Service of Clinical Pathology, Institute of Pathology.
Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, The Netherlands.
Am J Surg Pathol. 2021 Apr 1;45(4):477-487. doi: 10.1097/PAS.0000000000001675.
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.
一些肝细胞腺瘤 (HCA) 亚型的特征是不同的 CTNNB1 突变，导致不同的β-连环蛋白激活水平，因此不同的谷氨酰胺合成酶 (GS) 表达免疫组化模式，以及不同的恶性转化风险。在一项回顾性多中心研究中，我们研究了 63 例经手术切除的炎症性 (n=33) 和非炎症性 (n=30) 分子上证实的 CTNNB1 突变的β-(I)HCA，探讨了 3 种已知的 GS 模式作为 CTNNB1 外显子 3、7/8 突变标志物的预测潜力。模式 1(弥漫均匀)可识别 21 例外显子 3 非 S45 突变的β-(I)HCA。模式 2(弥漫异质)鉴定了所有携带外显子 3 S45 突变的β-(I)HCA(20/20)。模式 3(局灶性斑片状)区分了 22 例外显子 7/8 突变的β-(I)HCA。在外显子 3 S45 和 7/8 突变中，b-HCA 和 b-IHCA 均显示出 GS+/CD34- 环，病变中心弥漫性 CD34 阳性。外显子 3 突变的观察者间重复性极好。GS 模式与分子数据的比较分析显示，外显子 3 非 S45 的敏感性分别为 83%和 80%(b-HCA/b-IHCA)，特异性为 100%。对于外显子 3 S45，b-(I)HCA 的敏感性为 100%，b-HCA 和 b-IHCA 的特异性分别为 93%和 92%。对于外显子 7/8，两种亚型的敏感性均为 55%，特异性均为 100%和 96%(b-HCA/b-IHCA)。来自同一患者的 16 例术前针吸活检的初步数据表明，该面板也可适用于小样本。在手术切除的 HCA 中，2 种不同的 GS 模式可可靠地预测 CTNNB1 外显子 3 突变，这些突变具有较高的恶性转化风险，因此具有重要意义。第三种模式虽然具有特异性，但对于识别外显子 7/8 突变的敏感性较低，但 GS+/CD34- 环是一个有价值的辅助手段，可以指示外显子 3 S45 或外显子 7/8 突变。
