Hepatocellular Carcinoma (HCC) in Egypt: A comprehensive overview
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Worldwide, hepatocellular carcinoma (HCC) is a universal problem and its epidemiological data showed variation from place to place. Hepatocellular carcinoma (HCC) is the sixth and fourth common cancer in worldwide and Egypt, respectively. Egypt ranks the third and 15th most populous country in Africa and worldwide, respectively. The aim of this review is to compare the status of HCC in Egypt to that in the worldwide from different issues; risk factors, screening and surveillance, diagnosis and treatment, prevention, as well as research strategy.
The risk factors for HCC in Egypt are of great importance to be reported. The risk factor for HCC are either environmental- or host/genetic-related risk factors. In the last years, there is a tangible improvement of both screening and surveillance strategies of HCC in Egypt. The unprecedented national screening campaign launched by the end of 2018 is a mirror image of this improvement. While the improvement of the HCC prevention requires the governmental health administration to implement health policies. Although the diagnosis of Egyptian HCC patients follows the international guidelines but HCC treatment options are limited in terms of cost. In addition, there are limited Egyptian reports about HCC survival and relapse. Both basic and clinical HCC research in Egypt are still limited compared to worldwide.
Deep analysis and understanding of factors affecting HCC burden variation worldwide help in customization of efforts exerted to face HCC in different countries especially large country like Egypt. Overall, the presence of a research strategy to fight HCC in Egyptian patients will help in the optimum allocation of available resources to reduce the numbers of HCC cases and deaths and to improve the quality of life.
KeywordsHepatocellular carcinoma Epidemiology Screening and Surveillance Prevention Diagnosis and treatment Research
American Joint Committee on Cancer
The Barcelona Clinic Liver Cancer system
Body mass index
Direct acting antiviral
- EARN HCC
Egyptian Research Network for HCC
Genome-wide association studies
Hepatitis B virus
Hepatitis C virus
Human leukocyte antigen
Independent Data Monitoring Committee
Insulin-like growth factor-1
Ministry of Health
Magnetic resonance irradiation
Nonalcoholic fatty liver disease
Vinyl chloride monomer
World Health Organization
Worldwide, hepatocellular carcinoma (HCC) is a universal problem and its epidemiological data showed variation from place to place. Egypt ranks the third and 15th most populous country in Africa and worldwide, respectively. In Egypt, the health authorities consider HCC as the most challenging health problem. The number of HCC patients increased twofold over a decade . The aim of this review is to compare the status of HCC in Egypt to that in the worldwide from different issues; risk factors, screening and surveillance, diagnosis and treatment, prevention, as well as research strategy. Deep understanding of these issues help in customization of efforts exerted to face HCC in different countries especially large country like Egypt.
Epidemiology and disease burden in Egypt
Hepatocellular carcinoma (HCC) represents the sixth most common cancer worldwide . In Egypt, it represents the fourth common cancer . Many hospital-based studies [1, 4, 5, 6] reported increasing the incidence of HCC. The reason for increased incidence could be attributed to (1) improvement in screening programs and diagnostic tools , (2) increasing the survival rate of cirrhotic patients that increases the chance of developing HCC, and (3) increasing the incidence and complications of hepatitis C virus (HCV)  which is the most important risk factor in developing liver cancer including HCC in Egypt .
Worldwide, HCC is the fourth most common cause of death from cancer . It was estimated to be responsible for nearly 9.1% of the total deaths in 2012 (746,000 deaths) . In Egypt, It is the most common cause of mortality- and morbidity-related cancer.
Risk factors for HCC development
I-Environmental-related risk factors
II-Host/genetic-related risk factors
1- Host-related risk factors
e)- Oral contraceptives (OCs)
f)- Autoimmune Hepatitis
g)- Diabetes Mellitus
a) Chemical compounds
b) Alcohol abuse
c) Smoking tobacco
2- Genetic-related risk factors
i)- Monogenic risk factors:
a)- Alpha 1 antitrypsin deficiency
ii)- polygenic risk factors:
a)- Family history
(I) Environmental-related risk factors
1. Infectious risk factors
Globally, HCV infection is the leading cause of cirrhosis (93%)  which is a risk factor for HCC . It induces both hepatic inflammation and fibrosis. Mutation and malignant transformation of the infected cells are promoted by the HCV protein expression [14, 18, 19]. HCV infection is characterized by its long time progression to cirrhosis-related HCC . Based on the phylogenetic and sequence analyses of HCV genomes, there are seven genotypes of HCV strains and 67 subtypes upon further classification of each genotype . HCV genotype 4 is considered the most predominant HCV genotype in Egypt . In Egypt, HCV prevalence may be attributed to the initiation of the mass schistosomiasis treatment campaigns in the 1950s and the 1960s . Different HCV prevalence in Egypt were reported. The HCV prevalence in the age group (15–59 years) was 14.7% in 2008 while it became 10% in 2015. This decline in prevalence was related to aging of infected people receiving anti-schistosomal injections [24, 25].
2. Non-infectious risk factors
Occupational activities may include work exposure to a variety of chemical compounds. Liver is an important organ involved in detoxification, metabolic and excretory processes . Therefore, HCC can be caused by the adverse effects of organic and inorganic chemical compounds exposure of the liver.
In general, the tobacco ingredients are metabolized in liver and their carcinogenic effect is well-documented. Recently, a systematic review of 81 epidemiological studies  showed that there is an increase in the incidence of HCC risk and mortality among cigarette smokers. In Egypt, conflicting results were found regarding the association between tobacco smoking and the overall risk of HCC [5, 30, 31].
(II) Host-/genetic-related risk factors
1. Host-related risk factors
Nonalcoholic fatty liver disease
It is characterized by abnormal increase of hepatic triglycerides (> 5%) without extra alcohol intake . In general, nonalcoholic fatty liver disease (NAFLD) increases the risk of HCC through developing NASH. In NASH patients, HCC is independent risk factor for mortality with hazard ratio = 7.9 . Many genetic polymorphisms have been reported to be associated with NASH. In patients who have not consumed alcohol, NAFLD spectrum range from fatty liver to NASH that may end with cirrhosis. Worldwide, there are 20% of adults diagnosed with NAFLD, whereas up to 3% of adults are diagnosed with NASH . In Egypt, an epidemiological study was conducted over 15 years on HCC patients and revealed that 5.3% of patients suffered from NASH . This percentage is higher than the worldwide report.
2. Genetic-related risk factors
Monogenic risk factors
Hereditary hemochromatosis or dietary iron overload
Polygenic risk factors
Family history of HCC
The global burden of aflatoxin-induced HCC ranges between 4.6 and 28.2% . There are many studies conducted in Egypt that confirmed the presence of both aflatoxin-albumin adducts in human blood [67, 68] and aflatoxin in food . Aflatoxins are carcinogenic metabolites of certain fungi called Aspergillus flavus and Aspergillus parasiticum that contaminate many agricultural crops especially maize, peanuts, and cottonseed. The aflatoxins from these crops play an important role in the incidence of hepatocarcinogenesis worldwide [26, 28] and also in Egypt . The World health organization (WHO) classified aflatoxins as group 1 carcinogen . The most carcinogenic type of aflatoxin is Aflatoxin B1 (AFB1). The genetic hallmark of AFB1 exposure and HCC risk is a specific mutation as a single-base substitution at the third base of codon 249 in the TP53 gene. This mutation replaces an arginine by a serine (R249S) [72, 73, 74]. In addition, genetic polymorphism in the enzymes of activation (CYP enzymes) and deactivation (glutathione S-transferase) of pro-mutagenic aflatoxins may affect the level of pro-mutagenic aflatoxins and consequently the HCC risk .
It should be noted that immigration to Egypt after revolutions and wars in the Middle Eastern countries in the recent years may have an impact on all these risk factors. Screening for immigrants regarding the HCC risk factors, in general, and both HBV and HCV, in particular, should be encouraged.
Screening and surveillance of HCC
There are conflicting reports about the impact of HCC detection at an early stage on both the cure rate and the overall survival (OS) [11, 75]. Globally, HCC surveillance include both ultrasound and alpha fetoprotein (AFP) level measurement .
Several guidelines are available for screening high-risk populations including those diagnosed with cirrhosis and/or HBV/HCV infection (with or without cirrhosis) . Screening methods and surveillance intervals are the main differences between these guidelines. Although these guidelines affected greatly medical practice but due to poor adherence to screening, HCC mortality worldwide is increasing .
In Egypt, a national screening campaign was started by the Egyptian Ministry of Health (MOH) in 2018 to combat high HCV prevalence in Egypt by 2020 . All screened participants with confirmed HCV infection are enrolled in government-subsidized treatment program using direct acting antiviral (DAA); sofosbuvir-based regimen. However, a nationwide campaign for HCC surveillance is still not available. Many studies showed conflicting results regarding the outcome of DAA treatment and HCC recurrence exit. Given the size of the HCV and HCC problems in Egypt, the HCV treatment program could yield important results on the efficiency of HCV treatment using DAA agents on HCC risk in the near future [78, 79, 80, 81].
Diagnosis and treatment approach
During surveillance, finding a suspicious lesion using ultrasound in cirrhotic liver is followed by diagnostic confirmation using contrast enhanced helical computed tomography (CT) or dynamic magnetic resonance irradiation (MRI). Also, non-pathological confirmation of HCC diagnosis is achieved by AFP testing combined with previously mentioned imaging techniques .
HCC treatment centres in Egypt
Liver institutes that affiliated to Egyptian Ministry of Health (MOH), Universities, and Non-governmental organizations (NGO).
Cancer centers affiliated to Egyptian MOH: there are ten specialized oncology center till now in nine governorates.
Cancer centers affiliated to Ministry of Higher Education.
Oncology/hepatology/tropical units in MOH and university hospitals.
NGO Cancer Centers: there is only one in the upper Egypt.
Military oncology Units that treat both military and civilian patients.
Private cancer centers and oncology clinics inside private hospitals.
The geographical distribution of these treatment centers all over Egypt should be assessed in relation to healthcare service provision, and the heterogeneity of patients’ flow from different governorates. This will help in balanced geographical distribution of healthcare system.
The median overall survival (OS) of late diagnosis of HCC ranges between 6 and 20 months. In US, the 2- and 5-year OS were < 50% and 10%, respectively . In Egypt, HCC survival and relapse are not reported extensively. The median OS of untreated HCC patients was 2.3 months . Although all reports about the OS for treated HCC patients were slightly different but the OS is still poor [92, 93].
Many systemic cytotoxic chemotherapy drugs are used in HCC treatment as single agents, e.g.,: cisplatin, doxorubicin, 5-flurouracil, or combined regimen. All these chemotherapeutic agents are available in Egyptian market. These systemic treatments had three main disadvantages [94, 95]: (1) They have between 10 to 25% response rate with marginal survival improvement, (2) patients with underlying liver cirrhosis are poorly tolerating these treatments, and (3) HCC is highly resistance to single agent regimen.
FDA-approved targeted and immune therapies for HCC
Availability in Egyptian Market
Cabometyx and Cometriq
Stivarga, and Regonix
Immune check point inhibitors
Immune check point inhibitors
Human monoclonal antibody against vascular endothelial growth factor 2(VEGFR 2)
Prevention of HCC
Clear determination of HCC risk factors is very helpful for well-designed strategies for HCC prevention. Generally, prevention of HCC is based on early prevention of HCC risk factors (primary prevention), treatment of risk factors at an early stage (secondary prevention), and preventing or decreasing HCC relapse after successful curative treatment (tertiary prevention) [97, 98].
There are different methods for HCC primary prevention. Routine HBV immunization to all newborns (within 24 h) and high-risk groups is recommended by WHO . This universal vaccination along with other behavioral pattern changes that decrease the risk of infection are very important primary prevention together with implementation of surveillance programs. In addition, antiviral treatment for chronic HBV and HCV patients is used for HCC secondary prevention [97, 98].
In Egypt, there are two methodologies for HCC primary and secondary prevention; HBV vaccination program , and, recently, HCV eradication through national campaign . On the other hand, the principle of HCC prevention through education is the number one recommendation by World Gastroenterology organization’s global guidelines . Education intervention study as a pilot study had been conducted and showed promising results . Designing an education-based intervention programs that show relation between the best preventive practice (e.g., pesticide handling and food storage) and HCC risk is highly needed. This is recommended especially for habitants of rural areas (high risk) .
In addition, HCC prevention should be supported by health care provider, patients, and health care system as a whole . Each one has a definite responsibility. Health care provider who has a good knowledge should identify HCC risk factors and patients at risk then refer them for screening and surveillance. There is an Egyptian study that confirmed this role for academic physicians working in University Hospitals . Patients should show compliance with health care provider recommendations. Furthermore, the health care system should have the capacity and responsibility to deliver surveillance tests. To sum up, it is the responsibility of governmental health administrations to implement health policies regarding HCC prevention.
Hepatocellular carcinogenesis has been attributed to many biological aberrations, e.g., mutations, epigenetic dysregulations, and chromosomal anomalies. Six predominant molecular pathways have been identified in HCC by whole-exome sequencing (WES). They include TERT promoter mutation, Wnt/β-catenin, the P53 cell-cycle pathway, epigenetic modifiers in histone methylation and chromatin remodeling, mutations in oxidative stress pathways (including NFE2L2 and KEAP1), PI3K/AKT/mTOR, and RAS/MAPK pathways . This is in addition to various molecular pathways that were recently discovered in a large study conducted on 363 HCC cases using WES and DNA copy number analysis and on 196 HCC cases using DNA methylation, RNA, miRNA, and proteomic expression . Recently, Calderaro and colleagues proposed molecular and clinical features-based classification for HCC . A recent systematic review identified 544 articles (16.2%) published in PubMed about HCC in Egypt . In Egypt, some abnormalities in molecular pathways involved in HCC have been identified [107, 108] but other abnormalities need to be identified on a large scale of HCC Egyptian patients using advanced technology. Identification of molecular characteristics of HCC Egyptian patients will pave the way for personalized therapy toward improvement of their overall survival .
Clinical trials of HCC
Currently, in the era of precisian medicine, genomic profiling-based clinical trial has been started. NCI-MATCH (ClinicalTrials.gov Identifier: NCT02465060) is the largest precision medicine that started in July 2015 . It contains different targeted-therapies for each genetic abnormality arm/group in its design. It enrolls patients with specific “matching” genetic aberration and irrespective of their cancer type. Recently, ComboMATCH is another example of precisian trial that will be conducted but for combined targeted agents.
HCC clinical Trials in Egypt
Clinical trial number
Not yet recruiting
•Drug: Sofosbuvir •Drug: Ribavirin •Drug: Simeprevir •Drug: daclatasvir •Drug: Ledipasvir
Administration of DAA-based treatment
•Drug: Sorafenib •Drug: Best Supportive care
•Drug: Pregabalin 150 mg •Other: Placebo
•Drug: Transarterial chemoembolization (TACE) •Procedure: Radiofrequency ablation combined with TACE •Procedure: Microwave ablation combined with TACE
•Drug: Sorafenib •Drug: sorafenib plus tegafur-uracil
•Biological: CIK •Procedure: TACE
•Drug: Doxorubicin •Drug: Best Standard of Care
Active, not recruiting
•Drug: ABT-869/Linifanib •Drug: Sorafenib
In general, there is no structured national research program for HCC in place. The same notice was reported on liver research in Egypt . There are many important research topics in HCC are still untouched deeply. The economic burden of HCC treatment and its relation to the health outcome, the effect of immigrants on HCC distribution in Egypt, the effect of diet on HCC risk, education-based intervention studies especially in rural area inhabitants (high risk), and molecular and epigenetic characteristics of HCC in Egyptian patients are good examples for these research topics.
Research in HCC can be stimulated at many levels. On the institutional level, forming coordinated multidisciplinary research team who will study different aspects of HCC (epidemiological, diagnostic, treatment, and palliation aspects). On national level, establishing Egyptian Research Network for HCC (EARN HCC) is highly recommended. It will ease linking between different HCC specialized institutions to foster application of their respective expertise accumulated over years. On the international level, collaboration between Egyptian institutions and peer international specialized HCC institutions in different domains (training, twining research) should be supported by government health administration.
Hepatocellular carcinoma (HCC) is a universal problem and its epidemiological data showed variation from place to place. Deep analysis and understanding of factors affecting HCC burden variation worldwide help in customization of efforts exerted to face HCC in different countries especially large country like Egypt.
The authors thanks Mohamed H. Abdel Rahman (Department of Ophthalmology, Ohio State University, Wexner Medical Center, Columbus, OH, United States) for helpful comments and suggestions.
MAKQ, MOM, and SE proposed the design of the work. They did a critical review of the manuscript. WMR did the literature review and data curation. She was a major contributor in writing the manuscript. All authors have read and approved the manuscript.
Ethics approval and consent to participate
Consent for publication
The authors declare that they have no competing interests.
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