title: Diagnostic use of cytokeratins, CD34, and neuronal cell adhesion molecule staining in focal nodular hyperplasia and hepatic adenoma.
abstract: Cytokeratins 7 and 19 and neuronal cell adhesion molecule (CD56) are differentially expressed in the hepatocytes and biliary epithelium. CD34 is an endothelial marker that is expressed in hepatic sinusoids in conditions associated with altered vascular flow and neoplasms. Distinct staining patterns using these markers have been shown in resected specimens of focal nodular hyperplasia, telangiectatic focal nodular hyperplasia, and hepatic adenoma. The purpose of this study was to examine the diagnostic use of these markers in needle biopsies. Needle biopsies from focal nodular hyperplasia (n = 21), telangiectatic focal nodular hyperplasia (n = 2), and hepatic adenoma (n = 14) were included in the study. These cases represent typical examples of each entity that have been diagnosed on the basis of clinical, imaging, and histologic features. Corresponding resection specimens available in 9 cases were also included in the study for comparison. Immunohistochemical analysis was performed on 4-mum-thick formalin-fixed and paraffin-embedded sections using antibodies against cytokeratin 7, cytokeratin 19, neuronal cell adhesion molecule, and CD34. The staining patterns and intensity for each marker were analyzed in a blinded fashion, and the patterns were recorded as focal nodular hyperplasia-like, hepatic adenoma-like, or indeterminate for each case. Presence of normal tissue was also recorded in each case. The hepatic adenoma-like pattern is characterized by strong cytokeratin 7 positivity in hepatocytes in patches with a gradual decrease in the staining intensity as the cells differentiate toward mature hepatocytes. Hepatic adenomas lack bile ducts and ductules as highlighted by cytokeratin 7, cytokeratin 19, and neuronal cell adhesion molecule stains. The focal nodular hyperplasia-like pattern is characterized by milder and focal cytokeratin 7 staining of hepatocytes. Cytokeratin 7, cytokeratin 19, and neuronal cell adhesion molecule show a strong staining of bile ductules in the fibrous septa. Normal liver shows cytokeratin 7, cytokeratin 19, and neuronal cell adhesion molecule staining of bile ducts, whereas the hepatocytes are generally negative. Of the 21 focal nodular hyperplasia cases, 20 cases (95.2%) showed a focal nodular hyperplasia-like pattern, whereas 13 (92.2%) of 14 hepatic adenoma cases showed a hepatic adenoma-like pattern. Both cases of telangiectatic focal nodular hyperplasia showed a hepatic adenoma-like pattern. CD34 stain showed areas of diffuse endothelial staining in 2 cases of hepatic adenoma, 3 cases of focal nodular hyperplasia, and both cases of telangiectatic focal nodular hyperplasia, whereas the remaining cases showed staining of endothelial cells only in the inflow areas of the sinusoids. A mixed (diffuse and inflow) pattern of CD34 staining was seen in 1 focal nodular hyperplasia, 1 hepatic adenoma, and 2 telangiectatic focal nodular hyperplasia cases. For statistical analysis, the telangiectatic focal nodular hyperplasia were considered as variants of hepatic adenoma. The findings were found to be highly statistically significant (P < .05) for cytokeratin 7, cytokeratin 19, and neuronal cell adhesion molecule stains. An inflow staining pattern favors a diagnosis of focal nodular hyperplasia; however, overall, CD34 stain was not helpful in differentiating focal nodular hyperplasia and hepatic adenoma. Corresponding resection specimens (hepatic adenoma = 5, focal nodular hyperplasia = 2) showed staining patterns that were identical to the biopsy, whereas resections of the telangiectatic focal nodular hyperplasia cases showed both focal nodular hyperplasia and hepatic adenoma-like areas. Considering that telangiectatic focal nodular hyperplasia is now thought to be a variant of hepatic adenoma, the staining patterns correctly identified all cases, except one case each of focal nodular hyperplasia and hepatic adenoma. In summary, a combination of cytokeratin 7, cytokeratin 19, and neuronal cell adhesion molecule immunostains performed on needle biopsies of liver shows distinctive patterns similar to that of resection specimen. The stains, especially cytokeratins 7 and 19, are very helpful in distinguishing normal from lesional tissue, as well as hepatic adenoma from focal nodular hyperplasia, and could be diagnostically helpful in challenging cases. Prospective studies to evaluate use of these stains in challenging cases are needed to validate these findings.
authors.affiliation: Department of Pathology, Yale School of Medicine, PO Box 208023 New Haven, CT 06520-8023, USA.
authors.forename: Imran
authors.initials: I
authors.lastname: Ahmad
authors.forename: Anita
authors.initials: A
authors.lastname: Iyer
authors.forename: Celia E
authors.initials: CE
authors.lastname: Marginean
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Yeh
authors.forename: Linda
authors.initials: L
authors.lastname: Ferrell
authors.forename: Lihui
authors.initials: L
authors.lastname: Qin
authors.forename: Carlo B
authors.initials: CB
authors.lastname: Bifulco
authors.forename: Dhanpat
authors.initials: D
authors.lastname: Jain
mesh_terms: D018248:Adenoma, Liver Cell / Q000378:metabolism* / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000368:Aged; D018952:Antigens, CD34 / Q000096:biosynthesis; D014408:Biomarkers, Tumor / Q000032:analysis; D001707:Biopsy, Needle; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002648:Child; D002675:Child, Preschool; D003937:Diagnosis, Differential; D005260:Female; D020518:Focal Nodular Hyperplasia / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D053539:Keratin-19 / Q000096:biosynthesis; D053552:Keratin-7 / Q000096:biosynthesis; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged
chemical_list: D018952:Antigens, CD34; D014408:Biomarkers, Tumor; D015815:Cell Adhesion Molecules; D053539:Keratin-19; D053552:Keratin-7; C491152:NRCAM protein, human