{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T12:55:24Z","timestamp":1760100924075,"version":"3.41.0"},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,7,22]],"date-time":"2016-07-22T00:00:00Z","timestamp":1469145600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,7,22]],"date-time":"2016-07-22T00:00:00Z","timestamp":1469145600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Clinical manifestations between hepatocellular carcinoma (HCC) and extra-hepatic primary malignancy (EHPM) are lack of large-scale study. We enrolled 14555 HCC patients between 1986 and 2013 retrospectively. The EHPM was classified as prior, synchronous and metachronous group based on before, within and after 6 months of HCC diagnosis, respectively. The incidence rate of EHPM is 3.91% (95% confidence interval [CI]: 3.60\u20134.23%). Urogenital cancers, kidney and bladder, were at unexpected higher ranks. Older in age, Child-Pugh A cirrhosis, negativity of HBsAg and anti-HCV, and earlier BCLC staging are independent factors associated with EHPM. The survival rates of EHPM improve over time and also better than HCC-alone. Cox proportional-hazards regression shows independent poor prognostic factors are age &gt;60, male, AFP levels \u2265400\u2009ng\/ml, positivity of HBsAg, Child-Pugh B vs. A, Non-metachronous group, respectively, treated with local ablation, transcatheter arterial embolization, radiotherapy and supportive care vs. surgery, respectively, TNM stage IIIA vs. I, and BCLC stages A, B, C and D vs. 0, respectively. Survival of EHPM improve could be explained by early diagnosis and improve treatment of cancers.<\/jats:p>","DOI":"10.1038\/srep30156","type":"journal-article","created":{"date-parts":[[2016,7,22]],"date-time":"2016-07-22T09:13:18Z","timestamp":1469178798000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Hepatocellular Carcinoma associated with Extra-hepatic Primary Malignancy: its Secular change, Clinical Manifestations and Survival"],"prefix":"10.1038","volume":"6","author":[{"given":"Kwong Ming","family":"Kee","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing-Houng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chih-Chi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu-Fan","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sheng-Nan","family":"Lu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2016,7,22]]},"reference":[{"key":"BFsrep30156_CR1","unstructured":"National Cancer Institute. SEER Cancer Statistics Review, 1975\u20132007. http:\/\/seer.cancer.gov\/csr\/1975_2007 (Cited in 15 September, 2014)."},{"key":"BFsrep30156_CR2","doi-asserted-by":"publisher","first-page":"2893","DOI":"10.1002\/ijc.25516","volume":"127","author":"J Ferlay","year":"2010","unstructured":"Ferlay, J. et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 127, 2893\u20132917, doi: 10.1002\/ijc.25516 (2010).","journal-title":"Int J Cancer"},{"key":"BFsrep30156_CR3","doi-asserted-by":"publisher","first-page":"1906","DOI":"10.1001\/2012.jama.11975","volume":"308","author":"CY Wu","year":"2012","unstructured":"Wu, C. Y. et al. Association between nucleoside analogues and risk of hepatitis B virus-related hepatocellular carcinoma recurrence following liver resection. JAMA 308, 1906\u20131914 (2012).","journal-title":"JAMA"},{"key":"BFsrep30156_CR4","first-page":"364","volume":"26","author":"T Riesz","year":"1979","unstructured":"Riesz, T., Jako, J. M. & Juhasz, J. Secondary malignant tumors accompanied by primary hepatocellular carcinoma. Acta hepato-gastroenterologica 26, 364\u2013367 (1979).","journal-title":"Acta hepato-gastroenterologica"},{"key":"BFsrep30156_CR5","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1111\/j.1600-0676.1987.tb00325.x","volume":"7","author":"DY Lin","year":"1987","unstructured":"Lin, D. Y. et al. Hepatocellular carcinoma associated with second primary malignancy. Liver 7, 106\u2013109 (1987).","journal-title":"Liver"},{"key":"BFsrep30156_CR6","first-page":"202","volume":"46","author":"CR Lai","year":"1990","unstructured":"Lai, C. R. & Liu, H. C. Hepatocellular carcinoma coexisted with second malignancy\u2013a study of 13 cases from a consecutive 440 autopsy cases of HCC. Zhonghua Yi Xue Za Zhi (Taipei) 46, 202\u2013207 (1990).","journal-title":"Zhonghua Yi Xue Za Zhi (Taipei)"},{"key":"BFsrep30156_CR7","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1007\/bf01888509","volume":"17","author":"M Kanematsu","year":"1992","unstructured":"Kanematsu, M. et al. Hepatocellular carcinoma with extrahepatic primary neoplasms. Gastrointestinal radiology 17, 53\u201357, doi: 10.1007\/bf01888509 (1992).","journal-title":"Gastrointestinal radiology"},{"key":"BFsrep30156_CR8","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1002\/1097-0142(19920101)69:1<45::AID-CNCR2820690110>3.0.CO;2-G","volume":"69","author":"K Takayasu","year":"1992","unstructured":"Takayasu, K. et al. A clinical and radiologic study of primary liver cancer associated with extrahepatic primary cancer. Cancer 69, 45\u201351 (1992).","journal-title":"Cancer"},{"key":"BFsrep30156_CR9","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1159\/000227383","volume":"51","author":"M Di Stasi","year":"1994","unstructured":"Di Stasi, M. et al. Extrahepatic primary malignant neoplasms associated with hepatocellular carcinoma: high occurrence of B cell tumors. Oncology 51, 459\u2013464 (1994).","journal-title":"Oncology"},{"key":"BFsrep30156_CR10","doi-asserted-by":"publisher","first-page":"2765","DOI":"10.1002\/1097-0142(19941115)74:10<2765::AID-CNCR2820741005>3.0.CO;2-Q","volume":"74","author":"UC Nzeako","year":"1994","unstructured":"Nzeako, U. C., Goodman, Z. D. & Ishak, K. G. Association of hepatocellular carcinoma in North American patients with extrahepatic primary malignancies. Cancer 74, 2765\u20132771 (1994).","journal-title":"Cancer"},{"key":"BFsrep30156_CR11","first-page":"128","volume":"80","author":"A Onitsuka","year":"1995","unstructured":"Onitsuka, A. et al. Clinical study on hepatocellular carcinoma with extrahepatic malignancies. International surgery 80, 128\u2013130 (1995).","journal-title":"International surgery"},{"key":"BFsrep30156_CR12","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1177\/030089169608200313","volume":"82","author":"V de Pangher Manzini","year":"1996","unstructured":"de Pangher Manzini, V. et al. Multiple primary malignant tumors in patients with hepatocellular carcinoma. A review of 29 patients. Tumori 82, 245\u2013248 (1996).","journal-title":"Tumori"},{"key":"BFsrep30156_CR13","first-page":"754","volume":"91","author":"M Shimada","year":"1996","unstructured":"Shimada, M. et al. Characteristics of hepatocellular carcinoma associated with extrahepatic primary malignancies in southern Japan. Am J Gastroenterol 91, 754\u2013758 (1996).","journal-title":"Am J Gastroenterol"},{"key":"BFsrep30156_CR14","doi-asserted-by":"publisher","first-page":"1424","DOI":"10.1111\/j.1440-1746.2009.05793.x","volume":"24","author":"M Fernandez-Ruiz","year":"2009","unstructured":"Fernandez-Ruiz, M. et al. Multiple primary malignancies in Spanish patients with hepatocellular carcinoma: analysis of a hospital-based tumor registry. J Gastroenterol Hepatol 24, 1424\u20131430, doi: 10.1111\/j.1440-1746.2009.05793.x (2009).","journal-title":"J Gastroenterol Hepatol"},{"key":"BFsrep30156_CR15","doi-asserted-by":"publisher","first-page":"495950","DOI":"10.1155\/2012\/495950","volume":"2012","author":"K Kai","year":"2012","unstructured":"Kai, K. et al. Analysis of Extrahepatic Multiple Primary Malignancies in Patients with Hepatocellular Carcinoma according to Viral Infection Status. International journal of hepatology 2012, 495950, doi: 10.1155\/2012\/495950 (2012).","journal-title":"International journal of hepatology"},{"key":"BFsrep30156_CR16","doi-asserted-by":"crossref","first-page":"E129","DOI":"10.1177\/000313481207800305","volume":"78","author":"E Tsujita","year":"2012","unstructured":"Tsujita, E. et al. Characteristics of extrahepatic second primary malignancies after hepatectomy for hepatocellular carcinoma in Japan. The American surgeon 78, E129\u2013E131 (2012).","journal-title":"The American surgeon"},{"key":"BFsrep30156_CR17","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1186\/1471-2407-12-148","volume":"12","author":"QA Zeng","year":"2012","unstructured":"Zeng, Q. A. et al. Clinical features and outcome of multiple primary malignancies involving hepatocellular carcinoma: A long-term follow-up study. BMC Cancer 12, 148, doi: 10.1186\/1471-2407-12-148 (2012).","journal-title":"BMC Cancer"},{"key":"BFsrep30156_CR18","doi-asserted-by":"publisher","first-page":"1085","DOI":"10.1111\/liv.12161","volume":"33","author":"A Hiraoka","year":"2013","unstructured":"Hiraoka, A. et al. Importance of screening for synchronous malignant neoplasms in patients with hepatocellular carcinoma: impact of FDG PET\/CT. Liver Int 33, 1085\u20131091, doi: 10.1111\/liv.12161 (2013).","journal-title":"Liver Int"},{"key":"BFsrep30156_CR19","first-page":"206","volume":"66","author":"LL Wong","year":"2007","unstructured":"Wong, L. L., Lurie, F. & Takanishi, D. M., Jr. Other primary neoplasms in patients with hepatocellular cancer: prognostic implications? Hawaii medical journal 66, 204, 206\u2013208 (2007).","journal-title":"Hawaii medical journal"},{"key":"BFsrep30156_CR20","doi-asserted-by":"publisher","first-page":"616","DOI":"10.1111\/liv.12103","volume":"33","author":"WC Wu","year":"2013","unstructured":"Wu, W. C. et al. Second primary cancers in patients with hepatocellular carcinoma: a nationwide cohort study in Taiwan. Liver Int 33, 616\u2013623, doi: 10.1111\/liv.12103 (2013).","journal-title":"Liver Int"},{"key":"BFsrep30156_CR21","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1016\/S0168-8278(01)00130-1","volume":"35","author":"J Bruix","year":"2001","unstructured":"Bruix, J. et al. Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL conference. European Association for the Study of the Liver. J Hepatol 35, 421\u2013430 (2001).","journal-title":"J Hepatol"},{"key":"BFsrep30156_CR22","doi-asserted-by":"publisher","first-page":"1208","DOI":"10.1002\/hep.20933","volume":"42","author":"J Bruix","year":"2005","unstructured":"Bruix, J. & Sherman, M. Management of hepatocellular carcinoma. Hepatology 42, 1208\u20131236, doi: 10.1002\/hep.20933 (2005).","journal-title":"Hepatology"},{"key":"BFsrep30156_CR23","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1159\/000151868","volume":"40","author":"H Krueger","year":"2008","unstructured":"Krueger, H., McLean, D. & Williams, D. Meaning of SPC. Prog Exp Tumor Res 40, 7\u201316, doi: 10.1159\/000151868 (2008).","journal-title":"Prog Exp Tumor Res"},{"key":"BFsrep30156_CR24","unstructured":"Edge, S. B. et al. AJCC cancer staging manual (7th ed). New York, NY: Springer, 2010. pp. 191-200."},{"key":"BFsrep30156_CR25","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1055\/s-2007-1007122","volume":"19","author":"JM Llovet","year":"1999","unstructured":"Llovet, J. M., Bru, C. & Bruix, J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 19, 329\u2013338, doi: 10.1055\/s-2007-1007122 (1999).","journal-title":"Semin Liver Dis"},{"key":"BFsrep30156_CR26","doi-asserted-by":"publisher","first-page":"1402","DOI":"10.1093\/jnci\/84.18.1402","volume":"84","author":"RE Tarone","year":"1992","unstructured":"Tarone, R. E. & Chu, K. C. Implications of birth cohort patterns in interpreting trends in breast cancer rates. J Natl Cancer Inst 84, 1402\u20131410 (1992).","journal-title":"J Natl Cancer Inst"},{"key":"BFsrep30156_CR27","doi-asserted-by":"publisher","first-page":"756","DOI":"10.1016\/j.ejca.2008.11.033","volume":"45","author":"DM Parkin","year":"2009","unstructured":"Parkin, D. M. & Bray, F. Evaluation of data quality in the cancer registry: principles and methods Part II. Completeness. Eur J Cancer 45, 756\u2013764, doi: 10.1016\/j.ejca.2008.11.033 (2009).","journal-title":"Eur J Cancer"},{"key":"BFsrep30156_CR28","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1016\/j.cgh.2010.10.014","volume":"9","author":"E Kalaitzakis","year":"2011","unstructured":"Kalaitzakis, E., Gunnarsdottir, S. A., Josefsson, A. & Bjornsson, E. Increased risk for malignant neoplasms among patients with cirrhosis. Clin Gastroenterol Hepatol 9, 168\u2013174, doi: 10.1016\/j.cgh.2010.10.014 (2011).","journal-title":"Clin Gastroenterol Hepatol"},{"key":"BFsrep30156_CR29","doi-asserted-by":"publisher","first-page":"1700","DOI":"10.1054\/bjoc.2001.2140","volume":"85","author":"V Bagnardi","year":"2001","unstructured":"Bagnardi, V., Blangiardo, M., La Vecchia, C. & Corrao, G. A meta-analysis of alcohol drinking and cancer risk. Br J Cancer 85, 1700\u20131705, doi: 10.1054\/bjoc.2001.2140 (2001).","journal-title":"Br J Cancer"},{"key":"BFsrep30156_CR30","doi-asserted-by":"publisher","first-page":"934","DOI":"10.1002\/lt.22307","volume":"17","author":"G Sapisochin","year":"2011","unstructured":"Sapisochin, G., Fidelman, N., Roberts, J. P. & Yao, F. Y. Mixed hepatocellular cholangiocarcinoma and intrahepatic cholangiocarcinoma in patients undergoing transplantation for hepatocellular carcinoma. Liver Transpl 17, 934\u2013942, doi: 10.1002\/lt.22307 (2011).","journal-title":"Liver Transpl"},{"key":"BFsrep30156_CR31","unstructured":"Taiwan Cancer Registry. Cancer Incidence rates in Taiwan, 1998\u20132002 & 2003\u20132007. http:\/\/cph.ntu.edu.tw\/main.php?Page=N2 (Cited in 15 September, 2014)."},{"key":"BFsrep30156_CR32","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1038\/nrclinonc.2013.41","volume":"10","author":"LB Travis","year":"2013","unstructured":"Travis, L. B., Demark Wahnefried, W., Allan, J. M., Wood, M. E. & Ng, A. K. Aetiology, genetics and prevention of secondary neoplasms in adult cancer survivors. Nature reviews. Clinical oncology 10, 289\u2013301, doi: 10.1038\/nrclinonc.2013.41 (2013).","journal-title":"Nature reviews. Clinical oncology"},{"key":"BFsrep30156_CR33","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1007\/s00535-007-2134-9","volume":"43","author":"CS Changchien","year":"2008","unstructured":"Changchien, C. S. et al. Analysis of 6381 hepatocellular carcinoma patients in southern Taiwan: prognostic features, treatment outcome, and survival. J Gastroenterol 43, 159\u2013170, doi: 10.1007\/s00535-007-2134-9 (2008).","journal-title":"J Gastroenterol"},{"key":"BFsrep30156_CR34","doi-asserted-by":"publisher","first-page":"1000","DOI":"10.1016\/j.ejca.2008.02.018","volume":"44","author":"JH Wang","year":"2008","unstructured":"Wang, J. H. et al. The efficacy of treatment schedules according to Barcelona Clinic Liver Cancer staging for hepatocellular carcinoma - Survival analysis of 3892 patients. Eur J Cancer 44, 1000\u20131006, doi: 10.1016\/j.ejca.2008.02.018 (2008).","journal-title":"Eur J Cancer"},{"key":"BFsrep30156_CR35","doi-asserted-by":"crossref","unstructured":"Kee, K. M. et al. Validation of the 7th Edition TNM Staging System for Hepatocellular Carcinoma: An Analysis of 8,828 Patients in a Single Medical Center. Dig Dis Sci, doi: 10.1007\/s10620-013-2716-8 (2013).","DOI":"10.1007\/s10620-013-2716-8"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep30156.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep30156","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep30156.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T03:54:07Z","timestamp":1749009247000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep30156"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,7,22]]},"references-count":35,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,7,28]]}},"alternative-id":["BFsrep30156"],"URL":"https:\/\/doi.org\/10.1038\/srep30156","relation":{},"ISSN":["2045-2322"],"issn-type":[{"type":"electronic","value":"2045-2322"}],"subject":[],"published":{"date-parts":[[2016,7,22]]},"assertion":[{"value":"3 June 2015","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 June 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 July 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"30156"}}