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3 Hepatocellular Cancer: Pathologic Considerations 45 Fig. 3.10 Nodule-in-nodule growth pattern in early HCC. The central nodule, less differentiated, will entirely replace the peripheral well-differentiated lesion that preceded it Ancillary Studies Various techniques, including immunohistochemistry, cytogenetics, fluorescent in-situ hybridization (FISH), and comparative genomic hybridization (CGH) [62, 63], can be used to confirm a diagnosis of HCC, distinguishing it from a metastasis or a peripheral cholangiocarcinoma (uncommonly), and, importantly, differentiating a well-differentiated HCC from benign hepatocellular proliferations such as hepato-cellular adenoma. We will focus on only a few ancillary tests in the context of the usual clinical dilemmas. Hepatocellular Carcinoma vs. Metastatic Adenocarcinoma and Cholangiocarcinoma Mucin Although mucin is noted in the lumen of acinar HCC [26], the intracytoplas-mic demonstration of mucin generally rules out this diagnosis. In such cases, the working differential diagnosis includes metastatic adenocarcinoma and cholangio-carcinoma. Using MUC antibodies against glycoprotein cores of mucin, HCCs are uniformly negative for MUC-1, MUC-2, and MUC-5AC. Conversely, MUC-1 and MUC-5AC are positive in 73 and 45% of cholangiocarcinomas respectively, as well as in gastrointestinal cancers likely to metastasize to the liver [64]. Albumin Albumin, exclusively synthesized by hepatocytes, is a highly specific marker of hepatocytic lineage [65]. Unfortunately, immunohistochemistry is not a well-suited 46 G.Y. Lauwers detection tool, because of the abundance of the protein in the serum. Less com-monly available, in-situ hybridization is a better technique, with albumin mRNA demonstrated in up to 96% of HCC [65]. Polyclonal CEA and CD10 Both polyclonal CEA and CD10 (neprilysin) antibodies have cross-reactivity with glycoprotein I and exhibit a canalicular distribution pattern. In both instances, their detection offers evidence of hepatocellular differentiation [66, 67]. Alpha-Fetoprotein Alpha-fetoprotein, an oncofetal glycoprotein and established serologic marker of HCC, is not a useful immunohistochemical marker, with a low sensitivity (15–60%) [68–70]. However, its specificity is close to 100%, after exclusion of rare lesions such as yolk sac tumors [71–73]. Hepatocyte Paraffin 1 Antibody (HepPar1) HepPar1 is a marker of both benign and neoplastic hepatocellular proliferations [74–76]. Its sensitivity is reported to be about 91%, with only 4% of non-hepatic tumors staining positively [76]. However, poorly differentiated HCCs can be negative, and occasional metastatic adenocarcinomas have been reported to be immunoreactive [76]. Cytokeratin Low molecular weight keratins, including CAM 5.2 and cytokeratins 8 and 18, usu-ally decorate neoplastic hepatocytes. Conversely, HCCs are negative for keratins 7 and 19, which stain cholangiocarcinomas. However, the diagnostic applicability of cytokeratin is limited by common overlap in the immunophenotype of HCC and CCs as well as metastases [71–73]. Adjunct Methods Used for Distinguishing Benign from Malignant Hepatic Tumors CD 34 “Capillarization” of sinusoids, as expressed by various degrees of CD34 immunore-activity, has been noted in hepatic adenoma, cirrhotic liver, adenomatous hyper-plasia, and HCC [62, 77, 78]. Diffuse CD34 sinusoidal reactivity would support a diagnosis of HCC [79] and can help differentiate dysplastic nodules and early HCCs from macroregenerative nodules [80]. However, there is considerable overlap in the staining profiles of hepatocellular lesions (benign and malignant), and therefore 3 Hepatocellular Cancer: Pathologic Considerations 47 caution is necessary. Of note, one series reported the lack of CD34 immunore-activity in a series of metastatic carcinomas to the liver, suggesting a role in this situation [81]. Novel immunohistochemical markers have been developed with the goal of supple-menting the morphologic evaluation of transforming hepatocyte nodules. Heat Shock Protein 70 HSP70, a heat shock protein implicated in regulation of cellular apoptosis and cell cycle progression, is markedly upregulated in HCC. HSP70 immunoreactivity has been reported in the majority of HCCs, particu-larly in early and well-differentiated tumors (90 and 72%, reportedly). However, the staining may be difficult to evaluate, as it can be patchy [82]. Glypican 3 Glypican 3 is a marker of the glypican family of hepatic sulfate proteoglycan linked to the cell surface. It is believed to play a negative role in cell proliferation and in inducing apoptosis. Glypican 3 is overexpressed in HCC with focal and weak staining in precursor lesions of HCC but diffuse staining in a large majority of HCC [82–86] (see Table 3.1 and Fig. 3.11). In most cases, the use of a panel of several markers is best practice to avoid misconstrued conclusions. However, in closing, it is important to emphasize that these markers are best used to support a methodical histologic evaluation of small hepatocytic lesions, but do not supersede it. Table 3.1 Glypican 3 expression in hepatocytic nodules [82–84, 86] Benign Cirrhotic nodules Macroregenerative nodules Hepatocellular adenoma Low-grade dysplastic nodules Borderline and malignant High-grade dysplastic nodules eHCC Grade I HCC Grade II HCC Grade III HCC Grade IV HCC % of positive cases 0–17 0–17 0 0–8 9–43 50–60 56–90 64–83 57–89 43 Number of cases tested 224 127 22 47 69 40 63 166 77 7 48 G.Y. Lauwers Fig. 3.11 Example of strong glypican 3 positivity in grade II HCC arising in cirrhotic lines (negative background) References 1. Nzeako UC, Goodman ZD, Ishak KG (1996) Hepatocellular carcinoma in cirrhotic and non-cirrhotic livers. 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