We searched Medline, Embase, and the Cochrane Library (from January, 2000, to November, 2011) with the terms “hepatocellular carcinoma”, “liver cancer”, and “primary liver carcinoma”. We also searched and reviewed the reference lists of retrieved publications for other relevant papers. We only considered papers published in English and Spanish. We selected publications largely from the past 5 years, but we did not exclude commonly referenced and highly regarded older publications.
SeminarHepatocellular carcinoma
Introduction
Hepatocellular carcinoma is the sixth most common neoplasm and the third most frequent cause of cancer death.1 More than 700 000 cases of this malignant disease were diagnosed in 2008, with an age-adjusted worldwide incidence of 16 cases per 100 000 inhabitants.1 Hepatocellular carcinoma is the leading cause of death among patients with cirrhosis.2 Here, we update our 2003 Lancet Seminar3 to include major advances in prevention, detection, diagnosis, and treatment that have happened since then.
Section snippets
Risk factors and prevention
In most cases, hepatocellular carcinoma develops within an established background of chronic liver disease (70–90% of all patients).4 The worldwide heterogeneous incidence reflects variations in the main risk factors (table 1).1, 5 Most cases of hepatocellular carcinoma (80%) arise in eastern Asia and sub-Saharan Africa, where the dominant risk factor is chronic infection with hepatitis B virus (HBV), together with exposure to aflatoxin B1. By contrast, in North America, Europe, and Japan,
Molecular pathogenesis
Hepatocarcinogenesis is a complex multistep process in which many signalling cascades are altered, leading to a heterogeneous molecular profile.28, 29 The main mutations include the tumour suppressor gene TP53 (present in about 25–40% of cancers, depending on tumour stage), and the gene for β catenin, CTNNB1 (about 25%, predominantly in HCV-related hepatocellular carcinoma). Other mutations are less frequent. Chromosomal amplifications (1q, 6p, 8q, 17q, and 20q) and deletions (4q, 8p, 11q, 13q,
Molecular classification of hepatocellular carcinoma
Molecular profiling is relevant in cancers such as those of breast, lung, colon, and melanoma, and in some instances molecular subclasses and response to treatment are linked—eg, amplification of ERBB2 and response to trastuzumab. Outcome prediction depends on both tumour profiling (defining Wnt subclass, tumour growth factor β [TGF β], and epithelial cell adhesion molecule [EPCAM] and inflammation class)29, 35 and gene expression of adjacent non-tumoral tissue.36, 37 Transfer of this
Surveillance and diagnosis
Surveillance for hepatocellular carcinoma aims to reduce disease-related mortality. In uncontrolled studies, survival seemed to be improved with surveillance but these studies are affected by biases of lead time (the apparent improvement in survival that comes from the diagnosis being made early in the course of a disease) and length time (the apparent improvement in survival that arises because surveillance preferentially detects slow-growing cancers).38 One randomised controlled trial of
Staging and prognosis assessment
Assessment of prognosis is a crucial step in management of patients with hepatocellular carcinoma. Years ago, most affected individuals were diagnosed at an advanced symptomatic stage, when treatment was not feasible and short-term prognosis was dismal. Diagnosis has now advanced, and effective early treatment of patients is associated with median survival beyond 5 years. Any attempt to assess prognosis should account for tumour stage, degree of liver function impairment, and presence of
Treatment
For treatment to be most effective, patients should be selected carefully and the treatment applied skilfully. In view of the complexity of hepatocellular carcinoma and the many potentially useful treatments, patients diagnosed with this malignant disease should be referred to multidisciplinary teams that include hepatologists, radiologists, surgeons, pathologists, and oncologists. By contrast with other highly prevalent cancers, the level of evidence for most therapeutic options for
Future perspectives
Treatment of hepatocellular carcinoma has changed greatly within the past decade and has become a major area for research. Patients diagnosed with this malignant disease can benefit from effective options that will improve their survival, whatever the evolutionary stage at which they have been diagnosed. Obviously, improvement in several areas is still needed. Recurrence after ablation or resection is a major drawback, and effective preventive agents are needed. Also, progression after
Search strategy and selection criteria
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