Liver: Adenoma

Identity

ICD-Topo	C220 LIVER
ICD-Morpho	8170/0
Atlas_Id	5420
Phylum	Digestive organs: Liver::Hepatic adenoma
WHO/OMS Classification	Digestive organs
Other names	Hepatocellular adenoma
	Liver cell adenoma

Clinics and Pathology

Disease	Hepatocellular adenomas (HA) are rare benign liver tumors, most frequently occurring in women using oral contraception. HA are single or more rarely multiple nodules; the presence of more than ten nodules in the liver indicates a specific nosological entity: liver adenomatosis
Etiology	In 90% of the cases, adenomas are sporadic and only rare cases are developed in a familial context: ( Familial liver adenomatosis). Patients with an inherited mutation in one allele of TCF1/HNF1a may develop maturity onset diabetes of the young type 3 (MODY3) and familial liver adenomatosis, when the second allele is inactivated in hepatocytes by somatic mutation or chromosome deletion.
Epidemiology	Hepatocellular adenomas are usually related to oral contraceptive use. The other risk factors are : glycogen storage diseases and the androgen therapy. HA are rare tumours: their estimated incidence in France is approximately one case per 100,000 women. Over the past fifteen years, their incidence has seen a sustained decline in industrialised countries; this trend is probably linked to the reduction in ethinylestradiol doses in oral contraceptives.
Pathology	These tumours result from a benign proliferation of hepatocytes which destroy the normal architecture of the liver. They are usually hyper-vascularised and typical adenoma corresponds to a proliferation of benign hepatocytes, intermingled with numerous thin-walled vessels, without portal tracts.
Treatment	Surgery is usually proposed for lesion of more than 3 cm
Evolution	Hepatocellular adenoma may bleed, or rarely, undergo malignant transformation.
Prognosis	The molecular and pathological classification of hepatocellular adenomas permits the identification of strong genotype-phenotype correlations and suggests that adenomas with beta-catenin activation have a higher risk of malignant transformation.

Genetics

Note	Germline TCF1/HNF1A mutation can predispose to familial liver adenomatosis

Genes involved and Proteins

Note

Half of the adenoma cases are mutated for TCF1 gene encoding HNF1a. These mutations are inactivating and both allele are mutated in tumors. Patients with an inherited mutation in one allele of HNF1a may develop maturity onset diabetes of the young type 3 (MODY3) and familial liver adenomatosis, when the second allele is inactivated in hepatocytes by somatic mutation or chromosome deletion. Mutations of CTNNB1 activating the beta-catenin was also found in 15% of the HA cases. The molecular and pathological classification of hepatocellular adenomas permited the identification of strong genotype-phenotype correlations and suggested that adenomas with beta-catenin activation have a higher risk of malignant transformation.

Gene Name	HNF1A (HNF1 homeobox A)
Location	12q24.31
Note	Alias: HNF1A, hepatocyte nuclear factor 1 alpha, HNF1, LFB1, M57732, MODY3
	More than 50 different HNF1a mutations have been identified in HA. These mutations are distributed mainly from exon 1 to 6. Point mutations, small deletions and insertions were identified. Gene deletions are less frequent.

Gene Name	CTNNB1 (Catenin, beta-1)
Location	3p22.1
Note	Description: catenin (cadherin-associated protein), beta 1
	Activating mutations are amino-acid substitution in exon 3 or in-frame deletion including part or all exon 3.
Protein	Beta-catenin is an adherens junction protein. Adherens junctions are critical for the establishment and maintenance of epithelial layers, cells adhesion, signal communication, anchorage of the actin cytoskeleton. CTNNB1 has important functions in the E-cadherin-mediated cell-cell adhesion system and also as a dowstream signaling molecule in the Wnt pathway. Cytoplasmic accumulation of b catenin allows it to translocate to the nucleus to form complexes with transcription factors of the T cell factor-lymphoid enhancer factor (Tcf-Lef) family. b-catenin is assumed to transactivate mostly unknown target genes, which may stimulate cell proliferation (acts as an oncogene) or inhibit apoptosis. The b-catenin level in the cell is regulated by its association with the adenomatous polyposis coli ( APC) tumor suppressor protein, axin and GSK-3b. Phosphorylation of b-catenin by the APC-axin-GSK-3b complex leads to its degradation by the ubiquitin-proteasome system.

Bibliography

Familial liver adenomatosis associated with hepatocyte nuclear factor 1alpha inactivation.

Bacq Y, Jacquemin E, Balabaud C, Jeannot E, Scotto B, Branchereau S, Laurent C, Bourlier P, Pariente D, de Muret A, Fabre M, Bioulac-Sage P, Zucman-Rossi J

Gastroenterology. 2003 ; 125 (5) : 1470-1475.

PMID 14598263

Bi-allelic inactivation of TCF1 in hepatic adenomas.

Bluteau O, Jeannot E, Bioulac-Sage P, Marqués JM, Blanc JF, Bui H, Beaudoin JC, Franco D, Balabaud C, Laurent-Puig P, Zucman-Rossi J

Nature genetics. 2002 ; 32 (2) : 312-315.

PMID 12355088

P53 gene and Wnt signaling in benign neoplasms: beta-catenin mutations in hepatic adenoma but not in focal nodular hyperplasia.

Chen YW, Jeng YM, Yeh SH, Chen PJ

Hepatology (Baltimore, Md.). 2002 ; 36 (4 Pt 1) : 927-935.

PMID 12297840

Liver adenomatosis: reappraisal, diagnosis, and surgical management: eight new cases and review of the literature.

Chiche L, Dao T, Salamé E, Galais MP, Bouvard N, Schmutz G, Rousselot P, Bioulac-Sage P, Ségol P, Gignoux M

Annals of surgery. 2000 ; 231 (1) : 74-81.

PMID 10636105

Liver-cell adenomas associated with use of oral contraceptives.

Edmondson HA, Henderson B, Benton B

The New England journal of medicine. 1976 ; 294 (9) : 470-472.

PMID 173996

Liver adenomatosis. An entity distinct from liver adenoma?

Flejou JF, Barge J, Menu Y, Degott C, Bismuth H, Potet F, Benhamou JP

Gastroenterology. 1985 ; 89 (5) : 1132-1138.

PMID 2412930

Familial liver-cell adenomas and diabetes mellitus.

Foster JH, Donohue TA, Berman MM

The New England journal of medicine. 1978 ; 299 (5) : 239-241.

PMID 207987

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.

Reznik Y, Dao T, Coutant R, Chiche L, Jeannot E, Clauin S, Rousselot P, Fabre M, Oberti F, Fatome A, Zucman-Rossi J, Bellanne-Chantelot C

The Journal of clinical endocrinology and metabolism. 2004 ; 89 (3) : 1476-1480.

PMID 15001650

Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3)

Yamagata K, Oda N, Kaisaki PJ, Menzel S, Furuta H, Vaxillaire M, Southam L, Cox RD, Lathrop GM, Boriraj VV, Chen X, Cox NJ, Oda Y, Yano H, Le Beau MM, Yamada S, Nishigori H, Takeda J, Fajans SS, Hattersley AT, Iwasaki N, Hansen T, Pedersen O, Polonsky KS, Bell GI

Nature. 1996 ; 384 (6608) : 455-458.

PMID 8945470

Genotype-phenotype correlation in hepatocellular adenoma: new classification and relationship with HCC.

Zucman-Rossi J, Jeannot E, Nhieu JT, Scoazec JY, Guettier C, Rebouissou S, Bacq Y, Leteurtre E, Paradis V, Michalak S, Wendum D, Chiche L, Fabre M, Mellottee L, Laurent C, Partensky C, Castaing D, Zafrani ES, Laurent-Puig P, Balabaud C, Bioulac-Sage P

Hepatology (Baltimore, Md.). 2006 ; 43 (3) : 515-524.

PMID 16496320

Citation

This paper should be referenced as such :

Zucman-Rossi, J

Liver adenoma

Atlas Genet Cytogenet Oncol Haematol. 2006;10(3):201-202.

Free journal version : [ pdf ]   [ DOI ]

On line version : http://AtlasGeneticsOncology.org/Tumors/LiverAdenomID5420.html

External links

arrayMap	Topo ( C22) arrayMap ((UZH-SIB Zurich)   [auto + random 100 samples .. if exist ]   [tabulated segments]
Disease database	Liver: Adenoma

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