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Benign liver tumours: understanding molecular physiology to adapt clinical management

Abstract

Improvements in understanding the pathophysiology of the different benign liver nodules have refined their nosological classification. New criteria have been identified using imaging, histology and molecular analyses for a precise diagnosis of these tumours. Improvement in the classification of liver tumours provides a more accurate prediction of disease progression and has modified patient management. Haemangioma and focal nodular hyperplasia, the most common benign liver tumours that develop in the absence of chronic liver disease, are usually easy to diagnose on imaging and do not require specific treatment. However, hepatocellular adenomas and cirrhotic macronodules can be difficult to discriminate from hepatocellular carcinoma. The molecular subtyping of hepatocellular adenomas in five major subgroups defined by HNF1A inactivation, β-catenin mutation in exon 3 or exon 7/8, and activation of inflammatory or Hedgehog pathways helps to identify the tumours at risk of malignant transformation or bleeding. New clinical, biological and molecular tools have gradually been included in diagnostic and treatment algorithms to classify benign liver tumours and improve patient management. This Review aims to explain the main pathogenic mechanisms of benign liver tumours and how this knowledge could influence clinical practice.

Key points

  • Hepatic haemangioma (HH) and focal nodular hyperplasia (FNH) are frequent benign liver tumours not related to contraception and are mostly diagnosed at imaging even if some FNH require a biopsy to reach a diagnosis.

  • FNH and HH do not require any treatment owing to the absence of complications.

  • Hepatocellular adenoma occurs mostly in young women (20–50 years) who have taken oestrogen-based contraception and could be complicated by tumour bleeding or malignant transformation to hepatocellular carcinoma.

  • Hepatocellular adenomas are divided into molecular subgroups: HNF1A inactivated, inflammatory, CTNNB1 mutations in exon 3 (high risk of transformation), CTNNB1 mutations in exon 7/8 and Sonic Hedgehog activated (high risk of bleeding).

  • Low-grade and high-grade dysplastic nodules are preneoplastic lesions developed in a cirrhotic liver that could progress to hepatocellular carcinoma through the acquisition of somatic mutations in the TERT promoter.

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Fig. 1: Hepatic haemangioma and focal nodular hyperplasia.
Fig. 2: Pathophysiology of hepatocellular adenoma and the mechanisms of malignant transformation.
Fig. 3: Management of benign liver tumours in the non-cirrhotic liver.
Fig. 4: Premalignant nodules on cirrhosis and mechanisms of malignant transformation.

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Acknowledgements

J.-C.N. and J.Z.-R. are funded by the INCA PRENEO grant (PREMALHEP).

Review criteria

We searched MEDLINE with the terms “hepatic haemangioma”, “liver haemangioma”, “hepatic angioma”, “liver angioma”, “focal nodular hyperplasia”, “cirrhotic nodule”, “cirrhotic premalignant lesion”, “liver premalignant lesion”, “hepatic adenoma”, “hepatocellular adenoma”, “liver adenoma” and “benign liver tumour”, for articles published from 1970 to 2022. In addition, we selected the most relevant clinical trials, systematic reviews and high-quality review articles. We also manually searched reference lists of identified articles to retrieve additional studies.

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Correspondence to Jean-Charles Nault or Jessica Zucman-Rossi.

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Nature Reviews Gastroenterology & Hepatology thanks Jan Ijzermans, who co-reviewed with Julia Klompenhouwer; Massimo Colombo; Alejandro Forner; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Nault, JC., Paradis, V., Ronot, M. et al. Benign liver tumours: understanding molecular physiology to adapt clinical management. Nat Rev Gastroenterol Hepatol 19, 703–716 (2022). https://doi.org/10.1038/s41575-022-00643-5

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