Clinical, Imaging And Biological Characteristics Of Lung Adenocarcinoma With Lepidic Growth

Background:The heterogeneity of tumor cells is an important pathological basis for the prognosis and treatment of cancer.According to the main growth pattern,lung adenocarcinoma can be divided into several subtypes,lepidic,acinar,papillary,micropapillary,solid and etc.In the lepidic growth(LG)pattern,neoplastic cells grow along the alveolar structures without pulmonary interstitial,vascular,or pleural infiltration.It is generally considered that the progression and development of lung adenocarcinoma follows a stepwise manner,from atypical adenomatous hyperplasia to adenocarcinoma in situ,and then from minimally invasive adenocarcinoma to invasive adenocarcinoma with a lepidic pattern.In the WHO classification of thoracic tumors(5th edition)published in 2021,adenocarcinoma in situ is no longer classified as lung cancer.This major change is based on the biological characteristics of lepidic growth.Under this background,it is of great clinical significance to rediscover and furtherly study lung adenocarcinoma with lepidic growth.Objective:Proceeding from the practical clinical problems,our study aimed at the research hotspot of the histologic heterogeneity of lung adenocarcinoma in recent years.We investigated the differences of clinical characteristics,imaging features,and prognosis between lepidic growth pattern and non-lepidic growth pattern.The present study was designed to provide references for the clinical diagnosis and prognosis evaluation of patients with the specific imaging manifestations based on clinical pathology,and make the treatment more individualized and more accurate.Methods:1.Patients diagnosed with lung adenocarcinoma pathologically after surgical resection at Shanghai Changhai Hospital between January 2015 and December 2016were retrospectively reviewed.The cases were screened according to inclusion and exclusion criteria.Relevant clinicopathological data were collected,including age,gender,smoking history,symptoms,tumor markers,original chest CT images,pathological subtypes(and immunohistochemistry),TNM stages,and treatment.2.All patients were clinically followed up through outpatient visits or telephone contact.The starting point for the retrospective follow-up was the date of pathological diagnosis,and the endpoint was the date of death.The deadline for follow-up was December 31,2021.Censoring events including patients still alive at end of follow-up,loss of follow-up,or death from other cause.3.All data were analyzed with IBM SPSS 26.0 software and Graph Pad prism 8.0.Continuous variables were presented as means±standard deviations(M±SD),with Student’s t-test or the Mann-Whitney U test performed for comparison.Categorical variables were expressed as frequency(N)and proportion(%),and evaluated byχ~2tests or Fisher’s exact tests.We used Kaplan-Meier method and Log rank test for univariate survival analysis,Cox regression model for multivariate survival analysis,as appropriate.The inspection level was alpha=0.05,and if P<0.05 the differences were considered to be statistically significant.Result:1.General clinical featuresA total of 499 patients were enrolled in the present study,including 167 cases of LGA,and 332 cases of NLGA.There were significant differences between LGA and NLGA in terms of gender,smoking history,tumor location,TNM stage and operation mode.Significant difference was not observed on age and ECOG score.And there was no statistically significant difference in the expression levels of 5 serum tumor markers.2.Imaging featuresExcept for nodule shape and vacuole sign,there were significant differences in the nodule type,density,tumor-lung interface,solid component,CT value,lobulation sign,air-bronchogram sign,spicule sign,pleural indentation sign and vascular convergence sign(all P<0.05).3.Common gene mutationThe overall gene frequencies were as follows:EGFR mutations,65.7%(328/499);EML4-ALK fusion,2.4%(12/499);only 7 patients(1.4%)with ROS1 mutation.Significant differences were observed in the incidence of EGFR and ALK gene mutation between LGA and NLGA patients(both P<0.05).The statistical results of block design showed that the average rank values of EGFR,ALK and ROS1 were 2.71,1.68 and 1.61respectively,χ2=402.23,P<0.001.Therefore,mutations in the three genes were mutually exclusive.4.Survival analysisIn LGA patients,the 5-year survival rate was 98.2%±1%,the average overall survival(OS)time was 82.93±0.66 months,95%CI[81.64,84.22]and the average progression free survival(PFS)was 78.44±1.27months,95%CI[75.95,80.93].While for NLGA patients,they had an average OS of 69.76±1.35months,95%CI[67.12,72.40],the average PFS was 59.67±1.74months,95%CI[56.26,63.07]and the 5-year survival was 73.8%±2.5%,respectively.The average OS and PFS had statistically significant differences between LGA and NLGA according to the P value(both P<0.001).Univariate analysis showed that there were significant differences in age,smoking history,pathological type,TNM stage,ECOG score,operation method,EGFR mutation and ALK mutation between LGA and NLGA.The results of multivariable COX model showed that age,lepidic growth,TNM stage and operation mode were identified as independent factors affecting the prognosis and survival of lung adenocarcinoma.Conclusion:1.LGA is more commonly found in women than men and in non-smokers.The early symptoms of LGA are usually mild or even without any discomfort.The majority of patients were detected occasionally during physical examination or due to other reasons.The traditional tumor markers,CEA、SCC、NSE、Pro-GRP and CYFRA21-1,present a different degree of detection sensitivity or specificity problems,which limit their clinical value for the early diagnosis of LGA.2.Lung adenocarcinomas with lepidic histology typically have the appearance of ground glass opacity on imaging,with unclear tumor-lung interface,round or oval shadow,and homogeneous density.Invasive adenocarcinoma such as acinar and solid predominant subtype,are more likely to appear as solid or subsolid nodule with high density,have better chances of malignant appearance such as spiculation sign,pleural indentation sign and vascular convergence sign.3.EGFR mutations are frequently associated with adenocarcinoma with a lepidic growth pattern.The frequency of EGFR gene mutations in LGA was higher compared with NLGA,reflected by the predominance of LPA.While lung adenocarcinoma lack of lepidic growth was shown to be more common in ALK-positive patients.The correlation between ROS1 mutation and lepidic growth has not been found in this study.4.LGA is characterized by slow growth and a low rate of recurrence and distant metastasis.The 5-year survival rate after resection reaches almost 100%.Also,the patients with LG had better OS and PFS than those with NLG.Lepidic growth is an independent and important prognostic factor in patients with adenocarcinoma,with a longer survival time and a better prognosis.