Saito T, Oda Y, Sugimachi K, Kawaguchi K, Tamiya S, Tanaka K, Matsuda S, Sakamoto A, Iwamoto Y, Tsuneyoshi M
Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Am J Pathol. 2001 Dec;159(6):2117-24. doi: 10.1016/s0002-9440(10)63063-5.
Synovial sarcoma is a mesenchymal tumor that has an epithelial character and two major histological subtypes, the biphasic type and the monophasic fibrous type. However, the mechanisms involved in its epithelial differentiation are unknown, and furthermore, the determinants for histological subtype in synovial sarcoma remain unclear. In this study, we immunohistochemically examined E-cadherin expression and screened for genetic alterations in the E-cadherin gene from exon 4 to exon 9 in 49 cases of synovial sarcoma. In addition, we also examined the mRNA expressions of E-cadherin and Snail, a direct repressor of E-cadherin gene expression, by reverse transcriptase-polymerase chain reaction in 20 samples of frozen material. Immunohistochemical E-cadherin membranous expression was observed in 12 cases (24.5%), and was predominant in biphasic tumors. Single-strand conformation polymorphism analysis followed by DNA direct sequencing revealed 15 missense E-cadherin mutations in 12 cases (24.5%: monophasic, 11 of 42; biphasic, 1 of 6; poorly, 0 of 1) and 7 silent mutations (14.3%) in 7 cases. Ten of the 12 cases with E-cadherin missense mutations did not show E-cadherin membranous expression. Reverse transcriptase-polymerase chain reaction demonstrated E-cadherin and Snail mRNA expressions in 14 cases (70%) and in all cases, respectively. E-cadherin gene expression was inactivated by missense mutations in three of the eight cases (37.5%) of monophasic fibrous tumors that showed E-cadherin mRNA expressions. The E-cadherin gene was potentially inactivated in a significant number of synovial sarcomas. E-cadherin dysfunction because of its mutation in the central region of the molecule was associated with its decreased immunohistochemical expression and histological fibroblastic and spindle-shaped features of monophasic tumors. Thus, E-cadherin gene mutation may be one of the determinants of histological subtype in synovial sarcoma.
滑膜肉瘤是一种具有上皮特征的间叶性肿瘤，有两种主要的组织学亚型，即双相型和单相纤维型。然而，其上皮分化所涉及的机制尚不清楚，此外，滑膜肉瘤组织学亚型的决定因素仍不明确。在本研究中，我们对49例滑膜肉瘤进行免疫组织化学检测E-钙黏蛋白的表达，并筛选E-钙黏蛋白基因外显子4至外显子9的基因改变。此外，我们还通过逆转录聚合酶链反应检测了20份冷冻材料样本中E-钙黏蛋白和Snail（E-钙黏蛋白基因表达的直接抑制因子）的mRNA表达。免疫组织化学检测发现12例（24.5%）有E-钙黏蛋白膜表达，且在双相型肿瘤中占主导。单链构象多态性分析后进行DNA直接测序，发现12例（24.5%：单相型，42例中的11例；双相型，6例中的1例；低分化型，1例中的0例）有15个E-钙黏蛋白错义突变，7例（14.3%）有7个沉默突变。在12例有E-钙黏蛋白错义突变的病例中，有10例未显示E-钙黏蛋白膜表达。逆转录聚合酶链反应分别在14例（70%）和所有病例中检测到E-钙黏蛋白和Snail的mRNA表达。在8例显示E-钙黏蛋白mRNA表达的单相纤维型肿瘤中，有3例（37.5%）因错义突变导致E-钙黏蛋白基因表达失活。大量滑膜肉瘤中E-钙黏蛋白基因可能失活。由于分子中部区域的突变导致的E-钙黏蛋白功能障碍与其免疫组织化学表达降低以及单相肿瘤的组织学成纤维细胞和梭形特征相关。因此，E-钙黏蛋白基因突变可能是滑膜肉瘤组织学亚型的决定因素之一。
