Retrospective Analysis Of The Clinicopathological And Molecular Characteristics Of Primary Lung Mucinous Adenocarcinoma

Research objectives:Primary invasive mucinous adenocarcinoma is an uncommon variant of lung adenocarcinoma with specific clinicopathological and molecular characteristics.A retrospective analysis of clinical pathological data was done in118 cases of primary pulmonary mucinous adenocarcinoma patients in Qilu Hospital of Shandong University from August 2005 to May 2019 who underwent biopsy or surgery.Factors which might affect prognosis was explored by survival analysis.The goal of our study was to better define the clinical,pathologica and genetic characteristics of invasive mucinous adenocarcinoma and provide a basis for future individulized treatment decisions.Methods:118 consecutive patients diagnosed as primary invasive mucinoius adenocarcinoma were retieved from Qilu Hospital of Shandong Unviersity from the year 2005 to 2019.These cases were then divided into two cohorts from Jan 1st,2014,since then ALK protein was routinely detected for all patinets with lung adenocarcinoma,cohort 1(60 patients,pre-ALK)and cohort 2(58 patients,post-ALK).They underwent surgery or needle biopsy and diagnosed as mucin producing adenocarcinoma(MPA)in cohort 1 based on 2004 WHO lung cancer classification or primary invasive mucinous adenocarcinoma(PIMA)in cohort 2 based on 2011 IASLC and 2015 WHO lung cancer classification.Clinical,pathological and imaging characteristics were retrieved and correlated with survival in cohort 1,the cut-off date of last follow-up was July 31st,2020.ALK fusion protein was detected by immunohistochemisty in cohort 2.Correlation of ALK protein expression with mucinous adenocarcinoma and mixed mucinous/non-mucinous adenocarcinoma,other non-mucinous subtypes were explored.GraphPad Prism.5 and SPSS 22.0 software were used and the comparative analysis was done with Chi-square tes.Log-rank test and cox-regression analsis were used to explore the factors that predicted the survival.Results:1.Combined analysis of two cohorts:there were118 patients in the two cohorts,with 60 males(50.8%)and 58 females(49.2%).The average age is 56.4 years and most of them were non-smokers(70.3%).Nearly half of the cases(49.2%)were asymptomatic and more patients were diagnosed asymptomatic in cohort 2 than cohort 1(62.1%vs 36.7%,p=0.0354).The other half patients developed the non-specific symptoms,such as dry cough(12.7%),white and sticky sputum(12.7%),chest tightness(11.9%),hemotysis(10.1%)and other symptoms related to distant metastasis(3.4%).In this combined cohort of primary mucinous adenocarcinoma,more cases were stage ?(38.1%)and stage ?(24.6%)than stage ?(23.7%)and?(13.6%).Cohort 2 has more stage ? and ? patients than cohort 1(74.2%vs 51.7%)?Twenty-nine patients in cohort 1 were tested for tumor markers,the sensitivity of elevated plasma CEA level was 69.0%,followed by elevated CYFRA21-1(31.0%)and CA19-9(24.1%).The lesions were more likely to be right-sided(67.8%),peripheral(89.8%)and nodular(93.2%)on chest computer tomography.By contrast,much less lesions were seen on left-sided(32.2%),central(7.6%)and solid pattern(4.4%).High positive rate of TTF-1(77.3%)and CK7(90%)protein expression,together with low expression of CK20(11.1%)and CDX2(10.0%)might help to differentially diagnose the primary and secondary mucinous adenocarcinoma.In cohort 2,mixed mucinous/non-mucinous adenocarcinoma was more likely to develop lymph node metastasis than pure mucinous adenocarcinoma(44.4%vs 25.8%,p=0.03).2.In cohort 1,Univariant survival analysis showed that females(p=0.0301)?without lymphnode metastasis(p=0.0017)?no distant metastasis(p=0.0004))?early TNM stage(p<0.0001)correlated with better survival?In multivariant analysis,tumor staging was the only significant factor that predicted survival(p<0.001).3.During the same period of cohort 2,1817 patients were diagnosed as adenocarcinoma derived from the electrinic registry system and 58 cases(3.2%)were classificated as primary invasive mucinous adenocarcinoma.All cases were routinely tested for ALK protein expression,and 11 cases(19.0%)were ALK positive in cohort 2.No significant difference of ALK protein expression could be seen between pure mucinous adenocarcinoma and mixed mucinous/non-mucinous adenocarcinoma(16.1%vs 22.2%,p=0.7389).Both were much higher than the ALK protein expression in other adenocarcinoma subtypes(1.1%,p<0.0001).Furthermore,comparative analysis between ALK positive and negative mucinous adenocarcinoma showed that,there was no significant difference in sex,smoking history,age,tumor location,CT imaging pattern,and also TNM staging.ALK positive PIMA seemed to be inclined to develop lymph node metastasis than ALK negative cases(63.6%vs 27.7%,p=0.069).Conclusion:Primary invasive mucinous adenocarcinoma is an uncommon variant of lung adenocarcinoma.The symptoms were non-specific and nearly half of cases were found by routine physical examination.Both females and males have the same tendency to develop PIMA and it occures moe likely in non-smokers.The lesions were more likely to be right-sided,peripheral and nodular on chest computer tomography.Positive TTF-1and CK7 protein expression,together with negative expression of CK20 and CDX2 might help to differentially diagnose the primary and secondary mucinous adenocarcinoma.In cohort 2,mixed mucinous/non-mucinous adenocarcinoma was more likely to develop lymph node metastasis than pure mucinous adenocarcinoma(44.4%vs 25.8%,p=0.03).Multivariant analysis indicated that distant metastasis was the only factor that predicted the poorer survival.Both pure mucinous adenocarcinoma and mixed mucinous/non-mucinous adenocarcinoma were characterized by higher expression of ALK protein than other subtypes,which would underlie the basis for further individulized therapy.