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
Research background

Hepatocellular carcinoma (HCC) is diagnosed at a late stage. Therefore, the prognosis of patients with HCC is generally poor. The recommended screening strategy for patients with liver cirrhosis includes the determination of serum alpha fetoprotein (AFP) levels and an abdominal ultrasound every 6 mo to detect HCC at an earlier stage. AFP, however, is a marker characterized by poor sensitivity and specificity, and abdominal ultrasound is highly dependent on the operator's experience. Vascular endothelial growth factor (VEGF) is a primary driving force for both physiological and pathological angiogenesis, and its overexpression is observed in HCC. VEGF is one of the most important angiogenic factors and it promotes angiogenesis in most human tumors. One of the notable features of most HCCs is hypervascularity and it has been reported that VEGF expression is correlated with tumor vascularity. The circulating VEGF level was reported to be correlated with the stage of HCC and the highest VEGF levels are found in patients with metastasis

Research motivation

Try 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.

Research objectives

The present study provides important data for the early diagnosis of HCC, enabling an increase in the number of cases treated worldwide. The main aim of this work was to assess the usefulness of serum VEGF and VEGF/PLT as tumor markers in patients with HCV-related liver cirrhosis and HCC and to compare them with the control group (patients with chronic HCV without cirrhosis or HCC) in order to detect their sensitivity and specificity as diagnostic markers for HCC. These two markers were also compared to AFP, the conventional marker of HCC, and were then correlated with tumor size, stage, vascular invasion, and Child-Pugh classification. Also, this study aimed to verify the possibility of using combined measurement of serum VEGF, VEGF/PLT, and AFP for diagnosing HCC early and accurately.

Research methods

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 (ROC) were constructed to determine the optimal cut-off values of 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.

Research results

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%.

Research conclusions

Serum VEGF and VEGF/PLT appear to be additional diagnostic markers for HCC detection and prognostic markers during the follow-up of HCC patients since these markers showed significant correlations with tumor size, and stage, and the presence of vascular invasion among HCC cases. Combined measurements of serum VEGF, VEGF/PLT, and AFP significantly increase the sensitivity, specificity, accuracy, area under the ROC curve, and positive and negative predictive values for detecting HCC among cirrhotic patients rather than using AFP, VEGF, or VEGF/PLT separately.

Research perspectives

Most of the current biomarkers for early and accurate diagnosis of HCC have limited sensitivity or specificity, so patients with HCC are diagnosed at a late stage and have low survival and poor prognosis. Therefore, a combination of two or three biomarkers with high specificity might provide the optimal diagnosis of early HCC is suggested. In this study, we conducted an observational study with 100 patients to assess the usefulness of serum VEGF and VEGF/PLT as tumor markers for early and accurate diagnosis of HCC in patients with HCV-related liver cirrhosis, and comparing them to serum AFP, the conventional marker of HCC. Also, this study aimed to verify the possibility of using combined measurement of serum VEGF, VEGF/PLT, and AFP for HCC diagnosis.