The Relationship Between EGFR Gene Mutation And Clinicopathological Features In Multifocal Lung Cancer

Objective To invegtigate the relationship between the Epidermal Growth Factor Receptor（EGFR）gene mutation of simultaneous multifocal lung adenocarcinoma and the clinicopathological features of patients,and its role in the differential diagnosis of multiple primary lung adenocarcinoma and multiple metastatic carcinoma in the lung.Methods To collect 111 cases of simultaneous resection of multiple lung adenocarcinomas in our hospital with totally 256 tumours from January 2013 to December 2018,to detect EGFR gene mutation by Amplification Refractory Mutation System（ARMS）and to analyze EGFR gene mutations between different lesions in the same patient and its relationship with clinical pathological features.Results 1.There are 111 patients with multi-focal lung adenocarcinoma,including 31 males and 80 females（male:female=1:2.6）,aged between 30 and 75 with a median age of 59years,41 patients older than 59 years old and 70 patients equal or younger than 59 years old,19 smokers and 92 non-smokers,87 cases with 2 lesions and 15 cases with 3 lesions as well as 9 cases with equal to or more the 4 lesions,103 cases whose largest lesion tumour diameter is equal to or smaller than 3cm and 8 cases bigger than 3cm,34 cases whose tumours are located in the ipsilateral lung and the same lobe as well as 53 cases in the ipsilateral lung and 24 in the bilateral lung,65 cases in the same histopathology and 46 in the different histopathology,5 cases having lymphatic metastasis and 106 without.Among the256 tumours,the histological type showed 165 tumours with wall-growth growth,69 tumours with acinar-based tumours,13 with papillary tumours,4 with micro papillary tumours,and5 with solid tumours.2.EGFR gene mutations occurred in 124 tumours among 256 tumours and the other 132tumours showed wild type.The types and numbers of mutations are as follows:there are 69cases of L858R（69/256,27.0%）,41 cases of 19-Del（41/256,16.0%）,4 cases of 20Ins,4cases of 19-Del/L858R（2/256,0.8%）,1 cases of 19-Del/G719X（1/256,0.4%）,1 cases of L858R/T790M（1/256,0.4%）,1 cases of S768I（1/256,0.4%）,and 132 cases of wild type（132/256,51.5%）.There are 75 cases of EGFR gene mutation in 111 patients,and the overall mutation rate was 67.6%（75/111）.There are 60 cases with inconsistent EGFR gene mutations in different lesions of the same patient,and the mutation inconsistency rate was 54.1%（60/111）,44 cases of which are“mutant+wild type”,accounting for 39.6%（44/60）and 16 cases of which are‘mutant A+B’,accounting for 14.4%（16/60）.（A and B represent two different genetic mutations respectively）3.Among the 111 patients,92 are non-smokers whose inconsistent rate of EGFR gene mutation was 59.8%（55/92）and 19 are smokers whose inconsistent rate of EGFR gene mutation was 26.3%（5/19）.The inconsistent rate of gene mutation in non-smokers was higher than that in smokers,showing a statistical significance（p<0.05）.There were 87 cases with 2 lesions,15 cases with 3 lesions and 9 with equal to or more than 4 lesions.There are46 patients in different histological types whose gene mutation inconsistency rate is 47.1%（41/87）and 65 patients in the same histological type whose gene mutation inconsistency rate is 44.6%（29/65）.The inconsistency rate of genetic mutations with different histological subtypes is higher than that of histological subtypes,showing a statistical significance（p<0.05）.According to MPLC diagnostic criteria（ACCP version）^[4],there are 80 patients with multiple primary lung adenocarcinoma whose genetic mutation inconsistency rate is62.5%（50/80）and 31 patients with intrapulmonary metastatic cancer whose genetic mutation inconsistency rate is 29.0%（9/31）.The inconsistent rate of multiple primary lung adenocarcinoma gene mutations is higher than that of intrapulmonary metastasis gene mutations,and the difference is statistically significant（p<0.05）.The result shows no significant correlation between heterogeneity of multi-focal lung adenocarcinoma gene mutations and age,gender,tumor size,lesion location,and lymph node metastasis（p>0.05）.4.The mutation patterns of EGFR gene in non-smoking patients were 43.5%（40/92）and16.3%（15/92）,respectively,while those in smoking patients were 21.1%（4/19）and 5.3%（1/19）.Non-smoking patients had more complex mutation patterns.The mutation patterns of EGFR gene in different pathological types were 56.5%（26/46）and 56.5%（26/46）,respectively.19.6%（9/46）,27.7%（18/65）and 10.8%（7/65）of the patients with the same pathological type had more complex mutation patterns.Conclusion:More than half of the patients with multifocal lung adenocarcinoma had heterogeneity in EGFR gene mutation types among different lesions,which mostly occurred in non-smokers,patients with many lesions and different pathological types.Patients who did not smoke and had different pathological types had more complex EGFR gene mutation patterns.Therefore,the detection of EGFR gene in each lesion of patients with multiple lung adenocarcinoma is helpful to evaluate the mutation status of EGFR gene and to differentiate multiple primary lung adenocarcinoma from intrapulmonary metastasis.