Hepatoma; Liver cancer; Primary liver cancer; Liver cell carcinoma; Primary liver cell carcinoma; HCC
Definition and Characteristics
Hepatocellular carcinoma (HCC) is a malignant liver tumor that arises from parenchymal epithelial liver cells (hepatocytes). HCCs have a generally very poor prognosis with a 5-year survival rate of <5% in symptomatic patients. Furthermore, these tumors have been shown to be quite resistant to chemotherapy. The natural course of the disease and the median survival of patients with HCC depend on the stage of the disease at the time of diagnosis. In patients with CLIP score O or Okuda stage I (see below) the median survival is in the range of 23–69 months, while in patients with CLIP score 3–5 or Okuda stage III median survival is only 1–14 months . The staging system is clinically most important for the appropriate choice of the therapeutic strategy for individual patients. Cirrhotic patients developing a HCC during the last 5 years of surveillance survived longer than previously, due to improved management of the tumor and of the complications of cirrhosis. Importantly, however, in a population-based study in the US underutilization of potentially curative therapies even among patients with favorable HCC features is a problem that needs to be addressed.
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide and has been recently reviewed [1,2]. The incidence ranges from <10 cases per 100,000 population in North America and Western Europe to 50–150 cases per 100,000 population in parts of Africa and Asia where HCC is responsible for a large proportion of cancer deaths. However, a rise in the incidence of and mortality from HCC, most likely reflecting the increased prevalence of hepatitis C virus (HCV) infection, has recently been observed in most industrialized countries.
Central to the concept of molecular carcinogenesis are mutations of oncogenes and tumor suppressor genes as well as genetic instability, including mismatch repair deficiency and impaired chromosomal segregation. As for most cancers, hepatocarcinogenesis is a multistep process involving different genetic alterations that ultimately lead to the malignant transformation of the hepatocyte . While significant progress has been made in recognizing the sequence of events involved in other forms of cancer, most notably in colorectal cancer and certain hematopoietic malignancies, the molecular contribution of the multiple factors and their interactions in hepatocarcinogenesis are still poorly understood. HCCs are phenotypically (morphology, microscopy) and genetically very heterogenous tumors, possibly reflecting in part the heterogeneity of etiologic factors implicated in HCC development, the complexity of hepatocyte functions and the late stage at which HCCs usually are detected. Malignant transformation of hepatocytes may occur regardless of the etiologic agent through a pathway of increased liver cell turnover, induced by chronic liver injury and regeneration in a context of inflammation, immune response and oxidative DNA damage. This may result in genetic alterations, such as the activation of cellular oncogenes, the inactivation of tumor suppressor genes, possibly in cooperation with genomic instability, including DNA mismatch repair defects and impaired chromosomal segregation, overexpression of growth and angiogenic factors, and telomerase activation. Chronic viral hepatitis B, C and D, alcohol, metabolic liver diseases such as hemochromatosis and alpha-1-antitrypsin deficiency as well as non-alcoholic fatty liver disease may act predominantly through the pathway of chronic liver injury, regeneration, and cirrhosis. The major clinical risk factor for HCC development, therefore, is liver cirrhosis that coexists in 70–90% of HCCs. Most HCCs occur after many years of chronic hepatitis that provides the mitogenic and mutagenic environment to precipitate random genetic alterations resulting in the malignant transformation of hepatocytes and HCC development.
There is evidence that HBV – and possibly also HCV – may under certain circumstances play an additional direct role in the molecular pathogenesis of HCC. Finally, aflatoxins have been shown to induce mutations of the p53 tumor suppressor gene, thus pointing to the contribution of an environmental factor to tumor development at the molecular level. Further, in a transgenic mouse model it has been shown that chronic immune-mediated liver cell injury without environmental or infectious agents is sufficient to cause HCC and that inhibition of cytotoxic T lymphocyte-induced apoptosis and chronic inflammation by neutralization of the Fas ligand prevents HCC development in this model. In addition, also in a transgenic mouse model it has been demonstrated that NF-kappaB may be the link between inflammation and HCC development. Finally, individual polymorphisms of drug metabolizing enzymes, e.g., various cytochrome P450 oxidases, N-acetyltransferases and glutathione-S-transferase, may contribute to the genetic susceptibility to HCC development.
Molecular and Systemic Pathophysiology
The molecular pathogenesis of HCC is very complex and involves alterations in the structure or expression of several tumor suppressor genes, oncogenes and, possibly, mechanisms leading to genetic instability due to mismatch repair deficiency or chromosomal instability and aneuploidy due to defective chromosomal segregation.
The HCC risk in patients with liver cirrhosis depends on the activity, duration and the etiology of the underlying liver disease. In general, HCCs are more frequent in males than in females. Major HCC risk factors are chronic hepatitis B, C and D, toxins (e.g., alcohol, tobacco, aflatoxins), hereditary metabolic liver diseases (e.g., hereditary hemochromatosis, alpha-1-antitrypsin deficiency, autoimmune hepatitis and states of insulin resistance, e.g., overweight in males, diabetes mellitus as well as non-alcoholic steatohepatitis (NASH) or non-alcoholic fatty liver disease (NAFLD). Clinical and biological variables (age, anti-HCV positivity, PTT and platelet count) allow to further identify a subset of cirrhotic patients with the highest HCC risk. While in HBsAg positive patients the level of serum hepatitis B virus (HBV) DNA seems to correlate with the risk to develop a HCC, also in HBeAg negative patients with normal liver function tests. Also occult HBV infection (anti-HBc and HBV DNA positive only) carries a significant HCC risk. Coexistence of etiologies, e.g., HBV and HCV infection, HBV infection and aflatoxin B1, HBV or HCV infection and alcohol or diabetes mellitus, HCV infection and liver steatosis, environmental factors, e.g., alcohol as well as diabetes mellitus, obesity and tobacco increase the relative risk of HCC development. The contribution of tobacco use is controversial, however, while coffee consumption appears to reduce the HCC risk.
Diagnosis is based on laboratory tests and imaging analyses, including histopathology. Apart from laboratory parameters defining the etiology, grade and stage of the underlying liver disease, an elevated alpha-fetoprotein (AFP) level strongly suggests a HCC (sensitivity 40–60%, specificity 80–90%). Two additional tumor markers, des-gamma-carboxyprothrombin (DCP) and the lens culinaris agglutinin-reactive fraction of AFP (AFP-L3), seem to add to HCC detection  but are not routinely used in clinical practice. The most widely used imaging analysis is abdominal ultrasound complemented by color duplex sonography and contrast media. Further imaging analyses that are particularly important for the selection and monitoring of therapeutic strategies are dynamic spiral computed tomography (CT), angio-CT and lipiodol-CT as well as magnetic resonance imaging (MRI). In patients with low or moderate AFP elevations and a liver lesion detected by imaging analyses biopsy and histopathological examination is recommended.
For the staging of HCCs seven systems have been proposed to assess the extent and of the prognosis of the disease: the Okuda staging system, the TNM classification and its modification by the “Union Internationale contre le Cancer (UICC),” the “Barcelona Clinic Liver Cancer (BCLC)” classification, the “Cancer of the Liver Italian Program (CLIP)” score, the “Japan Integrated Staging (JIS)” score, the Groupe d’Etude de Traitement du Carcinome Hépatocellulaire (GRETCH) score and the Chinese University Prognostic Index (CUPI).
Therapeutic options for HCCs fall into five categories: surgical interventions (tumor resection and liver transplantation, LTx), percutaneous interventions (e.g., ethanol or acetic acid injection, radiofrequency thermal ablation), transarterial interventions (embolization, chemoperfusion, or chemoembolization), radiation and drugs.
To date, surgical, percutaneous and transarterial interventions, including systemic internal radiotherapy (SIRT), have not systematically been compared in randomized controlled trials. In selected patients, tumor resection and LTx result in 5-year survival rates of 60–70%, with LTx being the best treatment for patients with single lesions and advanced liver disease, e.g., decompensated cirrhosis, or multicentric small tumors. Percutaneous interventions, again in selected patients, result in 5-year survival rates of 40–50%. In the following, the different therapeutic options as well as primary and secondary HCC prevention will be discussed in some detail.
In patients without coexisting liver cirrhosis (5% in Western countries, 40% in Subsaharan Africa and Asia) HCC resection is the treatment of choice with low rates of life-threatening complications. By comparison, in the majority of patients with cirrhosis, strict selection is required to avoid resection-related complications, especially postoperative liver failure. Resection-related mortality should be <1–3%, and the 5-year survival rates should be >50%. LTx is in principle the optimal therapeutic option for HCCs because it simultaneously removes the tumor and the underlying cirrhosis, including the risk of HCC recurrence.
Percutaneous interventions are the best options for small unresectable HCCs. Tumor ablation can be achieved chemically by percutaneous ethanol injection (PEI) or acetic acid injection (PAI) or thermally by radiofrequency thermal ablation (RFA), microwave-heat induced thermotherapy (HiTT), laser induced thermotherapy (LiTT), or cryoablation. Apart from an US- or CT-guided percutaneous approach, these techniques can also be applied laparoscopically or at laparotomy. PEI was the technique most widely used. It is safe, easy to perform, inexpensive and achieves complete tumor response rates of 90–100% in HCCs <2 cm in diameter, 70% in HCCs <3 cm diameter and 50% in HCCs <5 cm in diameter. Patients with liver cirrhosis Child-Pugh stage A with complete responses can achieve 5-year survival rates of 50% and more. Therefore, PEI was the procedure of choice for patients with a single HCC lesion <5 cm in diameter or with up to three lesions <3 cm in diameter. Survival is predicted by the initial response to PEI. In recent years, however, RFA was used more frequently than PEI, primarily because of patient comfort, requiring a single intervention only in most patients.
Transarterial chemoperfusion (TAC), embolization (TAE) and chemoembolization (TACE) are the most widely used treatment modalities for HCCs that are unresectable or cannot be treated by percutaneous interventions. Embolization agents may be administered alone (TAE) or after selective intra-arterial chemotherapy (generally doxorubicin, mitomycin or cisplatin mixed with lipiodol) without (TAC) or with subsequent embolization (TACE). Transarterial interventions yield partial responses in 15–55% of patients, delay tumor progression and vascular invasion and result in a survival benefit compared with best supportive care (BSC). The most important aspect is the selection of patients, i.e., patients should have preserved liver function (liver cirrhosis Child-Pugh stage A) and asymptomatic multinodular tumors without vascular invasion or extrahepatic spread. In patients with advanced liver disease (Child B or C) treatment-induced liver failure may offset the antitumor effect or the survival benefit from the intervention. In a randomized controlled clinical study the combination of TACE and PEI improved the survival of patients with HCC Okuda stage I, as compared to TACE alone. Further, postoperative adjuvant TACE may improve survival in patients with risk factors for residual tumor.
While radiotherapy has played a minor role in HCC treatment in the past, selective intra-arterial injection of 131iodine-labeled lipiodol has been performed in some patients but needs further clinical evaluation before a recommendation can be made. Further, high dose proton beam radiotherapy and modulated external beam radiation as well as Yttrium-90 microsphere treatment have been recently studied in clinical trials in patients with unresectable HCC. These strategies will certainly be further explored in clinical studies and may become a treatment option in the future.
A number of systemic chemotherapies, hormonal and other drugs have been evaluated in clinical trials. While most chemotherapeutic agents, tamoxifen, octreotide and interferon-alpha have not been shown to be effective in randomized controlled clinical trials. A number of substances may deserve further clinical evaluation alone or in combination with other drugs, e.g., gemcitabine, thymostimulin, alpha-1-thymosin, pravastatin, thalidomide and megestrol acetate as well as several antiangiogenic small molecules, e.g., erlotinib, sorafenib, gefitinib, as well as antiangiogenic monoclonal antibodies, e.g., bevacizumab or cetuximab, Cox-2 inhibitors in combination with capecitabine, pamidronate and others. To date, however, none of these drugs can be recommended outside of clinical studies.
In view of the limited therapeutic options for advanced HCCs a number of experimental strategies are being evaluated, incl. gene and immune therapies based on suicide, cytokine and antiangiogenic genes or DNA vaccination with tumor-specific genes, oncolytic viruses as well as novel drugs, e.g., 3-bromopyruvate.
Apart from exploring new and refining existing HCC treatment strategies, primary prevention is of major importance. After successful surgical or non-surgical HCC treatment, secondary HCC prevention of local recurrence or new HCC lesions is central to the improvement of disease-free and overall patient survival. Based on rapid scientific advances, molecular diagnosis, gene therapy and molecular prevention are becoming increasingly part of our patient management and will eventually complement and in part replace existing diagnostic, therapeutic and preventive strategies.