The TNM (tumor size-lymph nodes-metastasis) staging was established through a multicenter international study for management of patients with HCC [3]. This classification depends on tumor extension, microvascular invasion, and liver fibrosis. Its main role relies on using it as a surgical staging system while it has no role in non surgical patients [4].

It is the first known staging system for HCC, with a wide use in Japan and Eastern countries since its publication in 1985. It depends on factors related to tumor extension (more or less than 50% of liver involved) and to liver functions [5]. Okuda staging system is much suitable for patients with advanced HCC and who are not usually fit for any intervention maneuvers. Recent advances in diagnostic modalities created a large group of patients with small lesions which are not well dealt with this staging system. Another drawback for this system is the lack of prognostic indicators.

The CLIP score has been established after a retrospective Italian study that included new prognostic factors, like alpha-fetoprotein and portal vein thrombosis [6]. Many following studies validated this system and proved its superiority and accuracy compared to systems like Okuda or TNM staging systems [7], with specific advantage as a prognostic module even more than some recent and widely accepted systems like Barcelona Clinic Liver Cancer (BCLC) and the Japan Integrated Scoring (JIS) system [8]. The most important criticism is the weak differentiation in early tumor stages, the difficult application for treatment strategy based on this system beside the poor efficacy in terms of survival [9].

This French staging system developed from results of a multicenter international study that included the performance status as one of its parameters [10]. This system is not widely used and was not well validated due to presence of some weak points like the poor differentiation of tumor spread.

The CUPI system was performed in Hong Kong after a study on Chinese patients who suffered from HCC [11]. The score system depends on variables such as tumor extension (with TNM classification), liver profile and presence of symptoms at presentation. The main drawback is its suitability for advanced rather than early cases and its dependence on a study population with a predominant HBV background [12].

The JIS score is a simple and easy used staging system which combines the Child-Pugh grade with the TNM classification with some modifications introduced by Liver Cancer Study Group of Japan [13]. For the time being, this score is used only by the local Japanese guidelines [14].

This staging system is one of the most accepted and widely used systems. It was developed after a retrospective analysis of several cohort studies for several HCC stages [15]. This system depends on classification of HCC into five major categories: very early, early, intermediate, advanced, and terminal stages. For each stage, many prognostic variables are considered, life expectancy is estimated and the most suitable management plan is suggested. The system includes variables related to tumor specifications, liver profile, and performance status of the patient. BCLC is the most commonly used staging system in Europe and it has been approved by the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD) [16]. The most commonly used staging systems and the main characteristics, uses and comments on each one are listed in Table 1.

Notably, there is wide heterogeneity in HCC presentation, patient variations as candidates for recommended treatments, and increasingly complex available therapeutic options with diverse responses to these therapies in clinical practice [17]. HCC is also known by its highly variable biologic behavior and the frequent coexistence of chronic liver disease and cirrhosis with HCC in affected patients [18]. In context of these reasons, it is important to manage HCC patients by multidisciplinary HCC teams. The multidisciplinary clinic includes heaptologists, medical and surgical oncologists, transplantation surgeons, diagnostic and interventional radiologists, pathologists, nurses and nurse practitioners [19].

Surgery is the cornerstone of HCC management. Resection and transplantation represent the best treatment options for patients who are candidates for such treatment modality in terms of survival [20].

Liver transplantation is the first treatment choice for patients with small multinodular tumors (≤3 nodules ≤3 cm) or those with single tumors ≤5 cm and advanced liver dysfunction.

One of the most famous guidelines for transplantation in HCC patients is the Milan criteria applied for patients with a single HCC ≤5 cm or multinodular lesions with a maximum of three nodules ≤3 cm each [21]. Two main approaches were followed in many trials; the first approach was to study the extension of transplantation legibility criteria to cover more patients in terms of tumor size and number. The most validated trial was the expansion to UCSF criteria (single nodule ≤6.5 cm or 2 - 3 nodules ≤4.5 cm and total tumor diameter ≤8 cm)— which involves around 5% - 10% of all transplant enlisted patients [22]. The second approach was the attempts for down staging of cases with much advanced HCC for adaption to Milan criteria before transplantation [23].

Local ablation techniques have been developed for patients who are not surgically fit. They are performed either through percutaneous approach or less commonly by laparoscopic introduction. These maneuvers include percutaneous ethanol injection (PEI), percutaneous acetic acid injection, radiofrequency ablation (RFA), microwave ablation, cryoablation, laser-induced thermotherapy, high-intensity focused ultrasound, and irreversible electroporation [24].

The first used technique was PEI, which induces coagulative necrosis of the lesion as a result of cellular dehydration, protein denaturation, and chemical occlusion of small tumor vessels as an effect of the injected absolute alcohol. The use of temperature in ablation techniques appeared later, with either using the heating techniques like radiofrequency ablation (RFA), microwave ablation, and laser ablation or through using cryoablation which causes direct tumor freezing [25]. The estimated 5 year survival in patients with early HCC was 47% - 53% [26]. RFA is the most commonly used local ablative technique and it has largely replaced PEI with proven superiority regarding the survival and recurrence in fewer treatment sessions [27]. It depends on energy production that induces coagulative necrosis of the tumor with safety margins of the apparently healthy tissue around the lesion.

Transarterial chemoembolization (TACE) is considered as the most commonly used initial treatment for unresectable HCC [28]. The well characterized angiogenic activity of HCC was the rationale behind TACE use. This technique depends on the intra-arterial infusion of a cytotoxic chemotherapeutic agent emulsioned with Lipiodol followed by embolization of the feeding vessels through a trans-arterial catheter [29].

The maximum and sustained retention of the chemical agent is used as a measure for the success of TACE. This allows the use of embolic microspheres which have the ability to sequester chemotherapeutic agents and release them in a controlled manner over a one week period and a subsequent increase of the local concentration of the drug with minimal systemic toxicity [30].

It is the delivery of radioactive substances such as Iodine-131 labelled Lipiodol [31] or microspheres containing Yttrium-90 [32]. The injected microspheres will reach the tumor area with selective production of highenergy, low-penetration radiation. Radioembolization carries the advantage of the ability to perform it safely in patients with portal vein thrombosis owing to the minimally embolic effect of 90Y microspheres [33].

Many advances changed the management of HCC. Notably, description of molecular and proteomic profiles for HCC prognosis, disease subtyping, and drug selection paved the way for identification of new molecular targeted therapies [34]. Due to the late presence of HCC affected patients, only 15% can perform curative treatments [35]. In addition, some patients may suffer from HCC recurrence post surgical resection. For those patients with advanced or recurrent HCC, systemic therapies can have a role [36].

Pathogenesis of HCC is a multistep complex process. This long process is associated with a large number of epigenetic and genetic alterations that will eventually leads to an alteration in the molecular pathways. These alterations are considered new potential therapeutic targets and include signal transduction pathways, oncogenes and growth factors and their receptors [37]. However, most of the molecular targeted therapies are associated with low tumor response rate. Inhibition of a single signaling pathway may induce feedback activation of other pathways. This may be an important rationale to use combination therapy in clinical trials for a possible beneficial synergistic activity [38].

Due to the limited efficacy of sorafenib, still there is an urgent need to look beyond sorafenib and develop more effective therapy for HCC [51]. In addition, the multiplicity of pathognomonic molecular mechanisms and pathways in hepatocarcinogenesis predicts that dependence on a single-targeted agent might not achieve sustained complete response in HCC. Inhibition of signals at different levels of one of the main pathways or inhibition of two or three different pathways at the same time is more convenient [42]. The different pathways and the corresponding drugs will be presented (Table 2):

VEGF (vascular endothelial growth factor), VEGFR (VEGF receptor), PDGF (platelet-derived growth factor), PDGFR (PDGF receptor), FGR (fibroblast growth factor), FGFR (FGF receptor), EGF (epidermal growth factor) EGFR (EGF receptor), PI3K (Wnt/β-catenin, and phosphatidylinositol-3-kinase), PTEN (phosphatase and tensin homologue deleted on chromosome ten), mTOR (Akt/mammalian target of rapamycin), HGF (hepatocyte groth factor), IGF (insulin-like growth factor), IGFR (IGF receptor).

The aim of downstaging is to decrease the patient’s tumor size and number that do not meet locally acceptable criteria for liver transplantation. A study was performed by Yu et al. [70] for HCC patients who exceeded the University of California-San Francisco (UCSF) criteria, were downstaged to fit criteria using locoregional therapy and finally underwent liver transplantation. Patients who were successfully downstaged patients before transplantation had excellent tumor-free and overall survival rates, even similar to fit-criteria group.

In 2010, an important international consensus conference was held to implement guidelines for HCC related liver transplantation. Liver transplantation after successful downstaging should achieve a 5-year survival comparable to that of “within criteria” HCC patients. Successful downstaging should include tumor size and number of viable tumors and α-fetoprotein concentrations before and after downstaging, then a minimum observation period of 3 months is recommended before considering liver transplantation. Bridging is another strategy that has been developed to treat patients whose HCC is at risk or shows signs of progression while waiting for a graft for 6 months or longer. This strategy is appropriate for patients with UNOS T2 lesions (one nodule 2 - 5 cm or three or fewer nodules each ≤3 cm) [23].

Aiming for better overall survival, decreasing HCC recurrence and better drug delivery to the tumor, many studies were performed while others are still ongoing to try achieving these goals. A recent study tested the in vitro use of gold nanoparticles (GNPs) conjugated with conventional chemotherapy drugs [71]. The cellular proliferation rates in the presence of this combination were statistically lower than those of cells exposed to the chemotherapeutic agents alone. Another study was concerned with hepatic cancer stem cells to pave the way for development of new diagnostic, therapeutic and prognostic products that will improve HCC management [72].

In another study performed by Sawada et al. [73], they looked for the development of an anticancer immunotherapy using the carcinoembryonic antigen glypican-3. Generally it was well tolerated with partial response of a patient and stable disease for 2 months for another group of patients after initiation of treatment.

Two systematic reviews were recently performed for the randomized controlled trials performed for adjuvant therapies and adoptive immunotherapies for post operative HCC patients [74,75]. Adoptive immunotherapy was investigated using anti-CD3-activated peripheral blood lymphocytes, cytokine-induced killer cells and lymphokine-activated killer cells. The treatment group with these effector cells could not improve overall survival rate or prevent the multicenteric relapse although they were somewhat able to enhance immunological function and eliminate the small intrahepatic metastases. For adjuvant therapies using, interferon, vitamin K2 analog, acyclic retinoids, transarterial chemotherapies and heparanase inhibitor, results were suboptimal but still promising requiring further studies for some of them. Yet, there is no clear recommendation to use systemic chemotherapy, tamoxifen, immunotherapy, antiandrogen, and herbal drugs for the clinical management of HCC patients [42].

Success of genome-wide association studies (GWAS) and pharmacogenomics raised the possibility of personalized medicine in managing HCC. Three virus-related HCC GWAS were reported for HCV and HBV related HCC, each with different locus. This may play a role in future to tailor the best therapeutic targets for HCC patients [76].