1232例病灶最大径≤1 cm肺腺癌EGFR、ALK、ROS1基因状态及临床病理特征的回顾分析研究

Analysis of relationship between gene status(EGFR,ALK,ROS1)and clinicopathological features in 1232 cases of lung adenocarcinoma with lesion of maximum diameter≤1 cm

目的:研究病灶最大径≤1 cm肺腺癌患者EGFR、ALK及ROS1基因状态。方法:收集2013年1月至2020年10月经华东医院病理科确诊为肺腺癌且病灶最大径≤1 cm,并行表皮生长因子受体(epidermal growth factor receptor,EGFR)、间变性淋巴瘤激酶(anaplastic lymphoma kinase,ALK)和(或)原癌基因酪氨酸蛋白激酶ROS(ROS protooncogene 1,receptor tyrosine kinase,ROS1)检测的患者的临床病理资料,回顾性分析其EGFR、ALK、ROS1基因状态及其临床病理学特点。结果:纳入1232例病灶最大径≤1 cm肺腺癌患者,平均年龄54岁,男性387例,女性845例;多发病灶患者只选1个病灶。本组原位腺癌182例(14.8%),微浸润性腺癌778例(63.1%),浸润性非黏液性腺癌249例(20.2%),浸润性黏液腺癌23例(1.9%)。43.1%(352/817例)存在EGFR基因突变,其中46.9%(165/352例)为21L858R突变,40.6%(143/352例)为19Del突变,0.9%(3/352例)为18G719X/20S768I和21L858R/20S768I双突变。原位腺癌、微浸润性腺癌、浸润性非黏液性腺癌、浸润性黏液腺癌患者的EGFR突变率分别为31.0%(40/129)、42.0%(208/495)、58.4%(104/178)、0(0/15)。23.1%(3/13例)同一患者不同病灶EGFR突变检测结果不同(13例先后发生肺腺癌2灶,其中2例首次术后病灶为19Del突变阳性,第2次手术病灶示EGFR野生型;1例首次术后病灶为EGFR野生型,第2次病灶显示21L858R突变型。EGFR位点突变率与组织学类型、年龄相关,>60岁年龄者及浸润性非黏液性腺癌者突变率高,而与性别、吸烟无关。1.9%(22/1168例)ALK基因重排阳性,浸润性非黏液性腺癌(5.2%)及≤60岁年龄组2.6%)患者中阳性率高,含实性成分的腺癌ALK重排阳性率(22.2%,4/18)明显高于浸润性非黏液腺癌的阳性率(5.2%,12/233)和不含实性成分的腺癌(1.1%,12/1095)(P<0.05),且与性别、吸烟无关。0.8%(6/795例)的患者ROS1基因重排阳性,阳性率与性别、年龄、吸烟、组织学类型无关。382例患者同时检测EGFR、ALK、ROS1,其中40.6%(155/382)的肿瘤含此三者中一种突变或基因重排,未发现其中两者或三者共存现象。结论:本次单中心研究显示,病灶最大径≤1 cm的肺腺癌中,微浸润腺癌占多数(63.1%);至少40%存在EGFR、ALK、ROS1三者之一基因突变或重排改变,三者均与性别、吸烟无关。EGFR突变以21L858R和19Del最常见,在>60岁的患者及浸润性非黏液性腺癌患者中发生率高。ALK重排阳性率在60岁以下的患者及含实性成分的腺癌中高。最大径≤1 cm肺脉癌病灶中ROS1重排阳性率低。同一患者不同病灶间的分子检测结果可存在差异,对于多发病灶有必要分别进行多分子检测。

Objective To study relationship between gene status[epidermal growth factor receptor(EGFR),anaplastic lymphoma kinase(ALK)and ROS proto-oncogene 1,receptor tyrosine kinase(ROS1)]in cases with pathological lung adenocarcinoma lesion of maximum diameter≤1 cm.Methods A total of 1232 patients with lung adenocarcinoma lesion of maximum diameter≤1 cm were enrolled in the Pathology department of Huadong Hospital from January 2013 to October 2020.For patients with multiple lesions,only the biggest lesion was selected.The gene status of EGFR,ALK and ROS1were identified and clinicopathological characteristics were retrospectively analyzed.Results There were 387 males and 845 females,with a mean age of 54 years.There were 182(14.8%)cases of adenocarcinomas in situ,778(63.1%)cases of minimal invasive adenocarcinomas,249(20.2%)invasive non-mucinous adenocarcinomas,and 23(1.9%)invasive mucinous adenocarcinomas.It revealed that 43.1%(352/817 cases)had EGFR gene mutations,of which 46.9%(165/352 cases)were 21L858R mutations and 40.6%(143/352 cases)were 19Del mutations,and 0.9%(3/352 cases)were 18G719X/20S768I and 21L858R/20S768I double mutations.The rate of EGFR mutation were 31.0%(40/129),42.0%(208/495),58.4%(104/178),and 0(0/15)for adenocarcinoma in situ,minimal invasive adenocarcinoma,invasive non-mucinous adenocarcinoma,and invasive mucinous adenocarcinoma,respectively.And 23.1%(3/13 cases)had different EGFR mutation detected for different lesions in the same patient(In 13 cases with 2 lesions of lung adenocarcinoma successively,2 cases were positive for 19Del mutation in the first postoperative lesion and EGFR wild-type in the second lesion:one case was EGFR wild type in the first postoperative lesion and 21L858R mutation in the second lesion).The rate of EGFR mutations was correlated with histological type and age,and not associated with sex or smoking.EGFR mutations was more likely to occur in the age group over 60 years and in invasive non-mucinous adenocarcinomas.It showed that 1.9%(22/1168 cases)were positive for ALK rearrangements,with a positive rate of 5.2%in invasive non-mucinous adenocarcinomas and of 2.6%in patients≤60 years.The positive rate of ALK rearrangement in adenocarcinomas with solid components(22.2%,4/18)was significantly higher than that in invasive non-mucinous adenocarcinomas(5.2%,12/233)and adenocarcinomas without solid components(1.1%,12/1095).It showed that 0.8%(6/795 cases)were positive for ROS1 rearrangements,independent of sex,age,smoking and histological type.A total of 382 cases were tested for EGFR,ALK and ROS1 simultaneously,of which 40.6%(155/382)of the tumours containing one of these three mutations or rearrangements status,and no co-exist in either or all three.Conclusions In this single-center study,minimal invasive adenocarcinomas accounts for the majority(63.1%)of lung adenocarcinomas with a lesion size≤1 cm.At least 40%of them have mutations or rearrangements in one of the three genes(EGFR,ALK and ROS1),and none of which were significantly associated with sex or smoking.The most common EGFR mutations are 21L858R and 19Del,which occur more frequently in invasive non-mucinous adenocarcinomas in the>60 age group,while ALK rearrangements occur more frequently in solid-component adenocarcinomas in the≤60 age group.The incidence of ROS1 rearrangements is low.The molecular change may be different in the same patien to with multiple adenocarcinomas,molecular testing foci is necessary for each lesion.