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      Clinicopathological characteristics and prognostic factors of pulmonary large cell neuroendocrine carcinoma: A large population‐based analysis

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          Abstract

          Background

          The study was conducted to compare the clinicopathological characteristics, survival outcomes, and metastatic patterns between pulmonary large cell neuroendocrine carcinoma (LCNEC) and other non‐small cell lung cancer (ONSCLC), and to identify the prognostic factors of LCNEC.

          Methods

          Data of patients diagnosed with LCNEC and ONSCLC from 2004 to 2014 were obtained from the Surveillance, Epidemiology, and End Results dataset. Pearson’s chi‐square tests were used to compare differences in clinicopathological characteristics. The Kaplan–Meier method was used for survival analysis. A propensity score was used for matching and a Cox proportional hazards model was used for multivariate and subgroup analyses.

          Results

          A total of 2368 LCNEC cases and 231 672 ONSCLC cases were identified. LCNEC incidence increased slightly over time. Except for marital status, LCNEC patients had obviously different biological features to ONSCLC patients. Survival analysis showed that LCNEC had poorer outcomes than ONSCLC. Multivariate analysis revealed that female gender, black race, surgery, radiation, and chemotherapy were protective factors for LCNEC. Matched subgroup analysis further demonstrated that most subgroup factors favored ONSCLC, especially in early stage. Early‐stage LCNEC patients had a higher risk of lung cancer‐specific death than early‐stage ONSCLC patients. Moreover, metastatic patterns were different between LCNEC and ONSCLC. LCNEC patients with isolated liver metastasis or combined invasion to other organs had poorer survival rates.

          Conclusions

          LCNEC has totally different clinicopathological characteristics and metastatic patterns to ONSCLC. LCNEC also has poorer survival outcomes, primarily because of isolated liver metastasis or combined invasion to other organs. Most subgroup factors are adverse factors for LCNEC.

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          Most cited references27

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          Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cranial Irradiation Overview Collaborative Group.

          Prophylactic cranial irradiation reduces the incidence of brain metastasis in patients with small-cell lung cancer. Whether this treatment, when given to patients in complete remission, improves survival is not known. We performed a meta-analysis to determine whether prophylactic cranial irradiation prolongs survival. We analyzed individual data on 987 patients with small-cell lung cancer in complete remission who took part in seven trials that compared prophylactic cranial irradiation with no prophylactic cranial irradiation. The main end point was survival. The relative risk of death in the treatment group as compared with the control group was 0.84 (95 percent confidence interval, 0.73 to 0.97; P= 0.01), which corresponds to a 5.4 percent increase in the rate of survival at three years (15.3 percent in the control group vs. 20.7 percent in the treatment group). Prophylactic cranial irradiation also increased the rate of disease-free survival (relative risk of recurrence or death, 0.75; 95 percent confidence interval, 0.65 to 0.86; P<0.001) and decreased the cumulative incidence of brain metastasis (relative risk, 0.46; 95 percent confidence interval, 0.38 to 0.57; P<0.001). Larger doses of radiation led to greater decreases in the risk of brain metastasis, according to an analysis of four total doses (8 Gy, 24 to 25 Gy, 30 Gy, and 36 to 40 Gy) (P for trend=0.02), but the effect on survival did not differ significantly according to the dose. We also identified a trend (P=0.01) toward a decrease in the risk of brain metastasis with earlier administration of cranial irradiation after the initiation of induction chemotherapy. Prophylactic cranial irradiation improves both overall survival and disease-free survival among patients with small-cell lung cancer in complete remission.
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            Next-Generation Sequencing of Pulmonary Large Cell Neuroendocrine Carcinoma Reveals Small Cell Carcinoma-like and Non-Small Cell Carcinoma-like Subsets.

            Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a highly aggressive neoplasm, whose biologic relationship to small cell lung carcinoma (SCLC) versus non-SCLC (NSCLC) remains unclear, contributing to uncertainty regarding optimal clinical management. To clarify these relationships, we analyzed genomic alterations in LCNEC compared with other major lung carcinoma types.
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              Pulmonary Large-Cell Neuroendocrine Carcinoma

              Lung neuroendocrine tumors are a heterogeneous subtype of pulmonary cancers representing approximately 20% of all lung cancers, including small-cell lung cancer (SCLC) and large-cell neuroendocrine carcinoma (LCNEC). The frequency appears to be approximately 3% for LCNEC. Diagnosis of LCNEC requires attention to neuroendocrine features by light microscopy and confirmation by immunohistochemical staining for neuroendocrine markers. Both SCLC and pulmonary LCNEC are high-grade and poor-prognosis tumors, with higher incidence in males and smokers and peripheral localization. LCNEC is very rare, and the precise diagnosis on small specimens is very difficult, so we have still too few data to define a standard of treatment for pulmonary LCNECs. Data of literature, most based on retrospective analysis, indicated a poor 5-year overall survival, with a high incidence of recurrence after surgery, even in stage I disease. Primary surgery should be the first option in all operable patients because there is no validate therapeutic approach for LCNEC due to lack of clinical trials in this setting. Neoadjuvant platinum-based regimens remain only an option for potentially resectable tumors. In advanced stages, SCLC-like chemotherapy seems the best option of treatment, with a good response rate but a poor overall survival (from 8 to 16 months in different case series). New agents are under clinical investigation to improve LCNEC patients’ outcome. We reviewed all data on treatment options feasible for pulmonary LCNEC, both for localized and extensive disease.
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                Author and article information

                Contributors
                sunjg09@aliyun.com
                Journal
                Thorac Cancer
                Thorac Cancer
                10.1111/(ISSN)1759-7714
                TCA
                Thoracic Cancer
                John Wiley & Sons Australia, Ltd (Melbourne )
                1759-7706
                1759-7714
                07 February 2019
                April 2019
                : 10
                : 4 ( doiID: 10.1111/tca.2019.10.issue-4 )
                : 751-760
                Affiliations
                [ 1 ] Cancer Institute of People's Liberation Army Xinqiao Hospital, Army Medical University Chongqing China
                [ 2 ] Medical English Department College of Basic Medicine, Army Medical University Chongqing China
                Author notes
                [*] [* ] Correspondence

                Jianguo Sun, Cancer Institute of People's Liberation Army, Xinqiao Hospital, Army Medical University, Chongqing 400037, China.

                Tel: +86 23 6877 4490

                Fax: +86 23 6877 4631

                Email: sunjg09@ 123456aliyun.com

                [†]

                These authors contributed equally to this work and should be considered co‐first authors.

                Author information
                https://orcid.org/0000-0001-5499-4803
                https://orcid.org/0000-0001-5214-6413
                Article
                TCA12993
                10.1111/1759-7714.12993
                6449250
                30734490
                4d9dbafc-9fc5-4511-85bd-f0b7ca2087f1
                © 2019 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 25 November 2018
                : 06 January 2019
                : 07 January 2019
                Page count
                Figures: 4, Tables: 3, Pages: 10, Words: 5676
                Funding
                Funded by: National Natural Science Foundation of China
                Award ID: 81773245
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                tca12993
                April 2019
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.2.1 mode:remove_FC converted:04.04.2019

                clinicopathological characteristic,metastasis,prognostic factor,pulmonary large cell neuroendocrine carcinoma,seer

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