Koh J S, Trent J, Chen L, El-Naggar A, Hunt K, Pollock R, Zhang W
Departments of Pathology, Sarcoma Oncology, and Surgical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.
Histol Histopathol. 2004 Apr;19(2):565-74. doi: 10.14670/HH-19.565.
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. These tumors develop at any site but are most commonly reported in the stomach. They originate from the neoplastic transformation of the intestinal pacemaker cell, the interstitial cell of Cajal. GISTs strongly express the receptor tyrosine kinase KIT and have mutations in the KIT gene, most frequently in exon 11 encoding the intracellular juxtamembranous region. Expression of KIT is seen in almost all GISTs, regardless of the site of origin, histologic appearance, or biologic behavior, and is therefore regarded as one of the key diagnostic markers. Distinction from smooth muscle tumors, such as leiomyosarcomas, and other mesenchymal tumors is very important because of prognostic differences and therapeutic strategies. Predicting the biologic behavior of GISTs is often difficult by conventional pathologic examination; tumor size and mitotic rate are the most important prognostic indicators. The prognostic significance of KIT mutations is controversial and thus far has not been clearly linked with biologic behavior. KIT mutations are associated with tumor development, and cytogenetic aberrations are associated with tumor progression. The pathogenesis of GISTs involves a gain-of-function mutation in the KIT proto-oncogene, leading to ligand-independent constitutive activation of the KIT receptor. KIT-wild-type GISTs have shown mutually exclusive platelet-derived growth factor receptor (PDGFR) mutation and activation. The use of imatinib mesylate (also known as Gleevec or STI-571) has greatly increased the therapeutic efficacy for this otherwise chemotherapy-resistant tumor. GISTs with very low levels of KIT expression may respond to imatinib mesylate therapy if the receptors are activated by specific mechanisms. KIT-activating mutations fall into two groups: the regulatory type and the enzymatic site type. The regulatory type of mutation is conserved at the imatinib binding site, whereas the enzymatic site mutation has a structurally changed drug-binding site, resulting in drug resistance. Resistance to the drug is the major cause of treatment failure in cancer therapy, emphasizing the need for researchers to understand KIT signaling pathways so as to identify new therapeutic targets. This review summarizes the pathologic features of GISTs, recent advances in understanding their molecular and biologic features, and therapy with imatinib mesylate.
胃肠道间质瘤（GISTs）是胃肠道最常见的间叶组织肿瘤。这些肿瘤可发生于胃肠道的任何部位，但最常见于胃。它们起源于肠道起搏细胞即 Cajal 间质细胞的肿瘤性转化。GISTs 强烈表达受体酪氨酸激酶 KIT，且 KIT 基因存在突变，最常见于编码细胞内近膜区域的第 11 外显子。几乎所有 GISTs 均可见 KIT 表达，无论其起源部位、组织学表现或生物学行为如何，因此 KIT 被视为关键诊断标志物之一。由于预后差异和治疗策略不同，将其与平滑肌肿瘤（如平滑肌肉瘤）及其他间叶组织肿瘤区分开来非常重要。通过传统病理检查往往难以预测 GISTs 的生物学行为；肿瘤大小和有丝分裂率是最重要的预后指标。KIT 突变的预后意义存在争议，迄今为止尚未与生物学行为明确关联。KIT 突变与肿瘤发生相关，而细胞遗传学异常与肿瘤进展相关。GISTs 的发病机制涉及 KIT 原癌基因的功能获得性突变，导致 KIT 受体的配体非依赖性组成性激活。KIT 野生型 GISTs 表现出相互排斥的血小板衍生生长因子受体（PDGFR）突变和激活。甲磺酸伊马替尼（也称为格列卫或 STI - 571）的使用极大地提高了对这种原本对化疗耐药的肿瘤的治疗效果。KIT 表达水平极低的 GISTs 如果受体通过特定机制被激活，可能对甲磺酸伊马替尼治疗有反应。KIT 激活突变分为两组：调节型和酶位点型。调节型突变在伊马替尼结合位点保守，而酶位点突变具有结构改变的药物结合位点，导致耐药。对该药物的耐药是癌症治疗中治疗失败的主要原因，这强调了研究人员需要了解 KIT 信号通路以便确定新的治疗靶点。本综述总结了 GISTs 的病理特征、在理解其分子和生物学特征方面的最新进展以及甲磺酸伊马替尼治疗情况。
