Teaching Case 2
Relevant clinical history
The patient is a 69 year old female with cirrhosis secondary to Hepatitis C who underwent cholecystectomy, at which time the gallbladder was found to be partially replaced by malignant tumor.
H&E stained sections of this tumor revealed an epithelioid tumor composed of clear cells, somewhat reminiscent of renal cell carcinoma.
The questions posed by the referring pathologist are: (a) can this tumor be more precisely subclassified?; and (b) where is its primary site? Immunohistochemical studies can address both of these questions.
Results of immunohistochemistry studies
Cytokeratin (AE1/AE3)
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| Initial studies were performed to confirm the suspicion that this represents carcinoma. As the image suggests, the tumor cells show a uniform pattern of expression of cytokeratin, as identified by the AE1/AE3 antibody cocktail. This is our favorite "pan-cytokeratin" reagent here at PhenoPath, as it identifies a broad spectrum of cytokeratins and is positive, with appropriate epitope retrieval techniques, on virtually all carcinomas. In clear cell carcinomas, such as this, it is expected that the pattern of immunostaining is a 'blotchy' or 'feathery' one. The cytoplasm of clear cell tumors is generally filled with either glycogen or lipid (or both), which usually displace the (cytokeratin) intermediate filaments to the periphery of the cell, yielding this pattern of immunostaining. |
Cytokeratin 7 |
Cytokeratin 20 |
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| The initial panel of antibodies to determine carcinoma subtype often will include antibodies to cytokeratin 7 and 20. Coordinate expression of cytokeratins 7 and 20 can provide important information in determining the site of origin of carcinomas presenting at a metastatic site, as first described in our studies published several years ago (Wang NP, Zee S, Zarbo RJ, Bacchi CE, Gown AM. Appl Immunohistochem 3:99-107, 1995). The use of antibodies to cytokeratin 7 and 20 in stratifying carcinomas of different organs was confirmed and extended in the recent publication of Chu et al (Chu P, Wu E, Weiss LM. Mod Pathol 13:962-72, 2000). This tumor is demonstrated to have a cytokeratin 7-negative, cytokeratin 20-negative immunophenotype, which is characteristic of a very restricted subset of carcinomas, which includes: (a) hepatocellular carcinoma; (b) renal cell carcinoma; (c) neuroendocrine carcinoma; (d) prostatic carcinoma. In this clinical setting, the diagnoses of hepatocellular and renal cell carcinoma should be most strongly entertained. |
Vimentin
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| One characteristic feature of renal cell carcinoma is co-expression of cytokeratin and vimentin; indeed, in many cases the apparent levels of vimentin expression exceed that of cytokeratin. Nonetheless, as is evident in this photomicrograph, antibodies to vimentin decorate only the endothelial cells and macrophages present in the tumor, but are negative on the tumor itself. These studies argue against the diagnosis of metastatic renal cell carcinoma. |
CEA |
HEPPAR1 |
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| The clear cell nature of the tumor notwithstanding, this carcinoma marks as hepatocellular carcinoma. This tumor displays two independent markers of hepatocellular differentiation. First, expression of 'CEA' (left) in a bile canalicular pattern has been described as a sensitive and specific marker of hepatocellular carcinoma (Christensen WN et al Mod Pathol 1989;2(1):8-12; Ma CK et al Am J Clin Pathol 1993;99(5):551-7). (Note that this is not true CEA expression, as monoclonal antibodies to CEA, such as the II-7 clone, are negative on hepatocellular carcinomas. Polyclonal anti-CEA antibodies which cross react with biliary glycoprotein, another member of the CEA family of proteins, show the characteristic pattern of reactivity such as shown in the photomicrograph.) There is also expression of the HepPar1 antigen (identified with clone OCH1E5.2.10), a hepatocyte/hepatocellular carcinoma-restricted protein (Leong A S-Y et al. Histopathol 33:318-24, 1998; Wennerberg AE et al, Am J Pathol 143;1050-4, 1993.). |
A clear cell variant of hepatocellular carcinoma, to which this tumor corresponds, has been described, but this does not appear to have a 'biologic behavior' different from that of 'garden variety' hepatocellular carcinoma. The carcinoma in this case had spread along the bile ducts with direct extension in to the gallbladder.
Final Diagnosis
Hepatocellular carcinoma, clear cell variant
