Is the intraductal papillary mucinous neoplasia of the biliary tract a counterpart of pancreatic papillary mucinous neoplasm?

Abstract

Two types of biliary intraductal neoplastic lesions have been identified. The first is a flat type of biliary dysplasia that is referred to in the most recent WHO classification of liver tumors as biliary intraepithelial neoplasia (BilIn). The second type is a papillary type. Biliary papillary tumors are uncommon lesions, but their existence has been known for a long time. These neoplasms, which occur in the intra- and/or extrahepatic biliary tree, have been designated as biliary papillomatosis [[1]Lee S.S. Kim M.H. Lee S.K. Jang S.J. Song M.H. Kim K.P. et al.Clinicopathologic review of 58 patients with biliary papillomatosis.Cancer. 2004; 100: 783-793Crossref PubMed Scopus (191) Google Scholar], bile duct papillomatosis [[2]Hubens G. Delvaux G. Willems G. Bourgain C. Klöppel G. Papillomatosis of the intra- and extrahepatic bile ducts with involvement of the pancreatic duct.Hepatogastroenterology. 1991; 38: 413-418PubMed Google Scholar], mucin-hypersecreting cholangiocarcinoma [[3]Chen M.F. Jan Y.Y. Chen T.C. Clinical studies of mucin-producing cholangiocellular carcinoma: a study of 22 histopathology-proven cases.Ann Surg. 1998; 227: 63-69Crossref PubMed Scopus (92) Google Scholar] or mucin hypersecreting bile duct tumors [[4]Kim H.J. Kim M.H. Lee S.K. Yoo K.S. Park E.T. Lim B.C. et al.Mucin-hypersecreting bile duct tumor characterized by a striking homology with an intraductal papillary mucinous tumor (IPMT) of the pancreas.Endoscopy. 2000; 32: 389-393Crossref PubMed Scopus (121) Google Scholar]. The current WHO classification recognises both benign (e.g. biliary papillomatosis) and malignant (e.g. papillary cholangiocarcinoma) types of biliary papillary neoplasm [[5]Nakanuma Y. Sripa B. Vatanasapt V. Leong A.S.Y. Ponchon T. Ishak K.G. Intrahepatic cholangiocarcinoma.in: Hamilton S.R. Aaltonen L.A. Pathology and genetics. Tumors of the digestive system. IARC Press, Lyon2000: 173-180Google Scholar]. Recent studies revealed striking similarities between the biliary intraductal papillary neoplasms and pancreatic intraductal papillary mucinous neoplasms (IPMN). In both organs these neoplasms arise within the duct system and show a predominantly intraductal grown pattern, commonly an overproduction of mucin and an association with invasive adenocarcinoma [[6]Klöppel G. Clinicopathologic view of intraductal papillary-mucinous tumor of the pancreas.Hepatogastroenterology. 1998; 45: 1981-1985PubMed Google Scholar]. In this issue, Zen et al. describe the differing expression of mucin core proteins and cytokeratins in biliary intraepithelial neoplasia, biliary intraductal papillary neoplasms and intrahepatic cholangiocarcinomas [[7]Zen Y. Sasaki M. Fujii T. Chen T.-C. Chen M.-F. Yeh T.-S. et al.Different expression patterns of mucin core proteins and cytokeratins during intrahepatic cholangiocarcinogenesis from biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct—an immunohistochemical study of 110 cases of hepatolithiasis.J Hepatol. 2006; 44: 350-358Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar]. They show that different types of biliary papillary neoplasms can be distinguished on the basis of their immunophenotypes (mucin core proteins and cytokeratins). (a) Tubular adenocarcinomas with biliary intraepithelial neoplasia (BilIn) are characterised by the expression of MUC1 and CK7 (and negativity for CK20 and MUC2); (b) tubular adenocarcinomas with biliary papillary neoplasm are characterised by increased MUC1 positivity and (c) colloid carcinomas with biliary papillary neoplasm are characterised by MUC2 positivity. On the basis of these findings, they discuss three distinct pathways of carcinogenesis. The first pathway (MUC1+/MUC2−) is from biliary intraepithelial neoplasia to tubular cholangiocarcinoma, the second pathway (MUC1+/MUC2−) from intraductal papillary neoplasm to tubular cholangiocarcinoma and the third pathway (MUC1−/MUC2+) from intraductal papillary neoplasm to colloid carcinoma. Recent studies on pancreatic intraductal papillary-mucinous neoplasms (IPMNs) have shown that IPMNs are heterogeneous. On the basis of their histology and mucin expression 4 subtypes of IPMN are currently defined. They include the gastric type, intestinal type, pancreatobiliary type and oncocytic type [[8]Furukawa T. Klöppel G. Volkan A.N. Albores-Saavedra J. Fukushima N. Horii A. et al.Classification of types of intraductal papillary-mucinous neoplasm of the pancreas: a consensus study.Virchows Arch. 2005; Aug 9 ([Epub ahead of print]): 1-6Google Scholar]. The gastric type of IPMN consists of cells resembling gastric foveolae. They express MUC5AC but are negative for MUC1 and MUC2. This IPMN subtype usually is a relatively small cystic lesion in peripheral branches with a low degree of atypia corresponding to intraductal papillary mucinous adenoma. The intestinal type resembles intestinal villous neoplasms with tall columnar epithelial cells that usually show moderate or severe atypia corresponding to borderline or in situ carcinoma. The neoplastic cells consistently express MUC2 and MUC5AC but not MUC1. When this IPMN subtype becomes invasive, the invasive tumor component shows a colloid pattern with consistent positivity for MUC2 and negativity for MUC1. The pancreatobiliary type of IPMN consists of cells resembling cholangiopapillary neoplasm and shows complex thin branching papillae and severe atypia corresponding to carcinoma in situ. This type is often positive for MUC1 but negative for MUC2. When invasive, this IPMN subtype presents as a tubular adenocarcinoma with positivity for MUC1 and negativity for MUC2. The oncocytic type of IPMN consists of cells with abundant intensely eosinophilic cytoplasm and shows complex thick papillae with severe atypia corresponding to carcinoma in situ. This IPMN subtype consistently expresses MUC5AC and expresses MUC1 focally but is negative for MUC2. Finally, pancreatic intraepithelial neoplasia grade 3 (PanIN-3) and ductal adenocarcinoma are both MUC1 positive. When we compare the data from Zen's study on biliary papillary intraductal tumors with that in the pancreas, it is evident that there are close parallels between the various intraductal tumors in the pancreas and the biliary system. Thus the intestinal type of IPMN has its counterpart in the MUC2+/MUC1− biliary intraepithelial neoplasia; the pancreatobiliary type of IPMN in the MUC1+/MUC2− biliary intraepithelial neoplasia and the MUC1+/MUC2− ductal adenocarcinomas arising from PanIN-3 in the MUC1+/MUC2− biliary intraepithelial neoplasia that precedes tubular cholangiocarcinoma. In addition, it was also demonstrated that the oncocytic type of IPMN has its parallel in hepatic intraductal oncocytic papillary carcinoma [[9]Martin R.C.G. Klimstra D.S. Schwartz L. Yilmaz A. Blumgart L.H. Jarnagin W. Hepatic intraductal oncocytic papillary carcinoma.Cancer. 2002; 95: 2180-2187Crossref PubMed Scopus (38) Google Scholar]. No counterpart, however, has so far been found for the gastric type of IPMN, which is characterised by its sole expression of MUC5AC [8Furukawa T. Klöppel G. Volkan A.N. Albores-Saavedra J. Fukushima N. Horii A. et al.Classification of types of intraductal papillary-mucinous neoplasm of the pancreas: a consensus study.Virchows Arch. 2005; Aug 9 ([Epub ahead of print]): 1-6Google Scholar, 10Adsay N.V. Merati K. Basturk O. Iacobuzio-Donahue C. Levi E. Cheng J.D. et al.Pathologically and biologically distinct types of epithelium in intraductal papillary mucinous neoplasms. Delineation of an ‘intestinal’ pathway of carcinogenesis in the pancreas.Am J Surg Pathol. 2004; 28: 839-848Crossref PubMed Scopus (390) Google Scholar]. Zen et al.'s study also reveals some minor differences between biliary and pancreatic intraductal neoplasia. Whereas MUC2 positivity is rare in PanIN [10Adsay N.V. Merati K. Basturk O. Iacobuzio-Donahue C. Levi E. Cheng J.D. et al.Pathologically and biologically distinct types of epithelium in intraductal papillary mucinous neoplasms. Delineation of an ‘intestinal’ pathway of carcinogenesis in the pancreas.Am J Surg Pathol. 2004; 28: 839-848Crossref PubMed Scopus (390) Google Scholar, 11Kim G.E. Bae H.I. Park H.U. Kuan S.F. Crawley S.C. Ho J.J. et al.Aberrant expression of MUC5AC and MUC6 gastric mucins and sialyl Tn antigen in intraepithelial neoplasms of the pancreas.Gastroenterology. 2002; 123: 1052-1060Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar], they found positivity in BilIn in nearly 20% of the cases. All of the cases were associated with hepatolithiasis and I is well known that MUC2 expression in the intrahepatic large bile duct is one of the key events in stone formation. In conclusion, a comparison of Zen's study with recent work in the pancreas reveals a conspicuous similarity between the intraductal tumors. It, therefore, seems appropriate to call the biliary papillary tumors intraductal papillary intraepithelial neoplasia, in analogy to their pancreatic counterpart.