Clinical features and prognosis of patients with extrahepatic metastases from hepatocellular carcinoma

Uka, Kiminori; Aikata, Hiroshi; Takaki, Shintaro; Shirakawa, Hiroo; Jeong, Soo Cheol; Yamashina, Keitaro; Hiramatsu, Akira; Kodama, Hiroyuki; Takahashi, Shoichi; Chayama, Kazuaki

doi:10.3748/wjg.v13.i3.414

Cited by 392 publications

(389 citation statements)

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“…Exclusion of metastatic hepatocellular carcinoma was clinically relevant because both hepatitis C patients were at risk to develop hepatocellular carcinoma and lung is the most common site for extrahepatic metastasis. 21 However, CT scans showed no liver masses in both hepatitis C patients and the immunophenotypic signature was inconsistent with hepatocellular carcinoma (Table 2) TTF-1 immunostains localize to the cytoplasm in both hepatocellular carcinoma and hepatoid adenocarcinoma of lung, unlike nuclear localization in conventional adenocarcinoma of lung, thyroid carcinoma and neuroendocrine carcinoma. Cytoplasmic TTF-1 staining in hepatocytes is due to a crossreacting epitope on a cytoplasmic protein with a molecular weight of 160 000.…”

Section: Discussionmentioning

confidence: 99%

Hepatoid adenocarcinoma of the lung: report of five cases and review of the literature

et al. 2014

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The current diagnostic criteria for hepatoid adenocarcinoma of lung include typical acinar or papillary adenocarcinoma and a component resembling hepatocellular carcinoma and expressing a-fetoprotein (AFP). Distinguishing hepatoid adenocarcinoma of lung from hepatocellular carcinoma metastatic to lung is difficult in patients with both lung and liver masses and in patients at risk for lung and liver cancer because of smoking and viral hepatitis, respectively. We studied morphologic features of hepatoid adenocarcinoma of lung and established an immunohistochemical panel to facilitate distinction of hepatoid adenocarcinoma of lung from hepatocellular carcinoma metastatic to lung. Five cases of hepatoid adenocarcinoma of lung were stained with hematoxylin and eosin and mucicarmine for histomorphologic evaluation. The 14-marker immunohistochemical profile was established for hepatoid adenocarcinoma of lung and compared with that of hepatocellular carcinoma. Two cases of hepatoid adenocarcinoma of lung had signet-ring cell components. Three cases were pure hepatoid adenocarcinoma without components of acinar or papillary adenocarcinoma, signet-ring cells or neuroendocrine carcinoma. Like hepatocellular carcinoma, hepatoid adenocarcinoma of lung expresses CK8 (5/5), CK18 (5/5), AFP (3/5) and HepPar1 (5/5), shows cytoplasmic staining with TTF-1 (5/5) and does not express CK14 (0/5). Unlike hepatocellular carcinoma, it expresses CK5/6 (1/5), CK7 (3/5), CK19 (4/5), CK20 (1/5), HEA125 (5/5), MOC31 (5/5), monoclonal CEA (3/5) and napsin A (1/5). An immunohistochemical panel that includes a variety of cytokeratins, monoclonal CEA and EpCAM markers (HEA125 and MOC31) facilitates distinction of hepatoid adenocarcinoma of lung from hepatocellular carcinoma metastatic to lung, especially when correlated with clinical and radiologic findings. We propose modification of the current diagnostic criteria for hepatoid adenocarcinoma of lung. Tumor composition can be either pure hepatoid adenocarcinoma or hepatoid adenocarcinoma with components of typical acinar or papillary adenocarcinoma, signet-ring cells or neuroendocrine carcinoma. AFP expression is not requisite for diagnosis as long as other markers of hepatic differentiation are expressed.

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Section: Discussionmentioning

confidence: 99%

Hepatoid adenocarcinoma of the lung: report of five cases and review of the literature

et al. 2014

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“…20 Another study demonstrated that 15% of patients were found to have extrahepatic metastases, and lung metastasis was detected in 6% of 995 consecutive HCC patients. 21 When compared with these data from large-scale studies, the frequency of lung metastasis among responders to sorafenib seems quite high. In addition, a poorly differentiated histological type tended to be more common among responders, although the correlation was not significant.…”

Section: Discussionmentioning

confidence: 99%

FGF3/FGF4 amplification and multiple lung metastases in responders to sorafenib in hepatocellular carcinoma

et al. 2013

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The response rate to sorafenib in hepatocellular carcinoma (HCC) is relatively low (0.7%-3%), however, rapid and drastic tumor regression is occasionally observed. The molecular backgrounds and clinico-pathological features of these responders remain largely unclear. We analyzed the clinical and molecular backgrounds of 13 responders to sorafenib with significant tumor shrinkage in a retrospective study. A comparative genomic hybridization analysis using one frozen HCC sample from a responder demonstrated that the 11q13 region, a rare amplicon in HCC including the loci for FGF3 and FGF4, was highly amplified. A real-time polymerase chain reaction-based copy number assay revealed that FGF3/ FGF4 amplification was observed in three of the 10 HCC samples from responders in which DNA was evaluable, whereas amplification was not observed in 38 patients with stable or progressive disease (P 5 0.006). Fluorescence in situ hybridization analysis confirmed FGF3 amplification. In addition, the clinico-pathological features showed that multiple lung metastases (5/13, P 5 0.006) and a poorly differentiated histological type (5/13, P 5 0.13) were frequently observed in responders. A growth inhibitory assay showed that only one FGF3/FGF4-amplified and three FGFR2-amplified cancer cell lines exhibited hypersensitivity to sorafenib in vitro. Finally, an in vivo study revealed that treatment with a low dose of sorafenib was partially effective for stably and exogenously expressed FGF4 tumors, while being less effective in tumors expressing EGFP or FGF3. Conclusion: FGF3/FGF4 amplification was observed in around 2% of HCCs. Although the sample size was relatively small, FGF3/FGF4 amplification, a poorly differentiated histological type, and multiple lung metastases were frequently observed in responders to sorafenib. Our findings may provide a novel insight into the molecular background of HCC and sorafenib responders, warranting further prospective biomarker studies.

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“…However, our data support the use of HAIC in HCC patients with extrahepatic metastasis because extrahepatic metastasis was not a significant factor in survival (Figure 3). The mortality in advanced HCC is related to intrahepatic tumors, and the leading cause of death in these patients is intrahepatic tumor progression [27,28] . In this study, all patients had advanced intrahepatic HCC with vascular invasion.…”

Section: Discussionmentioning

confidence: 99%

Hepatic arterial infusion chemotherapy in hepatocellular carcinoma with portal vein tumor thrombosis

Song

Bae²,

Song³

et al. 2013

WJG

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AIM:To evaluate the prognostic factors and efficacy of hepatic arterial infusion chemotherapy in hepatocellular carcinoma with portal vein tumor thrombosis. METHODS:Fifty hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT) were treated using hepatic arterial infusion chemotherapy (HAIC) via a subcutaneously implanted port. The epirubicin-cisplatin-5-fluorouracil (ECF) chemotherapeutic regimen consisted of 35 mg/m 2 epirubicin on day 1, 60 mg/m 2 cisplatin for 2 h on day 2, and 500 mg/m 2 5-fluorouracil for 5 h on days 1-3. The treatments were repeated every 3 or 4 wk. RESULTS:Three (6%) of the 50 patients achieved a complete response (CR), 13 (26%) showed partial responses (PR), and 22 (44%) had stable disease (SD).The median survival and time to progression were 7 and 2 mo, respectively. After 2 cycles of HAIC, CR was achieved in 1 patient (2%), PR in 10 patients (20%) and SD in 26 patients (52%). Significant pre-treatment prognostic factors were a tumor volume of < 400 cm 3 (P = 0.01) and normal levels of protein induced by vitamin K absence or antagonist (PIVKA)-Ⅱ (P = 0.022). After 2 cycles of treatment, disease control (CR + PR + SD) (P = 0.001), PVTT response (P = 0.003) and α-fetoprotein reduction of over 50% (P = 0.02) were independent factors for survival. Objective response (CR + PR), disease control, PVTT response, and combination therapy during the HAIC were also significant prognostic factors. Adverse events were tolerable and successfully managed. CONCLUSION: HAIC may be an effective treatment modality for advanced HCC with PVTT in patients with tumors < 400 cm 3 and good prognostic factors.© 2013 Baishideng. All rights reserved. Key words: Hepatocellular carcinoma; Hepatic arterial infusion chemotherapy; Portal vein tumor thrombosisCore tip: The aim of this study was to investigate the prognostic factors of hepatic arterial infusion chemotherapy in advanced hepatocellular carcinoma patients with portal vein tumor thrombosis. The primary findings of this study were as follows: (1) The median survival and time to progression were 7 and 2 mo, respectively; (2) A tumor volume of < 400 cm 3 and protein induced by vitamin K absence or antagonist-Ⅱ were independent pre-treatment prognostic factors; (3) Disease control and ≥ 50% tumor marker reduction were significant prognostic factors after the second cycle of hepatic arterial infusion chemotherapy (HAIC); and (4) Objective tumor response, disease control and portal vein tumor thrombosis response were independent post-treatment prognostic factors at the end of the HAIC. ORIGINAL ARTICLE

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Clinical features and prognosis of patients with extrahepatic metastases from hepatocellular carcinoma

Cited by 392 publications

References 24 publications

Hepatoid adenocarcinoma of the lung: report of five cases and review of the literature

Hepatoid adenocarcinoma of the lung: report of five cases and review of the literature

FGF3/FGF4 amplification and multiple lung metastases in responders to sorafenib in hepatocellular carcinoma

Hepatic arterial infusion chemotherapy in hepatocellular carcinoma with portal vein tumor thrombosis

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