Elsevier

The Lancet

Volume 379, Issue 9822, 31 March–6 April 2012, Pages 1245-1255
The Lancet

Seminar
Hepatocellular carcinoma

https://doi.org/10.1016/S0140-6736(11)61347-0Get rights and content

Summary

Hepatocellular carcinoma is the sixth most prevalent cancer and the third most frequent cause of cancer-related death. Patients with cirrhosis are at highest risk of developing this malignant disease, and ultrasonography every 6 months is recommended. Surveillance with ultrasonography allows diagnosis at early stages when the tumour might be curable by resection, liver transplantation, or ablation, and 5-year survival higher than 50% can be achieved. Patients with small solitary tumours and very well preserved liver function are the best candidates for surgical resection. Liver transplantation is most beneficial for individuals who are not good candidates for resection, especially those within Milano criteria (solitary tumour ≤5 cm and up to three nodules ≤3 cm). Donor shortage greatly limits its applicability. Percutaneous ablation is the most frequently used treatment but its effectiveness is limited by tumour size and localisation. In asymptomatic patients with multifocal disease without vascular invasion or extrahepatic spread not amenable to curative treatments, chemoembolisation can provide survival benefit. Findings of randomised trials of sorafenib have shown survival benefits for individuals with advanced hepatocellular carcinoma, suggesting that molecular-targeted therapies could be effective in this chemoresistant cancer. Research is active in the area of pathogenesis and treatment of hepatocellular 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

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.

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