title: TTF-1 and Napsin-A are expressed in a subset of cholangiocarcinomas arising from the gallbladder and hepatic ducts: continued caveats for utilization of immunohistochemistry panels.
abstract: Thyroid transcription factor-1 (TTF-1) and Napsin-A (NapA) are frequently used to classify a tumor of unknown origin as lung or thyroid primary. Although recent studies have shown that nuclear TTF-1 positivity occasionally occurs in adenocarcinoma of nonpulmonary or thyroid origin dependent upon the antibody clone, TTF-1 has been reported as negative or infrequently positive in tumors of biliary origin. On the basis of an index case of cholangiocarcinoma expressing TTF-1, we were prompted to study TTF-1 and NapA positivity in cholangiocarcinoma. Archived paraffin-embedded tissue blocks from liver, gallbladder, and pancreato-biliary resections were chosen for cholangiocarcinoma (n=33) and non-neoplastic intrahepatic and extrahepatic biliary epithelium control tissue (n=26). Immunohistochemical analysis for TTF-1 and NapA was performed and graded for intensity and quantity. TTF-1 was negative in control biliary tissue but positive in 27.2% of cholangiocarcinomas. All TTF-1-positive cases (n=9) were extrahepatic (P=0.01), and most arose from the upper biliary tract (gallbladder and hepatic ducts). TTF-1 positivity was associated with age 60 years and above (P=0.01) but not with sex. Three TTF-1-positive cases were also NapA positive. NapA staining showed apical granular staining of the adjacent non-neoplastic epithelium in 6 cases (18.1%). In summary, 47.4% of extrahepatic cholangiocarcinoma expressed TTF-1, 33.3% of which coexpressed NapA. Cholangiocarcinoma should be considered in the differential when evaluating a TTF-1-positive tumor of unknown primary. As TTF-1 and NapA are not known for biliary system development or detected in non-neoplastic biliary epithelium, the significance of this "pulmonary" phenotype in a subset of extrahepatic cholangiocarcinoma is unknown and needs further investigation.
authors.affiliation: Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA.
authors.forename: Lea F
authors.initials: LF
authors.lastname: Surrey
authors.forename: Renee
authors.initials: R
authors.lastname: Frank
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Zhang
authors.forename: Emma E
authors.initials: EE
authors.lastname: Furth
mesh_terms: D016282:Aspartic Acid Endopeptidases / Q000032:analysis*; D001650:Bile Duct Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000601:surgery; D001653:Bile Ducts, Intrahepatic / Q000201:enzymology* / Q000473:pathology / Q000601:surgery; D014408:Biomarkers, Tumor / Q000032:analysis*; D001706:Biopsy; D016022:Case-Control Studies; D018281:Cholangiocarcinoma / Q000201:enzymology* / Q000473:pathology / Q000601:surgery; D003937:Diagnosis, Differential; D005260:Female; D005706:Gallbladder Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000601:surgery; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000032:analysis*; D016612:Paraffin Embedding; D010641:Phenotype; D011237:Predictive Value of Tests; D011379:Prognosis; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000032:analysis*
chemical_list: D014408:Biomarkers, Tumor; C000614412:NKX2-1 protein, human; D009687:Nuclear Proteins; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D016282:Aspartic Acid Endopeptidases; C498549:NAPSA protein, human