- Email: [email protected]
Focal nodular hyperplasia, hepatocellular adenomas: Past, present, future
Gastroentérologie Clinique et Biologique (2010) 34, 355—358
MINI REVIEW
Focal nodular hyperplasia, hepatocellular adenomas: Past, present, future Hyperplasie nodulaire focale, adénomes hépatocellulaires : passé, présent, futur P. Bioulac-Sage a,b, C. Balabaud b,∗,c, J. Zucman-Rossi d a
Service d’anatomie pathologique, hôpital Pellegrin, CHU de Bordeaux, 33076 Bordeaux, France Inserm U889, université Bordeaux 2, 33076 Bordeaux, France c Service d’hépatologie, hôpital Saint-André, CHU de Bordeaux, 33075 Bordeaux, France d Inserm U674 génomique fonctionnelle des tumeurs solides, 27, rue Juliette-Dodu, 75010 Paris, France b
Available online 2 June 2010
Past In the 1958 monograph on liver tumors, Edmondson established that we have to distinguish between two basically different forms of benign liver tumors. For one, he reserved the designation hepatocellular adenoma (HCA), for the second the term focal nodular hyperplasia (FNH) [1].
Present HCA The estimate prevalence is 3—4/100,000 in Europe and North America. Genomic and molecular studies [2,3], together with the analysis of the genotype/phenotype correlations [4,5], have led to the recognition of three major HCA subgroups: HNF1␣ inactivated, inflammatory and -catenin activated HCA. Sixty per cent of the inflammatory HCA are also gp130 mutated [6]. While immunohistochemistry (Fig. 1) identifies the three major subgroups, MRI identi-
∗
Corresponding author. E-mail address: [email protected] (C. Balabaud).
fies HNF1␣ inactivated HCA and inflammatory HCA [5,7]. Unusual clinical manifestations such as inflammatory anemia or nephrotic syndrome can be observed in inflammatory HCA [8]. Familial cases of adenomatosis can also be found in HNF1␣ inactivated HCA [9,10].
FNH The estimate prevalence is 10 times greater than HCA. Most of the FNH are polyclonal tumors [11,12]. Molecular analyses has identified ANGPT1/ANGPT2 and NTS/HAL ratio of gene expression that are highly increased in FNH compared with normal liver, hepatocellular carcinoma or adenoma [12,13]. The -catenin pathway is activated heterogeneously in FNH without -catenin or Axin1 mutation [14]. Glutamine synthase has been proposed as a marker to identify FNH [15]. Contrast ultrasound and MRI allows the identification of FNH in the great majority of cases. What remains true of the past What remains true of the past are: • the great majority of HCA occurs in women taking oral contraceptives [16]. Once discovered, oral contraception should be stopped;
0399-8320/$ – see front matter © 2010 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.gcb.2010.03.014
356
P. Bioulac-Sage et al. (≥ 5 cm) is an important determinant for these two risks [17,18]. What remains true but needs to be updated What remains true but needs to be updated are: • familial diabetes [19]. In rare families with an inherited mutation in one allele of HNF1A, MODY3 (Maturity Onset Diabetes of the Young type 3) patients are predisposed to develop familial liver adenomatosis with HNF1␣ inactivated HCA [9,10]. Obesity is also a risk factor for inflammatory HCA development [5,20]. Thus, relationship between metabolism perturbations and adenoma occurrence remains to be explored in detailed [21]; • HCA and hepatocellular carcinoma [22]. Malignant transformation occurs mainly in the -catenin mutated group [4,17]. However, other HCA subtypes can also transform and these rare at risk lesions have to be identified.
Figure 1 Phenotypic classification of HCA in patients without known etiology except OC (Bordeaux experience based on 130 cases). The dotted line separates the different subgroups in women. The different subgroups in men are in between the thick lines.
• all possible causes should be considered (Table 1); • the main risk factor is bleeding (incidence 25%). Malignant transformation of HCA is rare (5—7%). Size
Table 1
What needs revision What needs revision are: • adenomatosis [23]. It is no longer a specific entity [17,18]. If used the term should mean many HCA (more than 10 and preferably unnumbered); • telangiectatic FNH described as a subtype of FNH [24] are, at least for many of them, inflammatory HCA [20,25] (Fig. 1). To avoid confusion this term should be banned
Hepatocellular adenomas: rare causes.
Sex/age
Causes
Genotypic/phenotypic classificationa
Women (young) Polycystic ovary syndromeb Women/Men/Children Metabolic Glycogenosis (I and III) Galactosemiab Tyrosinemiab Genetic MODY 3 diabetes FAPb Peutz—Jeghers Syndromeb Drugs Anabolic androgenic steroids ie Danazol Antiepileptic Carmabazepineb Valproateb Iron overload ie Fanconi anemiab Vascular disordersc Portal vein (agenesis, shunts, HPS) Hepatic vein (Budd Chiari)
-catenin, IHCA -catenin
HNF1␣ -catenin, HNF1␣
-catenin
IHCA
HPS: hepatoportal sclerosis; FAP: familial adenomatosis polyposis. a There is very little information in the literature (in our institution, nine patients are included in this series). b Case report. c Case report: focal nodular hyperplasia are more often reported.
Focal nodular hyperplasia, hepatocellular adenomas [26]. FNH with major sinusoidal dilatation do however exist; • absence of ductules, a classical hallmark in HCA definition [27]. Ductules can be seen in inflammatory HCA [21].
Future HCA Basic science The search for new gene mutations needs to go on and the present known mutations looked for on a large scale in different countries, particularly those where the use of oral contraception is not widespread. To understand the molecular steps in carcinogenesis particularly via the -catenin pathway but also how HNF1␣ inactivation promotes lipogenesis and activation of several carcinogenetic pathways [28,29]. To define the role of cofactors such as obesity present in 50% of inflammatory HCA and steatohepatitis. Clinical science To find the relevance of the genotype/phenotype classification in the management/follow-up and treatment [30]. To define the role of the biopsy and the place of new radical treatment avoiding surgery (radio frequency, embolization). Ultimately to test drugs that may block pathways involved in the tumoral process.
FNH To identify (imaging, pathology) FNH lacking full blown criteria, and understand the genesis of their formation (normal and pathologic livers particularly cirrhotic ones), and the relationship between FNH (often multiple) and associated disorders such as brain tumors [25]. FNH, for the first time, will now have an International Classification of Disease (ICD) code, as it was decided for the next WHO revision book [31].
Conclusion The differential diagnosis between FNH and HCA and between HCA and hepatocellular carcinoma is occasionally difficult and this difficulty increases when tumors are developed on pathological livers. The genotypic/phenotypic classification and we hope its further refinement, will remain the best way to avoid erroneous or doubtful diagnosis, and to adapt treatment according to each subtype.
References [1] Edmondson HA. Tumors of the liver and intrahepatic bile ducts. Atlas of tumor pathology, VII, 25 (Armed forces Institute of pathology);1958. [2] Bluteau O, Jeannot E, Bioulac-Sage P, Marqués JM, Blanc JF, Bui H, et al. Bi-allelic inactivation of TCF1 in hepatic adenomas. Nat Genet 2002;32:312—5. [3] Chen YW, Jeng YM, Yeh SH, Chen PJ. P53 gene and Wnt signaling in benign neoplasms: -catenin mutations in hepatic adenoma but not in focal nodular hyperplasia. Hepatology 2002;36:927—35.
357 [4] 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—24. [5] 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—8. [6] Rebouissou S, Amessou M, Couchy G, Poussin K, Imbeaud S, Pilati C, et al. Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours. Nature 2009;457:200—4. [7] Laumonier H, Bioulac-Sage P, Laurent C, Zucman-Rossi J, Balabaud C, Trillaud H. Hepatocellular adenomas: magnetic resonance imaging features as a function of molecular pathological classification. Hepatology 2008;48:808—18. [8] 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—9. [9] Bacq Y, Jacquemin E, Balabaud C, Jeannot E, Scotto B, Branchereau S, et al. Familial liver adenomatosis associated with hepatocyte nuclear factor-1 alpha inactivation. Gastroenterology 2003;125:1470—5. [10] 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—80. [11] 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—5. [12] Rebouissou S, Bioulac-Sage P, Zucman-Rossi J. Molecular pathogenesis of focal nodular hyperplasia and hepatocellular adenoma. J Hepatol 2008;48:163—70. [13] Paradis V, Bièche I, Dargère D, Laurendeau I, Nectoux J, Degott C, et al. A quantitative gene expression study suggests a role for angiopoietins in focal nodular hyperplasia. Gastroenterology 2003;124:651—9. [14] Rebouissou S, Couchy G, Libbrecht L, Balabaud C, Imbeaud S, Auffray C, et al. The -catenin pathway is activated in focal nodular hyperplasia but not in cirrhotic FNH-like nodules. J Hepatol 2008;49:61—71. [15] Bioulac-Sage P, Laumonier H, Rullier A, Cubel G, Laurent C, Zucman-Rossi J, et al. Over-expression of glutamine synthetase in focal nodular hyperplasia: a novel easy diagnostic tool in surgical pathology. Liver Int 2009;29:459—65. [16] Baum JK, Bookstein JJ, Holtz F, Klein EW. Possible association between benign hepatomas and oral contraceptives. Lancet 1973;2:926—9. [17] Bioulac-Sage P, Laumonier H, Couchy G, Le Bail B, Sa Cunha A, Rullier A, et al. Hepatocellular adenoma management and phenotypic classification: the Bordeaux experience. Hepatology 2009;5:481—9. [18] Dokmak S, Paradis V, Vilgrain V, Sauvanet A, Farges O, Valla D, et al. A single-center surgical experience of 122 patients with single and multiple hepatocellular adenomas. Gastroenterology 2009;137:1698—705. [19] Foster JH, Donohue TA, Berman MM. Familial liver-cell adenomas and diabetes mellitus. N Engl J Med 1978;299: 239—41. [20] Paradis V, Champault A, Ronot M, Deschamps L, Valla DC, Vidaud D, et al. Telangiectatic adenoma: an entity associated with increased body mass index and inflammation. Hepatology 2007;46:140—6. [21] Jeannot E, Mellottee L, Bioulac-Sage P, Balabaud C, Scoazec JY, Tran Van Nhieu, et al. Spectrum of HNF1A somatic mutations
358
[22] [23]
[24]
[25]
[26]
P. Bioulac-Sage et al. in hepatocellular adenoma differs from that in MODY3 patients and suggests genotoxic damage. Diabetes 2010, 14 (online). Foster JH, Berman MM. The malignant transformation of liver cell adenomas. Arch Surg 1994;129:712—7. 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—8. 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—62. 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—8. Bioulac-Sage P, Balabaud C, Zucman-Rossi J. What’s in a name? Hepatology 2010;51:1086—7.
[27] Terminology of nodular hepatocellular lesions. International working party. Hepatology 1995;22:983—93. [28] Rebouissou S, Imbeaud S, Balabaud C, Boulanger V, BertrandMichel 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—46. [29] Pelletier L, Rebouissou S, Paris A, Rathahao-Paris E, Perdu E, Bioulac-Sage P, et al. Loss of hepatocyte nuclear factor-1 alpha function in human hepatocellular adenomas leads to aberrant activation of signaling pathways involved in tumorigenesis. Hepatology 2010;51:557—66. [30] Terkivatan T, Ijzermans JN. Hepatocellular adenoma: should phenotypic classification direct management? Nat Rev Gastroenterol Hepatol 2009;6:697—8. [31] Bosman FT, Carneiro F, Hruban RH, Theise ND. ‘‘World Health Organization (WHO) Classification of Tumours of the Digestive System’’, 4th ed; 2010 (in press).
MINI REVIEW
Focal nodular hyperplasia, hepatocellular adenomas: Past, present, future Hyperplasie nodulaire focale, adénomes hépatocellulaires : passé, présent, futur P. Bioulac-Sage a,b, C. Balabaud b,∗,c, J. Zucman-Rossi d a
Service d’anatomie pathologique, hôpital Pellegrin, CHU de Bordeaux, 33076 Bordeaux, France Inserm U889, université Bordeaux 2, 33076 Bordeaux, France c Service d’hépatologie, hôpital Saint-André, CHU de Bordeaux, 33075 Bordeaux, France d Inserm U674 génomique fonctionnelle des tumeurs solides, 27, rue Juliette-Dodu, 75010 Paris, France b
Available online 2 June 2010
Past In the 1958 monograph on liver tumors, Edmondson established that we have to distinguish between two basically different forms of benign liver tumors. For one, he reserved the designation hepatocellular adenoma (HCA), for the second the term focal nodular hyperplasia (FNH) [1].
Present HCA The estimate prevalence is 3—4/100,000 in Europe and North America. Genomic and molecular studies [2,3], together with the analysis of the genotype/phenotype correlations [4,5], have led to the recognition of three major HCA subgroups: HNF1␣ inactivated, inflammatory and -catenin activated HCA. Sixty per cent of the inflammatory HCA are also gp130 mutated [6]. While immunohistochemistry (Fig. 1) identifies the three major subgroups, MRI identi-
∗
Corresponding author. E-mail address: [email protected] (C. Balabaud).
fies HNF1␣ inactivated HCA and inflammatory HCA [5,7]. Unusual clinical manifestations such as inflammatory anemia or nephrotic syndrome can be observed in inflammatory HCA [8]. Familial cases of adenomatosis can also be found in HNF1␣ inactivated HCA [9,10].
FNH The estimate prevalence is 10 times greater than HCA. Most of the FNH are polyclonal tumors [11,12]. Molecular analyses has identified ANGPT1/ANGPT2 and NTS/HAL ratio of gene expression that are highly increased in FNH compared with normal liver, hepatocellular carcinoma or adenoma [12,13]. The -catenin pathway is activated heterogeneously in FNH without -catenin or Axin1 mutation [14]. Glutamine synthase has been proposed as a marker to identify FNH [15]. Contrast ultrasound and MRI allows the identification of FNH in the great majority of cases. What remains true of the past What remains true of the past are: • the great majority of HCA occurs in women taking oral contraceptives [16]. Once discovered, oral contraception should be stopped;
0399-8320/$ – see front matter © 2010 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.gcb.2010.03.014
356
P. Bioulac-Sage et al. (≥ 5 cm) is an important determinant for these two risks [17,18]. What remains true but needs to be updated What remains true but needs to be updated are: • familial diabetes [19]. In rare families with an inherited mutation in one allele of HNF1A, MODY3 (Maturity Onset Diabetes of the Young type 3) patients are predisposed to develop familial liver adenomatosis with HNF1␣ inactivated HCA [9,10]. Obesity is also a risk factor for inflammatory HCA development [5,20]. Thus, relationship between metabolism perturbations and adenoma occurrence remains to be explored in detailed [21]; • HCA and hepatocellular carcinoma [22]. Malignant transformation occurs mainly in the -catenin mutated group [4,17]. However, other HCA subtypes can also transform and these rare at risk lesions have to be identified.
Figure 1 Phenotypic classification of HCA in patients without known etiology except OC (Bordeaux experience based on 130 cases). The dotted line separates the different subgroups in women. The different subgroups in men are in between the thick lines.
• all possible causes should be considered (Table 1); • the main risk factor is bleeding (incidence 25%). Malignant transformation of HCA is rare (5—7%). Size
Table 1
What needs revision What needs revision are: • adenomatosis [23]. It is no longer a specific entity [17,18]. If used the term should mean many HCA (more than 10 and preferably unnumbered); • telangiectatic FNH described as a subtype of FNH [24] are, at least for many of them, inflammatory HCA [20,25] (Fig. 1). To avoid confusion this term should be banned
Hepatocellular adenomas: rare causes.
Sex/age
Causes
Genotypic/phenotypic classificationa
Women (young) Polycystic ovary syndromeb Women/Men/Children Metabolic Glycogenosis (I and III) Galactosemiab Tyrosinemiab Genetic MODY 3 diabetes FAPb Peutz—Jeghers Syndromeb Drugs Anabolic androgenic steroids ie Danazol Antiepileptic Carmabazepineb Valproateb Iron overload ie Fanconi anemiab Vascular disordersc Portal vein (agenesis, shunts, HPS) Hepatic vein (Budd Chiari)
-catenin, IHCA -catenin
HNF1␣ -catenin, HNF1␣
-catenin
IHCA
HPS: hepatoportal sclerosis; FAP: familial adenomatosis polyposis. a There is very little information in the literature (in our institution, nine patients are included in this series). b Case report. c Case report: focal nodular hyperplasia are more often reported.
Focal nodular hyperplasia, hepatocellular adenomas [26]. FNH with major sinusoidal dilatation do however exist; • absence of ductules, a classical hallmark in HCA definition [27]. Ductules can be seen in inflammatory HCA [21].
Future HCA Basic science The search for new gene mutations needs to go on and the present known mutations looked for on a large scale in different countries, particularly those where the use of oral contraception is not widespread. To understand the molecular steps in carcinogenesis particularly via the -catenin pathway but also how HNF1␣ inactivation promotes lipogenesis and activation of several carcinogenetic pathways [28,29]. To define the role of cofactors such as obesity present in 50% of inflammatory HCA and steatohepatitis. Clinical science To find the relevance of the genotype/phenotype classification in the management/follow-up and treatment [30]. To define the role of the biopsy and the place of new radical treatment avoiding surgery (radio frequency, embolization). Ultimately to test drugs that may block pathways involved in the tumoral process.
FNH To identify (imaging, pathology) FNH lacking full blown criteria, and understand the genesis of their formation (normal and pathologic livers particularly cirrhotic ones), and the relationship between FNH (often multiple) and associated disorders such as brain tumors [25]. FNH, for the first time, will now have an International Classification of Disease (ICD) code, as it was decided for the next WHO revision book [31].
Conclusion The differential diagnosis between FNH and HCA and between HCA and hepatocellular carcinoma is occasionally difficult and this difficulty increases when tumors are developed on pathological livers. The genotypic/phenotypic classification and we hope its further refinement, will remain the best way to avoid erroneous or doubtful diagnosis, and to adapt treatment according to each subtype.
References [1] Edmondson HA. Tumors of the liver and intrahepatic bile ducts. Atlas of tumor pathology, VII, 25 (Armed forces Institute of pathology);1958. [2] Bluteau O, Jeannot E, Bioulac-Sage P, Marqués JM, Blanc JF, Bui H, et al. Bi-allelic inactivation of TCF1 in hepatic adenomas. Nat Genet 2002;32:312—5. [3] Chen YW, Jeng YM, Yeh SH, Chen PJ. P53 gene and Wnt signaling in benign neoplasms: -catenin mutations in hepatic adenoma but not in focal nodular hyperplasia. Hepatology 2002;36:927—35.
357 [4] 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—24. [5] 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—8. [6] Rebouissou S, Amessou M, Couchy G, Poussin K, Imbeaud S, Pilati C, et al. Frequent in-frame somatic deletions activate gp130 in inflammatory hepatocellular tumours. Nature 2009;457:200—4. [7] Laumonier H, Bioulac-Sage P, Laurent C, Zucman-Rossi J, Balabaud C, Trillaud H. Hepatocellular adenomas: magnetic resonance imaging features as a function of molecular pathological classification. Hepatology 2008;48:808—18. [8] 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—9. [9] Bacq Y, Jacquemin E, Balabaud C, Jeannot E, Scotto B, Branchereau S, et al. Familial liver adenomatosis associated with hepatocyte nuclear factor-1 alpha inactivation. Gastroenterology 2003;125:1470—5. [10] 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—80. [11] 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—5. [12] Rebouissou S, Bioulac-Sage P, Zucman-Rossi J. Molecular pathogenesis of focal nodular hyperplasia and hepatocellular adenoma. J Hepatol 2008;48:163—70. [13] Paradis V, Bièche I, Dargère D, Laurendeau I, Nectoux J, Degott C, et al. A quantitative gene expression study suggests a role for angiopoietins in focal nodular hyperplasia. Gastroenterology 2003;124:651—9. [14] Rebouissou S, Couchy G, Libbrecht L, Balabaud C, Imbeaud S, Auffray C, et al. The -catenin pathway is activated in focal nodular hyperplasia but not in cirrhotic FNH-like nodules. J Hepatol 2008;49:61—71. [15] Bioulac-Sage P, Laumonier H, Rullier A, Cubel G, Laurent C, Zucman-Rossi J, et al. Over-expression of glutamine synthetase in focal nodular hyperplasia: a novel easy diagnostic tool in surgical pathology. Liver Int 2009;29:459—65. [16] Baum JK, Bookstein JJ, Holtz F, Klein EW. Possible association between benign hepatomas and oral contraceptives. Lancet 1973;2:926—9. [17] Bioulac-Sage P, Laumonier H, Couchy G, Le Bail B, Sa Cunha A, Rullier A, et al. Hepatocellular adenoma management and phenotypic classification: the Bordeaux experience. Hepatology 2009;5:481—9. [18] Dokmak S, Paradis V, Vilgrain V, Sauvanet A, Farges O, Valla D, et al. A single-center surgical experience of 122 patients with single and multiple hepatocellular adenomas. Gastroenterology 2009;137:1698—705. [19] Foster JH, Donohue TA, Berman MM. Familial liver-cell adenomas and diabetes mellitus. N Engl J Med 1978;299: 239—41. [20] Paradis V, Champault A, Ronot M, Deschamps L, Valla DC, Vidaud D, et al. Telangiectatic adenoma: an entity associated with increased body mass index and inflammation. Hepatology 2007;46:140—6. [21] Jeannot E, Mellottee L, Bioulac-Sage P, Balabaud C, Scoazec JY, Tran Van Nhieu, et al. Spectrum of HNF1A somatic mutations
358
[22] [23]
[24]
[25]
[26]
P. Bioulac-Sage et al. in hepatocellular adenoma differs from that in MODY3 patients and suggests genotoxic damage. Diabetes 2010, 14 (online). Foster JH, Berman MM. The malignant transformation of liver cell adenomas. Arch Surg 1994;129:712—7. 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—8. 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—62. 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—8. Bioulac-Sage P, Balabaud C, Zucman-Rossi J. What’s in a name? Hepatology 2010;51:1086—7.
[27] Terminology of nodular hepatocellular lesions. International working party. Hepatology 1995;22:983—93. [28] Rebouissou S, Imbeaud S, Balabaud C, Boulanger V, BertrandMichel 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—46. [29] Pelletier L, Rebouissou S, Paris A, Rathahao-Paris E, Perdu E, Bioulac-Sage P, et al. Loss of hepatocyte nuclear factor-1 alpha function in human hepatocellular adenomas leads to aberrant activation of signaling pathways involved in tumorigenesis. Hepatology 2010;51:557—66. [30] Terkivatan T, Ijzermans JN. Hepatocellular adenoma: should phenotypic classification direct management? Nat Rev Gastroenterol Hepatol 2009;6:697—8. [31] Bosman FT, Carneiro F, Hruban RH, Theise ND. ‘‘World Health Organization (WHO) Classification of Tumours of the Digestive System’’, 4th ed; 2010 (in press).