Abstract
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.
Highlights
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver with an estimated annual death incidence of approximately 700,000 worldwide [1]
We found that normal AFP HCC (N-HCC) patients were generally older (P = 0.020) with male predominance (P = 0.001), having more co-morbidities such as diabetes mellitus (P < 0.001), and having less hepatitis B virus (HBV) infection (P < 0.001) (Table 1)
The current study demonstrated that the clinicopathological characteristics of N-HCC were different from those of AFP HCC (A-HCC) in many aspects
Summary
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver with an estimated annual death incidence of approximately 700,000 worldwide [1]. Chronic liver disease, and liver cirrhosis are most common etiologies of HCC. Curative treatments for early-stage lesions have been improved dramatically, few alternatives exist for late-stage HCC [3]. Effective screening and accurate early diagnosis, subsequently, are mandatory to optimize the outcome of patients with HCC. The diagnosis of HCC nowadays relies primarily on serum biomarkers and radiologic examinations. Common radiologic examinations employed include ultrasonography (US), computed tomography [6], angiography, and magnetic resonance imaging (MRI). The nature of operator-dependence for US and contrast/radiation exposure for CT/Angiography/MRI has limited the value of these tests for regular screening and early diagnosis. In order to achieve early diagnosis and improve clinical outcomes, the identification of a reliable serum biomarker or a combination of markers is of paramount importance
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