title: Correlation of exon 3 β-catenin mutations with glutamine synthetase staining patterns in hepatocellular adenoma and hepatocellular carcinoma.
abstract: The current clinical practice is based on the assumption of strong correlation between diffuse glutamine synthetase expression and β-catenin activation in hepatocellular adenoma and hepatocellular carcinoma. This high correlation is based on limited data and may represent an oversimplification as glutamine synthetase staining patterns show wide variability in clinical practice. Standardized criteria for interpreting diverse glutamine synthetase patterns, and the association between each pattern and β-catenin mutations is not clearly established. This study examines the correlation between glutamine synthetase staining patterns and β-catenin mutations in 15 typical hepatocellular adenomas, 5 atypical hepatocellular neoplasms and 60 hepatocellular carcinomas. Glutamine synthetase staining was classified into one of the three patterns: (a) diffuse homogeneous: moderate-to-strong cytoplasmic staining in >90% of lesional cells, without a map-like pattern, (b) diffuse heterogeneous: moderate-to-strong staining in 50-90% of lesional cells, without a map-like pattern, and (c) patchy: moderate-to-strong staining in <50% of lesional cells (often perivascular), or weak staining irrespective of the extent, and all other staining patterns (including negative cases). Sanger sequencing of CTNNB1 exon 3 was performed in all cases. Of hepatocellular tumors with diffuse glutamine synthetase staining (homogeneous or heterogeneous), an exon 3 β-catenin mutation was detected in 33% (2/6) of typical hepatocellular adenoma, 75% (3/4) of atypical hepatocellular neoplasm and 17% (8/47) of hepatocellular carcinomas. An exon 3 mutation was also observed in 15% (2/13) of hepatocellular carcinomas with patchy glutamine synthetase staining. The results show a modest correlation between diffuse glutamine synthetase immunostaining and exon 3 β-catenin mutations in hepatocellular adenoma and hepatocellular carcinoma with discrepancy rates >50% in both hepatocellular adenoma and hepatocellular carcinoma. The interpretation of β-catenin activation based on glutamine synthetase staining should be performed with caution, and the undetermined significance of various glutamine synthetase patterns should be highlighted in pathology reports.
authors.affiliation: Department of Pathology, University of California, San Francisco, CA, USA.
authors.forename: Gillian
authors.initials: G
authors.lastname: Hale
authors.affiliation: Department of Gastrointestinal Surgery, Northern Jiangsu People's Hospital, Clinical Medical School of Yangzhou University, Yangzhou, People's Republic of China.|Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA.|School of Pharmacy, Hubei University of Chinese Medicine, Hubei, People's Republic of China.
authors.forename: Junjie
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA.|Department of Gastroenterology, Guizhou Provincial People's Hospital, The Affiliated People's Hospital of Guizhou Medical University, Guizhou, People's Republic of China.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Che
authors.affiliation: Department of Pathology, University of California, San Francisco, CA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Solomon
authors.affiliation: Department of Pathology, University of California, San Francisco, CA, USA.
authors.forename: Christos
authors.initials: C
authors.lastname: Tsokos
authors.affiliation: Pathology, California Permanente Medical Group, Woodland Hills, CA, USA.
authors.forename: Nafis
authors.initials: N
authors.lastname: Shafizadeh
authors.affiliation: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA.|School of Pharmacy, Hubei University of Chinese Medicine, Hubei, People's Republic of China.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Pathology, University of California, San Francisco, CA, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Gill
authors.affiliation: Department of Pathology, University of California, San Francisco, CA, USA.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Kakar
mesh_terms: D018248:Adenoma, Liver Cell / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D000293:Adolescent; D000328:Adult; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D005091:Exons / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D005974:Glutamate-Ammonia Ligase / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D055815:Young Adult; D051176:beta Catenin / Q000235:genetics*
chemical_list: C495270:CTNNB1 protein, human; D051176:beta Catenin; D005974:Glutamate-Ammonia Ligase