Staging systems are key to predict the prognosis of patients with cancer, to stratify the patients according to prognostic variables in the setting of clinical trials, to allow the exchange of information among researchers, and finally to guide the therapeutic approach. The current knowledge of the disease, however, prevents recommendation of a staging system that can be used world-wide. The conventional staging systems for hepatocellular carcinoma HCC , such as the Okuda stage or the TNM stage have shown important limitations in classifying patients. Several new systems have been proposed recently, and only three of them have been validated at this point.
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Staging systems are key to predict the prognosis of patients with cancer, to stratify the patients according to prognostic variables in the setting of clinical trials, to allow the exchange of information among researchers, and finally to guide the therapeutic approach. The current knowledge of the disease, however, prevents recommendation of a staging system that can be used world-wide. The conventional staging systems for hepatocellular carcinoma HCC , such as the Okuda stage or the TNM stage have shown important limitations in classifying patients.
Several new systems have been proposed recently, and only three of them have been validated at this point. The BCLC staging classification links the stage of the disease to a specific treatment strategy. The CLIP score is used in patients with advanced tumors. Several reasons explain the difficulty in identifying a world-wide system. First, HCC is a complex neoplasm inserted on a pre-neoplastic cirrhotic liver, and thus variables of both diseases leading to death should be taken into account.
Second, the disease is very heterogeneous around the world, and this reflects different underlying epidemiological backgrounds and risk factors. Third, HCC is the sole cancer treated by transplantation in a small proportion of patients.
Finally, the potential relevance of a molecular signature identified in terms of outcome prediction is unknown, and further research is needed to obtain this valuable biological information that may aid in classifying the patients. Hepatocellular carcinoma HCC is a major health problem worldwide. It is the fifth most common neoplasm in the world, with more than half million new cases yearly 1.
The incidence of HCC rose in the last decade. HCC is now the leading cause of death among cirrhotic patients 3.
Afiatoxin B 1 intake further enhances the risk. In Western countries and Japan, hepatitis C virus HCV infection is the main risk factor, together with other causes of cirrhosis 4 , 6. The natural history of this neoplasm is not completely known. First, there are no data regarding the timescale of the whole hepatocarcinogenetic process, which evolves from the onset of the neoplasm until the time in which it is diagnosed in the setting of surveillance programmes.
Second, early diagnosis of HCC still relies on pathological data rather than molecular data, and thus the accuracy of differentiating premalignant lesions and early neoplasm is still ill defined. Finally, once diagnosis is established, the prognosis of patients will vary according to the evolutionary stage at which the neoplasm is diagnosed and the treatment received. Survival of HCC patients has improved because of the advancement of the time of diagnosis and the increase in therapeutic efficacy.
The prognosis of HCC was dismal two decades ago 7. These treatments are assumed to improve the natural history of the disease. The natural course of advanced stage HCC is better known. The molecular pathogenesis of HCC is complex 12 , The most accepted hypothesis describes a step-by-step process through which external stimuli induce genetic alterations in mature hepatocytes leading to cell death and cellular proliferation regeneration.
In the progression of chronic inflammation to fibrosis and cirrhosis, the up-regulation of mitogenic pathways leads to the production of monoclonal populations. These populations harbor dysplastic hepatocytes as a result of altered gene expression, telomerase erosions and even chromosome aberrations. This process may last 10—30 years At this point, proliferation may be detected in isolated groups of cells, resulting in foci of small cell dysplasia or, more frequently, surrounded by a fibrotic ring resulting in low-grade dysplastic nodules LGDN or high-grade dysplastic nodules HGDN These are the major preneoplastic entities, although HCC may also arise from isolated small dysplastic cells, nonconforming clear hepatic nodules, or even from progenitor cells, which may develop mixed tumors.
Differentiation of early well-differentiated HCC from preneoplastic lesions is a histopathologic challenge, and molecular markers are awaited in this setting 14 , In these cases, it is assumed that therapies actively modify the natural course of the disease. These outcomes are the result of applying the so-called treatment-dependent variables in the selection of candidates. Percutaneous treatments provide good results, but are unable to match the outcomes achieved with surgery Recurrence is the major drawback of potentially curative treatments.
Kojiro et al. Prognosis of HCC was assumed to be poor when radical treatments were not feasible. These figures have also been recently reproduced when analysing survival estimates gathered from population-based cancer registries Thus, the outcome of untreated HCC has dramatically changed. Nowadays, the natural history of HCC at intermediate-advanced stages can be assessed with recent data obtained from patients randomized to the untreated arm in the setting of randomized controlled trials RCTs.
More than 20 RCTs have been published, including an untreated arm of conservative management Thereby, two subgroups with a markedly different life expectancy can be identified among patients in an intermediate evolutionary stage.
Patients with end-stage disease are characterized by presenting Okuda stage III, or Performance Status of 3—4, that reflects a severe tumor-related disability. Similarly, advanced tumors in Child-Pugh C patients also account for a very poor prognosis. Cancer staging should serve to select the appropriate primary and adjuvant therapy, to estimate the prognosis, and also to assist in the evaluation of the results of treatment, and to exchange information without ambiguity In oncology, the prognosis of patients with solid tumors is solely related to tumor stage, and other co-factors such as age or histologic grade are only seldom considered.
However, HCC patients constitute a particular case, as cirrhosis underlies the neoplasm in most individuals and thus, their outcome is related to these two entities, which simultaneously determine the applicability and efficacy of treatments. Accordingly, prognostic modeling in HCC patients is highly complex. The EASL panel of experts recommended the consideration of four related aspects: tumor stage, degree of liver function impairment, general condition of the patient, and treatment efficacy Survival of early stage patients is modified by treatment and thus, prognostic prediction has to include treatment-related variables.
At more advanced stages, treatment might not be identified as a relevant survival predictor and the use of a single prognostic model for all patients may appear adequate. Nowadays, experts in HCC management may choose among eight different staging systems 7 , 11 , 26 , 27 , 28 , 29 , 30 , 31 Table I , none of them with universal acceptance The variables included in each classification are different, reflecting the heterogeneous methodology used, and the population used to construct the models Table II.
Therefore, a consensus staging classification for HCC is needed. The Okuda classification 7 has been widely applied in HCC patients in the last decade. It is useful to identify end-stage patients Okuda stage III , that should not be included in therapeutic trials to assess the potential benefits of new therapeutic agents due to their grim prognosis.
Nowadays, however, the time of diagnosis has been advanced and thus, this classification is not adequate to stratify patients prior to radical or palliative therapies, even when dividing Okuda stage I patients into two subgroups according to tumor size. When compared with modern staging systems, it has been shown to have lower predictive capacity 32 , 33 , 34 , 35 , This classification combines five variables in a score system that stratifies patients in three stages.
A recent comparison with other staging systems has shown that it has limited prognostic capacity in patients with early HCC The Cancer of the Liver Italian Program CLIP score 27 was constructed in a retrospective study and validated by the authors and other groups 35 , 36 , This score combines four variables that provide a seven-stage classification system. It has been compared with Okuda stage and TNM stage with better discriminatory power. Asian groups have reported survival rates clearly different to the original authors, thus compromising their external validation It is also limited by the fact that it does not serve to select the appropriate therapy for each patient.
This proposal is not a scoring system as it derives from the identification of independent prognostic factors in the setting of several studies, conforming a staging classification. This classification uses variables related to tumor stage, liver functional status, physical status, and cancer-related symptoms, and links the four stages described with a treatment algorithm Figure 1. In brief, patients at stage 0 with very early HCC are optimal candidates for resection. Patients at stage A with early HCC are candidates for radical therapies resection, liver transplantation or percutaneous treatments.
Patients at stage B with intermediate HCC may benefit from chemoembolization. Patients at stage C with advanced HCC may receive new agents in the setting of RCT, and patients at stage D with end-stage disease will receive symptomatic treatment.
Adapted from Llovet JM et al. It has been suggested that this classification is best suited for treatment guidance, and particularly to select early stage patients who could benefit from curative therapies In that sense, it has recently been validated as the best staging system in a cohort of patients with early HCC Investigators in Hong Kong described a staging system analysing their experience in patients, most of them with HBV-related cirrhosis The conventional TNM system, which only contains variables related to tumor stage, has been mostly tested in the surgical setting, and showed poor prognostic prediction in HCC patients undergoing either resection 39 or transplantation Based on the results of a series of patients who underwent resection 29 , a recent modification has been proposed, including tumor stage and presence of fibrosis.
The new four-stage system may improve the stratification of resected tumors, even though it is controversial whether they will apply to nonsurgical patients. It lacks external validation in Western countries. There is no doubt that the classical staging systems have already been improved. The Okuda staging and the Child-Pugh classification might be used as a part of any new clinical staging system, but should no longer be used alone. Attempts to improve the classification and prognosis prediction of HCC are still evolving, and there is no agreement on the best staging that can be recommended worldwide In these studies, treatment-related variables might not be identified as a relevant survival predictor and the use of the same set of variables for all patients may appear adequate.
Conversely they face the same difficulty in early cases, as prognostic modeling for early HCC has specific requirements 26 , 27 , They use rough descriptions of tumor stage that are not in accordance with the predictive value of tumor size and multicentricity.
The new TNM according with the AJCC has only internal validation, and is based on series of patients undergoing resection 29 , as is the case with the seminal paper proposing JIS classification Pathologic information is needed in all cases, this representing a limitation for wide clinical use.
This study includes the widest comparison among staging systems, in comparison with other retrospective studies in which the limited collection of data impairs the ability to test all the systems available. The BCLC staging system may discriminate patients at early stages, and guide the treatment strategy.
More recently, new systems have appeared, suggesting a stronger discriminatory power when compared with published ones Even some societies have endorsed one of the systems 42 , with controversial acceptance 43 , Our current level of knowledge prevents recommendation of a staging system to be used worldwide. HCC is a complex neoplasm, in most cases on a background of a preneoplastic damaged liver. Both diseases may lead to death. In that sense, several human malignant tumors have recently been classified with respect to their prognostic outcome or response to treatment according to gene expression profile identified through micro-array technology.
Investigators have developed gene expression-based classifications for breast cancer, non-Hodgkin's B-cell lymphoma, leukemia, lung carcinoma, prostate cancer, bladder cancer, and melanoma. Thus, molecular markers are needed in HCC.
2018, Número 1
Barcelona clinic liver cancer BCLC staging uses a set of criteria to guide the management of patients with hepatocellular carcinoma HCC. Please Note: You can also scroll through stacks with your mouse wheel or the keyboard arrow keys. Updating… Please wait. Unable to process the form. Check for errors and try again. Thank you for updating your details. Log In.
Staging systems in hepatocellular carcinoma