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Background: Combined small-cell lung cancer (CSCLC) refers to the simultaneous presence of small cell lung cancer (SCLC) and any subtype of the non-small cell lung cancer (NSCLC). This study aimed to explore the prognosis of CSCLC, NSCLC, and pure SCLC patients, and to develop a nomogram to estimate the overall survival (OS) for CSCLC patients., Methods: Patients diagnosed with NSCLC, CSCLC, and pure SCLC between 2004 and 2015 were identified from the Surveillance Epidemiology and End Results (SEER) database. Survival analyses were performed by using the Kaplan Meier curves and Cox proportional hazards regression. All CSCLC patients were randomly split 7:3 into training and validation sets. A nomogram was developed by integrating all independent predictors for OS. The performance of the nomogram was determined by discrimination, calibration ability, clinical usefulness, and risk stratification ability., Results: A total of 326,695 lung cancer patients, including 871 with CSCLC, 280,391 with NSCLC, and 45,433 with pure SCLC were enrolled. CSCLC was associated with worse survival compared with NSCLC both in the unmatched and matched cohorts. However, compared to pure SCLC, CSCLC was associated with significantly better survival in the unmatched cohorts only, while showed marginally non-significantly better survival after propensity score matching (PSM). For CSCLC, a nomogram was constructed for the 6-month, 1-year, and 3-year OS prediction by combining the independent risk factors, including age, gender, tumor, node, and metastasis stage, surgery, and chemotherapy. The nomogram showed good discrimination and calibration both in the training and validation sets, and better performance than the tumor-node-metastasis staging system. Risk stratification analysis indicated that the nomogram scores efficiently divided CSCLC patients into low-, intermediate-, and high-risk groups (P < 0.001)., Conclusions: CSCLC patients presented a significantly worse prognosis than patients with NSCLC, but comparable prognosis when compared with pure SCLC patients in the matched cohorts. In addition, we developed and validated a nomogram for predicting the 6-month, 1-year, and 3-year OS in CSCLC patients., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/tlcr-21-804). The authors have no conflicts of interest to declare., (2021 Translational Lung Cancer Research. All rights reserved.)

Background: Combined small cell lung cancer (CSCLC) is an uncommon and heterogeneous subtype of small cell lung cancer (SCLC). However, there is limited data concerning the different molecular changes and clinical features in CSCLC compared to pure SCLC., Methods: The clinical and pathological characteristics of pure SCLC and CSCLC patients were analyzed. Immunohistochemistry and microdissection were performed to isolate the CSCLC components. Further molecular analysis was carried out by next-generation sequencing (NGS) in 12 CSCLC and 30 pure SCLC., Results: There were no significant differences in clinical features between CSCLC and pure SCLC. Overall survival (OS) of CSCLC patients was worse than pure SCLC (P=0.005). NGS results indicated that TP53 and RB1 were the most frequently mutated genes in both CSCLC (83.33% and 66.67%) and pure SCLC (80.00% and 63.33%) groups. However, less than 10% common mutations were found in both CSCLC and pure SCLC. When analyzing the data of SCLC and non-small cell lung cancer (NSCLC) components of CSCLC, more than 50% common mutations, and identical genes with mutations were detected. Moreover, there were also common biological processes and signaling pathways identified in CSCLC and pure SCLC, in addition to SCLC and NSCLC components., Conclusions: There were no significant differences in terms of clinical features between CSCLC and pure SCLC. However, the prognosis for CSCLC was worse than pure SCLC. NGS analysis suggested that CSCLC components might derive from the same pluripotent single clone with common initial molecular alterations and subsequent acquisitions of other genetic mutations., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037tlcr-20-1099). Dr. JM serves as an unpaid editorial board member of Translational Lung Cancer Research from Aug 2019 to Aug 2021. The authors have no other conflicts of interest to declare., (2021 Translational Lung Cancer Research. All rights reserved.)

Background: Combined small cell lung cancer (CSCLC) is a subtype of small cell lung cancer (SCLC) which contains both components of SCLC and non-small cell lung cancer (NSCLC). The prognostic outcomes and treatment strategy of it are still unclear. A large-scale retrospective study was performed to investigate proper treatments for CSCLC., Methods: All cases of CSCLC were identified from the SEER database during the period of 2004-2016. Clinical characteristics, first-line treatments, surgical procedures and survival data including overall survival (OS) and cancer-specific survival (CSS) were analyzed., Results: A total of 37,639 SCLC patients were identified. CSCLC accounted for 2.1% (784/37,639). The mean age of CSCLC cohort is 67.3±9.9 years old. Male and white ethnicity patients were accounted for larger proportions (55.7% and 80.4%). The oncological characteristics of CSCLC were consistent with SCLC that most of patients were diagnosed as higher grade and advanced stages. The prognosis of CSCLC was better than SCLC but worse than NSCLC in IA-IIIA stages. No difference was observed in IIIB-IV. Surgery was beneficial in IA-IB stage CSCLC. Adjuvant chemotherapy seemed to have few effects on early stage patients. Trimodality treatment could significantly improve OS in IIA-IIIA CSCLC patients. Chemotherapy-based treatment is predominant choice in advanced stage patients., Conclusions: CSCLC is a rare and special subtype of SCLC. It has better survival outcome than non-CSCLC in early stage. Surgical treatment is crucial in early stage of CSCLC. Prognostic improvement might be achieved from trimodality treatment in stage IIA-IIIA. Chemotherapy-based treatments should be considered in advanced stage. The effect of surgical treatments in advanced stage patients should be further investigated., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-20-437). The authors have no conflicts of interest to declare., (2020 Translational Lung Cancer Research. All rights reserved.)