| Objective:To verify the prognostic value of the IASLC newly proposed grading system and the accuracy of the grade of complex glands(CG).To explore the correlation between pathological grade and preoperative computed tomography(CT)performance and the prognostic value of the grading system in different subsets of CT performance in patients with clinical stage I.To discuss the optimal surgical procedure regarding different pathological grade in patients with clinical stage I.Methods:2335 patients with invasive lung adenocarcinoma who underwent complete surgical resection in Shanghai Pulmonary Hospital from January 2013 to December 2014 were retrospectively included,among which 1187 were with clinical stage I.Recurrence-free survival(RFS)and overall survival(OS)were assessed by KaplanMeier method and compared by Log-rank test.Multivariable COX regression analysis was applied to discover independent predictors of prognosis.Results:Among all 2335 patients,the new grading system significantly differentiated RFS and OS(Grade 2 vs Grade 1,p<0.001;Grade 3 vs Grade 2,p<0.001).Prognosis of patients with CG component beyond 20%was closer to Grade 3:RFS(CG vs Grade 3,p=0.116);OS(CG vs Grade 3,p=0.014).Multivariable COX regression analysis revealed that pathological grade was an independent predictor of RFS(Grade 2 vs Grade 1:HR 3.47,95%CI:2.01-5.99,p<0.001;Grade 3 vs Grade 1:HR:5.93,95%Cl:3.43-10.27,p<0.001)and OS(Grade 2 vs Grade 1:HR:4.34,95%CI:2.02-9.33,p<0.001;Grade 3 vs Grade 1:HR:6.55,95%CI:3.04-14.13,p<0.001).Among the 1187 patients with clinical stage Ⅰ,the proportion of patients with pure-solid appearance on CT image increased with pathological upgrade(Grade 1:2.7%;Grade 2:51.1%;Grade 3:86.4%,p<0.001).Among patients with pure-solid appearance on CT image,those with grade 2 and 3 had higher RFS(p<0.001)and OS(p=0.002).Patients who underwent wedge resection in Grade 3 had significantly worse RFS(p=0.012)and OS(p=0.011)compared with those who underwent lobectomy.Conclusions:The IASLC newly proposed grading system can effectively distinguish patients’ prognosis;CG should be grade 3.There is a significant correlation between CT performance and pathological grade;Combination of preoperative CT performance and pathological grade can better evaluate prognosis.Sublobar resection is feasible in patients with grade 1 and 2.Background:The IASLC newly proposed grading system for lung adenocarcinomas(ADC)has been shown to be of prognostic significance,and sublobar resection has been proposed as a treatment of choice for early-stage lung ADC.Hence,intraoperative consultation for the grading system was important to surgeons regarding the surgical decision-making.Here we evaluated the accuracy and interobserver agreement for grading system on frozen section(FS),and further investigated the prognostic performance of grading system on FS.Methods:FS and final pathology(FP)slides were reviewed by three pathologists for tumor grading in 373 patients with stage Ⅰ lung ADC who underwent surgery from January to June 2013(retrospective cohort).A prospective cohort(January to June 2021,n=212)derive from the ongoing phase Ⅲ clinical trial were included to confirm the results.Results:The overall concordance rates between FS and FP were 79.1%(κ=0.650)and 89.6%(κ=0.729)with substantial agreement in retrospective and prospective cohorts,respectively.Presence of complex gland was the only independent predictor of discrepancy between FS and FP(presence versus.absence:odds ratio,2.193;95%confidence interval,1.163 to 4.135;P=0.015).The interobserver agreement for IASLC grading system on FS among three pathologists were satisfactory(κ=0.672 for retrospective cohort;κ=0.752 for prospective cohort).Moreover,we found that the IASLC grading system by FS diagnosis could well predict recurrence-free survival(RFS)and overall survival(OS)for patients with stage I invasive lung ADC.Conclusions:Our results suggest that FS had high diagnostic accuracy and satisfactory interobserver agreement for IASLC grading system.Future prospective studies are merited to validate the feasibility of using FS to select patients for sublobar resection.Background:Epidermal growth factor receptor(EGFR)gene mutation,which is more frequent in lepidic predominant adenocarcinoma(LPA),acinar predominant adenocarcinoma(APA)and papillary predominant type.predominant adenocarcinoma,PPA)in lung adenocarcinoma.is the most common driver gene mutation in lung adenocarcinoma,However,the characteristics of EGFR mutations in lung adenocarcinoma with different histological gradings and their prognostic relationship are rarely reported.In addition,the impact of different EGFR mutation subtypes on the prognosis of early invasive lung adenocarcinoma remains to be explored.In this part of the study,we aimed to explore the clinical association and prognostic correlation between the novel grading system of lung adenocarcinoma and EGFR gene mutation,and to clarify the prognostic significance of different EGFR mutation subtypes.Methods:This study retrospectively enrolled 992 patients with invasive lung adenocarcinoma who underwent complete surgical resection and EGFR examination in Shanghai Pulmonary Hospital from January 2013 to December 2014,and 414 patients with rare EGFR gene mutation from January 2015 to December 2016.Survival outcomes were assessed using the Kaplan-Meier method and compared with the logrank test.Univariate and multivariate Cox proportional hazards regression analyses were used to identify independent prognostic factors.Results:In the entire cohorts,the frequency of EGFR gene mutation was 67.0%.Its mutation rates in Grade 1,Grade 2,and Grade 3 patients were 73.7%,73.7%,and 57.2%,respectively.Furthermore,EGFR mutations frequently occurred in women(67.3%vs 39.2%,p<0.001)and never smokers(87.6%vs 70.9%,p<0.001)and tumors without STAS(30.5%vs 44.8%,p<0.001).Patients with rare EGFR mutations have a higher proportion of males and stage Ⅱ-Ⅲ patients than common mutations.The novel grading system can significantly differentiate RFS and OS in both EGFR-mutanted and wildtype patients.Among 655 patients with EGFR mutations,the 5-year RFS rates were 99.2%,89.2%,and 57.1%for Grade 1,Grade 2,and Grade 3 patients,respectively,and the 5-year OS was 100%,98.1%,and 90.7%,respectively.Among the 337 EGFR wildtype patients,the 5-year RFS rates were 100%,88.0%,and 58.8%for Grade 1,Grade 2,and Grade 3 patients,respectively,and the 5-year OS was 100%,96.4%,and 80.4%,respectively.There was no significant difference in 5-year RFS between the three grades of EGFR mutant and wild-type patients,but the 5-year OS of Grade 3 EGFR mutant patients was significantly better.In the subgroup analysis of EGFR subtypes,the 5-year RFS of patients with rare mutation was not significantly different from those with common mutations,while the 5-year OS was worse than those of common mutation.Among all EGFR mutation subtypes,L861Q mutation had the worst RFS and OS.Cox regression analysis showed that EGFR mutation was not associated with RFS[HR(95%CI)=1.171(0.946-2.333),p=0.348],but an independent protective factor for OS[HR(95%CI=0.535(0.335-0.855),p<0.001].The L861Q mutation was an independent risk factor for RFS and OS.Conclusions:The novel grading system can significantly differentiate RFS and OS in both EGFR-negative and positive patients.However,EGFR mutation was not an independent prognostic factor for RFS or OS.In the subgroup analysis,the prognoses of rare EGFR mutations were generally similar with common mutations,but L861Q was the subtype with worst prognosis.Background:The main method of adjuvant therapy for early-stage lung adenocarcinoma is still chemotherapy,but the indications remain to be unclear,especially in patients with stage IB.Secondly,with the development of EGFR-TKI adjuvant targeted therapy,it is remained to be solved whether patients with EGFR mutation need postoperative chemotherapy in clinical practice.In this part of the study,we aimed to explore the predictive significance of the novel grading system and EGFR mutation status on adjuvant chemotherapy,and to select suitable populations for adjuvant chemotherapy combining these two elements.Methods:We retrospectively enrolled patients with invasive lung adenocarcinoma who underwent complete surgical resection and EGFR examination in the Thoracic Surgery Department of Shanghai Pulmonary Hospital from January 2013 to December 2014.We recorded the relevant clinical information of the patients,including age,gender,smoking history,pathological tumor size,surgical method,TNM stage,EGFR gene mutation subtype,histopathological subtype,lymphovascular invasion(LVI),visceral pleural invasion(VPI),and adjuvant chemotherapy information.Kaplan-Meier method was used to assess the survival outcomes and log-rank test was used to identify the difference.Univariate and multivariate Cox proportional hazards regression analyses were used to identify independent prognostic factors.Results:In this study,we included 356 high-grade stage IB and 209 stage Ⅱ-Ⅲ invasive lung adenocarcinomas,respectively.Of these,188 and 146 patients,received adjuvant chemotherapy after surgical resection,respectively.Patients with LVI(p=0.018)and STAS(p=0.021)tended to receive adjuvant chemotherapy.In stage IB Grade 3 patients,we found that 5-year RFS and OS were significantly higher in those who received adjuvant chemotherapy than in those who did not(5y-RFS,77.2%vs 55.2%,p<0.001;5y-OS,95.8%vs 84.6%,p=0.012).Similarly,in the stage Ⅱ-Ⅲ population,adjuvant chemotherapy was associated with better RFS and OS(5y-RFS,41.6%vs 34.3%,p=0.014;5y-OS,82.7%vs 70.4%,p=0.052).In stage IB Grade 3 patients,subgroup analysis according to EGFR mutation status showed no significant difference concerning the 5-year RFS and OS between those with EGFR mutations who received adjuvant chemotherapy or not(5y-RFS,69.8%vs 65.9%,p=0.281;5y-RFS,69.8%vs 65.9%,p=0.281;5y-OS,96.4%vs 93.6%,p=0.806),while EGFR wild-type patients had significantly better RFS and OS after adjuvant chemotherapy(5y-RFS,87.4%vs 32.4%,p<0.001;5y-OS,94.9%vs 65.8%,p=0.001).Similarly,in stage Ⅱ-Ⅲ patients,there was no significant difference in 5-year RFS and OS between patients with EGFR mutations who received adjuvant chemotherapy or not(5y-RFS,39.1%vs 42.7%,p=0.334;5y-OS,87.0%vs 73.9%,p=0.119).Conversely,adjuvant chemotherapy could bring RFS benefits for wild-type patients(5y-RFS,41.2%vs 25.0%,p=0.010).Conclusions:Our study demonstrates that patients with stage IB Grade 3 and stage ⅡⅢ can benefit from adjuvant chemotherapy.However,in this population,only EGFR wild-type patients are suitable for adjuvant chemotherapy,but EGFR-mutated patients do not benefit from adjuvant chemotherapy. |
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