The Clinical Characteristics And Outcome Of Primary Pulmonary Lymphoepithelioma-like Carcinoma

Background Pulmonary lymphoepithelioma-like carcinoma(LELC)is a rare type lung cancer related to Epstein-Barr virus(EBV)and morphologically similar to undifferentiated nasopharyngeal carcinoma.Until now,more than 1200 patients have been reported worldwide.Due to lack of well understanding,it has been classified as the group of large-cell lung cancer in The World Health Organization Classification of Lung Tumor in 2004 and then reclassified into the group of other unclassified non-small cell lung cancer(NSCLC)in 2015.Besides,it also be easily misdiagnosed as poorly differentiated squamous cell carcinoma in several case reports.Currently,multimodality therapy is the mainstay treatment for pulmonary LELC,and surgery is given priority to patients at early stage,while chemotherapy and radiotherapy are primary treatment for patients at advanced stage.However,the chemotherapy regimens for NSCLC are used to pulmonary LELC,which are platinum-based combination with third-generation chemotherapeutic drugs and there is no consensus on the preferred option.Recently,some studies have reported that the mutation rate of the driver gene for pulmonary LELC was lower than non-LELC NSCLC,for example,the mutation rate of EGFR is lower at 0.0% to 9.1%,and the efficacy of targeted therapy reported from several case reports is unsatisfactory.However,there is lack of research on antiangiogenic therapy for pulmonary LELC.Surprisingly,the programmed deathligand 1(PD-L1)expression in pulmonary LELC is reported higher than non-LELC NSCLC from several small retrospective studies,and the respose to programmed death-1(PD-1)/ PD-L1 inhibitors reveraled in the other several case reports was good.Therefore,there are still some unexplored problems that deserve to take a further study.Objective 1.To analyze the clinical and the pathological features to improve our understandingof this disease.2.To explore the preferred first-line palliative chemotherapy regimens for pulmonaryLELC patients.3.To analyze the relationship between clinical data and the prognosis of pulmonaryLELC patients to explore its prognostic factors.Methods In this study,274 patients diagnosed with pulmonary LELC were matched to our inclusion criteria in The First Affiliated Hospital of Guangzhou Medical University from January 1,2013 to May 31,2019.The clinical data and follow-up information were collected,and then their clinical characteristics(including age,gender,smoking status,symptoms of onset)and imaging features,pathological features,molecular biological characteristics(EGFR,ALK,ROS1,KRAS,PD-L1),treatment and survival data(PFS,DFS,OS)were analyzed.The chi-square test or Fisher’s exact test was used to analyze the relationship between the expression of PD-L1 and various clinical data.Besides.Then the response rate,survival outcomes and prognosis of different first-line chemotherapy regimens were compared in patients at advanced stage and the prognostic factors were also explored in the available clinical data via Kaplan Meier method,the Log-Rank test and COX regression.Results 1.Among the 274 patients,99.6% were from southern China,especially fromGuangdong Province(90.2%),which was mimicked with the characteristic ofnasopharyngeal carcinoma.The median age was 55 years old(24-89 years old),64.6% of them were aged below 60 years old with a male/female ratio 1:1.2,and75.5% of them were nonsmokers.The clinical symptoms were mainly includingcough with or without sputum(63.5%),Some of them were initially asymptomatic(25.2%).Radiologically,the median diameter of the lesion was 4.6 cm(0.5-11.4cm),most of them(69.3%)with tumor diameter more than 3.5cm,and thepatients at advanced stage had central lesions more commonly(53.2% vs.46.8%,P< 0.0001),while patients at early stage had the peripheral lesions morecommonly(70.3% vs.29.7%,P < 0.0001).Therefore,the diameter of the centrallesion was larger than the peripheral lesion(5.2cm vs.4.0cm,P <0.001).2.274 patients in this group had positive expression of EBER.Epidermal growthfactor receptor(EGFR)mutation rate was lower at 4.7%,kirsten rat sarcoma viraloncogene(KRAS)mutation rate was 1.5%,while anaplastic lymphoma kinase(ALK),proto-oncogene-1 tyrosine kinase(ROS1)and BRAF were all wild-type.In addition,34 patients(70.8%/48)had positive expression of PD-L1 in the tumorcells,among which 22(45.8%/48)showed high positive expression(≥50%)ofPD-L1,while 39(81.3%/48)of them showed positive expression of PD-L1 intumor-infiltrating lymphocytes(TILs),and only 2(4.2%/48)of which showedhigh positive expression(≥50%)of PD-L1.However,these patients with positivePD-L1 expression were more occurred in peripheral tumors(64.7% vs.35.3%,P=0.006),and high PD-L1 expression was associated with positive PD-L1expression in TILs(95.5% vs.4.5%,P=0.042).3.The median follow-up duration was 17.3 months(1.1-94.7 months),and the 1-yearand 2-year OS rates of this group were 97% and 95%,respectively.The 1-year and2-year DFS rates for patients at early stage were 91% and 83%,respectively.Whilethe median PFS rates for patients at advanced stage were 12.5 months,and the 0.5,1-year,and 2-year PFS rates for them were 73%,49%,and 20%,respectively.Thefirst-line of palliative chemotherapy for 95 patients at advanced stage wereincluding platinum-based combination with gemcitabine(GP,n=39),paclitaxel(TP,n=32)and pemetrexed(AP,n=24),and the object response rate(ORR)anddisease control rate(DCR)for these group was 32.6% and 64.2%,respectively.Inthe subgroup,the DCR of the GP group(87.2% vs.81.3% vs.45.8%,P=0.001)was higher than TP and AP groups while there was no significant difference inORR(41% vs.34.4% vs.16.7%,P=0.130).The median PFS of GP group waslonger than TP group and AP group(13.9 months vs.11.0 months vs.8.2 months,P=0.020)as well as the median PFS was significantly longer(21.6 months vs.11.0months,P=0.004)in patient at advanced stage used the first-line palliativechemotherapy combined with radiotherapy(n=17)than those patients inchemotherapy alone(n=85).Otherwise,there were no statistically differenceeither in PFS or OS between whether receiving antiangiogenic therapy.4.In the univariate analysis,the less lymph nodes involvement(P = 0.013),theearlier of TNM staging(P < 0.001),more than 4 cycles of adjuvant chemotherapy(P = 0.029)and did not receive neoadjuvant therapy(P < 0.001)were associatedwith longer DFS in patients at early stage.While in multivariate analysis,TNMstaging(P < 0.001),the cycles of adjuvant chemotherapy(P < 0.001)and theneoadjuvant therapy(P < 0.001)were the independent prognostic factors for DFS.However,the PFS for patients at advanced stage were associated with tumormetastasis(P= 0.049),PS(P= 0.043),first-line chemotherapy regimen(P=0.020),and radiotherapy(P=0.004)in univariate analysis,while radiotherapy(P=0.014)was found to be an independent prognostic factor for PFS.Conclusion 1.Pulmonary LELC is a special subtype of NSCLC,with distinctive regional andethnic characteristics.Straightly,it is susceptible to young non-smoking Asian withno obvious clinical manifestations.2.Pulmonary LELC has a lower driver gene mutation rate,but the expression of PD-L1 in patients with pulmonary LELC is higher than non-LELC NSCLC.3.Complete resection is recommended to patients with pulmonary LELC at earlystage,while the multimodality therapy including chemotherapy and radiotherapyare mainstay treatment for patients at advanced stage.This study suggests thatGemcitabine combined with platinum is recommended as the preferred first-linechemotherapy regimen.4.Pulmonary LELC patients had a better prognosis.Tumor staging,the cycle ofadjuvant chemotherapy,and neoadjuvant therapy are independent prognosticfactors for DFS patients at early stage,and radiotherapy is independent prognosticfactors for PFS patients at advanced stage.