Cytokeratin expression in hepatocellular carcinoma: An immunohistochemical study

Eyken, Peter Van; Sciot, Raf; Paterson, Alan C.; Callea, Francesco; Kew, Michael C.; Desmet, Valeer

doi:10.1016/s0046-8177(88)80205-3

Cited by 144 publications

(87 citation statements)

References 19 publications

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“…The fact that some cases of hepatocellular carcinoma with ezrin expression showed negative CK19 expression may be due to the fact that cases of hepatocellular carcinoma that are consistent with a progenitor cell origin may not necessarily have positive CK19 expression, as previously described. 10 Several studies using detailed immunophenotyping, with CK19, CK7, or OV6 for example, showed that 28-50% of cases of hepatocellular carcinoma derive from progenitor cells and their progeny, 9,11,25,26 a frequency that is compatible with cases of hepatocellular carcinoma with ezrin expression. No specific marker for hepatic progenitor cell compartment has yet been described.…”

Section: Discussionmentioning

confidence: 99%

Ezrin expression is associated with hepatocellular carcinoma possibly derived from progenitor cells and early recurrence after surgical resection

et al. 2008

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Heterogeneous biological characteristics of hepatocellular carcinoma may be attributed to the cellular origin of the tumor. Patients with hepatocellular carcinoma probably derived from hepatic progenitor cells had early tumor recurrence after surgical resection or liver transplantation, suggesting that these tumors have aggressive characteristics. Ezrin, a member of the ERM (ezrin-radixin-moesin) cytoskeleton-associated protein family, is highly expressed in several types of human cancers and correlations between its immunoreactivity and patient outcome have been shown. In this study, ezrin expression, as well as cytokeratin19 and cytokeratin 7 expression, which are regarded as progenitor cell/ductular markers were immunohistochemically assessed in cases of hepatocellular carcinoma. In normal livers, ezrin expression was not found in any cell types, whereas cytokeratin 7 and cytokeratin 19 were exclusively stained in bile duct cells. In contrast, in livers with chronic hepatitis or cirrhosis, positive ezrin expression was observed in ductular reactions with strong intensity and intermediate hepatobiliary cells with various intensity. Of 77 cases of hepatocellular carcinoma, 28 (36%) had positive ezrin expression, 32 (42%) had cytokeratin 7 expression, and 11 (14%) had cytokeratin 19 expression. Ezrin expression in hepatocellular carcinoma was significantly associated with cytokeratin 19 expression, but not with cytokeratin 7 expression. Patients with ezrin-positive hepatocellular carcinoma had a significantly higher prevalence of elevated serum a-fetoprotein. Patients with immunohistochemical ezrin-positive hepatocellular carcinoma demonstrated significantly shorter recurrence-free and overall survival compared to patients with ezrin-negative hepatocellular carcinoma. Multivariate analysis revealed positive ezrin expression and multiple tumors to be independently associated with early recurrence in patients with hepatocellular carcinoma after curative surgical resection. These results suggested that hepatocellular carcinoma with ezrin expression might be at least partly derived from hepatic progenitor cells. Measurement of ezrin expression might be used to identify patients with an increased risk of early recurrence.

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Section: Discussionmentioning

confidence: 99%

Ezrin expression is associated with hepatocellular carcinoma possibly derived from progenitor cells and early recurrence after surgical resection

et al. 2008

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“…However, when limited material is available or when the tumor is poorly differentiated, various immunohistochemical panels have been used to aid in this distinction. The most commonly used markers include antibodies directed against AFP (1, 7), CEA (1, 2), and various cytokeratin subtypes (3)(4)(5)(6)8). Other markers that have been reported as useful include Factor XIII-A (2, 16), hepatitis B surface antigen (17), C-reactive protein (2), ␣-1 antitrypsin (16), HepPar 1 (18), Ber-EP4 (1,19), and molecular probes designed to identify albumin mRNA (20,21).…”

Section: Discussionmentioning

confidence: 99%

“…Immunohistochemical panels have been used to separate these tumors with variable success. ␣-Fetoprotein (AFP); polyclonal carcinoembryonic antigen (pCEA); and cytokeratins (CK) 7,8,18,19, and 20 are among some of the more commonly used markers in these panels (1)(2)(3)(4)(5)(6)(7)(8).…”

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confidence: 99%

Immunohistochemical Analysis of Hepatocellular and Adenocarcinoma in the Liver: MOC31 Compares Favorably with Other Putative Markers

Young

Proca

et al. 2000

Modern Pathology

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Distinguishing hepatocellular carcinoma (HCC) from metastatic adenocarcinoma (MA) and cholangiocarcinoma (CC) can, at times, be difficult and sometimes requires immunohistochemical analysis. Recently, MOC31, an antibody directed against a cell surface glycoprotein, has been shown to be useful in separating HCC from both MA and CC; however, no study has compared MOC31 and other frequently used immunostains. We compare MOC31 with other commonly used immunostains for HCC, MA, and CC. Formalin-fixed, paraffin-embedded tissue sections from 57 previously characterized hepatic neoplasms (13 HCC, 14 CC, 3 combined HCC-CC, and 27 MA) were immunostained with antibodies directed against MOC31, cytokeratin (CK) 7, CK20, ␣-fetoprotein (AFP), polyclonal carcinoembryonic antigen, Ber-EP4, and Factor XIII-A. Two pathologists reviewed slides, and positivity was defined as more than 1% of cells staining with the appropriate pattern. Positive MOC31 immunostaining was seen in 0 of 13 HCC, 13 of 14 CC, 3 of 3 HCC-CC, and 27 of 27 MA; the staining was strong and diffuse. CK20 reactivity was observed in 0 of 13 HCC, 2 of 14 CC, 0 of 3 HCC-CC, and 12 of 27 MA; CK7 immunostained 4 of 13 HCC, 13 of 14 CC, 3 of 3 HCC-CC, and 15 of 27 MA; AFP was detected in 4 of 13 HCC and 2 of 3 HCC-CC, whereas all CC and MA were negative; polyclonal carcinoembryonic antigen showed immunoreactivity in 12 of 13 HCC and 3 of 3 HCC-CC in a canalicular pattern, whereas diffuse positivity was identified in 13 of 14 CC and 26 of 27 MA; Ber-EP4 immunostained 1 of 13 HCC, 14 of 14 CC, 2 of 3 HCC-CC, and 26 of 27 MA; and Factor XIII-A was negative in all HCC, CC, and MA. MOC31 expression distinguished HCC from adenocarcinoma in 56 of 57 cases. AFP was specific for HCC but was not sensitive. CK7 and CK20 have limited utility in distinguishing HCC from CC or MA, and Factor XIII-A is not useful. Ber-EP4 staining was similar to MOC31, but one HCC did stain with Ber-EP4. Polyclonal CEA yields similar numerical results as MOC31, but the focal nature of the staining and occasional difficulty in evaluating the pattern can make interpretation problematic. We conclude that MOC31 should be a component of the immunohistochemical panel to distinguish HCC from CC and MA.

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“…18 Peter Van Eyken subsequently demonstrated by use of monoclonal antibodies against individual keratins that hepatocytes express keratin 8 (K8) and K18, whereas cholangiocytes express K7 and K19, 19 in addition, thus providing the basis for cell lineage studies in embryonic development of intrahepatic bile ducts 20,21 and in HCCs. 22,23 During embryonic development, K19 is not only a marker of cholangiocytes, but of primitive hepatoblasts as well, 24 and the liver cancer studies revealed that many tumors which were morphologically diagnosed as HCCs express bile duct-type K7 and/or K19, indicating a nonhepatocellular trait in HCCs. 22,24 This finding became of higher interest in later years.…”

Section: Histogenesis Of Liver Cancermentioning

confidence: 99%

“…22,23 During embryonic development, K19 is not only a marker of cholangiocytes, but of primitive hepatoblasts as well, 24 and the liver cancer studies revealed that many tumors which were morphologically diagnosed as HCCs express bile duct-type K7 and/or K19, indicating a nonhepatocellular trait in HCCs. 22,24 This finding became of higher interest in later years. Inspired by microscopic slides revealing strongly K7-positive small cells in periportal regions, my coworker, electron microscopist Rita DeVos, searched for such cells at the ultrastructural level, and thus discovered a novel cell type hitherto unmentioned in the human liver, corresponding to liver progenitor cells differentiating into both hepatocytes and bile duct cells 25 (Fig.…”

Section: Histogenesis Of Liver Cancermentioning

confidence: 99%

The amazing universe of hepatic microstructure

Desmet

2009

Hepatology

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An informal review is presented by the author of his 50 years of involvement in practice and research in hepatopathology. Some background for the author's attitude and meandering pathway into his professional career serves as introduction to a short discussion of the main topics of his interest and expertise. Histogenesis of liver cancer was the theme of early work for a Ph.D. thesis, the results of which were lost into oblivion due to local rules and circumstances, but were rescued three decades later. His conclusions about the cells of origin of liver cancer remain concordant with the newer concepts in the field after nearly half a century. Studies in the field of chronic hepatitis became a long saga, involving the first classification of this syndrome by "the Gnomes" in 1968, histochemical investigations of viral antigens, lymphocyte subsets and adhesion molecules, and a quarter century later, the creation of a new classification presently in use. Cholestasis was a broadening field in diagnostic entities and involved the study of liver lesions, comprising pathways of bile regurgitation (including reversed secretory polarity of hepatocytes) and so-called ductular reaction. The latter topic has a high importance for the various roles it plays in modulating liver tissue of chronic cholestasis into biliary cirrhosis, and as the territory of hepatic progenitor cells, crucial for liver regeneration in adverse conditions and in development of liver cancer. Study of the embryology of intrahepatic bile ducts helped to clarify the strange appearance of the ducts in "ductal plate configuration" in several conditions, including some forms of biliary atresia with poor prognosis and all varieties of fibrocystic bile duct diseases with "ductal plate malformation" as the basic morphologic lesion. (HEPATOLOGY 2009;50: 333-344.)

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Cytokeratin expression in hepatocellular carcinoma: An immunohistochemical study

Cited by 144 publications

References 19 publications

Ezrin expression is associated with hepatocellular carcinoma possibly derived from progenitor cells and early recurrence after surgical resection

Ezrin expression is associated with hepatocellular carcinoma possibly derived from progenitor cells and early recurrence after surgical resection

Immunohistochemical Analysis of Hepatocellular and Adenocarcinoma in the Liver: MOC31 Compares Favorably with Other Putative Markers

The amazing universe of hepatic microstructure

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