Development And Validation Of A Novel Prognostic Model For Patients With Atypical Bronchopulmonary Carcinoid Tumor Based On Real-world Data

Background:Atypical bronchopulmonary carcinoid is a rare lung cancer and a kind of well-differentiated neuroendocrine tumor,accounting for about 10%of lung carcinoids and less than 1%of all lung cancers.In recent years,the incidence of atypical carcinoids(ACs)continues to rise.Due to the rarity of cases,the epidemiological characteristics,biobehavioral characteristics,clinicopathological characteristics,treatment information and outcome information of ACs are very scarce.The existing clinical studies are mostly based on small-scale single-center cohorts,and the findings of these studies lack evidence support from clinical big data.According to the pathological classification of lung carcinoids by WHO,ACs refer to 2-10 mitoses per 2 mm2 visual field,with or without necrosis.Compared with typical carcinoids,ACs of the lung are more aggressive malignancies with poorer prognosis.Surgical resection remains the preferred treatment option for patients with limited-stage disease if lung function meets the conditions.At present,the choice of surgical methods for atypical lung carcinoid tumors is still controversial.Real-world clinical studies with a large sample size are urgently needed to evaluate the differences in perioperative complications,long-term survival rates and disease recurrence rates among different surgical methods,and provide reliable evidence for clinical decisions.There is currently no specific prognostic method for lung AC tumors in clinical practice.The eighth edition of the AJCC TNM staging system is mainly established by common pathological types such as lung adenocarcinoma and lung squamous cell carcinoma,while lung AC have different clinicopathological characteristics with these common pathological types.In addition,the AJCC TNM staging system does not involve some potential prognostic factors such as age,primary tumor site,and lymph node clearance situation,which makes it difficult to accurately evaluate the prognosis of patients with AC.This study aimed to systematically evaluate the clinicopathological characteristics of AC and the impact of different surgical methods on prognosis based on a large-scale cohort of lung AC patients,and to construct a novel prognostic prediction model to guide clinical decision.Materials and methods:In this study,clinical data of 507 and 56 patients who underwent surgical resection from 2001 to 2016 and were diagnosed as bronchopulmonary ACs by surgical pathology were collected from SEER database and the medical record system of Shandong Provincial Hospital,respectively.The clinical data of these AC patients we extracted included clinicopathological data,treatment and prognostic information.Kaplan-Merier survival analysis and univariate COX regression analysis were used to assess the potential effect of various factors,including age,gender,marital status,primary tumor site,maximum tumor diameter,TNM stage,surgical method,lymph node biopsy situation,radiotherapy and chemotherapy,on the overall survival(OS)and lung cancer specific survival(LCSS)of lung AC patients based on a cohort of 507 patients from SEER database.The cases with missing information on statistically significant prognostic factors were further excluded,and finally a cohort consisting of 464 patients with atypical lung carcinoid tumors were obtained for multivariate COX regression analysis and applied as the development cohort of the novel nomogram prognostic prediction model for this study.Based on the independent prognostic factors obtained from the multivariate COX proportional hazards model analysis,a nomogram prognostic model for predicting-the 3-year,5-year and 10-year survival rates of lung AC patients was constructed in the training cohort using R language.And Harrell Concordance Index(C-index),calibration curve and decision curve analysis(DCA)were used to evaluate the predictive accuracy and clinical applicability of the new model,respectively.The Integrated Improvement Index(IDI)was applied to compare the prognostic evaluation ability of the new model with the 8th edition of AJCC TNM staging system in patients with lung AC,and the significance was tested using the z-test.The predictive accuracy and clinical applicability of the newly constructed prognostic model were externally validated by an external validation cohort consisting of 56 patients with AC tumors from Shandong Provincial Hospital.The patients’ prognostic indices were calculated according to the risk coefficients of independent prognostic factors in the novel prognostic model.Results:In the cohort of 507 AC patients extracted from SEER database,the 1-year,3-year,5-year,and 10-year OS rates were 95.6%,85.2%,75.8%,and 59.0%,respectively.The 1-year,3-year,5-year,and 10-year LCSS rates were 97.0%,89.2%,80.2%,and 66.8%,respectively.Kaplan-Merier survival analysis and univariate COX regression analysis showed that older age,tumor diameter greater than 2.75 cm,distant metastasis,lymph node invasion,pneumonectomy,wedge resection and postoperative radiotherapy were closely related to poor prognosis of AC patients(p<0.05).Lobectomy,segmentectomy,and lymph node biopsy were found to be protective factors for AC patients(p<0.05).The results of multivariate COX analysis showed that age,maximum tumor diameter,N stage,M stage,surgical method and lymph node biopsy were independent prognostic factors for patients with lung AC(p<0.05),and were further included as prognostic factors in the new model.The nomogram of novel prognostic evaluation model revealed that surgical method has the highest influence on the prognostic evaluation.In the training cohort,the C-Index of the nomogram model for predicting 3-year,5-year,and 10-year OS was 0.722(95%CI:0.647-0.797,p<0.001),0.737(95%CI:0.675-0.799,p<0.001)and 0.712(95%CI:0.654-0.771,p<0.001);in the external validation cohort,the concordance index for predicting 3-,5-,and 10-year overall survival in patients was 0.714,respectively(95%CI:0.576-0.852,p<0.01),0.738(95%CI:0.607-0.869,p<0.01),and 0.729(95%CI:0.595-0.864,p<0.01).Both calibration curves for the training cohort and the validation cohort showed that the novel prognostic model predicted patient OS in excellent agreement with actual survival.The DCA curve comparison results of the new prognostic model and the 8th edition of the AJCC TNM staging system suggested that the new model significantly improved the clinical applicability and reliability of predicting the prognosis of AC patients.An online webserver was built based on the proposed nomogram for convenient clinical use.Conclusion:This study comprehensively analyzed the epidemiological and clinicopathological characteristics of bronchopulmonary AC tumors based on large-sample real-world data.The findings confirmed that AC tumors of the lung had unique clinical and prognostic features,and the surgical approach,as an independent prognostic factor,was an important indicator for evaluating the prognosis of patients.Lobectomy and segmentectomy significantly prolonged patients’ survival compared with pneumonectomy and wedge resection.Compared with the eighth edition AJCC TNM staging system for lung cancer,the new prognostic prediction model constructed by independent prognostic factors has higher accuracy,reliability and clinical applicability,which hopefully provided guiding information for clinical treatment decisions and long-term follow-up of patients with atypical lung carcinoid tumors.