{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T20:13:54Z","timestamp":1791663234999,"version":"4.3.4"},"reference-count":43,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2019,10,19]],"date-time":"2019-10-19T00:00:00Z","timestamp":1571443200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005795","name":"Chang Gung Memorial Hospital, Linkou","doi-asserted-by":"publisher","award":["CMRPG3G1301"],"award-info":[{"award-number":["CMRPG3G1301"]}],"id":[{"id":"10.13039\/501100005795","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005795","name":"Chang Gung Memorial Hospital, Linkou","doi-asserted-by":"publisher","award":["CMRPG3I0301"],"award-info":[{"award-number":["CMRPG3I0301"]}],"id":[{"id":"10.13039\/501100005795","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ministry of Science and Technology, Taiwan, R.O.C.","award":["MOST 107-2314-B-182A-119- \/ NMRPG3H0291"],"award-info":[{"award-number":["MOST 107-2314-B-182A-119- \/ NMRPG3H0291"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Introduction: serum alpha-fetoprotein (AFP) was routinely employed as a tumor marker for screening, diagnosis, and treatment follow-up of hepatocellular carcinoma (HCC). However, a substantial proportion of HCC patients had normal AFP level even at an advanced disease status. Few studies to date had tried to explore the nature and behavior of this normal AFP HCC (N-HCC). The purpose of this study was to investigate the clinicopathological characteristics and survival outcome of N-HCC after operation. In addition, potential tumor markers for N-HCC were also sought in an attempt to augment diagnostic ability. Methods: between 2005 and 2015, patients with hepatocellular carcinoma who were treated with hepatectomy in Chang Gung Memorial Hospital Linkou branch were divided into two groups according to their preoperative serum AFP level (&lt;15 ng\/mL: NHCC; \u226515 ng\/mL: abnormal AFP HCC (A-HCC)). Patient demographic data and clinicopathological variables were collected. Kaplan\u2013Meier and Cox regression multivariate analyses were performed to identify significant risk factors for disease-free survival (DFS) and overall survival (OS) for N-HCC. ELISA and immunohistochemical (IHC) studies were employed to determine the diagnostic accuracy of various tumor markers. Results: a total of 1616 patients (78% male) who underwent liver resection for HCC were included in this study. Of them, 761 patients (47.1%) were N-HCC. N-HCC patients were significantly older with more comorbidities and less hepatitis virus infections. Furthermore, N-HCC had fewer early recurrences (49.6% vs. 60.8%, p &lt; 0.001) and better DFS (44.6 months vs. 23.6 months, p &lt; 0.001) and OS (94.5 months vs. 81.7 months, p &lt; 0.001). Both ELISA and IHC studies demonstrated that glypican-3 (GPC3) would be a promising diagnostic tumor marker for N-HCC. Conclusion: N-HCC patients were significantly older and had less hepatitis virus infections or cirrhosis. Their tumors tended to be smaller, less vascular invaded, and well-differentiated. The carcinogenesis of N-HCC may thus not be identical to that of typical HCC. GPC3 would be a promising tumor marker for diagnosing N-HCC. Further study is warranted to validate our findings.<\/jats:p>","DOI":"10.3390\/jcm8101736","type":"journal-article","created":{"date-parts":[[2019,10,21]],"date-time":"2019-10-21T03:40:29Z","timestamp":1571629229000},"page":"1736","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":70,"title":["Normal Alpha-Fetoprotein Hepatocellular Carcinoma: Are They Really Normal?"],"prefix":"10.3390","volume":"8","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6853-4557","authenticated-orcid":false,"given":"Chao-Wei","family":"Lee","sequence":"first","affiliation":[{"name":"Division of General Surgery, Department of Surgery, Linkou Chang Gung Memorial Hospital, Taoyuan City 333, Taiwan"},{"name":"Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan City 333, Taiwan"},{"name":"College of Medicine, Chang Gung University, Taoyuan City 333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsin-I","family":"Tsai","sequence":"additional","affiliation":[{"name":"Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan City 333, Taiwan"},{"name":"College of Medicine, Chang Gung University, Taoyuan City 333, Taiwan"},{"name":"Department of Anesthesiology, Linkou Chang Gung Memorial Hospital, Taoyuan City 333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Chen","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of General Surgery, Department of Surgery, Linkou Chang Gung Memorial Hospital, Taoyuan City 333, Taiwan"},{"name":"College of Medicine, Chang Gung University, Taoyuan City 333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu-Wei","family":"Huang","sequence":"additional","affiliation":[{"name":"College of Medicine, Chang Gung University, Taoyuan City 333, Taiwan"},{"name":"Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, Taoyuan City 333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cheng-Yu","family":"Lin","sequence":"additional","affiliation":[{"name":"College of Medicine, Chang Gung University, Taoyuan City 333, Taiwan"},{"name":"Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, Taoyuan City 333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Chung","family":"Hsieh","sequence":"additional","affiliation":[{"name":"College of Medicine, Chang Gung University, Taoyuan City 333, Taiwan"},{"name":"Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, Taoyuan City 333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tony","family":"Kuo","sequence":"additional","affiliation":[{"name":"College of Medicine, Chang Gung University, Taoyuan City 333, Taiwan"},{"name":"Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, Taoyuan City 333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Wei","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Medicine, Chang Gung University, Taoyuan City 333, Taiwan"},{"name":"Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, Taoyuan City 333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6980-7123","authenticated-orcid":false,"given":"Ming-Chin","family":"Yu","sequence":"additional","affiliation":[{"name":"Division of General Surgery, Department of Surgery, Linkou Chang Gung Memorial Hospital, Taoyuan City 333, Taiwan"},{"name":"Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan City 333, Taiwan"},{"name":"College of Medicine, Chang Gung University, Taoyuan City 333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,10,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"87","DOI":"10.3322\/caac.21262","article-title":"Global cancer statistics, 2012","volume":"65","author":"Torre","year":"2015","journal-title":"CA A Cancer J. 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