virchows Arch 2005;447:794, Pancreatology 2017;17:738)
- 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 (Am J Surg Pathol 2015;39:1730)
1 of 3 precursor lesions of pancreatic adenocarcinoma (see also mucinous cystic neoplasm)

Essential features

Grossly visible (> 5 mm) cystic pancreatic neoplasm, usually in head of pancreas
> 90% 5 year survival with complete resection
Roughly 33% 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

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)
More common in men, usually ages 60 - 70 years (Hum Pathol 2012;43:1)

Sites

Main duct intraductal papillary mucinous neoplasm (IPMN) mostly involves head of pancreas, 33% 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 ~33% of cases (Hum Pathol 2012;43:1)

Pathophysiology

See Molecular / cytogenetics description

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:

Indications for surgery

Clinical features

Clinically divided into main duct IPMN, branch duct IPMN and mixed IPMN (most mixed type IPMN present and behave 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 is generally 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
Fine needle aspiration
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)
- Elevated CEA and identification of KRAS / GNAS mutations supports diagnosis of mucinous cyst

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
References: Diagn Interv Imaging 2016;97:1275, World J Gastroenterol 2016;22:9562

Radiology images

Images hosted on other servers:

MRCP demonstrating various types of IPMN

MRCP demonstrating side branch IPMNs

Differing radiologic
modalities demonstrating
various types of
IPMN and MCN

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 the 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 indicated if main pancreatic duct > 10 mm, jaundice or presence of mural nodules (Pancreatology 2017;17:738)
- Branch duct IPMN: surgical resection indicated if symptomatic, presence of mural nodule ≥ 5 mm, suspicious / positive cytology, obstructive jaundice or main pancreatic duct ≥ 10 mm (Pancreatology 2017;17:738)
- See Diagrams / tables

Clinical images

Images hosted on other servers:

Mucin extrusion from duodenal papilla

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
Branch duct involvement:
- Often in uncinate process
- Forms multicystic, grape-like structures; cystically dilated ducts, 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
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)
Greater than 5 mm in diameter
- Incipient IPMN is a term that can be used for lesions 0.5 - 1.0 cm in size

Gross images

Contributed by Dennis R. Dening, PA (ASCP)

Main duct IPMN

Frozen section description

Typically pancreatic resection margin status will be evaluated to exclude IPMN; additional margins will be submitted if invasive carcinoma is present or possibly for the presence of high grade dysplasia (Am J Surg Pathol 2015;39:1730, Pancreatology 2017;17:738)
If low grade dysplasia is seen, typically no additional resection done; this may represent pancreatic intraepithelial neoplasia (PanIN) versus IPMN (Am J Surg Pathol 2015;39:1730, Pancreatology 2017;17:738)

Frozen section images

Images hosted on other servers:

Normal pancreatic duct

Pancreatic duct with low grade dysplasia

Microscopic (histologic) description

Mucin producing epithelial cells with varied degrees of dysplasia (Am J Surg Pathol 2015;39:1730)
- 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 (i.e. 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)
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)
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

IPMN with high grade dysplasia

MUC1

MUC2

Virtual slides

Images hosted on other servers:

IPMN, low grade, intestinal type

Cytology description

Cannot distinguish IPMN from mucinous cystic neoplasm on cytology (neoplastic mucinous cyst)
Disordered mucinous epithelial clusters with nuclear overlap and variable cytologic atypia
Distinguishing a low grade mucinous neoplasm from gastrointestinal tract contaminant (particularly gastric mucosa) can be challenging

Cytology images

Images hosted on other servers:

Low grade epithelial atypia

High grade epithelial atypia with necrotic debris

Positive stains

General ductal markers are positive, including CK7, CK19, CA 19-9, B72.3 and CEA
Subtypes show various mucin glycoprotein (MUC) expression (as below):
- Gastric type IPMN: MUC5AC+, MUC6 variable (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+, 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-; similar staining pattern for associated invasive ductal adenocarcinoma (Am J Surg Pathol 2010;34:364, Mod Pathol 2016;29:977)

Molecular / cytogenetics description

KRAS, GNAS and RNF43 mutations seen in decreasing frequency in noninvasive IPMNs and 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

Sample pathology report

Pancreas, small bowel and stomach, pancreaticoduodenectomy (Whipple resection):
- Intraductal papillary mucinous neoplasm (IPMN), low grade, gastric phenotype, branch duct type, 3.0 cm (see comment)
- Negative for high grade dysplasia or malignancy.
- Margins are negative for IPMN.
- 23 lymph nodes with no significant histologic abnormality.
- Comment: The entire cyst is submitted for histologic examination.

Differential diagnosis

Intraductal oncocytic papillary neoplasm:
- 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)
- DNAJB1-PRKACA fusions (Mod Pathol 2020;33:648)
- MUC1+, 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
- Necrotic foci, more solid growth without visible mucin or scanty cytoplasmic mucin, no KRAS2 gene mutations
- MUC1+, MUC2-, MUC6+
Mucinous cystic neoplasm:
- Epithelial mucinous lining with ovarian type stroma
- No communication to pancreatic ductal system
Pancreatic intraepithelial neoplasia (PanIN):
- Only detectable microscopically
- No mass lesion, unlike IPMN
- Almost always has gastric foveolar differentiation
Simple mucinous cyst:
- Cyst > 1 cm with flat (not papillary) gastric mucinous lining and no significant atypia (Am J Surg Pathol 2015;39:1730, Am J Surg Pathol 2017;41:121)
Retention cyst:
- Cyst > 1 cm with flat (not papillary) ductal lining and no significant atypia in a background of obstruction (Am J Surg Pathol 2015;39:1730)

Additional references

Bosman: WHO Classification of Tumours of the Digestive System, 4th Edition, 2010, WHO Classification of Tumours Editorial Board: Digestive System Tumours, 5th Edition, 2019

Board review style question #1

Which morphologic type of intraductal papillary mucinous neoplasm is depicted in the above photo, seen arising from a branch of the main pancreatic duct?

Gastric
Intestinal
Invasive
Oncocytic
Pancreaticobiliary

Board review style answer #1

A. Gastric. The histologic features are typical of the gastric type of IPMN, no features of intestinal or pancreatobiliary differentiation are seen (choices B and E); choice D is not a morphologic type of IPMN; rather, intraductal oncocytic papillary neoplams are a distinct separate entity.

Comment Here

Reference: Intraductal papillary mucinous neoplasm

Board review style question #2

Which of the following clinical scenarios 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

Board review style answer #2

D. 66 year old man with 2 cm cystic pancreatic head mass. IPMNs are more often seen in older men and are cystic; thus choices A - C are incorrect (choice A would be more typical of a solid pseudopapillary neoplasm; choice B would more typical of a mucinous cystic neoplasm; choice C would be more typical of pancreatic ductal adenocarcinoma or a pancreatic neuroendocrine tumor).

Comment Here

Reference: Intraductal papillary mucinous neoplasm