Predictive Patterns of Glutamine Synthetase Immunohistochemical Staining in CTNNB1-mutated Hepatocellular Adenomas

Abstract

Some hepatocellular adenoma (HCA) subtypes are characterized by different CTNNB1 mutations, leading to different beta-catenin activation levels, hence variable immunostaining patterns of glutamine synthetase (GS) expression, and different risks of malignant transformation. In a retrospective multicentric study of 63 resected inflammatory (n = 33) and noninflammatory (n = 30) molecularly confirmed CTNNB1-mutated b-(I)HCA, we investigated the predictive potential of 3 known GS patterns as markers for CTNNB1 exon 3, 7/8 mutations. Pattern 1 (diffuse homogenous) allowed recognition of 17/21 exon 3 non-S45 mutated b-(I)HCA. Pattern 2 (diffuse heterogenous) identified all b-(I)HCA harboring exon 3 S45 mutation (20/20). Pattern 3 (focal patchy) distinguished 12/22 b-(I)HCA with exon 7/8 mutations. In exon 3 S45 and 7/8 mutations, both b-HCA and b-IHCA showed a GS + /CD34 − rim with diffuse CD34 positivity in the center of the lesion. Interobserver reproducibility was excellent for exon 3 mutations. Comparative analysis of GS patterns with molecular data showed 83% and 80% sensitivity (b-HCA/b-IHCA) and 100% specificity for exon 3 non-S45. For exon 3 S45, sensitivity was 100% for b-(I)HCA, and specificity 93% and 92% (b-HCA/b-IHCA). For exon 7/8, sensitivity was 55% for both subtypes and specificity 100% and 96% (b-HCA/b-IHCA). Preliminary data from 16 preoperative needle biopsies from the same patients suggest that this panel may also be applicable to small samples. In surgically resected HCA, 2 distinct GS patterns can reliably predict CTNNB1 exon 3 mutations, which are relevant because of the higher risk for malignant transformation. The third pattern, although specific, was less sensitive for the identification of exon 7/8 mutation, but the GS + /CD34 − rim is a valuable aid to indicate either an exon 3 S45 or exon 7/8 mutation.

Hepatocellular adenoma: what we know, what we do not know, and why it matters

“…Importantly, the patterns of GS expression are variable, depending on the type of CTNNB1 mutation 57 . A comprehensive description of the predictive patterns of GS in b‐HCA and b‐IHCA has been presented in a recent study, along with a diagnostic algorithm for subtyping HCA 69 . In short, CTNNB1 exon 3 non‐S45 mutation results in diffuse and homogeneous GS expression, whereas CTNNB1 exon 3 mutation in codon S45 results in diffuse and heterogeneous expression, and CTNNB1 exon 7/8 mutation results in a focal patchy pattern of, often faint, staining.…”

Proteomic Profiling of Hepatocellular Adenomas Paves the Way to Diagnostic and Prognostic Approaches

“…( 35 ) As an illustration, a positive GS rim has been reported with less or no expression in the tumor center in b‐HCA S45 and exon 7/8. ( 36 ) Second, we identified a protein profile that directly diagnoses malignant transformation regardless of HCA subtype. This profile was correlated with immune activation in response to cell degeneration, making sense for tumors transforming or differentiated tumors with active antitumor immunity.…”

Hepatocellular carcinoma: a clinical and pathological overview

“…HSP70 is normally expressed by apoptotic hepatocytes, isolated periseptal hepatocytes, and stellate cells. Finally, GS shows peculiar pattern of staining according to different clinico-pathological conditions 77 .…”