Miettinen Markku, Lasota Jerzy
Department of Soft Tissue Pathology, Armed Forces Institute of Pathology, Washington, DC 20306-6000, USA.
Arch Pathol Lab Med. 2006 Oct;130(10):1466-78. doi: 10.5858/2006-130-1466-GSTROM.
Gastrointestinal stromal tumors (GISTs) are specific, generally Kit (CD117)-positive, mesenchymal tumors of the gastrointestinal tract encompassing a majority of tumors previously considered gastrointestinal smooth muscle tumors. They are believed to originate from interstitial cells of Cajal or related stem cells.
To review current clinicopathologically relevant information on GIST.
Literature in Medline and authors' own experience.
GISTs usually occur in older adults (median age 55-60 years) and rarely in children in the second decade (<1%) throughout the gastrointestinal tract: 60% in stomach, 35% in small intestine, and less than 5% in rectum, esophagus, omentum, and mesentery; most GISTs in the latter 2 sites are metastatic. Five percent of GISTs occur in patients with neurofibromatosis type 1 syndrome (multiple small intestinal tumors) and in Carney triad (gastric epithelioid GISTs in young females). Familial GISTs occur in patients with inheritable germline Kit or platelet-derived growth factor receptor alpha (PDGFRA) mutations. Histologically GISTs vary from spindle cell tumors to epithelioid and pleomorphic tumors. Most GISTs (95%) express Kit (CD117), CD34 (70%), and heavy caldesmon (80%), whereas 25% are positive for smooth muscle actin and less than 5% for desmin. Tumor size and mitotic activity are best predictive prognostic features; small intestinal tumors behave more aggressively than gastric tumors with similar parameters. Mutually exclusive gain-of-function Kit or PDGFRA mutations occur in a majority of GISTs representing in-frame deletions, point mutations, duplications and insertions. Mutations in Kit juxtamembrane domain (exon 11) are the most common in GISTs of all sites, whereas rare Kit extracellular domain (exon 9) Ala502-Tyr503 duplication is specific for intestinal GISTs. Mutations in PDGFRA have been identified in juxtamembrane (exon 12) and tyrosine kinase domains (exons 14 and 18), nearly exclusively in gastric GISTs, mostly in epithelioid variants. Some Kit and PDGFRA mutations have a prognostic value. Kit/PDGFRA tyrosine kinase inhibitor imatinib has been successfully used in the treatment of metastatic GISTs for more than 5 years. However, primary and acquired secondary resistance linked to certain types of Kit and PDGFRA mutations is limiting long-term success necessitating the use of alternative treatments.
胃肠道间质瘤（GIST）是一种特殊的、通常为Kit（CD117）阳性的胃肠道间质肿瘤，涵盖了以前被认为是胃肠道平滑肌肿瘤的大多数肿瘤。它们被认为起源于 Cajal间质细胞或相关干细胞。
综述目前关于GIST的临床病理相关信息。
Medline文献及作者自身经验。
GIST通常发生于老年人（中位年龄55 - 60岁），在整个胃肠道的儿童中很少见（<1%）：60%位于胃，35%位于小肠，直肠、食管、网膜和肠系膜的比例不到5%；后两个部位的大多数GIST为转移性。5%的GIST发生于1型神经纤维瘤病综合征患者（多个小肠肿瘤）和Carney三联征患者（年轻女性的胃上皮样GIST）。家族性GIST发生于具有可遗传种系Kit或血小板衍生生长因子受体α（PDGFRA）突变的患者。组织学上，GIST从梭形细胞瘤到上皮样和多形性肿瘤不等。大多数GIST（95%）表达Kit（CD117）、CD34（70%）和重钙调蛋白（80%），而25%的平滑肌肌动蛋白呈阳性，结蛋白阳性率不到5%。肿瘤大小和有丝分裂活性是最佳的预测预后特征；具有相似参数的小肠肿瘤比胃肿瘤侵袭性更强。大多数GIST中发生相互排斥的功能获得性Kit或PDGFRA突变，表现为框内缺失、点突变、重复和插入。Kit近膜结构域（外显子11）突变在所有部位的GIST中最为常见，而罕见的Kit细胞外结构域（外显子9）Ala502 - Tyr503重复是小肠GIST所特有的。PDGFRA突变已在近膜结构域（外显子12）和酪氨酸激酶结构域（外显子14和18）中被鉴定，几乎仅见于胃GIST，主要见于上皮样变体。一些Kit和PDGFRA突变具有预后价值。Kit/PDGFRA酪氨酸激酶抑制剂伊马替尼已成功用于转移性GIST的治疗超过5年。然而，与某些类型的Kit和PDGFRA突变相关的原发性和获得性继发性耐药限制了长期疗效，因此需要使用替代治疗。
