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Open AccessArticle

Normal Alpha-Fetoprotein Hepatocellular Carcinoma: Are They Really Normal?

by Chao-Wei Lee 1,2,3, Hsin-I Tsai 2,3,4, Wei-Chen Lee 1,3, Shu-Wei Huang 3,5, Cheng-Yu Lin 3,5, Yi-Chung Hsieh 3,5, Tony Kuo 3,5, Chun-Wei Chen 3,5,*,† and Ming-Chin Yu 1,2,3,*,†
1
Division of General Surgery, Department of Surgery, Linkou Chang Gung Memorial Hospital, Taoyuan City 333, Taiwan
2
Graduate Institute of Clinical Medical Sciences, Chang Gung University, Taoyuan City 333, Taiwan
3
College of Medicine, Chang Gung University, Taoyuan City 333, Taiwan
4
Department of Anesthesiology, Linkou Chang Gung Memorial Hospital, Taoyuan City 333, Taiwan
5
Department of Gastroenterology and Hepatology, Linkou Chang Gung Memorial Hospital, Taoyuan City 333, Taiwan
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
J. Clin. Med. 2019, 8(10), 1736; https://doi.org/10.3390/jcm8101736
Received: 30 September 2019 / Revised: 12 October 2019 / Accepted: 17 October 2019 / Published: 19 October 2019
(This article belongs to the Section Gastroenterology & Hepatopancreatobiliary Medicine)
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 (<15 ng/mL: NHCC; ≥15 ng/mL: abnormal AFP HCC (A-HCC)). Patient demographic data and clinicopathological variables were collected. Kaplan–Meier 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 < 0.001) and better DFS (44.6 months vs. 23.6 months, p < 0.001) and OS (94.5 months vs. 81.7 months, p < 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. View Full-Text
Keywords: hepatocellular carcinoma; hepatoma; normal alpha-fetoprotein; glypican 3 hepatocellular carcinoma; hepatoma; normal alpha-fetoprotein; glypican 3
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MDPI and ACS Style

Lee, C.-W.; Tsai, H.-I.; Lee, W.-C.; Huang, S.-W.; Lin, C.-Y.; Hsieh, Y.-C.; Kuo, T.; Chen, C.-W.; Yu, M.-C. Normal Alpha-Fetoprotein Hepatocellular Carcinoma: Are They Really Normal? J. Clin. Med. 2019, 8, 1736.

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