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  • Review Article
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Benign liver tumours: understanding molecular physiology to adapt clinical management

Nature Reviews Gastroenterology & Hepatology volume 19, pages 703–716 (2022)Cite this article

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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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References

  1. Choi, S. H. et al. Focal hepatic solid lesions incidentally detected on initial ultrasonography in 542 asymptomatic patients. Abdom. Radiol. 41, 265–272 (2016).

    Article  Google Scholar 

  2. Kaltenbach, T. E.-M. et al. Prevalence of benign focal liver lesions: ultrasound investigation of 45,319 hospital patients. Abdom. Radiol. 41, 25–32 (2016).

    Article  PubMed Central  Google Scholar 

  3. Nault, J.-C., Bioulac-Sage, P. & Zucman-Rossi, J. Hepatocellular benign tumors — from molecular classification to personalized clinical care. Gastroenterology 144, 888–902 (2013).

    Article  CAS  PubMed  Google Scholar 

  4. Rooks, J. B. et al. Epidemiology of hepatocellular adenoma. The role of oral contraceptive use. J. Am. Med. Assoc. 242, 644–648 (1979). A study demonstrating the role of oestrogen-based oral contraception in the occurrence of hepatocellular adenomas in the 1970s.

    Article  CAS  Google Scholar 

  5. Di Tommaso, L. et al. Advanced precancerous lesions in the liver. Best Pract. Res. Clin. Gastroenterol. 27, 269–284 (2013).

    Article  PubMed  Google Scholar 

  6. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on the management of benign liver tumours. J. Hepatol. 65, 386–398 (2016). The only international guidelines available on the diagnosis and treatment of benign liver tumours, including hepatic haemangioma, FNH and HCA.

    Article  Google Scholar 

  7. Hoekstra, L. T. et al. Management of giant liver hemangiomas: an update. Expert Rev. Gastroenterol. Hepatol. 7, 263–268 (2013).

    Article  CAS  PubMed  Google Scholar 

  8. Gandolfi, L. et al. Natural history of hepatic haemangiomas: clinical and ultrasound study. Gut 32, 677–680 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Baranes, L. et al. Imaging benign hepatocellular tumors: atypical forms and diagnostic traps. Diagn. Interv. Imaging 94, 677–695 (2013).

    Article  CAS  PubMed  Google Scholar 

  10. Ridge, C. A., Shia, J., Gerst, S. R. & Do, R. K. G. Sclerosed hemangioma of the liver: concordance of MRI features with histologic characteristics. J. Magn. Reson. Imaging 39, 812–818 (2014).

    Article  PubMed  Google Scholar 

  11. Gill, R. M. et al. Hepatic small vessel neoplasm, a rare infiltrative vascular neoplasm of uncertain malignant potential. Hum. Pathol. 54, 143–151 (2016). The first description of hepatic small vessel neoplasm in the literature, an entity different from hepatic haemangioma and hepatic haemangioendothelioma.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Joseph, N. M. et al. Frequent GNAQ and GNA14 mutations in hepatic small vessel neoplasm. Am. J. Surg. Pathol. 42, 1201–1207 (2018).

    Article  PubMed  Google Scholar 

  13. Paisant, A. et al. Imaging features of hepatic small vessel neoplasm: case series. Hepatology 74, 2894–2896 (2021).

    Article  PubMed  Google Scholar 

  14. Toro, A. et al. What is changing in indications and treatment of hepatic hemangiomas. A review. Ann. Hepatol. 13, 327–339 (2014).

    Article  PubMed  Google Scholar 

  15. Rajakannu, M. et al. Revisiting the surgical management of giant hepatic hemangiomas: enucleation versus anatomical resection? J. Clin. Exp. Hepatol. 11, 321–326 (2021).

    Article  PubMed  Google Scholar 

  16. Torkian, P., Li, J., Kaufman, J. A. & Jahangiri, Y. Effectiveness of transarterial embolization in treatment of symptomatic hepatic hemangiomas: systematic review and meta-analysis. Cardiovasc. Interv. Radiol. 44, 80–91 (2021).

    Article  Google Scholar 

  17. Zavras, N., Dimopoulou, A., Machairas, N., Paspala, A. & Vaos, G. Infantile hepatic hemangioma: current state of the art, controversies, and perspectives. Eur. J. Pediatr. 179, 1–8 (2020).

    Article  PubMed  Google Scholar 

  18. Krowchuk, D. P. et al. Clinical practice guideline for the management of infantile hemangiomas. Pediatrics 143, e20183475 (2019).

    Article  PubMed  Google Scholar 

  19. Fukukura, Y., Nakashima, O., Kusaba, A., Kage, M. & Kojiro, M. Angioarchitecture and blood circulation in focal nodular hyperplasia of the liver. J. Hepatol. 29, 470–475 (1998).

    Article  CAS  PubMed  Google Scholar 

  20. Mathieu, D., Kobeiter, H., Cherqui, D., Rahmouni, A. & Dhumeaux, D. Oral contraceptive intake in women with focal nodular hyperplasia of the liver. Lancet 352, 1679–1680 (1998). A study demonstrating that oestrogen-based oral contraception has no effect on the risk of developing FNH.

    Article  CAS  PubMed  Google Scholar 

  21. Mathieu, D. et al. Oral contraceptive use and focal nodular hyperplasia of the liver. Gastroenterology 118, 560–564 (2000).

    Article  CAS  PubMed  Google Scholar 

  22. Rifai, K. et al. No evidence of substantial growth progression or complications of large focal nodular hyperplasia during pregnancy. Scand. J. Gastroenterol. 48, 88–92 (2013).

    Article  PubMed  Google Scholar 

  23. Sempoux, C. et al. Hepatocellular nodules expressing markers of hepatocellular adenomas in Budd– Chiari syndrome and other rare hepatic vascular disorders. J. Hepatol. 63, 1173–1180 (2015).

    Article  CAS  PubMed  Google Scholar 

  24. Buscarini, E. et al. High prevalence of hepatic focal nodular hyperplasia in subjects with hereditary hemorrhagic telangiectasia. Ultrasound Med. Biol. 30, 1089–1097 (2004).

    Article  PubMed  Google Scholar 

  25. Furlan, A. et al. Focal nodular hyperplasia after treatment with oxaliplatin: a multiinstitutional series of cases diagnosed at MRI. Am. J. Roentgenol. 210, 775–779 (2018).

    Article  Google Scholar 

  26. Scoazec, J. Y. et al. Focal nodular hyperplasia of the liver: composition of the extracellular matrix and expression of cell-cell and cell-matrix adhesion molecules. Hum. Pathol. 26, 1114–1125 (1995).

    Article  CAS  PubMed  Google Scholar 

  27. Rebouissou, S. et al. The beta-catenin pathway is activated in focal nodular hyperplasia but not in cirrhotic FNH-like nodules. J. Hepatol. 49, 61–71 (2008).

    Article  CAS  PubMed  Google Scholar 

  28. Paradis, V., Laurent, A., Flejou, J. F., Vidaud, M. & Bedossa, P. Evidence for the polyclonal nature of focal nodular hyperplasia of the liver by the study of X-chromosome inactivation. Hepatology 26, 891–895 (1997).

    Article  CAS  PubMed  Google Scholar 

  29. Wanless, I. R., Mawdsley, C. & Adams, R. On the pathogenesis of focal nodular hyperplasia of the liver. Hepatology 5, 1194–1200 (1985).

    Article  CAS  PubMed  Google Scholar 

  30. Paradis, V. et al. A quantitative gene expression study suggests a role for angiopoietins in focal nodular hyperplasia. Gastroenterology 124, 651–659 (2003).

    Article  PubMed  Google Scholar 

  31. Gouw, A. S. H. et al. Molecular characterization of the vascular features of focal nodular hyperplasia and hepatocellular adenoma: a role for angiopoietin-1. Hepatology 52, 540–549 (2010).

    Article  CAS  PubMed  Google Scholar 

  32. Vilgrain, V. et al. Benign and malignant hepatocellular lesions in patients with vascular liver diseases. Abdom. Radiol. 43, 1968–1977 (2018).

    Article  Google Scholar 

  33. van Rosmalen, B. V. et al. Long-term outcomes of resection in patients with symptomatic benign liver tumours. HPB (Oxford) 18, 908–914 (2016).

    Article  Google Scholar 

  34. Cherqui, D. et al. Management of focal nodular hyperplasia and hepatocellular adenoma in young women: a series of 41 patients with clinical, radiological, and pathological correlations. Hepatology 22, 1674–1681 (1995).

    Article  CAS  PubMed  Google Scholar 

  35. Tselikas, L. et al. Impact of hepatobiliary phase liver MRI versus contrast-enhanced ultrasound after an inconclusive extracellular gadolinium-based contrast-enhanced MRI for the diagnosis of benign hepatocellular tumors. Abdom. Radiol. 42, 825–832 (2016).

    Article  Google Scholar 

  36. Fabre, A. et al. Histologic scoring of liver biopsy in focal nodular hyperplasia with atypical presentation. Hepatology 35, 414–420 (2002).

    Article  PubMed  Google Scholar 

  37. Bertin, C. et al. Contrast-enhanced ultrasound of focal nodular hyperplasia: a matter of size. Eur. Radiol. 24, 2561–2571 (2014).

    Article  PubMed  Google Scholar 

  38. Grazioli, L., Morana, G., Kirchin, M. A. & Schneider, G. Accurate differentiation of focal nodular hyperplasia from hepatic adenoma at gadobenate dimeglumine-enhanced MR imaging: prospective study. Radiology 236, 166–177 (2005).

    Article  PubMed  Google Scholar 

  39. Bioulac-Sage, P. et al. Over-expression of glutamine synthetase in focal nodular hyperplasia: a novel easy diagnostic tool in surgical pathology. Liver Int. 29, 459–465 (2009).

    Article  PubMed  Google Scholar 

  40. Bioulac-Sage, P. et al. Immunohistochemical markers on needle biopsies are helpful for the diagnosis of focal nodular hyperplasia and hepatocellular adenoma subtypes. Am. J. Surg. Pathol. 36, 1691–1699 (2012).

    Article  PubMed  Google Scholar 

  41. Ronot, M. et al. MR findings of steatotic focal nodular hyperplasia and comparison with other fatty tumours. Eur. Radiol. 23, 914–923 (2013).

    Article  PubMed  Google Scholar 

  42. Birn, J. et al. Transarterial embolization of symptomatic focal nodular hyperplasia. J. Vasc. Interv. Radiol. 24, 1647–1655 (2013).

    Article  PubMed  Google Scholar 

  43. Ben Ismail, I., Zenaidi, H., Jouini, R., Rebii, S. & Zoghlami, A. Pedunculated hepatic focal nodular hyperplasia: a case report and review of the literature. Clin. Case Rep. 9, e04202 (2021).

    PubMed  PubMed Central  Google Scholar 

  44. Bröker, M. E. E. et al. Growth of focal nodular hyperplasia is not a reason for surgical intervention, but patients should be referred to a tertiary referral centre. World J. Surg. 42, 1506–1513 (2018).

    Article  PubMed  Google Scholar 

  45. Edmondson, H. A., Henderson, B. & Benton, B. Liver-cell adenomas associated with use of oral contraceptives. N. Engl. J. Med. 294, 470–472 (1976).

    Article  CAS  PubMed  Google Scholar 

  46. Flejou, J. F. et al. Liver adenomatosis. An entity distinct from liver adenoma? Gastroenterology 89, 1132–1138 (1985). A study describing liver adenomatosis, a rare entity characterized by the presence of >10 HCAs.

    Article  CAS  PubMed  Google Scholar 

  47. Lepreux, S. et al. The identification of small nodules in liver adenomatosis. J. Hepatol. 39, 77–85 (2003).

    Article  PubMed  Google Scholar 

  48. Sempoux, C. et al. Hepatocellular nodules expressing markers of hepatocellular adenomas in Budd–Chiari syndrome and other rare hepatic vascular disorders. J. Hepatol. 63, 1173–1180 (2015).

    Article  CAS  PubMed  Google Scholar 

  49. Labrune, P., Trioche, P., Duvaltier, I., Chevalier, P. & Odievre, M. Hepatocellular adenomas in glycogen storage disease type I and III: a series of 43 patients and review of the literature. J. Pediatr. Gastroenterol. Nutr. 24, 276–279 (1997).

    Article  CAS  PubMed  Google Scholar 

  50. Bacq, Y. et al. Familial liver adenomatosis associated with hepatocyte nuclear factor 1alpha inactivation. Gastroenterology 125, 1470–1475 (2003). In this study, the authors show that familial liver adenomatosis is due to a HNF1A germline mutation and is associated with MODY3 diabetes.

    Article  PubMed  Google Scholar 

  51. Sasaki, M., Yoneda, N., Kitamura, S., Sato, Y. & Nakanuma, Y. Characterization of hepatocellular adenoma based on the phenotypic classification: the Kanazawa experience. Hepatol. Res. 41, 982–988 (2011).

    Article  PubMed  Google Scholar 

  52. Laurent, C., Trillaud, H., Lepreux, S., Balabaud, C. & Bioulac-Sage, P. Association of adenoma and focal nodular hyperplasia: experience of a single French academic center. Comp. Hepatol. 2, 6 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Pilati, C. et al. Genomic profiling of hepatocellular adenomas reveals recurrent FRK-activating mutations and the mechanisms of malignant transformation. Cancer Cell 25, 428–441 (2014).

    Article  CAS  PubMed  Google Scholar 

  54. Zucman-Rossi, J. et al. Genotype-phenotype correlation in hepatocellular adenoma: new classification and relationship with HCC. Hepatology 43, 515–524 (2006). A pivotal study demonstrating the genotype–phenotype correlation in HCA and the link between the presence of CTNNB1 exon 3 mutations and the risk of malignant transformation.

    Article  CAS  PubMed  Google Scholar 

  55. Nault, J.-C. et al. Molecular classification of hepatocellular adenoma associates with risk factors, bleeding, and malignant transformation. Gastroenterology 152, 880–894.e6 (2017). The largest cohort demonstrating the correlation between molecular subclasses, risk factors and clinical behaviour; a new subclass of HCA characterized by activation of the Hedgehog pathway is described.

    Article  CAS  PubMed  Google Scholar 

  56. Bioulac-Sage, P. et al. Hepatocellular adenoma subtype classification using molecular markers and immunohistochemistry. Hepatology 46, 740–748 (2007).

    Article  CAS  PubMed  Google Scholar 

  57. van Aalten, S. M. et al. Validation of a liver adenoma classification system in a tertiary referral centre: implications for clinical practice. J. Hepatol. 55, 120–125 (2011).

    Article  PubMed  Google Scholar 

  58. Bellamy, C. O. C. et al. The value of immunophenotyping hepatocellular adenomas: consecutive resections at one UK centre. Histopathology 62, 431–445 (2013).

    Article  PubMed  Google Scholar 

  59. Odom, D. T. et al. Control of pancreas and liver gene expression by HNF transcription factors. Science 303, 1378–1381 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Bluteau, O. et al. Bi-allelic inactivation of TCF1 in hepatic adenomas. Nat. Genet. 32, 312–315 (2002).

    Article  CAS  PubMed  Google Scholar 

  61. Haddouche, A. et al. Liver adenomatosis in patients with hepatocyte nuclear factor-1 alpha maturity onset diabetes of the young (HNF1A-MODY): clinical, radiological and pathological characteristics in a French series. J. Diabetes 12, 48–57 (2020).

    Article  CAS  PubMed  Google Scholar 

  62. Pelletier, L. et al. Loss of hepatocyte nuclear factor 1alpha function in human hepatocellular adenomas leads to aberrant activation of signaling pathways involved in tumorigenesis. Hepatology 51, 557–566 (2010).

    Article  CAS  PubMed  Google Scholar 

  63. Rebouissou, S. et al. HNF1alpha inactivation promotes lipogenesis in human hepatocellular adenoma independently of SREBP-1 and carbohydrate-response element-binding protein (ChREBP) activation. J. Biol. Chem. 282, 14437–14446 (2007).

    Article  CAS  PubMed  Google Scholar 

  64. Laumonier, H. et al. Hepatocellular adenomas: magnetic resonance imaging features as a function of molecular pathological classification. Hepatology 48, 808–818 (2008). This study shows that imaging features by MRI could be useful for the non-invasive diagnosis of HNF1A-mutated and IHCAs.

    Article  PubMed  Google Scholar 

  65. Ronot, M. et al. Hepatocellular adenomas: accuracy of magnetic resonance imaging and liver biopsy in subtype classification. Hepatology 53, 1182–1191 (2011).

    Article  PubMed  Google Scholar 

  66. Rebouissou, S. et al. Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours. Nature 457, 200–204 (2009).

    Article  CAS  PubMed  Google Scholar 

  67. Pilati, C. et al. Somatic mutations activating STAT3 in human inflammatory hepatocellular adenomas. J. Exp. Med. 208, 1359–1366 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Nault, J.-C. et al. GNAS-activating mutations define a rare subgroup of inflammatory liver tumors characterized by STAT3 activation. J. Hepatol. 56, 184–191 (2012).

    Article  CAS  PubMed  Google Scholar 

  69. Bayard, Q. et al. Recurrent chromosomal rearrangements of ROS1, FRK and IL6 activating JAK/STAT pathway in inflammatory hepatocellular adenomas. Gut 69, 1667–1676 (2020).

    Article  CAS  PubMed  Google Scholar 

  70. Paradis, V. et al. Telangiectatic adenoma: an entity associated with increased body mass index and inflammation. Hepatology 46, 140–146 (2007).

    Article  PubMed  Google Scholar 

  71. Sa Cunha, A. et al. Inflammatory syndrome with liver adenomatosis: the beneficial effects of surgical management. Gut 56, 307–309 (2007).

    Article  CAS  PubMed  Google Scholar 

  72. Calderaro, J. et al. Systemic AA amyloidosis caused by inflammatory hepatocellular adenoma. N. Engl. J. Med. 379, 1178–1180 (2018).

    Article  PubMed  Google Scholar 

  73. Calderaro, J. et al. Inflammatory hepatocellular adenomas developed in the setting of chronic liver disease and cirrhosis. Mod. Pathol. 29, 43–50 (2016).

    Article  CAS  PubMed  Google Scholar 

  74. Dokmak, S. & Belghiti, J. Will weight loss become a future treatment of hepatocellular adenoma in obese patients? Liver Int. 35, 2228–2232 (2015).

    Article  PubMed  Google Scholar 

  75. Vernuccio, F. et al. Long-term evolution of hepatocellular adenomas at MRI follow-up. Radiology 292, 361–372 (2020).

    Article  Google Scholar 

  76. Klompenhouwer, A. J. et al. Development and validation of a model to predict regression of large size hepatocellular adenoma. Am. J. Gastroenterol. 114, 1292–1298 (2019).

    Article  PubMed  Google Scholar 

  77. Poussin, K. et al. Biochemical and functional analyses of gp130 mutants unveil JAK1 as a novel therapeutic target in human inflammatory hepatocellular adenoma. Oncoimmunology 2, e27090 (2013).

    Article  PubMed  Google Scholar 

  78. Chen, Y. W., Jeng, Y. M., Yeh, S. H. & Chen, P. J. P53 gene and Wnt signaling in benign neoplasms: beta-catenin mutations in hepatic adenoma but not in focal nodular hyperplasia. Hepatology 36, 927–935 (2002).

    CAS  PubMed  Google Scholar 

  79. Evason, K. J., Grenert, J. P., Ferrell, L. D. & Kakar, S. Atypical hepatocellular adenoma-like neoplasms with beta-catenin activation show cytogenetic alterations similar to well-differentiated hepatocellular carcinomas. Hum. Pathol. 44, 750–758 (2013).

    Article  CAS  PubMed  Google Scholar 

  80. Svrcek, M. et al. Regressive liver adenomatosis following androgenic progestin therapy withdrawal: a case report with a 10-year follow-up and a molecular analysis. Eur. J. Endocrinol. 156, 617–621 (2007).

    Article  CAS  PubMed  Google Scholar 

  81. Van der Borght, S. et al. Nuclear beta-catenin staining and absence of steatosis are indicators of hepatocellular adenomas with an increased risk of malignancy. Histopathology 51, 855–866 (2007).

    Article  PubMed  Google Scholar 

  82. Rebouissou, S. et al. Genotype-phenotype correlation of CTNNB1 mutations reveals different β-catenin activity associated with liver tumor progression. Hepatology 64, 2047–2061 (2016).

    Article  CAS  PubMed  Google Scholar 

  83. Reizine, E. et al. Hepatospecific MR contrast agent uptake on hepatobiliary phase can be used as a biomarker of marked β-catenin activation in hepatocellular adenoma. Eur. Radiol. 31, 3417–3426 (2021).

    Article  CAS  PubMed  Google Scholar 

  84. Henriet, E. et al. Argininosuccinate synthase 1 (ASS1): a marker of unclassified hepatocellular adenoma and high bleeding risk. Hepatology 66, 2016–2028 (2017).

    Article  CAS  PubMed  Google Scholar 

  85. Bieze, M., Phoa, S. S., Verheij, J., van Lienden, K. P. & van Gulik, T. M. Risk factors for bleeding in hepatocellular adenoma. Br. J. Surg. 101, 847–855 (2014).

    Article  CAS  PubMed  Google Scholar 

  86. van Aalten, S. M., de Man, R. A. I., Jzermans, J. N. & Terkivatan, T. Systematic review of haemorrhage and rupture of hepatocellular adenomas. Br. J. Surg. 99, 911–916 (2012). A large analysis of the literature assessing the frequency of bleeding and the risk factors predicting this complication in patients with HCA.

    Article  PubMed  Google Scholar 

  87. Dokmak, S. et al. A single-center surgical experience of 122 patients with single and multiple hepatocellular adenomas. Gastroenterology 137, 1698–1705 (2009).

    Article  PubMed  Google Scholar 

  88. Farges, O. et al. Changing trends in malignant transformation of hepatocellular adenoma. Gut 60, 85–89 (2011).

    Article  PubMed  Google Scholar 

  89. Silva, T. S., Sung, M., Nelson, D. W., DiFronzo, A. L. & O’Connor, V. V. A multicenter, 10-year experience with hepatocellular adenoma: risk factors and disease course. Am. Surg. https://doi.org/10.1177/00031348211011084 (2021).

    Article  PubMed  Google Scholar 

  90. Laurent, A. et al. European experience of 573 liver resections for hepatocellular adenoma: a cross-sectional study by the AFC-HCA-2013 study group. HPB (Oxford) 18, 748–755 (2016).

    Article  Google Scholar 

  91. Hirsch, T. Z. et al. Integrated genomic analysis identifies driver genes and cisplatin-resistant progenitor phenotype in pediatric liver cancer. Cancer Discov. 11, 2524–2543 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Nault, J.-C. et al. High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions. Nat. Commun. 4, 2218 (2013). A study identifying TERT promoter mutations as the most frequent somatic genetic alterations in HCC; it also demonstrates that TERT promoter mutations are involved in the malignant transformation of HCA together with CTNNB1 exon 3 mutations.

    Article  PubMed  Google Scholar 

  93. Sempoux, C. et al. Malignant transformation of a β-catenin inflammatory adenoma due to an S45 β-catenin-activating mutation present 12 years before. Hum. Pathol. 62, 122–125 (2017).

    Article  CAS  PubMed  Google Scholar 

  94. Bedossa, P. et al. Well-differentiated hepatocellular neoplasm of uncertain malignant potential: proposal for a new diagnostic category. Hum. Pathol. 45, 658–660 (2014).

    Article  PubMed  Google Scholar 

  95. Barbier, L. et al. Natural history of liver adenomatosis: a long-term observational study. J. Hepatol. 71, 1184–1192 (2019).

    Article  CAS  PubMed  Google Scholar 

  96. Klompenhouwer, A. J. et al. Retrospective study on timing of resection of hepatocellular adenoma. Br. J. Surg. 104, 1695–1703 (2017).

    Article  CAS  PubMed  Google Scholar 

  97. van Rosmalen, B. V. et al. Hepatocellular adenoma in men: a nationwide assessment of pathology and correlation with clinical course. Liver Int. 41, 2474–2484 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Dokmak, S. et al. Hemorrhage of hepatocellular adenoma: a complication that can be treated by conservative management without surgery. HPB 20, 1198–1205 (2018).

    Article  PubMed  Google Scholar 

  99. Bioulac-Sage, P. et al. Hepatocellular adenoma management and phenotypic classification: the Bordeaux experience. Hepatology 50, 481–489 (2009).

    Article  PubMed  Google Scholar 

  100. Klompenhouwer, A. J. et al. Evidence of good prognosis of hepatocellular adenoma in post-menopausal women. J. Hepatol. 65, 1163–1170 (2016).

    Article  PubMed  Google Scholar 

  101. de’Angelis, N. et al. Open and laparoscopic resection of hepatocellular adenoma: trends over 23 years at a specialist hepatobiliary unit. HPB 16, 783–788 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Gaspersz, M. P. et al. Growth of hepatocellular adenoma during pregnancy: a prospective study. J. Hepatol. 72, 119–124 (2020). A prospective study demonstrating that pregnancy is safe in women with HCAs of <5 cm.

    Article  PubMed  Google Scholar 

  103. van Rosmalen, B. V. et al. Safety and efficacy of transarterial embolization of hepatocellular adenomas. Br. J. Surg. 106, 1362–1371 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  104. van Vledder, M. G. et al. Safety and efficacy of radiofrequency ablation for hepatocellular adenoma. J. Vasc. Int. Radiol. 22, 787–793 (2011).

    Article  Google Scholar 

  105. Chiche, L. et al. Liver transplantation for adenomatosis: European experience. Liver Transpl. 22, 516–526 (2016).

    Article  PubMed  Google Scholar 

  106. Brunner, S. F. et al. Somatic mutations and clonal dynamics in healthy and cirrhotic human liver. Nature 574, 538–542 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Zhu, M. et al. Somatic mutations increase hepatic clonal fitness and regeneration in chronic liver disease. Cell 177, 608–621.e12 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. International Consensus Group for Hepatocellular Neoplasia. Pathologic diagnosis of early hepatocellular carcinoma: a report of the international consensus group for hepatocellular neoplasia. Hepatology 49, 658–664 (2009).

    Article  Google Scholar 

  109. Nault, J.-C. et al. Telomerase reverse transcriptase promoter mutation is an early somatic genetic alteration in the transformation of premalignant nodules in hepatocellular carcinoma on cirrhosis. Hepatology 60, 1983–1992 (2014).

    Article  CAS  PubMed  Google Scholar 

  110. Torrecilla, S. et al. Trunk mutational events present minimal intra- and inter-tumoral heterogeneity in hepatocellular carcinoma. J. Hepatol. 67, 1222–1231 (2017).

    Article  PubMed  Google Scholar 

  111. Marquardt, J. U. et al. Sequential transcriptome analysis of human liver cancer indicates late stage acquisition of malignant traits. J. Hepatol. 60, 346–353 (2014).

    Article  CAS  PubMed  Google Scholar 

  112. Llovet, J. M. et al. A molecular signature to discriminate dysplastic nodules from early hepatocellular carcinoma in HCV cirrhosis. Gastroenterology 131, 1758–1767 (2006).

    Article  CAS  PubMed  Google Scholar 

  113. Nault, J.-C., Ningarhari, M., Rebouissou, S. & Zucman-Rossi, J. The role of telomeres and telomerase in cirrhosis and liver cancer. Nat. Rev. Gastroenterol. Hepatol. 16, 544–558 (2019).

    Article  PubMed  Google Scholar 

  114. Xiong, J., Luo, J., Bian, J. & Wu, J. Overall diagnostic accuracy of different MR imaging sequences for detection of dysplastic nodules: a systematic review and meta-analysis. Eur. Radiol. 32, 1285–1296 (2022).

    Article  PubMed  Google Scholar 

  115. Forner, A. et al. Diagnosis of hepatic nodules 20 mm or smaller in cirrhosis: prospective validation of the noninvasive diagnostic criteria for hepatocellular carcinoma. Hepatology 47, 97–104 (2008).

    Article  PubMed  Google Scholar 

  116. Di Tommaso, L. et al. Diagnostic value of HSP70, glypican 3, and glutamine synthetase in hepatocellular nodules in cirrhosis. Hepatology 45, 725–734 (2007).

    Article  PubMed  Google Scholar 

  117. Borzio, M. et al. Impact of large regenerative, low grade and high grade dysplastic nodules in hepatocellular carcinoma development. J. Hepatol. 39, 208–214 (2003). A study analysing the risk of transformation in HCC of premalignant nodules (regenerative, LGDN and HGDN) in patients with cirrhosis.

    Article  PubMed  Google Scholar 

  118. Terasaki, S., Kaneko, S., Kobayashi, K., Nonomura, A. & Nakanuma, Y. Histological features predicting malignant transformation of nonmalignant hepatocellular nodules: a prospective study. Gastroenterology 115, 1216–1222 (1998).

    Article  CAS  PubMed  Google Scholar 

  119. Sato, T. et al. Natural history of large regenerative nodules and dysplastic nodules in liver cirrhosis: 28-year follow-up study. Hepatol. Int. 9, 330–336 (2015).

    Article  PubMed  Google Scholar 

  120. Roux, M. et al. Differentiating focal nodular hyperplasia from hepatocellular adenoma: is hepatobiliary phase MRI (HBP-MRI) using linear gadolinium chelates always useful? Abdom. Radiol. 43, 1670–1681 (2018).

    Article  Google Scholar 

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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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Authors and Affiliations

  1. Service d’hépatologie, Hôpital Avicenne, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Assistance-Publique Hôpitaux de Paris, Bobigny, France

    Jean-Charles Nault

  2. Unité de Formation et de Recherche Santé Médecine et Biologie Humaine, Université Paris Nord, Communauté d’Universités et Etablissements Sorbonne Paris Cité, Paris, France

    Jean-Charles Nault

  3. Centre de Recherche des Cordeliers, Sorbonne Université, Inserm, Université de Paris Cité, team «Functional Genomics of Solid Tumors», Paris, France

    Jean-Charles Nault & Jessica Zucman-Rossi

  4. Equipe labellisée Ligue Nationale Contre le Cancer, Labex OncoImmunology, Paris, France

    Jean-Charles Nault & Jessica Zucman-Rossi

  5. Service de Pathologie, Hôpital Beaujon, AP-HP Nord, Clichy, France

    Valérie Paradis

  6. Université de Paris, INSERM U1149 “Centre de Recherche sur l’inflammation”, CRI, Paris, France

    Valérie Paradis & Maxime Ronot

  7. Department of Radiology, Assistance-Publique Hôpitaux de Paris, Hôpital Beaujon, AP-HP Nord, Clichy, France

    Maxime Ronot

  8. Hôpital Européen Georges Pompidou, APHP, Paris, France

    Jessica Zucman-Rossi

Authors
  1. Jean-Charles Nault
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  2. Valérie Paradis
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  3. Maxime Ronot
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  4. Jessica Zucman-Rossi
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Contributions

The authors contributed equally to all aspects of the article.

Corresponding authors

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

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Competing interests

The authors declare no competing interests in the field of benign hepatocellular tumours.

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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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