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Title: [Differences in clinicopathological features, gene mutations, and prognosis between primary gastric and intestinal gastrointestinal stromal tumors in 1061 patients].
Author: Li JX, Sun L, Zhao S, Shao B, Guo YH, Chen S, Liang H, Sun Y.
Journal: Zhonghua Wei Chang Wai Ke Za Zhi; 2023 Apr 25; 26(4):346-356. PubMed ID: 37072312.
Abstract:
Objective: To analyze the clinicopathological features and gene mutations of primary gastrointestinal stromal tumors (GISTs) of the stomach and intestine and the prognosis of intermediate- and high-risk GISTs. Methods: This was a retrospective cohort study. Data of patients with GISTs admitted to Tianjin Medical University Cancer Institute and Hospital from January 2011 to December 2019 were collected retrospectively. Patients with primary gastric or intestinal disease who had undergone endoscopic or surgical resection of the primary lesion and were confirmed pathologically as GIST were included. Patients treated with targeted therapy preoperatively were excluded. The above criteria were met by 1061 patients with primary GISTs, 794 of whom had gastric GISTs and 267 intestinal GISTs. Genetic testing had been performed in 360 of these patients since implementation of Sanger sequencing in our hospital in October 2014. Gene mutations in KIT exons 9, 11, 13, and 17 and PDGFRA exons 12 and 18 were detected by Sanger sequencing. The factors investigated in this study included: (1) clinicopathological data, such as sex, age, primary tumor location, maximum tumor diameter, histological type, mitotic index (/5 mm²), and risk classification; (2) gene mutation; (3) follow-up, survival, and postoperative treatment; and (4) prognostic factors of progression-free survival (PFS) and overall survival (OS) for intermediate- and high-risk GIST. Results: (1) Clinicopathological features: The median ages of patients with primary gastric and intestinal GIST were 61 (8-85) years and 60 (26-80) years, respectively; The median maximum tumor diameters were 4.0 (0.3-32.0) cm and 6.0 (0.3-35.0) cm, respectively; The median mitotic indexes were 3 (0-113)/5 mm² and 3 (0-50)/5 mm², respectively; The median Ki-67 proliferation indexes were 5% (1%-80%) and 5% (1%-50%), respectively. The rates of positivity for CD117, DOG-1, and CD34 were 99.7% (792/794), 99.9% (731/732), 95.6% (753/788), and 100.0% (267/267), 100.0% (238/238), 61.5% (163/265), respectively. There were higher proportions of male patients (χ²=6.390, P=0.011), tumors of maximum diameter > 5.0 cm (χ²=33.593, P<0.001), high-risk (χ²=94.957, P<0.001), and CD34-negativity (χ²=203.138, P<0.001) among patients with intestinal GISTs than among those with gastric GISTs. (2) Gene mutations: Gene mutations were investigated in 286/360 patients (79.4%) with primary gastric GISTs and 74/360 (20.6%) with primary intestinal GISTs. Among the 286 patients with gastric primary GISTs, 79.4% (227/286), 8.4% (24/286), and 12.2% (35/286), had KIT mutations, PDGFRA mutations, and wild-type, respectively. Among the 74 patients with primary intestinal GISTs, 85.1% (63/74) had KIT mutations and 14.9% (11/74) were wild-type. The PDGFRA mutation rate was lower in patients with intestinal GISTs than in those with gastric GISTs[ 0% vs. 8.4%(24/286), χ²=6.770, P=0.034], whereas KIT exon 9 mutations occurred more often in those with intestinal GISTs [22.2% (14/63) vs. 1.8% (4/227), P<0.001]. There were no significant differences between gastric and intestinal GISTs in the rates of KIT exon 11 mutation type and KIT exon 11 deletion mutation type (both P>0.05). (3) Follow-up, survival, and postoperative treatment: After excluding 228 patients with synchronous and metachronous other malignant tumors, the remaining 833 patients were followed up for 6-124 (median 53) months with a follow-up rate of 88.6% (738/833). None of the patients with very low or low-risk gastric (n=239) or intestinal GISTs (n=56) had received targeted therapy postoperatively. Among 179 patients with moderate-risk GISTs, postoperative targeted therapy had been administered to 88/155 with gastric and 11/24 with intestinal GISTs. Among 264 patients with high-risk GISTs, postoperative targeted therapy had been administered to 106/153 with gastric and 62/111 with intestinal GISTs. The 3-, 5-, and 10-year PFS of patients with gastric or intestinal GISTs were 96.5%, 93.8%, and 87.6% and 85.7%, 80.1% and 63.3%, respectively (P<0.001). The 3-, 5-, and 10-year OS were 99.2%, 98.8%, 97.5% and 94.8%, 92.1%, 85.0%, respectively (P<0.001). (4) Analysis of predictors of intermediate- and high-risk GISTs: The 5-year PFS of patients with gastric and intestinal GISTs were 89.5% and 73.2%, respectively (P<0.001); The 5-year OS were 97.9% and 89.3%, respectively (P<0.001). Multivariate analysis showed that high risk (HR=2.918, 95%CI: 1.076-7.911, P=0.035) and Ki-67 proliferation index > 5% (HR=2.778, 95%CI: 1.389-5.558, P=0.004) were independent risk factors for PFS in patients with intermediate- and high-risk GISTs (both P<0.05). Intestinal GISTs (HR=3.485, 95%CI: 1.407-8.634, P=0.007) and high risk (HR=3.753,95%CI:1.079-13.056, P=0.038) were independent risk factors for OS in patients with intermediate- and high-risk GISTs (both P<0.05). Postoperative targeted therapy was independent protective factor for PFS and OS (HR=0.103, 95%CI: 0.049-0.213, P<0.001; HR=0.210, 95%CI:0.078-0.564,P=0.002). Conclusions: Primary intestinal GIST behaves more aggressively than gastric GISTs and more frequently progress after surgery. Moreover, CD34 negativity and KIT exon 9 mutations occur more frequently in patients with intestinal GISTs than in those with gastric GISTs. 目的： 分析胃部与肠道原发胃肠间质瘤（GIST）的临床病理特征、基因突变特点和中高危险度原发GIST预后间的差异及预后影响因素。 方法： 采用回顾性队列研究方法。收集2011年1月至2019年12月期间于天津医科大学肿瘤医院就诊的GIST病例资料。纳入初次诊断的胃部或肠道原发GIST、并行内镜或手术切除原发灶和术后经病理证实者；排除术前接受靶向治疗者。根据上述标准，共收集1 061例原发GIST患者入组，其中胃部和肠道原发GIST分别为794例和267例；其中360例为2014年10月本院开展一代测序检测以来，进行基因检测的病例。采用Sanger测序法检测KIT外显子9、11、13和17及PDGFRΑ外显子12和18的基因突变情况。本研究观察指标为：（1）临床病理资料：包括患者的性别、年龄、肿瘤原发位置、肿瘤最大径、组织学类型、核分裂象计数（/5 mm²）和危险度分级；（2）基因突变情况；（3）随访和生存及术后治疗情况；（4）中、高危险度原发GIST预后危险因素分析：包括疾病无进展生存率（PFS）和总体生存率（OS）。 结果： （1）临床病理特征：胃部和肠道原发GIST中位年龄分别为61（8~85）岁和60（26~80）岁；肿瘤最大径的中位值分别为4.0（0.3~32.0）cm和6.0（0.3~35.0）cm；核分裂象的中位值分别为3（0~113）/5 mm²和3（0~50）/5 mm²；中位Ki-67增殖指数为5%（1%~80%）和5%（1%~50%）；CD117、DOG-1和CD34的阳性率分别为99.7%（792/794）、99.9%（731/732）、95.6%（753/788）和100.0%（267/267）、100.0%（238/238）、61.5%（163/265）。与胃部GIST相比，肠道GIST中男性（χ²=6.390，P=0.011）、肿瘤最大径>5.0 cm（χ²=33.593，P<0.001）、高危险度（χ²=94.957，P<0.001）和CD34阴性（χ²=203.138，P<0.001）病例的比例更高。（2）基因突变情况：进行基因检测的360例原发GIST中，胃部和肠道分别为286例（79.4%）和74例（20.6%）。胃部原发GIST中，KIT突变、PDGFRA突变和野生型分别占79.4%（227/286）、8.4%（24/286）和12.2%（35/286）；肠道原发GIST中，KIT突变和野生型分别占85.1%（63/74）和14.9%（11/74）。与胃部原发GIST比较，肠道GIST中PDGFRA突变率更低［0比8.4%（24/286），χ²=6.770，P=0.034］、KIT外显子9突变率更高［22.2%（14/63）比1.8%（4/227），P<0.001］。而胃部与肠道GIST在KIT外显子11突变类型和KIT外显子11缺失突变的不同类型间的差异无统计学意义（均P>0.05）。（3）术后治疗及生存结果：排除228例同时或异时伴发其他恶性肿瘤的GIST后，对其余833例患者进行随访，中位随访53（6~124）个月，随访率为88.6%（738/833），其中295例极低危和低危险度胃部（239例）和肠道（56例）原发GIST术后均未接受靶向治疗。179例胃部（155例）和肠道（24例）原发中危险度GIST中，接受术后辅助治疗的病例分别为88例和11例。264例高危险度胃部（153例）和肠道（111例）原发GIST中，接受术后辅助治疗的病例分别为106例和62例。胃部和肠道原发GIST患者的3年、5年和10年PFS分别为96.5%、93.8%、87.6%和85.7%、80.1%、63.3%（P<0.001）；3年、5年、10年OS分别为99.2%、98.8%、97.5%和94.8%、92.1%、85.0%（P<0.001）。（4）中、高危险度GIST预后危险因素分析：对443例中、高危险度原发GIST患者行预后危险因素分析。与肠道原发GIST相比，胃部原发GIST患者的5年PFS更高（89.5%比73.2%，P<0.001），5年OS也更高（97.9%比89.3%，P<0.001）。多因素分析结果显示：高危险度（HR=2.918，95%CI：1.076~7.911，P=0.035）和Ki-67增殖指数>5%（HR=2.778，95%CI：1.389~5.558，P=0.004）是影响中、高危险度GIST患者PFS的独立危险因素（均P<0.05）；肠道原发（HR=3.485，95%CI：1.407~8.634，P=0.007）和高危险度（HR=3.753，95%CI：1.079~13.056，P=0.038）是影响中、高危险度GIST患者OS的独立危险因素（均P<0.05）。接受术后靶向治疗是中、高危险度GIST患者PFS和OS的保护因素（HR=0.103，95%CI：0.049~0.213，P<0.001；HR=0.210，95%CI：0.078~0.564，P=0.002）。 结论： 肠道原发GIST比胃GIST的临床生物学行为更具有侵袭性，术后更容易进展，且CD34阴性的比例和患者携带伊马替尼不敏感的基因突变类型KIT外显子9突变的比例高。.

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