59例血小板源性生长因子受体α突变型胃肠间质瘤的临床病理特征和预后分析

Clinicopathological features and prognosis of 59 patients with platelet-derived growth factorα-mutant gastrointestinal stromal tumor

目的血小板源性生长因子受体α(PDGFRA)突变的胃肠间质瘤(GIST)是一种发病率较低的GIST,有关其临床病理特点以及预后的研究很少。本文探讨PDGFRA突变型GIST的临床病理特征及预后因素,以期为治疗提供更多数据参考。方法采用回顾性病例对照研究方法,收集2015年1月至2019年8月期间,复旦大学附属中山医院进行手术切除并经术后病理诊断证实为GIST的患者病历资料,筛选出基因检测为PDGFRA突变型、并排除PDGFRA同义突变、非肿瘤相关死亡和临床病理资料缺失的患者。收集患者临床病理特征资料,并分析影响PDGFRA突变型GIST患者预后的危险因素。结果纳入的59例PDGFRA突变型GIST患者中,男性41例(69.5%),女性18例(30.5%),60岁以下患者31例(52.5%);肿瘤均来源于胃,肿瘤≤5 cm者33例(55.9%),>5 cm者26例(44.1%);核分裂象计数≤5个/50高倍镜视野(HPF)者49例(83.0%);改良美国国立卫生研究院(NIH)危险度分级标准:极低危8例(13.6%),低危25例(42.4%),中危14例(23.7%),高危12例(20.3%);7例PDGFRA第12外显子突变,52例第18外显子突变,其中D842V突变36例。D842V组与非D842V组的临床病理特点比较,差异无统计学意义(均P>0.05)。中位随访21(0~59)个月,全组患者的1年和3年无复发生存率(RFS)分别为96.6%和91.5%,8例出现复发,3例死亡;6例D842V突变的GIST患者术后发生了肿瘤的复发,其中4例服用dasatinib或avapritinib后获得不同程度的肿瘤缓解。log-rank分析显示,与女性相比,男性拥有较好的总生存率(OS)(100%比83.3%,P=0.046);D842V与非D842V、第12外显子与第18外显子突变患者的RFS和OS均相近(均P>0.05)。单因素Cox分析显示,RFS与性别(P=0.010)、肿瘤大小(P=0.042)、核分裂象计数(P=0.003)及NIH危险度分级(P=0.042)有关;而多因素分析结果显示,较高的危险度分级是导致PDGFRA突变型GIST复发的独立危险因素(HR=12.796,95%CI:1.326~123.501,P=0.028),男性的复发风险低于女性(HR=0.154,95%CI:0.028~0.841,P=0.031)。结论性别和改良NIH危险度分级是影响PDGFRA突变型GIST复发的独立因素,而D842V与非D842V,第12外显子与第18外显子突变患者的复发与死亡风险接近。

Objective Platelet-derived growth factorα(PDGFRA)-mutant gastrointestinal stromal tumor(GIST)is a relatively rare disease,whose clinicopathological characteristics and prognosis have been poorly studied.In this paper,the clinicopathological features and prognostic factors of PDGFRA-mutant GIST are investigated to provide more data for its understanding and treatment.Methods A retrospective case-control study was used to collect the medical records of patients with GIST who underwent surgical resection in Zhongshan Hospital of Fudan University from January 2015 to August 2019.Patients with PDGFRA-mutant GIST were enrolled,and those with synonymous PDGFRA mutations,non-tumor-related deaths,and lack of clinicopathological data were excluded.The clinicopathological data were collected and the risk factors associated with prognosis were analyzed.Results Among the enrolled 59 patients,there were 41 males(69.5%)and 18 females(30.5%)with the median age of 60(25-79)years.All tumors originated from the stomach.The tumor size was 5(3-7)cm,and the mitotic count was 2(1-4)/50 high-power fields(HPF).According to the modified NIH risk stratification,8 cases were classified as very low risk(13.6%),25 cases as low risk(42.4%),14 cases as moderate risk(23.7%),and 12 cases as high risk(20.3%).There were 7 cases of exon 12 mutation and 52 cases of exon 18 mutation(including 36 cases of D842V mutation).A comparison of clinicopathological features between the D842V mutation group and the non-D842V mutation group showed no statistically significant difference(all P>0.05).During a median follow-up of 21(0-59)months,the 1-and 3-year relapse-free survival(RFS)rates of all the patients were 96.6%and 91.5%,respectively.There were 8 cases of recurrence and 3 cases of death.Six GIST patients with D842V mutation had tumor recurrence after operation,of whom 4 cases achieved varying degrees of tumor remission after being treated with dasatinib or avapritinib.Log-rank analysis showed that the overall survival(OS)of male was better than that of female(100%vs.83.3%,P=0.046),but there was no significant difference in OS among patients with different risk grades(P=0.057).The RFS and OS of patients with D842V mutation and non-D842V mutation,exon 12 and exon 18 mutation were similar(all P>0.05).Univariate Cox analysis showed that RFS was associated with gender(P=0.010),tumor size(P=0.042),mitotic count(P=0.003),and the modified NIH risk stratification(P=0.042),while multivariate analysis revealed that higher risk grade was an independent risk factor for recurrence of PDGFRA-mutant GIST(HR=12.796,95%CI:1.326-123.501,P=0.028).Gender was an independent factor for recurrence,and the risk of recurrence in males was lower than that in females(HR=0.154,95%CI:0.028-0.841,P=0.031).Conclusions Gender and the modified NIH risk stratification are independent risk factors for recurrence of PDGFRA-mutant GIST,while patients with D842V and non-D842V mutation,and exon 12 and exon 18 mutation have a similar risk of recurrence and death.