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Exocrine tumors

PanIN (pancreatic intraepithelial neoplasia)

Reviewer: Deepali Jain, M.D. (see Reviewers page)
Revised: 9 December 2012, last major update August 2012
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.


● Most common precursor lesions of pancreatic ductal adenocarcinoma (other precursor lesions are IPMN and MCN); are microscopic papillary or flat, noninvasive epithelial neoplasms that are usually < 5 mm and confined to pancreatic ducts; composed of columnar to cuboidal cells with variable mucin, and divided into three grades according to degree of cytological and architectural atypia (WHO)
● First described in 1998 (Am J Surg Pathol 1998;22:163)

Clinical features

● Associated with common and uncommon pancreatic neoplasms (Hum Pathol 2011;42:18)
● Prevalence increases with age (Am J Surg Pathol 2006;30:36)
● May be present in heterotopic pancreas (Am J Surg Pathol 2007;31:1191)


● Applies only to small caliber ducts <5 mm, not the main pancreatic duct (lesions must be too small to be seen grossly or by radiologic imaging)
● Grade based on the highest grade component of a lesion
● Ki-67 immunostaining increases with PanIN grade (Figure 1, Mod Pathol 2002;15:441)


● Normal ductal and ductular epithelium is a cuboidal to low-columnar epithelium with amphophilic cytoplasm
● Mucinous cytoplasm, nuclear crowding and atypia are not seen

Squamous (transitional) metaplasia:
● Normal cuboidal ductal epithelium is replaced by mature squamous or transitional epithelium without atypia

● Flat epithelial lesions composed of tall columnar cells with basally located nuclei and abundant supranuclear mucin
● Nuclei are small, round to oval
● If oval, the nuclei are perpendicular to the basement membrane
● Also designated PanIN/L-1A to reflect that the neoplastic nature of many cases is not established
● May demonstrate Kras mutations, although they are present in 70% of normal pancreata at autopsy

● Epithelial lesions with a papillary, micropapillary or basally pseudostratified architecture, but otherwise identical to PanIN-1A

● Flat or papillary mucinous epithelial lesions with some nuclear abnormalities (some loss of polarity, nuclear crowding, enlarged nuclei, pseudo-stratification and hyperchromasia), but less than PanIN-3
● Rare mitoses are non-luminal (not apical) and not atypical
● Usually no true cribriforming luminal necrosis or marked cytologic abnormalities

● Papillary or micropapillary, rarely flat
● True cribriforming, budding off of small clusters of epithelial cells into the lumen and luminal necroses suggests PanIN-3
● Loss of nuclear polarity, dystrophic goblet cells (goblet cells with nuclei oriented towards the lumen and mucinous cytoplasm oriented toward the basement membrane), mitoses which may be abnormal, nuclear irregularities and prominent (macro) nucleoli
● References: Am J Surg Pathol 2001;25:579

Micro images

● See Johns Hopkins - Classification of Duct Lesions in the Pancreas (click on links for microscopic images)


PanIN-1, 2 and 3

Frozen section margins: PanIN-1, 2 and 3

PanIN2 and 3


Duct is lined by severely atypical epithelium which forms an irregular papillary projection showing a cribriform pattern and lacking a fibrovascular core; this lesion was found near an invasive ductal adenocarcinoma

Severe atypia of duct epithelium which abruptly replaces benign appearing duct cells

Positive stains

● MUC1, MUC5
● Ki-67 immunostaining increases with PanIN grade (Mod Pathol 2002;15:441)
● Also fascin, PSCA (prostate stem cell antigen), MMP7, survivin expression increases from PanIN1 to PanIN3 (Am J Surg Pathol 2006;30:754)

Negative stains

● MUC2 (Mod Pathol 2002;15:1087)

Molecular description

● Kras mutations appear to increase with severity of dysplasia (Neoplasia 2005;7:17)

Differential diagnosis

Cancerization of ducts: infiltrating carcinomas can extend into pancreatic ducts and ductules, mimicking PanIN-3; infiltrating carcinoma close to a duct lesion and an abrupt transition from a highly atypical lesion to normal duct epithelium suggests cancerization of the duct or ductule
IPMN: detected clinically; larger than PanIN, usually visible grossly or by radiologic imaging; grossly visible mucin, well formed papilla; may extend into small ducts
Mucinous cystic neoplasms: large cystic masses with ovarian stroma; no connection to the duct system
● Reactive changes: have significant inflammatory cell infiltrates, particularly neutrophils
● Vascular invasion in pancreatic ductal adenocarcinoma: see Am J Surg Pathol 2012;36:235

End of Pancreas > Exocrine tumors > PanIN (pancreatic intraepithelial neoplasia)

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