Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Etiology | Diagrams / tables | Clinical features | Diagnosis | Laboratory | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Gross description | Gross images | Microscopic (histologic) description | Microscopic (histologic) images | Positive stains | Negative stains | Molecular / cytogenetics description | Differential diagnosis | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Agostini-Vulaj D. Intraductal papillary mucinous neoplasm. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/pancreasipmn.html. Accessed January 24th, 2021.
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)
- Further classified as:
- 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)
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
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)
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.
AFIP images
Images hosted on other servers:
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 style answer #1
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 style answer #2