The Sol Goldman Pancreatic Cancer Research Center

Classification of Duct Lesions in the Pancreas

A Pancreas Cancer Think Tank sponsored by the National Cancer Institute was held in Park City, Utah from September 16-19, 1999. Several workshops were held at this Think Tank, including a pathology workshop focusing on the nomenclature of duct lesions in pancreas. The duct lesions discussed were those that involve the smaller caliber ducts. They do not involve the main pancreatic duct, and they generally are too small to be seen grossly or by radiologic imaging. The following nomenclature and diagnostic criteria were unanimously agreed upon (click here to see illustrations, click on the category name below to see photomicrographs):

Normal: The 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: A process in which the normal cuboidal ductal epithelium is replaced by mature squamous or transitional epithelium without atypia.

PanIN-1A: (Pancreatic Intraepithelial Neoplasia 1-A): These are flat epithelial lesions composed of tall columnar cells with basally located nuclei and abundant supranuclear mucin. The nuclei are small and round to oval in shape. When oval the nuclei are oriented perpendicular to the basement membrane. It is recognized that there is considerable histologic overlap between non-neoplastic flat hyperplastic lesions and flat neoplastic lesions without atypia. Therefore, some may choose to designate these lesions with the modifier lesion ("PanIN/[L]-1A") to reflect the fact that the neoplastic nature of many cases of PanIn-1A has not been established.

PanIN-1B: (Pancreatic Intraepithelial Neoplasia 1-B): These epithelial lesions have a papillary, micropapillary or basally pseudostratified architecture, but are otherwise identical to PanIN-1A.

PanIN-2: (Pancreatic Intraepithelial Neoplasia 2): Architecturally these mucinous epithelial lesions may be flat or papillary. Cytologically, by definition, these lesions must have some nuclear abnormalities. These abnormalities may include some loss of polarity, nuclear crowding, enlarged nuclei, pseudo-stratification and hyperchromatism. These nuclear abnormalities fall short of those seen in PanIN-3. Mitoses are rare, but when present are non-luminal (not apical) and not atypical. True cribriforming luminal necrosis and marked cytologic abnormalities are generally not seen, and when present should suggest the diagnosis of PanIN-3.

PanIN-3: (Pancreatic Intraepithelial Neoplasia 3): Architecturally, these lesions are usually papillary or micropapillary, however, they may rarely be flat. True cribriforming, budding off of small clusters of epithelial cells into the lumen and luminal necroses should all suggest the diagnosis of PanIN-3. Cytologically, these lesions are characterized by a 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 occasionally be abnormal, nuclear irregularities and prominent (macro) nucleoli.

The Pathology Workshop participants felt that some ducts may have changes of more than one PanIn grade. PanINs should be graded based on the highest grade component of a lesion.

Mimickers of PanIn

  1. Cancerization of ducts: It was recognized that infiltrating carcinomas can extend into pancreatic ducts and ductules. When they do, they may mimic PanIN-3. An infiltrating carcinoma in close proximately to a duct lesion and an abrupt transition from a highly atypical lesion to normal duct epithelium should both suggest the possibility of cancerization of the duct or ductule. In these cases, serial (step) sections may be helpful in defining the relationship of the duct lesion to the infiltrating carcinoma.

  2. Intraductal Papillary Mucinous Neoplasms (IPMNs): IPMNs are mucinous epithelial neoplasms which involve the main pancreatic duct or its major branches. They are larger than PanINs and therefore usually visible grossly or by radiologic imaging. IPMNs may extend into small ducts. In these cases serial (step) sections may be helpful in defining the relationship of the two lesions.

  3. Mucinous cystic neoplasms: Mucinous cystic neoplasms are characterized by the presence of ovarian stroma and the absence of a connection to the duct system. These features and the larger size of mucinous cystic neoplasms help distinguish mucinous cystic neoplasms from PanINs.

Reactive changes: Reactive changes may mimic PanINs. The presence of significant inflammatory cell infiltrates, particularly when there are numerous polymorphonuclear leukocytes, should raise the possibility of reactive changes.

Other Terms

A variety of older terms have been used to describe PanINs. These include:

  • Squamous Metaplasia: Epidermoid metaplasia, multilayered metaplasia
  • PanIN-1A: Pyloric gland metaplasia, goblet cell metaplasia, mucinous hypertrophy, flat duct lesion without atypia, mucinous ductal hyperplasia, simple hyperplasia, mucinous cell hyperplasia, flat ductal hyperplasia, non-papillary epithelial hypertrophy.
  • PanIN-1B: Papillary hyperplasia, papillary duct lesion without atypia, and ductal hyperplasia.
  • PanIN-2: Atypical hyperplasia, papillary duct lesion with atypia, low-grade dysplasia, and some cases of moderate dysplasia. Mucous metaplasia and pyloric gland metaplasia commonly involve small branch ducts or extend into lobules surrounding PanIN in ducts. Such involvement has been called adenomatoid or adenomatous hyperplasia, especially when the change dominates involvement of ductal epithelium. It is regarded as part of the spectrum of PanIN-1.
  • PanIN-3: Carcinoma insitu, intraductal carcinoma, high-grade dysplasia, severe dysplasia, and some cases of moderate dysplasia.

This nomenclature and these diagnostic criteria are meant to be a "working formulation," not a permanent final product. It is hoped that this nomenclature and these diagnostic criteria will foster the study of duct lesions. These studies could include correlation of molecular genetic alterations with each grade of PanIN, the expression of antigens as determined immunohistochemically, correlation with cytologic findings and patient follow-up.

Ralph H. Hruban, M.D.The Johns Hopkins Hospital
N. Volkan Adsay, M.D.Harper Hospital & Wayne State Univ.
Jorge Albores-Saavedra, M.D.Univ. of Texas, Southwestern
Carolyn Compton, M.D.Massachusetts General Hospital
David Klimstra, M.D.Memorial Sloan-Kettering Cancer Center
Gnter Klppel, M.D.Univ. of Kiel
Daniel Longnecker, M.D.Dartmouth-Hitchcock Medical Center
Jutte Lttges, M.D.Univ. of Kiel
G. Johan Offerhaus, M.D., Ph.D.Univ. of Amsterdam

Hruban RH, Adsay NV, Albores-Saavedra J, Compton C, Garrett E, Goodman SN, Kern SE, Klimstra DS, Kloppel G, Longnecker DS, Luttges J, Offerhaus GJA. Pancreatic intraepithelial neoplasia (PanIN): A New nomenclature and classification system for pancreatic duct lesions. Am J Surg Pathol, In Press