Correlation of exon 3 β-catenin mutations with glutamine synthetase staining patterns in hepatocellular adenoma and hepatocellular carcinoma
Open accessAbstract
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.
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Ectopic Ctnnb1 activation by itself induces glutamine synthetase (Glul/GS) expression outside the endogenous GS expression normally observed in a two- to three-cell ring of hepatocytes around the central vein.
“In the liver, ectopic Ctnnb1 activation by itself induces glutamine synthetase (gene: Glul; protein: GS) expression outside of the endogenous GS expression normally observed in a two- to three-cell ring of hepatocytes around the central vein (CV) (28–32).”
From The origin of hepatocellular carcinoma depends on metabolic zonation (2026) · cites this paper as [29]
The Introduction (page not available) says that β-catenin activates GLUL transcription, that normal glutamine synthetase expression is confined to hepatocytes around terminal hepatic venules, and that expression extends through much of β-catenin-activated tumors. It does not specify a two- to three-cell ring or establish that ectopic Ctnnb1 activation by itself induces expression outside that ring; the Discussion (page not available) cautions that the relationship between β-catenin activation and glutamine synthetase staining is complex. (LLM, conf=0.85)
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- Authors
- Hale, G., Liu, X., Hu, J., Xu, Z., Che, L., Solomon, D., Tsokos, C., Shafizadeh, N., Chen, X., Gill, R., & Kakar, S.
- Affiliations
- University of California, San Francisco (US)
- Guiyang Medical University (CN)
- Kaiser Permanente (US)
- Corresponding author
- Kakar, Sanjay
- ORCID
- Venue
- Modern Pathology
- Publisher
- Elsevier BV
- Published
- 2016-11
- Volume
- 29
- Issue
- 11
- Pages
- 1370-1380
- ISSN
- 0893-3952 (ISSN-L)
- PMC
- PMC5149418
- OpenAlex
- W2477259156
- Cited by
- 73
- References
- 42
- Citations by year
- 2026: 6 · 2025: 9 · 2024: 3 · 2023: 5 · 2022: 5 · 2021: 10 · 2020: 8 · 2019: 4 · 2018: 13 · 2017: 8 · 2016: 2
- FWCI
- 6.51
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Modern Pathology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA136606)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK026743)
- Topics
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- CTNNB1 mutation, hepatocellular adenoma, hepatocellular carcinoma, β-catenin activation, immunohistochemical staining patterns, diagnostic discordance, hepatocellular tumors
- MeSH terms
- Adolescent, Adult, Exons, Female, Glutamate-Ammonia Ligase, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Male, Middle Aged, Mutation, Gene Expression Regulation, Neoplastic, Adenoma, Liver Cell, beta Catenin, Young Adult
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