Background: Hepatocellular carcinoma (HCC) is known to metastasize. However, there are few reports on patients with metastasis at the time of HCC diagnosis. Aims: To evaluate the incidence and characteristics of extrahepatic metastasis patients presenting at baseline with noncurable, advanced HCC. Results: The total HCC cohort was initially dichotomized into 2 subcohorts, with (n = 214) and without (n = 719) extrahepatic metastasis (‘metastasis'), and patient baseline characteristics were compared. The main findings for patients with metastasis (22.9% of total cohort) compared with other, nonmetastatic patients were: more advanced tumors, as judged by larger tumor diameters, more tumor multifocality and percent with portal vein thrombosis, higher blood α-fetoprotein and des γ-carboxy prothrombin levels and alkaline phosphatase (ALKP), but not bilirubin levels, and a lower incidence of cirrhosis. There was a strong correlation between increases in tumor size and percent of patients with metastasis. A subset of patients with larger tumors was identified with low blood ALKP levels and better survival. Survival in the total metastasis cohort was lower than in the non-metastasis cohort, as expected, but only in patients with smaller tumors. In patients with larger tumors, survival with or without metastasis was similar and poor. Conclusions: There was a lower incidence of cirrhosis in HCC patients with metastasis, and they had larger and more aggressive primary tumors. Patients with smaller, but not larger, tumors and metastasis had worse prognosis than patients without metastasis. A distinct subset of metastatic patients was identified that had better prognosis and low ALKP levels.

1.
Senthilnathan S, Memon K, Lewandowski RJ, Kulik L, et al: Extra-hepatic metastases occur in a minority of hepatocellular carcinoma patients treated with loco-regional therapies: analyzing patterns of progression in 285 patients. Hepatology 2012;55:1432-1442.
2.
Natsuizaka M, Omura T, Akaike T, Kuwata Y, et al: Clinical features of hepatocellular carcinoma with extrahepatic metastases. J Gastroenterol Hepatol 2005;20:1781-1787.
3.
Kanda M, Tateishi R, Yoshida H, Sato T, et al: Extrahepatic metastasis of hepatocellular carcinoma: incidence and risk factors. Liver Int 2008;28:1183-1185.
4.
Otegbayo JA, Atalabi OM, Yakubu A: Clinicoradiologic and sonographic patterns of metastasis in hepatocellular carcinoma. J Natl Med Assoc 2006;98:1620-1622.
5.
Hong SS, Kim TK, Sung KB, Kim PN, et al: Extrahepatic spread of hepatocellular carcinoma: a pictorial review. Eur Radiol 2003;13:874-882.
6.
Lee YT, Geer DA: Primary liver cancer: pattern of metastases. J Surg Oncol 1987;36:26-31.
7.
Olubuyide IO: Pattern of metastasis of primary liver cancer at autopsy: an African series. Trop Gastroenterol 1991;23:67-72.
8.
Sawabe M, Nakamura T, Kanno J, Kasuga T: Analysis of morphological factors of hepatocellular carcinoma in 98 autopsy cases with respect to pulmonary metastasis. Acta Pathol Jpn 1987;37:1389-1404.
9.
Katyal S, Oliver JH, Peterson MS, Ferris JV, Carr BI, Baron RL: Extrahepatic metastases of hepatocellular carcinoma. Radiology 2000;216:698-703.
10.
Uchino K, Tateishi R, Shiina S, Kanda M, et al: Hepatocellular carcinoma with extrahepatic metastasis: clinical features and prognostic factors. Cancer 2011;117:4475-4483.
11.
Yang Y, Nagano H, Ota H, Morimoto O, et al: Patterns and clinicopathologic features of extrahepatic recurrence of hepatocellular carcinoma after curative resection. Surgery 2007;141:196-202.
12.
Ochiai T, Ikoma H, Okamoto K, Kokuba Y, et al: Clinicopathologic features and risk factors for extrahepatic recurrences of hepatocellular carcinoma after curative resection. World J Surg 2012;36:136-143.
13.
Schlitt HJ, Neipp M, Weimann A, Oldhafer KJ, et al: Recurrence patterns of hepatocellular and fibrolamellar carcinoma after liver transplantation. J Clin Oncol 1999;17:324-331.
14.
Kornberg A, Küpper B, Tannapfel A, Katenkamp K, et al: Long-term survival after recurrent hepatocellular carcinoma in liver transplant patients: clinical patterns and outcome variables. Eur J Surg Oncol 2010;36:275-280.
15.
Ferris JV, Baron RL, Marsh JW Jr, Oliver JH, Carr BI, Dodd GD: Recurrent hepatocellular carcinoma after liver transplantation: spectrum of CT findings and recurrence patterns. Radiology 1996;198:233-238.
16.
Ishii T, Hatano E, Yasuchika K, Taura K, et al: High risk of lung metastasis after resection of hepatocellular carcinoma more than 7 cm in diameter. Surg Today 2014;44:1900-1905.
17.
Tanaka K, Shimada H, Matsuo K, Takeda K, et al: Clinical features of hepatocellular carcinoma developing extrahepatic recurrences after curative resection. World J Surg 2008;32:1738-1747.
18.
Yang Y, Nagano H, Ota H, Morimoto O, et al: Patterns and clinicopathologic features of extrahepatic recurrence of hepatocellular carcinoma after curative resection. Surgery 2007;141:196-202.
19.
Tanaka K, Shimada H, Matsuo K, Takeda K, et al: Clinical features of hepatocellular carcinoma developing extrahepatic recurrences after curative resection. World J Surg 2008;32:1738-1747.
20.
Otegbayo JA, Atalabi OM, Yakubu A: Clinicoradiologic and sonographic patterns of metastasis in hepatocellular carcinoma. J Natl Med Assoc 2006;98:1620-1622.
21.
Uka K, Aikata H, Takaki S, et al: Clinical features and prognosis of patients with extrahepatic metastases from hepatocellular carcinoma. World J Gastroenterol 2007;13:414-420.
22.
Yoo DJ, Kim KM, Jin YJ, Shim JH, et al: Clinical outcome of 251 patients with extrahepatic metastasis at initial diagnosis of hepatocellular carcinoma: does transarterial chemoembolization improve survival in these patients? J Gastroenterol Hepatol 2011;26:145-154.
23.
Carr BI, Irish W, Federle MP: Chemoembolization for unresectable hepatocellular carcinoma in patients with or without portal vein thrombosis. Hepatogastroenterology 2010;57:1375-1381.
24.
Carr BI, Kondragunta V, Buch SC, Branch RA: Therapeutic equivalence in survival for hepatic arterial chemoembolization and yttrium 90 microsphere treatments in unresectable hepatocellular carcinoma: a two-cohort study. Cancer 2010;116:1305-1314.
25.
Yoon YS, Kim HK, Kim J, Choi YS, et al: Long-term survival and prognostic factors after pulmonary metastasectomy in hepatocellular carcinoma. Ann Surg Oncol 2010;17:2795-2801.
26.
Poon RT, Fan ST, O'Suilleabhain CB, Wong J: Aggressive management of patients with extrahepatic and intrahepatic recurrences of hepatocellular carcinoma by combined resection and locoregional therapy. J Am Coll Surg 2002;195:311-318.
27.
Nakagawa T, Kamiyama T, Nakanishi K, Yokoo H, et al: Pulmonary resection for metastases from hepatocellular carcinoma: factors influencing prognosis. J Thorac Cardiovasc Surg 2006;131:1248-1254.
28.
Momoi H, Shimahara Y, Terajima H, Iimuro Y, et al: Management of adrenal metastasis from hepatocellular carcinoma. Surg Today 2002;32:1035-1041.
29.
Lee CH, Lin YJ, Lin CC, Yen CL, et al: Pretreatment platelet count early predicts extrahepatic metastasis of human hepatoma. Liver Int 2015;35:2327-2336.
30.
Addario L, Tritto G, Cavaglià E, Amodio F, et al: Preserved liver function, portal thrombosis and absence of oesophageal varices are risk factors for metastasis of hepatocellular carcinoma. Dig Liver Dis 2011;43:319-324.
31.
Seymour K, Charnley RM: Evidence that metastasis is less common in cirrhotic than normal liver: a systematic review of post-mortem case-control studies. Br J Surg 1999;86:1237-1242.
32.
Carr BI, Guerra V: Hepatocellular carcinoma size: platelets, γ-glutamyl transpeptidase, and alkaline phosphatase. Oncology 2013;85:153-159.
33.
Carr BI, Lin CY, Lu SN: Platelet-related phenotypic patterns in hepatocellular carcinoma patients. Semin Oncol 2014;41:415-421.
34.
Myszczyszyn A, Czarnecka AM, Matak D, et al: The role of hypoxia and cancer stem cells in renal cell carcinoma pathogenesis. Stem Cell Rev 2015;11:919-943.
35.
Tian Q, Xue Y, Zheng W, Sun R, et al: Overexpression of hypoxia-inducible factor 1α induces migration and invasion through Notch signaling. Int J Oncol 2015;47:728-738.
36.
Liu L, Zhu XD, Wang WQ, Shen Y, et al: Activation of beta-catenin by hypoxia in hepatocellular carcinoma contributes to enhanced metastatic potential and poor prognosis. Clin Cancer Res 2010;16:2740-2750.
37.
Dvorchik I, Carr BI: A simple prognostic scoring system for patients with unresectable hepatocellular carcinoma treated by chemo-embolization. Cancer Detect Prev 2007;31:154-160.
38.
Tournoux-Facon C, Paoletti X, Barbare JC, Bouché O, et al: Development and validation of a new prognostic score of death for patients with hepatocellular carcinoma in palliative setting. J Hepatol 2011;54:108-114.
39.
Piras-Straub K, Khairzada K, Gerken G, Saner F, et al: Glutamate dehydrogenase and alkaline phosphatase as very early predictors of hepatocellular carcinoma recurrence after liver transplantation. Digestion 2015;91:117-127.
40.
Song Y, Pan G, Chen L, Ma S, et al: Loss of ATOH8 increases stem cell features of hepatocellular carcinoma cells. Gastroenterology 2015;149:1068-1081.
41.
Couto OF, Dvorchik I, Carr BI: Causes of death in patients with unresectable hepatocellular carcinoma. Dig Dis Sci 2007;52:3285-3289.
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