Journal of Hepatology
Volume 48, Issue 1 , Pages 163-170, January 2008

Molecular pathogenesis of focal nodular hyperplasia and hepatocellular adenoma☆

  • Sandra Rebouissou

      Affiliations

    • Inserm, U674, Génomique fonctionnelle des tumeurs solides, Génétique des tumeurs hépatiques, 27 rue Juliette Dodu, Paris F-75010, France
    • Université Paris 7 Denis Diderot, Institut Universitaire d’Hématologie, CEPH, Paris F-75010, France
    • ,
  • Paulette Bioulac-Sage

      Affiliations

    • Inserm, U889, Université Victor Segalen Bordeaux 2, IFR66, Bordeaux F-33076, France
    • CHU de Bordeaux, Hopital Pellegrin, Service d’Anatomie Pathologique, Bordeaux F-33076, France
    • ,
  • Jessica Zucman-Rossi

      Affiliations

    • Inserm, U674, Génomique fonctionnelle des tumeurs solides, Génétique des tumeurs hépatiques, 27 rue Juliette Dodu, Paris F-75010, France
    • Université Paris 7 Denis Diderot, Institut Universitaire d’Hématologie, CEPH, Paris F-75010, France
    • Corresponding Author InformationCorresponding author. Tel.: +33 1 53 72 51 66; fax: +33 1 53 72 51 58.

published online 30 October 2007.

Associate Editor: J.M. Llovet

Article Outline

Focal nodular hyperplasia (FNH) and hepatocellular adenomas (HCAs) are benign tumors that occur in otherwise normal liver parenchyma. FNH is considered to be the result of a hyperplastic response to increased blood flow secondary to vascular malformations. Most FNH are polyclonal and to date, the molecular pathway and mechanisms that are altered in FNH have yet to be elucidated. In contrast, HCAs are consistently monoclonal tumors, which have been divided up into three subtypes of tumors depending on the molecular alteration detected in the tumors: HNF1α inactivation, β-catenin activation and/or an acute inflammatory response in the tumor. These molecular features are closely related to clinical and pathological characteristics, and one of the most critical correlations is the higher risk of malignant transformation for β-catenin activated HCA cases. Moreover, various risk factors, such as oral contraception and obesity, are associated with HCA occurrence and may collaborate with constitutional genetic predisposition related to HNF1α or CYP1B1 germline mutations. Altogether, the recent identification of different molecular pathways that contribute to tumor development has significantly increased our knowledge of benign hepatocellular tumorigenesis. These findings may modify our clinical practice, particularly in the diagnosis and follow-up of HCA patients.

Abbreviations: APC, adenomatosis polyposis coli, CTNNB1, gene coding for β-catenin, FAP, familial adenomatous polyposis coli, FNH, focal nodular hyperplasia, HCA, hepatocellular adenoma, HCC, hepatocellular carcinoma, HNF1α, hepatocyte nuclear factor 1 alpha, HUMARA, human androgen receptor, TCF1, transcription factor 1 coding for HNF1α

Keywords: Hepatocellular adenoma, Focal nodular hyperplasia, Chromosome, Gene mutation, Hepatocyte nuclear factor 1, β-Catenin, Inflammation, Benign tumor, Genetic alteration, SAA, CRP, FABP1, Estrogen, Steatosis

 

Focal nodular hyperplasia and hepatocellular adenomas are benign liver tumors that may be sometimes difficult to diagnose. The recent identification of various molecular pathways altered in these tumors has significantly increased our knowledge of benign hepatocellular tumorigenesis. Moreover, analysis of the genotype–phenotype correlation in hepatocellular adenoma also enabled the identification of a patho-molecular classification of these tumors. Novel markers specific to these subtypes have been developed, implicating a potential for use in clinical practice. In this review, we will focus on the recent progress in understanding of the molecular mechanisms in these two hepatocellular tumors.

Back to Article Outline

1. Focal nodular hyperplasia (FNH) 

1.1. Clinical and pathological characteristics of FNH 

Focal nodular hyperplasia (FNH), first described by Edmondson, are the second most frequent benign liver tumors after hemangioma [1]. FNH more frequently develops in women (M/F=1/8) between the ages of 20 and 50 [2]. An increased risk linked to oral contraceptive use is still under debate; however, some studies suggest that use of contraceptive pills may increase the size of the nodules [3], [4], [5]. In 1985, Wanless and collaborators proposed that FNH is a hyperplastic response of the hepatic parenchyma to a pre-existing local arterial spider-like malformation, likely with a developmentally abnormal origin [6]. FNH is also related to well-known vascular diseases, such as the hereditary hemorrhagic telangiectasia (Rendu–Osler–Weber disease) or the congenital absence of the portal vein [7], [8], [9].

FNH usually occurs in normal liver and is multinodular, composed of normal hepatocytes arranged in 1–2 cell-thick plates. Bile ductules are usually found at the interface between hepatocytes and fibrous regions [10], [11]. Increased arterial flow is thought to hyperperfuse the local parenchyma, leading to secondary hepatocellular hyperplasia. FNH is therefore considered the result of a hyperplastic response to increased blood flow [6], [12], [13], [14], and, accordingly, FNH usually does not bleed or undergo malignant transformation, justifying therapeutic abstention.

1.2. Molecular features associated with FNH 

Only few data describing molecular disorders observed in FNH have been described in the literature. Clonal analysis using the HUMARA test demonstrated the reactive polyclonal nature of liver cells in FNH in 50–100% of the cases, depending on the series [15], [16], [17], [18], [19] (Table 1). Other studies analyzing chromosome gains and losses by comparative genomic hybridization, allelotyping, or karyotype identified chromosome alterations, indicating a clonal origin of the FNH nodules in 14–50% of the cases [19], [20], [21], [22], [23] (Table 1). However, genetic analysis of FNH failed to identify somatic gene mutations in β-catenin gene (CTNNB1), TP53, APC or HNF1α [19], [24], [25]. Recent studies showed that the mRNA expression levels of the angiopoietin genes (ANGPT1 and ANGPT2) involved in vessel maturation are altered, with the ANGPT1/ANGPT2 ratio increased in all FNH samples analyzed [18], [19]. Apart from the dystrophic vessels, the phenotypic characteristics of parenchymal vessels in FNH confirm that the lesion retains the overall organization of the normal liver tissue [26]. The deposition of vitronectin in the central fibrous scar is likely a result of local hemodynamic disturbance, further strengthening the role of vascular abnormalities as a main determinant of FNH [26]. Recently, we identified an activation of the β-catenin pathway in FNH without β-catenin or Axin1 mutation (unpublished results). β-catenin pathway activation was restricted to enlarged perivenous areas in FNH, which may explain the slight polyclonal over-proliferation of hepatocytes at the origin of the lesion.

Table 1. Summary of FNH molecular analyses
Published studiesNumber of analyzed casesMonoclonal lesions (%)
Gaffey (1996)a86 (75)
Paradis (1997)a130
Chen (2001)a11
Bioulac-Sage (2005)a, b187 (38)
Zhang (2004)a10
Chen (2002)b63 (50)
Raidl (2004)a31 (33)
Kellner (2003)a71 (14)
Nakayama (2006)10
Heimann (1995)c11
Overall studies5920 (34)

aHUMARA test.

bGain or loss of chromosome by CGH or allelotype.

cKaryotype.

Back to Article Outline

2. Hepatocellular adenoma (HCA) 

2.1. Clinical and pathological characteristics of HCA 

In occidental countries, hepatocellular adenomas (HCA) are rare tumors that usually develop in women who use oral contraceptives. The relationship between oral contraception and HCA occurrence was suggested by Baum and collaborators in 1973 [27] and was subsequently confirmed in several case–control studies [28], [29], [30], [31], [32]. HCA occurrence may also be related to androgenic–anabolic steroid use [33], [34], [35], [36], [37], glycogenosis type I and III [38], [39], [40], [41], [42], [43]. HCA is a benign proliferation of hepatocytes in an otherwise normal liver. The HCA nodule, rarely encapsulated, varies from 0.5 to 15cm in diameter with arterial vascularization. Proliferating hepatocytes usually resemble normal cells that may be steatotic or show glycogen storage. The tumor is also characterized by the lack of frequent mitosis, portal tract and cholangiolar proliferation [11], [44]. HCA nodules are generally solitary, but two or three nodules occasionally develop simultaneously. The development of more than 10 HCA nodules is rare and has been specifically defined as adenomatosis by Flejou and collaborators in 1985. In this context, HCA development was described to be less significantly related to oral contraception and with women [45]; however, adenomatosis is also described more frequently in women [46], [47], and is also frequently associated with diabetes, sometimes in a familial context [46], [48].

During its natural evolution, HCA may remain stable, increase in size, or regress [49], [50], [51], [52]. Regression is more frequently described in HCA related to androgenic–anabolic steroids and glycogenosis after hormone withdrawal, or after an appropriate alimentary regimen [53], [54], [55], [56]. HCA occasionally bleeds and this risk increases with the nodule’s size [27], [57], [58]. Malignant transformation in hepatocellular carcinoma is considered to be extremely rare but has been consistently described [59], [60], [61], [62], [63]. The risk of malignant transformation seems to be more critical in HCA related to androgenic–anabolic steroid exposure or glycogenosis type I [36], [37], [64], [65].

2.2. Molecular features associated with HCA 

HCAs are monoclonal tumors [18], [19], [66]. However, in contrast with hepatocellular carcinomas that show a large number of recurrent chromosome and genetic alterations (see [67] for review), prior to 2002 only a few chromosome losses and gains were identified in HCA [68], [69], [70], [71]. In 2002, several recurrent mutations were identified in the TCF1 gene encoding hepatocyte nuclear factor 1α (HNF1α), CTNNB1 encoding β-catenin, and APC (adenomatosis polyposis coli). Methylation of p14(ARF) and p16(INK4a) has also been found in approximately 20% of HCA cases [72].

2.2.1. HNF1α inactivation 

The TCF1 gene is located at chromosome 12q24.2 [73], and encodes the hepatocyte nuclear factor 1α (HNF1α), a 681 amino-acid homeodomain transcription factor that is involved in hepatocyte differentiation [74]. HNF1α controls the expression of liver-specific genes, such as β-fibrinogen, α1-antitrypsin and albumin [74]. HNF1α is also expressed in several polarized epithelia, and inactivation of the protein in mice revealed its important role in renal, pancreatic and liver function [75], [76], [77], [78]. In mice, loss of HNF1α activity was associated with the development of fatty liver, hepatomegaly, hepatocyte dysplasia and proliferation [75], [76], [79]. Moreover, the mouse model also revealed a critical role for HNF1α in cholesterol/HDL and bile acid metabolism [77]. We identified HNF1α as a human tumor suppressor gene involved in liver tumorigenesis, as we found biallelic inactivating mutations of this gene in ∼35–50% of HCA as well as a few cases of well-differentiated hepatocellular carcinomas that developed in the absence of cirrhosis [80], [81], [82]. The mutations were predicted to inactivate the protein as they included mainly nonsense and frame-shift mutations within the N-terminal portion of the protein, or mutations leading to amino-acid substitutions within the homeodomain [80], [81], [82]. Mutations of HNF1α or HNF1β have also been identified in rare cases of colon, renal, breast and endometrial cancers [83], [84], [85], [86].

In two comprehensive analyses of genotype–phenotype correlations in large series of HCA, we showed that HNF1α mutations define a homogeneous group of tumors phenotypically characterized by the recurrent presence of marked steatosis without inflammation or cytological abnormalities [81], [82]. Furthermore, we identified a repression of gluconeogenesis coordinated with an activation of glycolysis, citrate shuttle and fatty acid synthesis, which predicted elevated rates of lipogenesis in HCA tumors harboring mutations in HNF1α [87]. In these tumors, lipid composition was dramatically modified and, surprisingly, lipogenesis activation did not operate through SREBP-1 and ChREBP, both of which instead were repressed. We also found a silencing of L-FABP, which encodes liver fatty acid binding protein 1, suggesting that impaired fatty acid trafficking may also contribute to the fatty phenotype. We showed that absence of L-FABP staining in HCA was specific to HNF1α inactivation among the different benign liver tumor subtypes [82], [87]. Together this indicates that steatosis, frequently observed in HCA, may contribute to tumorigenesis, and this occurs through a constant and specific mechanism in the HNF1α inactivated tumor subtype.

2.2.2. β-Catenin activation 

Chen and collaborators sought to analyze potential alterations of candidate critical genes in HCA [24]. They focused on the Wnt/β-catenin pathway, as activating mutations of β-catenin are found in 20–34% of hepatocellular carcinomas, suggesting that β-catenin is the most frequently activated oncogene in HCC [67], [88], [89]. Furthermore, this pathway plays a key role in liver physiological phenomena, such as lineage specification, differentiation, stem cell renewal, epithelial–mesenchymal transition, zonation, proliferation, cell adhesion and liver regeneration [90], [91], [92], [93], [94], [95], [96], [97]. Chen et al. identified a β-catenin activating mutation in 3 of a series of 10 tested HCA cases. Simultaneously, a β-catenin activating mutation was also identified in an HCA occurring in a female child [98]. Nuclear accumulation of β-catenin was also identified in 46% of 18 analyzed HCA cases by Torbenson et al., but none were activating mutated [99]. Other genes in the Wnt pathways, however, such as adenomatous polyposis coli (APC) or the Axin family genes, did not show any mutations in sporadic adenomas [24], [99].

In our two series of approximately 160 different genotyped HCAs, we identified an activating β-catenin mutation in 15–19% of the cases [81], [82]. In 67% of these cases, the mutations consist of a large in-frame deletion of exon 3 that excludes the amino-acids normally phosphorylated by GSK3β. In contrast to the other subtype of HCA, β-catenin activated adenomas were frequently found in males (38%), characterized by cytological abnormalities and an acinar pattern, and were frequently associated with malignant transformation [81], [82]. We did not find any HCA cases with both β-catenin mutations and biallelic inactivation of HNF1α, suggesting that these two tumorigenic pathways are mutually exclusive. Recently, we showed that β-catenin activated HCA may be robustly diagnosed using immunochemistry by assessing the over-expression of β-catenin and glutamine synthetase, a target of β-catenin [11]. This finding is important in a routine practice to identify HCA at highest risk of malignant transformation, while remembering that such a transformation also occurs in other molecular subtypes of HCA but at a lower frequency.

2.2.3. Other molecular alterations 

In 2005, Lehmann and collaborators analyzed the methylation levels of nine genes in a series of HCA, FNH, HCC, adjacent and unrelated normal liver tissues [100]. This analysis revealed that hepatocellular adenomas display a methylation profile much more similar to normal liver tissues and focal nodular hyperplasias than to hepatocellular carcinomas. Moreover, the lack of significant difference between methylation profiles observed in FNH when compared to HCA suggests that aberrant methylation may not play a major role in adenoma pathogenesis in contrast to HCC. Vander Borght and collaborators evaluated the expression and localization of hepatic transporters in HCA, different types of FNH and well- to moderately differentiated HCC in non-cirrhotic liver and compared them with normal liver [101]. They observed diffuse over-expression of MRP3 and down-regulation of OATP2/8 in HCA, while FNH had a completely different expression profile explaining their cholestatic features. In HCC, canalicular transporters were largely absent, probably as a consequence of dedifferentiation. Whereas transporter dysregulations can easily explain specific features, their role in benign tumor pathogenesis remained to be elucidated.

In our genotype–phenotype correlation study of HCA, we defined a subgroup of lesions characterized by the presence of inflammatory infiltrates [81]. Representing 35% of HCA cases, these nodules exhibited additional features such as sinusoidal dilatation, dystrophic vessels and ductular reaction, and included most of the previously described so-called “telangiectatic focal nodular hyperplasia” cases [19]. In these tumors, we detected elevated expression of members of the acute phase inflammatory response (serum amyloid A protein, SAA, and C-reactive protein, CRP) at both the mRNA and protein levels [82]. Interestingly, our immunohistochemical analysis showed that SAA was sharply over-expressed in the tumor lesion without particular reinforcement in proximity of the inflammatory infiltrates, which remained negative, as well as Kupffer cells and other sinusoidal cells in the HCA that did not over-express SAA. These results suggested that the inflammatory pathway was intrinsically deregulated in tumor hepatocytes, and inflammatory infiltrates could be a secondary effect. According to this hypothesis, we identified a typical case of inflammatory HCA with clinical manifestation of an inflammatory syndrome and SAA expression in the tumor; after complete resection of the nodule, the inflammatory syndrome disappeared, indicating that peripheral inflammatory proteins were effectively secreted by the tumor [102]. We also found that inflammatory HCAs more frequently developed in patients presenting a high body mass index and excessive alcohol consumption [82]. These results suggest that alcohol intake and obesity could have a direct role in the initiation of tumorigenesis of inflammatory HCA. Additional molecular studies are required to identify the molecular defect at the origin of these tumors and to better understand the relationship with β-catenin activation, as SAA over-expression and β-catenin activation are not mutually exclusive and coexist in a subset of cases. The main molecular findings in HCA are represented in Fig. 1.

  • View full-size image.
  • Fig. 1. 

    Schematic representation of the different molecular pathways altered in HCA. The main risk factors and known genetic predispositions are indicated on the left; the principal clinical and pathological features of the HCA subtypes defined by their molecular pathways altered are indicated on the right. Arrows indicate the significant relationships; mut.=mutation.

2.3. Genetic predisposition to HCA development 

Heterozygous germline mutations in the gene encoding HNF1α are responsible for an autosomal dominant form of non-insulin-dependent diabetes mellitus, or maturity onset diabetes of the young type 3 (MODY3, OMIM #600496), in which subjects usually develop hyperglycemia before 25 years of age [103]. In our series of 85 HCA cases exhibiting biallelic HNF1α inactivation, one allele was germline mutated in 8 cases and these patients developed adenomatosis. Familial analyses performed in 4 independent germline adenomatosis showed that all 11 relatives who developed adenomatosis displayed a germline HNF1α mutation [104], [105], and most of the patients who developed adenomatosis also had diabetes. Clearly, in these families, HNF1α germline mutations are predisposing to both diabetes and liver adenomatosis, and such an association between familial adenomas and diabetes was first described by Foster and collaborators in 1978 [48]. However, in our French families, 16 individuals with a germline HNF1α mutation did not develop any liver tumors. These observations suggested that germline HNF1α mutations predisposed to liver adenomatosis with an incomplete penetrance, and raised the possibility for modifier genes. In contrast, among the patients with somatic HNF1α inactivation, we identified 4 women who developed multiple HNF1α-mutated adenomas simultaneously. These cases could be due to a genetic predisposition to develop HNF1α mutated adenomas, possibly associated with estrogen metabolism and in the absence of HNF1α germline mutation.

Recently, as described by Chen [106], we identified 7 HCA cases with a monoallelic HNF1α mutation without inactivation of the second allele or modification of the HNF1α targeted gene expression (unpublished data). Six of these cases corresponded to a novel HNF1α germline missense mutation in the carboxy-terminal part of the protein, mutations never before detected in HCA. Moreover, 3 of these cases were mutated for β-catenin. We thus hypothesize that in rare cases, HNF1α germline missense mutations could participate in genetic predisposition towards and subsequent development of HCA via a carcinogenic pathway other than the complete HNF1α inactivation.

In order to identify a genetic predisposition in women with HCA with somatic mutations in HNF1α or to identify a gene modifying the penetrance of adenomatosis in germline HNF1α mutated patients, we searched for alterations in candidate genes involved in estrogen metabolism (CYP1A1, CYP1A2, CYP1B1, CYP3A4, CYP3A5, COMT, UGT2B7, NQO1, GSTM1, GSTP1, and GSTT1). We identified CYP1B1 germline heterozygous mutations in 14% of the women presenting HNF1α mutated HCA [107], and all mutations resulted in decreased enzymatic activity. Thus, CYP1B1 germline inactivating mutations appear to predispose women to the development of sporadic HNF1α mutated HCA. In addition, mutation of CYP1B1 modifies the penetrance of the liver adenomatosis phenotype in HNF1α germline mutated patients, as we found that all relatives in a large family presenting an adenomatosis were also germline mutated in both the HNF1α and CYP1B1 genes [107].

HCA is also detected as a rare extracolonic tumor developed in patients presenting familial adenomatous polyposis coli (FAP, OMIM #175100 [108], [109]). In colorectal tumors associated with FAP, biallelic inactivation of the APC gene is consistently detected, and inactivation of the APC gene in tumors leads to β-catenin accumulation, thus the activation of the Wnt/wingless pathway. Biallelic inactivation of the APC gene was recently described in two HCA cases that developed in FAP patients [25], [110]. We also reported the case of a FAP woman presenting a hepatocellular adenoma after estroprogestative oral contraception use. In this steatotic adenoma, we identified an inactivating biallelic mutation of HNF1α without inactivation of the second APC allele or an activation of the β-catenin target genes. These results suggest that benign hepatocellular tumorigenesis may be dependent on or independent of the Wnt/β-catenin pathway in patients with FAP. Finally, we genotyped three cases of HCA related to glycogenosis type 1a, and two nodules were inflammatory since one was β-catenin activated showing various possible alterations of carcinogenesis pathways related to the germline deficiency of glucose-6-phosphatase (G6Pase) catalytic activity.

Back to Article Outline

3. Conclusion 

Focal nodular hyperplasia are hyperplastic responses to a hemodynamic disturbance related to vascular abnormalities. Molecular pathways altered in these tumors are poorly understood. In contrast, in hepatocellular adenomas, at least 3 different molecular pathways (HNF1α inactivation, β-catenin and inflammatory activation) are known to be altered (Fig. 1). These molecular findings have enabled the division of HCA into homogeneous subtypes of tumors closely related to specific predisposition, clinical and pathological features.

Back to Article Outline

Acknowledgements 

We warmly thank all the other participants to the GENTHEP (Groupe d’étude Génétique des Tumeurs Hépatiques) network. This work was supported by the Inserm (Réseau de Recherche clinique et en santé des populations), ARC n°5188 and the SNFGE. S.R. is supported by a Ligue Nationale Contre le Cancer doctoral fellowship.

Back to Article Outline

References 

  1. Edmondson HA. In: Tumors of the liver and intrahepatic bile ducts. Atlas of tumor pathology. Washington (DC): Armed Forces Institute of Pathology; 1958;
  2. Nguyen BN, Flejou JF, Terris B, Belghiti J, Degott C. Focal nodular hyperplasia of the liver: a comprehensive pathologic study of 305 lesions and recognition of new histologic forms. Am J Surg Pathol. 1999;23:1441–1454
  3. Heinemann LA, Weimann A, Gerken G, Thiel C, Schlaud M, DoMinh T. Modern oral contraceptive use and benign liver tumors: the German Benign Liver Tumor Case–Control Study. Eur J Contracept Reprod Health Care. 1998;3:194–200
  4. Mathieu D, Kobeiter H, Cherqui D, Rahmouni A, Dhumeaux D. Oral contraceptive intake in women with focal nodular hyperplasia of the liver. Lancet. 1998;352:1679–1680
  5. Scalori A, Tavani A, Gallus S, La Vecchia C, Colombo M. Oral contraceptives and the risk of focal nodular hyperplasia of the liver: a case–control study. Am J Obstet Gynecol. 2002;186:195–197
  6. Wanless IR, Mawdsley C, Adams R. On the pathogenesis of focal nodular hyperplasia of the liver. Hepatology. 1985;5:1194–1200
  7. Altavilla G, Guariso G. Focal nodular hyperplasia of the liver associated with portal vein agenesis: a morphological and immunohistochemical study of one case and review of the literature. Adv Clin Path. 1999;3:139–145
  8. Buscarini E, Danesino C, Plauchu H, de Fazio C, Olivieri C, Brambilla G, et al. High prevalence of hepatic focal nodular hyperplasia in subjects with hereditary hemorrhagic telangiectasia. Ultrasound Med Biol. 2004;30:1089–1097
  9. De Gaetano AM, Gui B, Macis G, Manfredi R, Di Stasi C. Congenital absence of the portal vein associated with focal nodular hyperplasia in the liver in an adult woman: imaging and review of the literature. Abdom Imaging. 2004;29:455–459
  10. Makhlouf HR, Abdul-Al HM, Goodman ZD. Diagnosis of focal nodular hyperplasia of the liver by needle biopsy. Hum Pathol. 2005;36:1210–1216
  11. Bioulac-Sage P, Balabaud C, Bedossa P, Scoazec JY, Chiche L, Dhillon AP, et al. Pathological diagnosis of liver cell adenoma and focal nodular hyperplasia: Bordeaux update. J Hepatol. 2007;46:521–527
  12. Fukukura Y, Nakashima O, Kusaba A, Kage M, Kojiro M. Angioarchitecture and blood circulation in focal nodular hyperplasia of the liver. J Hepatol. 1998;29:470–475
  13. Gaiani S, Piscaglia F, Serra C, Bolondi L. Hemodynamics in focal nodular hyperplasia. J Hepatol. 1999;31:576
  14. Wanless IR, Albrecht S, Bilbao J, Frei JV, Heathcote EJ, Roberts EA, et al. Multiple focal nodular hyperplasia of the liver associated with vascular malformations of various organs and neoplasia of the brain: a new syndrome. Mod Pathol. 1989;2:456–462
  15. Gaffey MJ, Iezzoni JC, Weiss LM. Clonal analysis of focal nodular hyperplasia of the liver. Am J Pathol. 1996;148:1089–1096
  16. Chen TC, Chou TB, Ng KF, Hsieh LL, Chou YH. Hepatocellular carcinoma associated with focal nodular hyperplasia. Report of a case with clonal analysis. Virchows Arch. 2001;438:408–411
  17. Zhang SH, Cong WM, Wu MC. Focal nodular hyperplasia with concomitant hepatocellular carcinoma: a case report and clonal analysis. J Clin Pathol. 2004;57:556–559
  18. Paradis V, Laurent A, Flejou JF, Vidaud M, Bedossa P. Evidence for the polyclonal nature of focal nodular hyperplasia of the liver by the study of X-chromosome inactivation. Hepatology. 1997;26:891–895
  19. Bioulac-Sage P, Rebouissou S, Sa Cunha A, Jeannot E, Lepreux S, Blanc JF, et al. Clinical, morphologic, and molecular features defining so-called telangiectatic focal nodular hyperplasias of the liver. Gastroenterology. 2005;128:1211–1218
  20. Raidl M, Pirker C, Schulte-Hermann R, Aubele M, Kandioler-Eckersberger D, Wrba F, et al. Multiple chromosomal abnormalities in human liver (pre)neoplasia. J Hepatol. 2004;40:660–668
  21. Kellner U, Jacobsen A, Kellner A, Mantke R, Roessner A, Rocken C. Comparative genomic hybridization. Synchronous occurrence of focal nodular hyperplasia and hepatocellular carcinoma in the same liver is not based on common chromosomal aberrations. Am J Clin Pathol. 2003;119:265–271
  22. Heimann P, Ogur G, Debusscher C, De Valck C, Sariban E, Deprez C, et al. Multiple clonal chromosome aberrations in a case of childhood focal nodular hyperplasia of the liver. Cancer Genet Cytogenet. 1995;85:138–142
  23. Chen YJ, Chen PJ, Lee MC, Yeh SH, Hsu MT, Lin CH. Chromosomal analysis of hepatic adenoma and focal nodular hyperplasia by comparative genomic hybridization. Genes Chromosomes Cancer. 2002;35:138–143
  24. Chen YW, Jeng YM, Yeh SH, Chen PJ. P53 gene and Wnt signaling in benign neoplasms: beta-catenin mutations in hepatic adenoma but not in focal nodular hyperplasia. Hepatology. 2002;36:927–935
  25. Blaker H, Sutter C, Kadmon M, Otto HF, Von Knebel-Doeberitz M, Gebert J, et al. Analysis of somatic APC mutations in rare extracolonic tumors of patients with familial adenomatous polyposis coli. Genes Chromosomes Cancer. 2004;41:93–98
  26. Scoazec JY, Flejou JF, D’Errico A, Couvelard A, Kozyraki R, Fiorentino M, 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. 1995;26:1114–1125
  27. Baum JK, Bookstein JJ, Holtz F, Klein EW. Possible association between benign hepatomas and oral contraceptives. Lancet. 1973;2:926–929
  28. Edmondson HA, Henderson B, Benton B. Liver-cell adenomas associated with use of oral contraceptives. N Engl J Med. 1976;294:470–472
  29. Lansing PB, McQuitty JT, Bradburn DM. Benign liver tumors: what is their relationship to oral contraceptives?. Am Surg. 1976;42:744–760
  30. Vana J, Murphy GP, Aronoff BL, Baker HW. Primary liver tumors and oral contraceptives. Results of a survey. Jama. 1977;238:2154–2158
  31. Christopherson WM, Mays ET, Barrows G. A clinicopathologic study of steroid-related liver tumors. Am J Surg Pathol. 1977;1:31–41
  32. Rooks JB, Ory HW, Ishak KG, Strauss LT, Greenspan JR, Hill AP, et al. Epidemiology of hepatocellular adenoma. The role of oral contraceptive use. Jama. 1979;242:644–648
  33. Farrell GC, Joshua DE, Uren RF, Baird PJ, Perkins KW, Kronenberg H. Androgen-induced hepatoma. Lancet. 1975;1:430–432
  34. Lesna M, Spencer I, Walker W. Letter: liver nodules and androgens. Lancet. 1976;1:1124
  35. Sale GE, Lerner KG. Multiple tumors after androgen therapy. Arch Pathol Lab Med. 1977;101:600–603
  36. Johnson FL, Lerner KG, Siegel M, Feagler JR, Majerus PW, Hartmann JR, et al. Association of androgenic–anabolic steroid therapy with development of hepatocellular carcinoma. Lancet. 1972;2:1273–1276
  37. Henderson JT, Richmond J, Sumerling MD. Androgenic–anabolic steroid therapy and hepatocellular carcinoma. Lancet. 1973;1:934
  38. Bianchi L. Glycogen storage disease I and hepatocellular tumours. Eur J Pediatr. 1993;152:S63–S70
  39. Lee P, Mather S, Owens C, Leonard J, Dicks-Mireaux C. Hepatic ultrasound findings in the glycogen storage diseases. Br J Radiol. 1994;67:1062–1066
  40. Smit GP, Fernandes J, Leonard JV, Matthews EE, Moses SW, Odievre M, et al. The long-term outcome of patients with glycogen storage diseases. J Inherit Metab Dis. 1990;13:411–418
  41. de Parscau L, Guibaud P, Maire I. Glycogenoses type 1b and 1c. Pediatrie. 1988;43:661–665
  42. Talente GM, Coleman RA, Alter C, Baker L, Brown BI, Cannon RA, et al. Glycogen storage disease in adults. Ann Intern Med. 1994;120:218–226
  43. 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. 1997;24:276–279
  44. International Working Party. Terminology of nodular hepatocellular lesions. Hepatology 1995;22:983–993.
  45. Flejou JF, Barge J, Menu Y, Degott C, Bismuth H, Potet F, et al. Liver adenomatosis. An entity distinct from liver adenoma?. Gastroenterology. 1985;89:1132–1138
  46. Chiche L, Dao T, Salame E, Galais MP, Bouvard N, Schmutz G, et al. Liver adenomatosis: reappraisal, diagnosis, and surgical management: eight new cases and review of the literature. Ann Surg. 2000;231:74–81
  47. Grazioli L, Federle MP, Ichikawa T, Balzano E, Nalesnik M, Madariaga J. Liver adenomatosis: clinical, histopathologic, and imaging findings in 15 patients. Radiology. 2000;216:395–402
  48. Foster JH, Donohue TA, Berman MM. Familial liver-cell adenomas and diabetes mellitus. N Engl J Med. 1978;299:239–241
  49. Buhler H, Pirovino M, Akobiantz A, Altorfer J, Weitzel M, Maranta E, et al. Regression of liver cell adenoma. A follow-up study of three consecutive patients after discontinuation of oral contraceptive use. Gastroenterology. 1982;82:775–782
  50. Steinbrecher UP, Lisbona R, Huang SN, Mishkin S. Complete regression of hepatocellular adenoma after withdrawal of oral contraceptives. Dig Dis Sci. 1981;26:1045–1050
  51. Mariani AF, Livingstone AS, Pereiras RV, van Zuiden PE, Schiff ER. Progressive enlargement of an hepatic cell adenoma. Gastroenterology. 1979;77:1319–1325
  52. Svrcek M, Jeannot E, Arrive L, Poupon R, Fromont G, Flejou JF, 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. 2007;156:617–621
  53. Westaby D, Portmann B, Williams R. Androgen related primary hepatic tumors in non-Fanconi patients. Cancer. 1983;51:1947–1952
  54. Touraine RL, Bertrand Y, Foray P, Gilly J, Philippe N. Hepatic tumours during androgen therapy in Fanconi anaemia. Eur J Pediatr. 1993;152:691–693
  55. Socas L, Zumbado M, Perez-Luzardo O, Ramos A, Perez C, Hernandez JR, et al. Hepatocellular adenomas associated with anabolic androgenic steroid abuse in bodybuilders: a report of two cases and a review of the literature. Br J Sports Med. 2005;39:e27
  56. Parker P, Burr I, Slonim A, Ghishan FK, Greene H. Regression of hepatic adenomas in type Ia glycogen storage disease with dietary therapy. Gastroenterology. 1981;81:534–536
  57. Kerlin P, Davis GL, McGill DB, Weiland LH, Adson MA, Sheedy PF. Hepatic adenoma and focal nodular hyperplasia: clinical, pathologic, and radiologic features. Gastroenterology. 1983;84:994–1002
  58. Kent DR, Nissen ED, Nissen SE, Ziehm DJ. Effect of pregnancy on liver tumor associated with oral contraceptives. Obstet Gynecol. 1978;51:148–151
  59. Foster JH, Berman MM. The malignant transformation of liver cell adenomas. Arch Surg. 1994;129:712–717
  60. Grigsby P, Meyer JS, Sicard GA, Huggins MB, Lamar DJ, DeSchryver-Kecskemeti K. Hepatic adenoma within a spindle cell carcinoma in a woman with a long history of oral contraceptives. J Surg Oncol. 1987;35:173–179
  61. Gyorffy EJ, Bredfeldt JE, Black WC. Transformation of hepatic cell adenoma to hepatocellular carcinoma due to oral contraceptive use. Ann Intern Med. 1989;110:489–490
  62. Korula J, Yellin A, Kanel G, Campofiori G, Nichols P. Hepatocellular carcinoma coexisting with hepatic adenoma. Incidental discovery after long-term oral contraceptive use. West J Med. 1991;155:416–418
  63. Tao LC. Oral contraceptive-associated liver cell adenoma and hepatocellular carcinoma. Cytomorphology and mechanism of malignant transformation. Cancer. 1991;68:341–347
  64. Conti JA, Kemeny N. Type Ia glycogenosis associated with hepatocellular carcinoma. Cancer. 1992;69:1320–1322
  65. Franco LM, Krishnamurthy V, Bali D, Weinstein DA, Arn P, Clary B, et al. Hepatocellular carcinoma in glycogen storage disease type Ia: a case series. J Inherit Metab Dis. 2005;28:153–162
  66. Gong L, Su Q, Zhang W, Li AN, Zhu SJ, Feng YM. Liver cell adenoma: a case report with clonal analysis and literature review. World J Gastroenterol. 2006;12:2125–2129
  67. Laurent-Puig P, Zucman-Rossi J. Genetics of hepatocellular tumors. Oncogene. 2006;25:3778–3786
  68. Wilkens L, Bredt M, Flemming P, Becker T, Klempnauer J, Kreipe HH. Differentiation of liver cell adenomas from well-differentiated hepatocellular carcinomas by comparative genomic hybridization. J Pathol. 2001;193:476–482
  69. Nasarek A, Werner M, Nolte M, Klempnauer J, Georgii A. Trisomy 1 and 8 occur frequently in hepatocellular carcinoma but not in liver cell adenoma and focal nodular hyperplasia. A fluorescence in situ hybridization study. Virchows Arch. 1995;427:373–378
  70. Wilkens L, Bredt M, Flemming P, Schwarze Y, Becker T, Mengel M, et al. Diagnostic impact of fluorescence in situ hybridization in the differentiation of hepatocellular adenoma and well-differentiated hepatocellular carcinoma. J Mol Diagn. 2001;3:68–73
  71. De Souza AT, Hankins GR, Washington MK, Fine RL, Orton TC, Jirtle RL. Frequent loss of heterozygosity on 6q at the mannose 6-phosphate/insulin-like growth factor II receptor locus in human hepatocellular tumors. Oncogene. 1995;10:1725–1729
  72. Tannapfel A, Busse C, Geissler F, Witzigmann H, Hauss J, Wittekind C. INK4a-ARF alterations in liver cell adenoma. Gut. 2002;51:253–258
  73. Bach I, Galcheva-Gargova Z, Mattei MG, Simon-Chazottes D, Guenet JL, Cereghini S, et al. Cloning of human hepatic nuclear factor 1 (HNF1) and chromosomal localization of its gene in man and mouse. Genomics. 1990;8:155–164
  74. Courtois G, Morgan JG, Campbell LA, Fourel G, Crabtree GR. Interaction of a liver-specific nuclear factor with the fibrinogen and alpha 1-antitrypsin promoters. Science. 1987;238:688–692
  75. Pontoglio M, Barra J, Hadchouel M, Doyen A, Kress C, Bach JP, et al. Hepatocyte nuclear factor 1 inactivation results in hepatic dysfunction, phenylketonuria, and renal Fanconi syndrome. Cell. 1996;84:575–585
  76. Lee YH, Sauer B, Gonzalez FJ. Laron dwarfism and non-insulin-dependent diabetes mellitus in the Hnf-1alpha knockout mouse. Mol Cell Biol. 1998;18:3059–3068
  77. Shih DQ, Bussen M, Sehayek E, Ananthanarayanan M, Shneider BL, Suchy FJ, et al. Hepatocyte nuclear factor-1alpha is an essential regulator of bile acid and plasma cholesterol metabolism. Nat Genet. 2001;27:375–382
  78. Shih DQ, Screenan S, Munoz KN, Philipson L, Pontoglio M, Yaniv M, et al. Loss of HNF-1alpha function in mice leads to abnormal expression of genes involved in pancreatic islet development and metabolism. Diabetes. 2001;50:2472–2480
  79. Akiyama TE, Ward JM, Gonzalez FJ. Regulation of the liver fatty acid-binding protein gene by hepatocyte nuclear factor 1alpha (HNF1alpha). Alterations in fatty acid homeostasis in HNF1alpha-deficient mice. J Biol Chem. 2000;275:27117–27122
  80. Bluteau O, Jeannot E, Bioulac-Sage P, Marques JM, Blanc JF, Bui H, et al. Bi-allelic inactivation of TCF1 in hepatic adenomas. Nat Genet. 2002;32:312–315
  81. Zucman-Rossi J, Jeannot E, Nhieu JT, Scoazec JY, Guettier C, Rebouissou S, et al. Genotype–phenotype correlation in hepatocellular adenoma: new classification and relationship with HCC. Hepatology. 2006;43:515–524
  82. Bioulac-Sage P, Rebouissou S, Thomas C, Blanc JF, Sa Cunha A, Rullier A, et al. Hepatocellular adenoma subtype classification using molecular markers and immunohistochemistry. Hepatology. 2007;46:740–748
  83. Laurent-Puig P, Plomteux O, Bluteau O, Zinzindohoue F, Jeannot E, Dahan K, et al. Frequent mutations of hepatocyte nuclear factor 1 in colorectal cancer with microsatellite instability. Gastroenterology. 2003;124:1311–1314
  84. Rebouissou S, Rosty C, Lecuru F, Boisselier S, Bui H, Le Frere-Belfa MA, et al. Mutation of TCF1 encoding hepatocyte nuclear factor 1alpha in gynecological cancer. Oncogene. 2004;23:7588–7592
  85. Rebouissou S, Vasiliu V, Thomas C, Bellanne-Chantelot C, Bui H, Chretien Y, et al. Germline hepatocyte nuclear factor 1alpha and 1beta mutations in renal cell carcinomas. Hum Mol Genet. 2005;14:603–614
  86. Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, et al. The consensus coding sequences of human breast and colorectal cancers. Science. 2006;314:268–274
  87. Rebouissou S, Imbeaud S, Balabaud C, Boulanger V, Bertrand-Michel J, Terce F, 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. 2007;282:14437–14446
  88. Miyoshi Y, Iwao K, Nagasawa Y, Aihara T, Sasaki Y, Imaoka S, et al. Activation of the beta-catenin gene in primary hepatocellular carcinomas by somatic alterations involving exon 3. Cancer Res. 1998;58:2524–2527
  89. de La Coste A, Romagnolo B, Billuart P, Renard CA, Buendia MA, Soubrane O, et al. Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc Natl Acad Sci USA. 1998;95:8847–8851
  90. Nagafuchi A, Takeichi M. Transmembrane control of cadherin-mediated cell adhesion: a 94kDa protein functionally associated with a specific region of the cytoplasmic domain of E-cadherin. Cell Regul. 1989;1:37–44
  91. Micsenyi A, Tan X, Sneddon T, Luo JH, Michalopoulos GK, Monga SP. Beta-catenin is temporally regulated during normal liver development. Gastroenterology. 2004;126:1134–1146
  92. Suksaweang S, Lin CM, Jiang TX, Hughes MW, Widelitz RB, Chuong CM. Morphogenesis of chicken liver: identification of localized growth zones and the role of beta-catenin/Wnt in size regulation. Dev Biol. 2004;266:109–122
  93. Monga SP, Monga HK, Tan X, Mule K, Pediaditakis P, Michalopoulos GK. Beta-catenin antisense studies in embryonic liver cultures: role in proliferation, apoptosis, and lineage specification. Gastroenterology. 2003;124:202–216
  94. Benhamouche S, Decaens T, Godard C, Chambrey R, Rickman DS, Moinard C, et al. Apc tumor suppressor gene is the “zonation-keeper” of mouse liver. Dev Cell. 2006;10:759–770
  95. Cadoret A, Ovejero C, Terris B, Souil E, Levy L, Lamers WH, et al. New targets of beta-catenin signaling in the liver are involved in the glutamine metabolism. Oncogene. 2002;21:8293–8301
  96. Monga SP, Pediaditakis P, Mule K, Stolz DB, Michalopoulos GK. Changes in WNT/beta-catenin pathway during regulated growth in rat liver regeneration. Hepatology. 2001;33:1098–1109
  97. Tan X, Behari J, Cieply B, Michalopoulos GK, Monga SP. Conditional deletion of beta-catenin reveals its role in liver growth and regeneration. Gastroenterology. 2006;131:1561–1572
  98. Takayasu H, Motoi T, Kanamori Y, Kitano Y, Nakanishi H, Tange T, et al. Two case reports of childhood liver cell adenomas harboring beta-catenin abnormalities. Hum Pathol. 2002;33:852–855
  99. Torbenson M, Lee JH, Choti M, Gage W, Abraham SC, Montgomery E, et al. Hepatic adenomas: analysis of sex steroid receptor status and the Wnt signaling pathway. Mod Pathol. 2002;15:189–196
  100. Lehmann U, Berg-Ribbe I, Wingen LU, Brakensiek K, Becker T, Klempnauer J, et al. Distinct methylation patterns of benign and malignant liver tumors revealed by quantitative methylation profiling. Clin Cancer Res. 2005;11:3654–3660
  101. Vander Borght S, Libbrecht L, Blokzijl H, Faber KN, Moshage H, Aerts R, et al. Diagnostic and pathogenetic implications of the expression of hepatic transporters in focal lesions occurring in normal liver. J Pathol. 2005;207:471–482
  102. Sa Cunha A, Blanc JF, Lazaro E, Mellottee L, Le Bail B, Zucman-Rossi J, et al. Inflammatory syndrome with liver adenomatosis: the beneficial effects of surgical management. Gut. 2007;56:307–309
  103. Yamagata K, Oda N, Kaisaki PJ, Menzel S, Furuta H, Vaxillaire M, et al. Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3). Nature. 1996;384:455–458
  104. Bacq Y, Jacquemin E, Balabaud C, Jeannot E, Scotto B, Branchereau S, et al. Familial liver adenomatosis associated with hepatocyte nuclear factor 1alpha inactivation. Gastroenterology. 2003;125:1470–1475
  105. Reznik Y, Dao T, Coutant R, Chiche L, Jeannot E, Clauin S, et al. Hepatocyte nuclear factor-1 alpha gene inactivation: cosegregation between liver adenomatosis and diabetes phenotypes in two maturity-onset diabetes of the young (MODY)3 families. J Clin Endocrinol Metab. 2004;89:1476–1480
  106. Chen PJ. Genetic mutation in hepatic adenoma: seeing is believing. J Hepatol. 2006;45:767–769
  107. Jeannot E, Poussin K, Chiche L, Bacq Y, Sturm N, Scoazec JY, et al. Association of CYP1B1 germ line mutations with hepatocyte nuclear factor 1alpha-mutated hepatocellular adenoma. Cancer Res. 2007;67:2611–2616
  108. Joslyn G, Carlson M, Thliveris A, Albertsen H, Gelbert L, Samowitz W, et al. Identification of deletion mutations and three new genes at the familial polyposis locus. Cell. 1991;66:601–613
  109. Groden J, Thliveris A, Samowitz W, Carlson M, Gelbert L, Albertsen H, et al. Identification and characterization of the familial adenomatous polyposis coli gene. Cell. 1991;66:589–600
  110. Bala S, Wunsch PH, Ballhausen WG. Childhood hepatocellular adenoma in familial adenomatous polyposis: mutations in adenomatous polyposis coli gene and p53. Gastroenterology. 1997;112:919–922

☆ The authors declare that they do not have anything to disclose regarding conflict of interest with respect to this manuscript.

PII: S0168-8278(07)00570-3

doi:10.1016/j.jhep.2007.10.003

Journal of Hepatology
Volume 48, Issue 1 , Pages 163-170, January 2008

Article Tools

* Image Usage & Resolution