Gastrointestinal stromal tumours (GISTs): a clinicopathological and molecular study of 66 cases
Gastrointestinal stromal tumours (GISTs): a clinicopathological and molecular study of 66 cases
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DOI：
10.1080/00313020400023628
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发表时间：
2005-02-01
期刊：
影响因子：
4.5
通讯作者：
Spagnolo, DV
中科院分区：
文献类型：
--
作者：
Koay, MHE;Goh, YW;Spagnolo, DV
目的：预测胃肠道间质瘤（GIST）的临床行为很困难，并且尚未确定区分良性和恶性病例的标准。本研究的目的是确定 66 例 GIST 的临床病理学和分子特征，并确定是否有任何特定参数与患者预后相关。方法：对来自西澳大利亚两家主要教学医院的 GIST 档案病例进行了研究。研究的纳入标准为：(1) 适当的形态学，(2) CD117 阳性，(3) 研究所需的病理材料充足，以及 (4) 根据免疫表型和/或超微结构特征排除其他肿瘤类型。通过免疫组织化学测定 CD117、CD34、S100 蛋白、角蛋白（使用广谱 MNF116）、α-平滑肌肌动蛋白（SMA）的表达。采用PCR和单链构象多态性(PCR-SSCP)分析来筛查c-kit外显子11和9的突变。结果：男性和女性人数相等，诊断时平均年龄60岁，平均随访54个月。到研究结束时，已有 13 名患者 (21%) 死于胃肠道间质瘤。肿瘤主要位于胃（67%）和小肠（SI；25%）。细胞类型为纯纺锤体细胞（68%）、纯上皮样细胞（12%）和混合上皮样细胞/纺锤体细胞（20%）。在 69% 的 GIST 中发现了 c-kit 突变，其中大多数（91%）发生在外显子 11 中。尺寸大于或等于 10 cm、肿瘤坏死和纯上皮样细胞形态都是与不良生存显着相关的唯一因素（分别为 p=0.038、p=0.047 和 p=0.028）。有丝分裂活性大于或等于 5/50 HPF 显示出与不良生存存在明确的趋势相关性，但与其他一些研究不同，没有达到统计学显着性 (p=0.067)。 c-kit 突变在小肠 GIST 中 (p=0.05) 和纯梭形细胞形态 (p=0.023) 中更为常见，但与患者预后无关。结论：在本研究中，大小大于或等于 10cm、坏死和/或纯上皮样细胞形态与不良生存显着相关。有丝分裂活性与生存率有很强的相关性，但这并未达到统计学显着性。 c-kit 突变主要发生在 SI 的 GIST 和纯梭形细胞肿瘤中。虽然突变状态与该系列中的患者结果无关，但这仍然是一个有争议的问题，需要进一步的研究来评估突变类型是否影响转移性 GIST 对酪氨酸激酶抑制剂治疗的反应。为了准确分类，必须对胃肠道的任何间质病变进行 CD117 染色。 PCR-SSCP 分析是一种快速、灵敏且相对便宜的分析 c-kit 突变的方法，这对于预后可能很重要，并且在评估新的酪氨酸激酶抑制剂疗法中也具有治疗相关性。
Aims: Predicting the clinical behaviour of gastrointestinal stromal tumours (GISTs) is difficult and criteria delineating benign from malignant cases are not firmly established. The aims of this study were to define the clinicopathological and molecular features of 66 GISTs, and to determine whether any specific parameters were associated with patient outcome.Methods: Archival cases of GIST from two major teaching hospitals in Western Australia were studied. Inclusion criteria for the study were: (1) appropriate morphology, (2) CD117 positivity, (3) adequacy of pathological material for study, and (4) exclusion of other tumour types on the basis of immunophenortypic and/or ultrastructural features. Expression of CD117, CD34, S100 protein, keratin (using broad spectrum MNF116),) alpha-smooth muscle actin (SMA) was determined by immunohistochemistry. PCR and single strand conformation polymorphism (PCR-SSCP) analysis were used to screen for mutations in exons 11 and 9 of c-kit.Results: There were equal numbers of males and females with a mean age at diagnosis of 60 years, followed up for a mean of 54 months. Thirteen patients (21%) had died of GIST by the end of the study. Tumours were mostly located in the stomach (67%) and small intestine (SI; 25%). The cell types were pure spindle (68%), pure epithelioid (12%) and mixed epithelioid/spindle (20%). c-kit mutations were found in 69% of GISTs, with the large majority (91%) occurring in exon 11. Size greater than or equal to 10 cm, tumour necrosis and pure epithelioid cell morphology each were the only factors significantly associated with adverse survival (p=0.038, and p=0.047 and p=0.028, respectively). Mitotic activity greater than or equal to5/50 HPF showed a definite trend association with adverse survival, but unlike some other studies, did not achieve statistical significance (p=0.067). c-kit mutations were more frequent in small intestinal GISTs (p=0.05) and in those with pure spindle cell morphology (p=0.023) but were not associated with patient outcome.Conclusion: In this study, size greater than or equal to10cm, necrosis and/or pure epithelioid cell morphology correlated significantly with adverse survival. Mitotic activity showed a strong association with survival but this did not reach statistical significance. c-kit mutations occurred mainly in GISTs of the SI, and in purely spindle cell tumours. While the mutation status did not associate with patient outcome in this series, this remains a controversial issue, and further studies are needed to assess whether the type of mutation affects response to tyrosine kinase inhibitor therapy in metastatic GISTs. CD117 staining of any mesenchymal lesion of the gastrointestinal tract should be mandatory for accurate classification. PCR-SSCP analysis is a fast, sensitive and relatively inexpensive method of analysing c-kit mutations, which may be important prognostically and also of therapeutic relevance in the assessment of new tyrosine kinase inhibitor therapies.