Genotype-phenotype correlation in hepatocellular adenoma: new classification and relationship with HCC.
Hepatocellular adenomas are benign tumors that can be difficult to diagnose. To refine their classification, we performed a comprehensive analysis of their genetic, pathological, and clinical features. A multicentric series of 96 liver tumors with a firm or possible diagnosis of hepatocellular adenoma was reviewed by liver pathologists. In all cases, the genes coding for hepatocyte nuclear factor 1alpha (HNF1alpha) and beta-catenin were sequenced. No tumors were mutated in both HNF1alpha and beta-catenin enabling tumors to be classified into 3 groups, according to genotype. Tumors with HNF1alpha mutations formed the most important group of adenomas (44 cases). They were phenotypically characterized by marked steatosis (P < 10(-4)), lack of cytological abnormalities (P < 10(-6)), and no inflammatory infiltrates (P < 10(-4)). In contrast, the group of tumors defined by beta-catenin activation included 13 lesions with frequent cytological abnormalities and pseudo-glandular formation (P < 10(-5)). The third group of tumors without mutation was divided into two subgroups based on the presence of inflammatory infiltrates. The subgroup of tumors consisting of 17 inflammatory lesions, resembled telangiectatic focal nodular hyperplasias, with frequent cytological abnormalities (P = 10(-3)), ductular reaction (P < 10(-2)), and dystrophic vessels (P = .02). In this classification, hepatocellular carcinoma associated with adenoma or borderline lesions between carcinoma and adenoma is found in 46% of the beta-catenin-mutated tumors whereas they are never observed in inflammatory lesions and are rarely found in HNF1alpha mutated tumors (P = .004). In conclusion, 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.
Inserm, U674, IUH, CEPH, Paris, France. zucman@cephb.fr
Jessica
J
Zucman-Rossi
Emmanuelle
E
Jeannot
Jeanne Tran Van
JT
Nhieu
Jean-Yves
JY
Scoazec
Catherine
C
Guettier
Sandra
S
Rebouissou
Yannick
Y
Bacq
Emmanuelle
E
Leteurtre
Valérie
V
Paradis
Sophie
S
Michalak
Dominique
D
Wendum
Laurence
L
Chiche
Monique
M
Fabre
Lucille
L
Mellottee
Christophe
C
Laurent
Christian
C
Partensky
Denis
D
Castaing
Elie Serge
ES
Zafrani
Pierre
P
Laurent-Puig
Charles
C
Balabaud
Paulette
P
Bioulac-Sage
D018248:Adenoma, Liver Cell / Q000145:classification / Q000235:genetics* / Q000473:pathology; D000293:Adolescent; D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000145:classification / Q000235:genetics* / Q000473:pathology; D005260:Female; D005838:Genotype; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D012189:Retrospective Studies; D051176:beta Catenin / Q000235:genetics*
D051538:Hepatocyte Nuclear Factor 1-alpha; D051176:beta Catenin