**3. Staging systems for HCC**

One of the most fundamental steps in the field of Oncology once the diagnosis of cancer has been established is to determine the stage of this malignant process. This step is very important as it provides information about overall survival and prognosis, and could help

persons that are being diagnosed with hepatitis C-related cirrhosis over the last couple of decades (Davis, 2010). Hepatocellular carcinoma develops in this population at a rate of 1 to 4% per year, a worrisome statistic considering the escalating numbers of persons diagnosed

Alcohol consumption has also been linked to primary liver cancer. Mechanisms for direct toxic or carcinogenic effect have not been well-recognized, but it is clear that extended periods of heavy ingestion of more than 60g per day increment the risk for hepatoma. The synergistic effects of alcohol in the presence of hepatitis B or C or both have been established, and seem to have a greater impact in the risk to develop hepatocellular

A connection between the environmental exposure to aflatoxin, a mycotoxin produced by *Aspergillus* fungus, and primary liver cancer has also been documented. The chronic dietary exposure to high levels of this toxin is seen predominantly in developing countries, where hepatitis B is also prevalent. It has been postulated that the overall contribution of aflatoxin exposure to hepatocellular carcinoma cases worldwide is between 5 and 28% (Y. Liu 2010). However, taking into account that hepatitis B infection seems to play a much greater role in the risk of development of hepatoma in these developing countries, the true contribution of aflatoxins is considered minimal. It appears that the mechanism by which this toxin has carcinogenic effects is by causing mutations in the p53 tumor suppressor gene (Gursoy-

Nonalcoholic fatty liver disease is the most common form of chronic liver disease in developed countries. When aggressive, this disease can progress to cirrhosis and hepatocellular carcinoma. The alarming obesity epidemic affecting many of these nations, and components of the metabolic syndrome in particular insulin resistance and diabetes, are factors associated with the development of this chronic disease. These factors by themselves have also been related to an increased risk of primary liver cancer (Calle, 2003; El-Serag, 2004). Considering our current understanding of its rising prevalence, nonalcoholic fatty liver disease could also be responsible for a significant number of the idiopathic or cryptogenic cirrhosis cases as well as the cryptogenic cirrhosis-related hepatoma cases that are seen in industrialized countries (Bungianesi, 2002). Recent studies have shed some light of the molecular mechanisms by which fatty liver and obesity could eventually lead to

One of the most fundamental steps in the field of Oncology once the diagnosis of cancer has been established is to determine the stage of this malignant process. This step is very important as it provides information about overall survival and prognosis, and could help

with hepatitis C-related cirrhosis.

carcinoma (Donato et al., 2002).

**2.3.2 Alcohol** 

**2.3.3 Aflatoxin** 

Yuzugullu, 2011).

**2.3.4 Nonalcoholic fatty liver disease** 

**3. Staging systems for HCC** 

hepatic cancer (Beyazit, 2010; Park et al., 2010; Wree, 2011).

guide treatment strategies. The ideal staging system for hepatocellular carcinoma is one that has high discriminatory ability while remaining simple (Dohmen, 2004).

Many staging systems for hepatoma have been developed and presented in reputable medical journals and conferences. Nonetheless, more studies are constantly being published comparing these models, showing results of modifications made to some of these systems or simply introducing new staging classifications into this already complex field that tries to find the most accurate measure of prognosis and survival. The difficulty of coming up with a globally accepted staging system is related to multiple factors. One of the main causes for the current discrepancies is that the risk factors and their contribution to the development of primary liver cancer vary from one geographic area to another (Marrero, 2010). Another key issue is that overall survival of individuals that are diagnosed with hepatocellular carcinoma is not only determined by the extent and characteristics of this malignancy, but also by the liver function of that individual. Considering that over 80% of the cases of hepatoma occur in the presence of chronic liver disease and cirrhosis, the role of liver function in a prognosis model cannot be ignored. However, there is disagreement as to which markers of liver function should be used or included in such models. The use of the available staging classifications differ from one center or institution to another. It depends on their experience, available resources, and the predominant manifestations and characteristics of hepatocellular carcinoma in their region. Some of the main and most studied staging systems will be described below.

#### **3.1 Tumor-node metastasis (TNM) system**

The tumor-node-metastasis (TNM) staging system is one of the earliest models developed, and has been widely used for different solid tumors. This system describes the anatomic extent of cancer by evaluating size of the tumor at the primary site as well as the presence or absence of tumor in regional lymph nodes or beyond (Greene & Sobin, 2008). This classification has been studied in populations with hepatocellular carcinoma to assess prognosis. In a recent Chinese study looking at 243 patients with hepatoma undergoing curative resection, TNM classification was better at prognostic stratification and prognostic prediction than other three models (Lu, 2008). Similar conclusions were drawn from another smaller study comparing the prognostic value of TNM to 6 other staging systems (S.B. Choi, 2008). However, additional studies have shown no superiority to other staging classifications (Chen, 2007). There are some drawbacks to the use of this system in primary liver cancer. The main flaw is that liver function is not taken into consideration in this prognostic model. Another problem is that grading and pathologic staging cannot be assessed in the majority of the cases because very few patients with hepatoma undergo surgical therapies (Dohmen, 2004).

#### **3.2 Cancer of the Liver Italian Program (CLIP)**

The CLIP scoring system is another option available to evaluate overall survival in patients with hepatocellular carcinoma. This model combines Child-Pugh score, tumor morphology, alpha feto-protein (AFP) and portal vein thrombosis which were the four independent predictive factors of survival recognized in the multivariate analysis of the original retrospective study (Cancer of the Liver Italian Program [CLIP] Investigators, 1998). By tumor morphology the investigators meant percentage of parenchymal involvement (more than or less than 50%) and if these were uninodular, multinodular or extensive tumors. Several subsequent studies with large patient populations have demonstrated its prognostic usefulness, including a recent study from Taiwan that compared this system to four other models in 1713 patients with primary liver cancer (Hsu, 2010; Ueno, 2001). A downside to this system is that its tumor morphology classification is too broad for the current practices of aggressive hepatoma screening in high risk populations. Nowadays, more patients are being diagnosed with very small tumors which could limit the use the CLIP score. This model has also been criticized for not discriminating well the cases of advanced stage (CLIP score 4-6), and for classifying most of the patients as early stage (CLIP 0-2), which hampers its stratification capacity (Dohmen 2004; Marrero et al., 2010).

#### **3.3 Japanese Integrated Staging (JIS) and biomarker-combined JIS**

In an attempt to also combine liver function and tumor characteristics in order to provide a more precise prognostic appraisal to patients with hepatocellular carcinoma, researchers in Osaka, Japan integrated the Child-Pugh score and the Japanese TNM staging to create the JIS system. In their evaluation of 722 cases with primary liver cancer, they concluded that compared to the CLIP score, their system was better stratifying patients and superior discriminating those cases that were in the early hepatoma phase. Statistically significant differences were seen for the lower JIS scores (Kudo et al., 2003). These findings suggest that this staging system could be more useful in regions where early detection of hepatocellular carcinoma has become more common. Other studies have found encouraging results of this model's ability to predict survival (Chen, 2007; Kudo, 2004; Nanashima, 2005). The main disadvantage of the JIS classification is the inability to discriminate well the cases of advanced stage (JIS score >4).

Biomarkers have been combined to the JIS system to determine if this modification enhances its prognostic value. The biomarker-combined JIS includes the assessment of the following three tumor markers for hepatoma: AFP, *lens culinaris* agglutinin-reactive AFP, and desgamma-carboxyprothrombin. This modified system was studied in 1,924 patients with primary liver cancer, and proved to be more effective predicting prognosis and stratifying patients than the conventional JIS model (Kitai, 2008). Although this was a large provocative study, this combined system needs to be tested in populations outside of the Asian region.

#### **3.4 Barcelona Clinic Liver Cancer (BCLC) staging system**

The Barcelona Clinic Liver Cancer staging system has one peculiarity that is not present in any of the other available prognosis models: it incorporates treatment recommendations in its staging algorithm. The independent predictors of mortality in the original studies were constitutional syndrome, performance status, vascular invasion, and extrahepatic spread (Llovet, 1999a, Llovet, 1999b). By combining in a simple format the evaluation of liver function, tumor stage, performance status, and cancer-related symptoms, and providing suggestions to the best available therapeutic modalities for any particular stage, the BCLC system has demonstrated better predictive value of prognosis and survival stratification when compared to several other staging systems (Cillo, 2004; Guglielmi, 2008). This classification has been gaining wide acceptance as the main staging model used in multiple countries, and supported by several well-respected liver societies. This is related in part to the fact that the BCLC has been externally validated in Asia, Europe and the United States (Cillo, 2006; Marrero, 2005; J.H. Wang, 2008; Xu, 2010), which has not been accomplished by many of the other staging models. It is also the principal system used in major drug company trials. Some of the criticism to this model is that it includes the subjective factor of performance status, and portal hypertension measurement, which in clinical practice is not routinely done. It also does not provide a classification for patients with single tumors greater than 5 centimeters in diameter or for those with recurrent disease after treatment, situations not infrequently encountered by clinicians treating hepatocellular carcinoma (Sherman, 2011).

There are many other classifications that have been developed to evaluate overall survival and prognosis. Some of these include the Okuda classification, the Chinese University Prognostic Index, the Advanced Liver Cancer Prognostic system, the Groupe d'Etude et de Traitement du Carcinome Hepatocellulaire score, to name a few. Initial studies for several of these models have shown some prognostic value, but they all need further validation in larger more diverse populations.
