Demicco Elizabeth G, Wani Khalida, Fox Patricia S, Bassett Roland L, Young Eric D, Lev Dina, Aldape Kenneth D, Lazar Alexander J, Wang Wei-Lien
Department of Pathology, Mount Sinai Hospital, New York, NY 10029.
Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston TX 70030.
Hum Pathol. 2015 Jul;46(7):1015-26. doi: 10.1016/j.humpath.2015.03.014. Epub 2015 Apr 15.
This study aimed to evaluate expression of receptor tyrosine kinases, their ligands, and mutational status in solitary fibrous tumors, with correlation to histopathologic variants, tumor stage, and aggressive behavior. Immunohistochemical staining for PDGFα; PDGFβ; PDGFR-α; PDGFR-β; IGF1R; EGFR; VEGF; IGF2; c-Met; c-kit; c-erbB2; PTEN; and phosphorylated (p)AKT, pS6, and p4EBP1 was analyzed in 114 cases of solitary fibrous tumor using tissue microarray. Mutational analysis was performed using Sequenom MassARRAY-based platform. Multiple growth factors were overexpressed in most tumors, and increased numbers of overexpressed factors correlated with activation of the AKT pathway as measured by increased expression of p4EBP1(P = .0005). Compared to hypocellular tumors, localized hypercellular tumors were associated with high vascular endothelial growth factor (32% versus 8%; P = .008) and PDGFβ (41% versus 13%; P = .008). Metastatic tumors more frequently overexpressed PDGFR-α compared to localized tumors (75% versus 31%; P < .001). None of the factors examined had prognostic significance in primary tumors. Single-nucleotide polymorphisms involving MET were identified in 4 patients; these do not appear to drive tumor behavior and were not reflected in c-Met expression levels. Simultaneous overexpression of multiple growth factors is common in solitary fibrous tumors; variability in expression may contribute to tumor phenotype and aggressive behavior.
本研究旨在评估受体酪氨酸激酶、其配体的表达以及孤立性纤维瘤中的突变状态，并与组织病理学变异、肿瘤分期和侵袭性行为相关联。使用组织芯片对114例孤立性纤维瘤进行了血小板衍生生长因子α（PDGFα）、血小板衍生生长因子β（PDGFβ）、血小板衍生生长因子受体α（PDGFR-α）、血小板衍生生长因子受体β（PDGFR-β）、胰岛素样生长因子1受体（IGF1R）、表皮生长因子受体（EGFR）、血管内皮生长因子（VEGF）、胰岛素样生长因子2（IGF2）、肝细胞生长因子受体（c-Met）、干细胞生长因子受体（c-kit）、人表皮生长因子受体2（c-erbB2）、第10号染色体缺失的磷酸酶及张力蛋白同源物（PTEN）以及磷酸化（p）AKT、pS6和p4EBP1的免疫组化染色分析。使用基于Sequenom MassARRAY的平台进行突变分析。大多数肿瘤中多种生长因子过度表达，且过度表达因子数量的增加与通过p4EBP1表达增加所测量的AKT通路激活相关（P = 0.0005）。与细胞稀少的肿瘤相比，局限性细胞增多的肿瘤与高血管内皮生长因子（32%对8%；P = 0.008）和PDGFβ（41%对13%；P = 0.008）相关。与局限性肿瘤相比，转移性肿瘤中PDGFR-α过度表达更为频繁（75%对31%；P < 0.001）。所检测的因素在原发性肿瘤中均无预后意义。在4例患者中鉴定出涉及MET的单核苷酸多态性；这些似乎不会驱动肿瘤行为，也未在c-Met表达水平中体现。多种生长因子同时过度表达在孤立性纤维瘤中很常见；表达的变异性可能导致肿瘤表型和侵袭性行为。
