Two pathologic types of hepatocellular carcinoma with lymph node metastasis with distinct prognosis on the basis of CK19 expression in tumor

Zhuang, Peng–Yuan; Zhang, Jubo; Zhu, Xiao‐Dong; Zhang, Wei; Wu, Wei‐Zhong; Tan, Yaohong; Hou, Jun; Tang, Zhao–You; Qin, Lun–Xiu; Sun, Hui‐Chuan

doi:10.1002/cncr.23488

Cited by 74 publications

(58 citation statements)

References 26 publications

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“…EpCAM and CK19 positivity have also been associated with worse prognosis in hepatocellular carcinoma, possibly related to a progenitor cell phenotype. [44][45][46][47][48] Interestingly, hepatoblastomas 49,50 and hepatocellular carcinomas occurring in pediatric patients also show increased staining for biliary and progenitor cell markers. 51 The increased staining of fibrolamellar carcinomas with EpCAM may indicate that these tumors have a progenitor cell phenotype with both hepatocellular and biliary differentiation or may be related to the development of these tumors at a younger age.…”

Section: Discussionmentioning

confidence: 99%

Fibrolamellar carcinoma of the liver exhibits immunohistochemical evidence of both hepatocyte and bile duct differentiation

et al. 2010

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Fibrolamellar carcinoma is a rare malignant primary liver neoplasm with characteristic histological features that typically arises in young patients without viral hepatitis or cirrhosis. Previous studies on this entity have been limited by small numbers of patients. In contrast to classical hepatocellular carcinoma, individual cases of fibrolamellar carcinoma have been reported to express cytokeratin 7. In addition, ultrastructural and serological studies have suggested that fibrolamellar carcinoma may show neuroendocrine differentiation. The cellular differentiation of fibrolamellar carcinoma has not been studied and little is reported about its immunohistochemical profile. We studied 26 cases of fibrolamellar carcinoma and 62 cases of classical hepatocellular carcinoma by immunohistochemistry for HepPar1, glypican-3, pCEA, CD10, a-fetoprotein, cytokeratin 20, neuroendocrine markers, and surrogate markers for biliary differentiation (cytokeratin 7, cytokeratin 19, epithelial membrane antigen, EpCAM, mCEA, B72.3, and CA19.9). In situ hybridization for albumin mRNA was also performed. Tumor cells of fibrolamellar carcinoma and hepatocellular carcinoma showed positive signals for albumin mRNA by in situ hybridization in all cases. Both tumor types stained uniformly positively with HepPar1 and most showed a canalicular staining pattern for pCEA, confirming their hepatocellular differentiation. In addition, 39% of hepatocellular carcinoma cases and 59% of fibrolamellar carcinoma cases were positive for glypican-3. All 22 fibrolamellar carcinoma cases tested showed positive staining for cytokeratin 7 and epithelial membrane antigen, whereas less than one-third of hepatocellular carcinoma cases were positive for these markers (Po0.0001). Further, 36% of fibrolamellar carcinoma cases showed staining for B72.3, cytokeratin 19, EpCAM, or mCEA. Minimal evidence of neuroendocrine differentiation in either tumor was found with any of the usual immunohistochemical markers used for this purpose. Therefore, cytokeratin 7 and epithelial membrane antigen may be useful to differentiate between fibrolamellar carcinoma and hepatocellular carcinoma. On the basis of immunohistochemistry, fibrolamellar carcinoma seems to show both hepatocellular and bile duct differentiation.

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Section: Discussionmentioning

confidence: 99%

Fibrolamellar carcinoma of the liver exhibits immunohistochemical evidence of both hepatocyte and bile duct differentiation

et al. 2010

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“…Clinicopathologic features of this cohort of patients have been described elsewhere, with a median follow-up of 30.0 months (range, 1.0-105.0; SD, 27.6; ref. 37). Immunohistochemistry, quantification of immunomarkers, and statistics were conducted in the same manner.…”

Section: Translational Relevancementioning

confidence: 99%

Overexpression of PD-L1 Significantly Associates with Tumor Aggressiveness and Postoperative Recurrence in Human Hepatocellular Carcinoma

Gao

Wang²,

Qiu³

et al. 2009

Clinical Cancer Research

736

520

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Purpose: The aberrant expression of programmed cell death 1ligands 1and 2 (PD-Ls) on tumor cells dampens antitumor immunity, resulting in tumor immune evasion. In this study, we investigated the expression of PD-Ls in human hepatocellular carcinoma (HCC) to define their prognostic significance after curative surgery. Experimental Design: Immunohistochemistry was used to investigate PD-Ls expression as well as granzyme B + cytotoxic and FoxP3 + regulatory T cell infiltration on tissue microarrays containing 240 randomly selected HCC patients who underwent surgery. The results were further verified in an independent cohort of 125 HCC patients. PD-Ls expression on HCC cell lines was detected by Western blot assay. Results: Patients with higher expression of PD-L1 had a significantly poorer prognosis than patients with lower expression. Although patients with higher expression of PD-L2 also had a poorer survival, the difference in recurrence was not statistically significant. Multivariate analysis identified tumor expression of PD-L1 as an independent predictor for postoperative recurrence. No correlation was found between PD-Ls expression and granzyme B + lymphocyte infiltration, whereas a significant positive correlation was detected between PD-Ls expression and FoxP3 + lymphocyte infiltration. In addition, tumor-infiltrating cytotoxic and regulatory T cells were also independent prognosticators for both survival and recurrence. The prognostic value of PD-L1 expression was validated in the independent data set. Conclusion: Our data suggest for the first time that PD-L1 status may be a new predictor of recurrence for HCC patients and provide the rationale for developing a novel therapy of targeting the PD-L1/PD-1pathway against this fatal malignancy.

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“…Time to recurrence was calculated from the date of the operation to the date of recurrence. Treatment modalities after relapse were administered according to a uniform guideline as previously described (5,11,12). Briefly, when a diagnosis of LNM was made, external beam radiotherapy was focused on the involved lymph node.…”

Section: Follow-up and Postoperative Treatmentmentioning

confidence: 99%

Gene Expression Profiling of Fixed Tissues Identified Hypoxia-Inducible Factor-1α, VEGF, and Matrix Metalloproteinase-2 as Biomarkers of Lymph Node Metastasis in Hepatocellular Carcinoma

Xiang

Ren

Fan

et al. 2011

Clinical Cancer Research

Self Cite

112

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Purpose: Hepatocellular carcinoma (HCC) most often develops in patients infected with hepatitis B or hepatitis C virus. Differential gene expression profiling is useful for investigating genes associated with lymph node metastasis (LNM). We screened genes to identify potential biomarkers for LNM in HCC.Experimental Design: RNA was extracted from formalin-fixed specimens of paired intratumoral and peritumoral tissues of patients with lymph node-positive (n ¼ 36) or negative (n ¼ 36) HCC. A cDNAmediated annealing, selection, extension, and ligation assay was done with an array of 502 known cancerrelated genes to identify differentially expressed genes in 20 pairs of patients with or without LNM. Candidate biomarkers were evaluated by using immunohistochemistry and tissue microarrays in an independent cohort of 309 HCC patients who had undergone hepatectomy. Of the 309 patients, 235 (76.1%) patients were infected with hepatitis B.Results: Compared with lymph node-negative patients, lymph node-positive patients had 17 overexpressed genes and 19 underexpressed genes in intratumoral tissues, and 25 overexpressed genes and 22 underexpressed genes in peritumoral tissues. Hypoxia-inducible factor (HIF)-1a, VEGF, and matrix metalloproteinase (MMP)-2 were selected for analysis in the cohort of 309 HCC patients. We found that intratumoral protein levels of HIF-1a, VEGF, and MMP-2 were independent risk factors for developing LNM.Conclusion: We identified 83 cancer genes that were differentially expressed in lymph node-positive and lymph node-negative HCC. Our findings show that the combination of intratumoral HIF-1a, VEGF, and MMP-2 may be useful as a molecular prediction model for LNM.

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Two pathologic types of hepatocellular carcinoma with lymph node metastasis with distinct prognosis on the basis of CK19 expression in tumor

Cited by 74 publications

References 26 publications

Fibrolamellar carcinoma of the liver exhibits immunohistochemical evidence of both hepatocyte and bile duct differentiation

Fibrolamellar carcinoma of the liver exhibits immunohistochemical evidence of both hepatocyte and bile duct differentiation

Overexpression of PD-L1 Significantly Associates with Tumor Aggressiveness and Postoperative Recurrence in Human Hepatocellular Carcinoma

Gene Expression Profiling of Fixed Tissues Identified Hypoxia-Inducible Factor-1α, VEGF, and Matrix Metalloproteinase-2 as Biomarkers of Lymph Node Metastasis in Hepatocellular Carcinoma

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