Incidence, survival comparison, and novel prognostic evaluation approaches for stage iii-iv pulmonary large cell neuroendocrine carcinoma and small cell lung cancer

Abstract

Background: Pulmonary large cell neuroendocrine carcinoma (LCNEC) and small cell lung cancer (SCLC) are two types of high-grade neuroendocrine carcinomas of the lung with poor prognosis. LCNEC has not been thoroughly studied due to its rarity, data are also lacking regarding the survival comparison and prognosis analysis of patients with locally advanced or metastatic LCNEC and SCLC.

Methods: Data of patients with LCNEC, SCLC, and other NSCLC who were diagnosed from 1975 to 2019 were extracted from the Surveillance, Epidemiology and End Results (SEER) database to estimate incidence. Those in stage III-IV and being diagnosed from 2010 to 2015 were utilized further to investigate their clinical characteristics and prognosis. Propensity score matching (PSM) analyses at a ratio of 1:2 was used to compare their survival outcomes. Nomograms of LCNEC and SCLC were established with internal validation, and the nomogram of SCLC was externally validated by 349 patients diagnosed in Cancer hospital, Chinese Academy of Medical Sciences & Peking Union Medical College from January 1, 2012 to December 31, 2018.

Results: The incidence of LCNEC has been increasing in recent decades, meanwhile that of SCLC and other types of NSCLC were decreasing. A total of 91,635 lung cancer patients, including 785 with LCNEC, 15,776 with SCLC, and 75,074 with other NSCLC were enrolled for further analysis. The survival of stage III-IV LCNEC resembles that of SCLC, and significantly worse than other types of NSCLC before and after PSM analysis. In pretreatment prognostic analysis, age, T stage, N stage, M stage, bone metastasis, liver metastasis, and brain metastasis were found to be associated with the survival of both LCNEC and SCLC, besides sex, bilaterality, and lung metastasis were additional prognostic factors for SCLC. Two nomograms and convenient online tools respectively for LCNEC and SCLC were established accordingly with favorable predicting accuracy of < 1-year, < 2-year, < 3-year survival probabilities. In external validation of the SCLC nomogram with a Chinese cohort, the AUCs of 1-year, 2-year and 3-year ROC were 0.652, 0.669, and 0.750, respectively. All the results of 1-, 2-, 3- year variable-dependent ROC curves verified the superior prognostic value of our nomograms for LCNEC and SCLC over the traditional T/N/M staging system.

Conclusions: Based on large sample-based cohort, we compared the epidemiological trends and survival outcomes between locally advanced or metastatic LCNEC, SCLC, and other NSCLC. Furthermore, two prognostic evaluation approaches respectively for LCNEC and SCLC might present as practical tools for clinicians to predict the survival outcome of these patients and facilitate risk stratification.

Keywords: High-grade neuroendocrine carcinomas; Lung cancer; Pulmonary large cell neuroendocrine carcinoma; SEER database; Small cell lung cancer.

Fig. 1

Study flow diagram. Abbreviation: LCNEC, large cell neuroendocrine carcinoma; SCLC, small cell lung cancer; NSCLC, non-small cell lung cancer; OS, overall survival; SEER, the Surveillance Epidemiology and End Results; PSM, propensity score matching

Fig. 2

Annual age-adjusted incidence of lung cancer, LCNEC, SCLC, and other types of NSCLC. Abbreviation: LCNEC, large cell neuroendocrine carcinoma; SCLC, small cell lung cancer; NSCLC, non-small cell lung cancer; OS, overall survival

Fig. 3

The comparison of clinical characteristics of stage III-IV LCNEC, SCLC, and other types of NSCLC. a the proportion of different subtypes of lung cancer. b K-M curves of different histologies of lung cancer. c metastatic pattern. d treatment strategies. Abbreviation: LCNEC, large cell neuroendocrine carcinoma; ADC, adenocarcinoma; SCC, squamous cell carcinoma; LCC, NOS, large cell carcinoma, not otherwise specified; SCLC, small cell lung cancer; NSCLC: non-small cell lung cancer

Fig. 4

Comparison of overall survival before and after propensity score matching (PSM) analysis. a LCNEC and SCLC before PSM. b LCNEC and SCLC after PSM. c LCNEC and other NSCLC before PSM. d LCNEC and other NSCLC after PSM. Abbreviation: LCNEC, large cell neuroendocrine carcinoma; SCLC, small cell lung cancer; NSCLC, non-small cell lung cancer; OS, overall survival; PSM, propensity score matching

Fig. 5

The nomograms and risk stratification of stage III-IV LCNEC and SCLC. a nomogram of LCNEC. b risk stratification of LCNEC. c nomogram of SCLC. d risk stratification of SCLC. *The cut-off point for risk stratification of LCNEC was 168 calculated by the nomogram. The cut-off point for risk stratification of SCLC was 195. Abbreviation: LCNEC, large cell neuroendocrine carcinoma; SCLC, small cell lung cancer

Fig. 6

The 1-year, 2-year, and 3-year calibration plots of the training cohort and of LCNEC (a-c) and SCLC (d-f). Abbreviation: LCNEC, large cell neuroendocrine carcinoma; SCLC, small cell lung cancer

Fig. 7

The 1-year, 2-year, and 3-year ROC curves of the training cohort and internal validation cohort of LCNEC (a-b) and SCLC (c-d), and the external validation cohort of SCLC (e). Abbreviation: ROC, receiver operating characteristic; AUC, area under the curve; LCNEC, large cell neuroendocrine carcinoma; SCLC, small cell lung cancer

Fig. 8

The 3-year variable-dependent ROC curves of the training cohort and internal validation cohort of LCNEC (a-b) and SCLC (c-d), and the external validation cohort of SCLC (e). Abbreviation: ROC, receiver operating characteristic; AUC, area under the curve; LCNEC, large cell neuroendocrine carcinoma; SCLC, small cell lung cancer

Fig. 9

The DCA plots of the training cohort and validation cohort of LCNEC (a-b) and SCLC (c-d), and the external validation cohort of SCLC (e). Abbreviation: DCA, decision curve analysis; LCNEC, large cell neuroendocrine carcinoma; SCLC, small cell lung cancer. Note: “All” refers to intervention for all, and “None” refers to intervention for none. Intervention is considered to be any behavioral or external factor considered by high-risk patients when obtaining positive results from the model