Observational Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Jun 15, 2021; 13(6): 600-611
Published online Jun 15, 2021. doi: 10.4251/wjgo.v13.i6.600
Serum vascular endothelial growth factor as a tumor marker for hepatocellular carcinoma in hepatitis C virus-related cirrhotic patients
Ahmed Alzamzamy, Huda Elsayed, Mona Abd Elraouf, Hanan Eltoukhy, Tarek Megahed, Ashraf Aboubakr
Ahmed Alzamzamy, Ashraf Aboubakr, Department of Gastroenterology and Hepatology, Military Medical Academy, Cairo 11841, Egypt
Ahmed Alzamzamy, Ashraf Aboubakr, Department of Gastroenterology and Hepatology, Maadi Armed Forces Medical Complex, Cairo 11841, Egypt
Huda Elsayed, Mona Abd Elraouf, Hanan Eltoukhy, Department of Internal Medicine, Faculty of Medicine for Girls, Al-Azhar University, Cairo 11311, Egypt
Tarek Megahed, Department of Clinical Pathology, Military Medical Academy, Cairo 11311, Egypt
Author contributions: Alzamzamy A contributed to data acquisition, data analysis, interpretation, statistics, and drafting of the manuscript; Aboubakr A, Abd Elraouf M, Eltoukhy H edited the manuscript and supervised the study; Alzamzamy A, Elsayed H designed the study; Megahed T contributed to laboratory work and results analysis; all authors approved the final version of the manuscript.
Institutional review board statement: The study was reviewed and approved by (Egypt Center for research and regenerative medicine, and Al Azhar University) Institutional Review Board, No. IRB 00012517.
Informed consent statement: All study participants or their legal guardian provided informed written consent about personal and medical data collection prior to study enrolment.
Conflict-of-interest statement: None to declare.
Data sharing statement: Technical appendix, statistical code, and dataset available from the corresponding author at [dr_zamzamy@hotmail.com]. Participants gave informed consent for data sharing and risk of identification is low. No additional data are available.
STROBE statement: The authors have read the STROBE statement—checklist of items, and the manuscript was prepared and revised according to the STROBE statement—checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Ahmed Alzamzamy, MD, PhD, Lecturer, Department of Gastroenterology and Hepatology, Military Medical Academy, Ehsan Abdelkodous Street from Elkhalifa Elmaemoun Street, Heliopolis, Cairo 11841, Egypt. dr_zamzamy@hotmail.com
Received: January 27, 2021
Peer-review started: January 27, 2021
First decision: March 8, 2021
Revised: April 13, 2021
Accepted: May 22, 2021
Article in press: May 22, 2021
Published online: June 15, 2021

Hepatocellular carcinoma (HCC) accounts for 8.2% of all cancer-related deaths worldwide. Being a vascular tumor, vascular endothelial growth factor (VEGF) plays a vital role in HCC pathogenesis, growth, and spread.


To determine the accuracy of serum VEGF and VEGF/platelet (PLT) as tumor markers in the early detection of HCC cases in patients with hepatitis C virus (HCV)-related liver cirrhosis.


We conducted a case-control study with HCV patients from the outpatient and inpatient hepatology clinics. Patients were classified into three groups: (1) HCC group; (2) Cirrhosis group; and (3) HCV without cirrhosis (control group). Patients were clinically evaluated, and blood samples were drawn for the analysis; serum VEGF levels were measured by a specific VEGF human recombinant enzyme-linked immunosorbent assay kit. Data from the three study groups were compared by the one-way analysis of variance or Kruskal-Wallis test. Receivers operating characteristic curves were constructed to determine the optimal cut-off values of alpha fetoprotein (AFP), VEGF, and VEGF/PLT that provided the best diagnostic accuracy. The sensitivity and specificity at the optimal cut-off value of each biomarker were then calculated.


This study included one hundred patients (HCC, cirrhosis, and control groups: n = 40, 30, 30, respectively). HCC patients had significantly higher serum VEGF and VEGF/PLT levels than the non-HCC groups (P = 0.001). Serum VEGF and VEGF/PLT showed significant positive correlations with and HCC tumor size, stage, vascular invasion, and Child-Pugh classification. Moreover, a VEGF cut-off the value of 250 pg/mL provided 80% sensitivity and 81.7% specificity for discriminating HCC patient from non-HCC patients. Similarly, the ratio of VEGF/PLT provided sensitivity and specificity of 77.5% and 80%, respectively which is higher than the accuracy provided by AFP. The combination of AFP, VEGF, and VEGF/PLT increases the accuracy of diagnosing HCC to > 95%.


In HCV patients, serum VEGF and VEGF/PLT separately or in combination with AFP are reliable biomarkers for early and accurate HCC diagnosis.

Keywords: Hepatocellular carcinoma, Vascular endothelial growth factor, Biomarkers, Diagnosis

Core Tip: We conducted an observational study with 100 patients to assess the usefulness of serum vascular endothelial growth factor (VEGF) and VEGF/platelet (PLT) as tumor markers for hepatocellular carcinoma (HCC) diagnosis in hepatitis C virus-related cirrhotic patients, and comparing them to serum alpha fetoprotein (AFP); the conventional marker of HCC. It was found that serum VEGF and VEGF/PLT appear to be additional diagnostic markers for HCC detection and prognostic markers during HCC patients follow up. Also, combined measurement of serum VEGF, VEGF/PLT and AFP significantly increase the sensitivity, specificity and accuracy in detection of HCC among cirrhotic patients rather than using of AFP, VEGF, or VEGF/PLT separately.