An immunohistochemical profile of the so-called bile duct adenoma: clues to pathogenesis

The so-called bile duct adenoma and peribiliary glands are characterized by the expression of two foregut antigens (designated D10 and 1F6) and secretion of acid mucin. On account of this similarity in phenotype and their frequent close association with a large caliber bile duct, it was earlier suggested that bile duct adenoma represent a peribiliary gland hamartoma. Here, we compare the expression of 13 tissue antigens in bile duct adenomas, other benign bile duct lesions, and various foregut-derived tissues, to further investigate the bile duct adenoma phenotype and pathogenesis. Antibodies to 4 intestinal mucins, 3 cytokeratins, and CDX2, were not informative. Five foregut antigens (D10, 1F6, MUC6, MUC5AC, and TFF2) and secretion of acid mucin were of use in distinguishing bile duct adenoma from other hepatic lesions. 1F6 and MUC6 were normally present in bile ductules and canals of Hering, whereas the epithelium lining the larger bile ducts stained focally for D10, MUC5AC, MUC6, or TFF2 in, respectively, 21%, 36%, 43%, and 100% of the livers examined. Thirty-six bile duct adenomas examined were distinguished by expression of MUC6 (94% of bile duct adenoma), MUC5AC (90%), TFF2 (80%), D10 (67%), and 1F6 (61%), and varying degrees of acid mucin secretion (100%). Of 30 bile duct adenoma tested for all 5 antigens, 40% expressed all 5, 27% expressed 4, 17% expressed 3, 13% expressed 2, and 1 expressed only MUC6. Peribiliary glands invariably expressed D10, 1F6, MUC6, and TFF2, and showed acid mucin secretion, with MUC5AC present in the inflamed peribiliary glands of 3/4 livers with recurrent pyogenic cholangitis, but none of the glands of the other 23 normal or diseased livers tested. The acini of pyloric gland metaplasia in gallbladder and terminal ileum also stained for D10, 1F6, MUC6, and TFF2, with MUC5AC focally present in the gastric foveolar metaplasia overlying the pyloric gland metaplasia but not in the metaplastic glands. MUC6 was expressed in 92% of ductular reactions, 1F6 in 42%, and D10 in 25%. Focal expression of MUC6, or TFF2 was observed in 1 or 2 examples of 14 von Meyenburg complexes and 6 polycystic livers, with staining for acid mucin generally obvious only in the glycocalyx of the epithelium of these two types of lesions. The distinguishing feature of so-called bile duct adenoma is their display of the same phenotype as pyloric gland metaplasia. It is concluded that they develop as a localized biliary healing response equivalent to the function of a peribiliary gland or pyloric gland metaplasia in the foregut.