Irving Julie A, Lee Cheng-Han, Yip Stephen, Oliva Esther, McCluggage W Glenn, Young Robert H
*Department of Laboratory Medicine, Pathology, and Medical Genetics, Royal Jubilee Hospital, Victoria †Department of Pathology, University of British Columbia §Department of Pathology and Laboratory Medicine, Vancouver General Hospital, Vancouver, BC ‡Department of Laboratory Medicine and Pathology, University of Alberta and Royal Alexandra Hospital, Edmonton, AB, Canada ∥James Homer Wright Pathology Laboratories of the Massachusetts General Hospital, and the Department of Pathology, Harvard Medical School, Boston, MA ¶Department of Pathology, Belfast Health and Social Care Trust, Belfast, Northern Ireland, United Kingdom.
Am J Surg Pathol. 2015 Oct;39(10):1420-6. doi: 10.1097/PAS.0000000000000482.
Since our first description of the microcystic stromal tumor (MST) of the ovary, a rare and distinctive neoplasm with a definitional, usually striking microcystic pattern and a CD10+/vimentin+/inhibin-/calretinin- immunophenotype, 3 examples with β-catenin nuclear localization, and CTNNB1 mutation have been reported. We undertook a detailed immunohistochemical study and molecular analysis of CTNNB1 and FOXL2 of 15 cases of MST to further characterize this neoplasm and establish its histogenesis. Diffuse nuclear staining for FOXL2, WT-1, cyclin D1, and β-catenin was present in all tumors tested, and 12/15 were positive for steroidogenic factor-1 (SF-1). Heterozygous missense point mutations in exon 3 of CTNNB1 were detected in 8 of 14 cases, resulting in amino acid changes at codons 32, 34, 35, and 37. There was no correlation between CTNNB1 exon 3 mutation status and tumor immunophenotype. All 14 cases tested showed wild-type FOXL2. Our study establishes that MST of the ovary exhibits a characteristic FOXL2/SF-1/WT-1/cyclin D1/nuclear β-catenin-positive immunohistochemical profile, which may be useful in diagnosis and in the exclusion of histologic mimics. The presence of diffuse nuclear FOXL2 and WT-1 immunostaining in all cases and SF-1 in most supports the classification of MST within the sex cord-stromal category. Aberrant nuclear β-catenin expression, detected in all MSTs, appears to be the result of stabilizing CTNNB1 mutations in 57% of cases, providing further evidence that dysregulation of the Wnt/B-catenin pathway is involved in the tumorigenesis of MST and may involve activation of β-catenin with upregulation of cyclin D1.
自从我们首次描述卵巢微囊性间质瘤（MST）以来，这种罕见且独特的肿瘤具有明确的、通常显著的微囊性结构以及CD10+/波形蛋白+/抑制素-/钙视网膜蛋白-免疫表型，已有3例报告显示β-连环蛋白核定位及CTNNB1突变。我们对15例MST进行了详细的免疫组化研究以及CTNNB1和FOXL2的分子分析，以进一步明确该肿瘤特征并确定其组织发生。所有检测的肿瘤中均存在FOXL2、WT-1、细胞周期蛋白D1和β-连环蛋白的弥漫性核染色，15例中有12例类固醇生成因子-1（SF-1）呈阳性。14例中有8例检测到CTNNB1第3外显子的杂合错义点突变，导致密码子32、34、35和37处的氨基酸改变。CTNNB1第3外显子突变状态与肿瘤免疫表型之间无相关性。所有14例检测病例均显示FOXL2野生型。我们的研究证实，卵巢MST呈现特征性的FOXL2/SF-1/WT-1/细胞周期蛋白D1/核β-连环蛋白阳性免疫组化特征，这可能有助于诊断并排除组织学上的相似肿瘤。所有病例中均存在弥漫性核FOXL2和WT-1免疫染色，大多数病例中存在SF-1免疫染色，这支持将MST归类于性索间质肿瘤范畴。在所有MST中均检测到异常的核β-连环蛋白表达，在57%的病例中似乎是CTNNB1稳定突变的结果，这进一步证明Wnt/β-连环蛋白信号通路失调参与了MST的肿瘤发生，可能涉及β-连环蛋白激活及细胞周期蛋白D1上调。
