Combined Small Cell Lung Research Articles

Combined small cell lung carcinoma harboring ALK rearrangement: A case report and literature review

Combined small cell lung cancer (c‐SCLC) is a relatively rare subtype of SCLC and is defined by the combination of SCLC and any elements of non‐small cell carcinoma (NSCLC). Standard chemotherapy for patients with c‐SCLC has not yet been established. Gene mutations such as epidermal growth factor receptor (EGFR) mutations may be detected in patients with c‐SCLC. However, little is known about anaplastic lymphoma kinase (ALK) rearrangement in c‐SCLC patients. Here, we report a young female patient who was successfully treated with alectinib for ALK‐positive c‐SCLC after failure of immunochemotherapy for SCLC and cytotoxic chemotherapy for adenocarcinoma. Moreover, we performed a literature review of EGFR‐ or ALK‐positive c‐SCLC patients. Our report suggests that ALK testing may be justified in patients with SCLC that contain an adenocarcinoma component.Key pointsSignificant findings of the study• This is the first report describing the treatment course comprising immunochemotherapy and ALK‐TKI in a patient with c‐SCLC harboring ALK rearrangement.What this study adds• Our case and literature review suggest that although ALK mutation is rare in patients with c‐SCLC, its identification and treatment with ALK‐TKIs may contribute to clinical benefits.

Treatments for combined small cell lung cancer patients.

BackgroundCombined 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.MethodsAll 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.ResultsA 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.ConclusionsCSCLC 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.

1789P Fewer liver and lymph node metastases may contribute to survival benefits for patients with c-SCLC compared with SCLC

This study was mainly aimed to evaluate clinicopathological characteristics and prognosis differences between patients with combined small cell lung cancer (c-SCLC) and small cell lung cancer (SCLC). We screened a total of 400 patients diagnosed with c-SCLC and 20841 patients with SCLC between 2010 and 2015 from SEER database. The chi-square test was used to compare patient baseline characteristics differences between c-SCLC and SCLC. Propensity Score Matching (PSM) was used to eliminate any bias between patients with c-SCLC and SCLC. Logistic regression was used to identify independent risk factors for c-SCLC and SCLC patients. In addition, univariate and multivariate Cox proportional hazards regression models were used to analyze the influence of different variables on overall survival (OS). Our result revealed that the OS of c-SCLC patients was significantly better than that patients with SCLC before PSM (P < 0.001). Further multivariable analysis showed that liver metastasis (HR: 1.218; 95% CI: 0.858-1.729; P = 0.269) and lung metastasis (HR: 1.057; 95% CI: 0.729-1.534; P = 0.768) were not significant and independent factors on c-SCLC patients’ survival. Then, we conducted PSM to eliminate bias between patients with c-SCLC and SCLC. However, the result showed that there was no significant difference on OS between c-SCLC and SCLC patients after PSM (P = 0.789). Multivariate logistic regression analysis revealed that the risk of N metastasis (OR: 0.555; 95% CI: 0.439-0.703; P < 0.001) and liver metastasis (OR: 0.591; 95% CI: 0.448-0.779; P < 0.001) was lower for c-SCLC patients compared with SCLC patients. C-SCLC patients’ prognosis was better than that of SCLC patients, which may be due to fewer liver and lymph node metastases at the time of diagnosis. However, if we limited the clinical variables, there was no difference in survival between c-SCLC and SCLC patients.

Prognostic factors, treatment, and outcomes in combined small cell lung cancer: a SEER survey from 2004 to 2015.

BackgroundThe epidemiological characteristics of combined small cell lung cancer (C-SCLC) are still unclear. Therefore, in this study, we aimed to investigate the prognostic factors and treatment modalities for C-SCLC.MethodsThe clinical data from patients with primary C-SCLC from 2004 to 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Next, we applied the 8th edition of the TNM classification. A Cox regression model was used to identify the relevant variables and treatment modalities which affected the overall survival (OS) and cancer-specific survival (CSS).ResultsIn total, 1,010 patients were included in the analysis. The median OS and median CSS were 9 months and 10 months, respectively. Individuals aged 65 and younger, female, and classified as being in an earlier stage were independent predictors of an improved OS and CSS. For patients with stage I, surgery alone significantly improved the OS (HR, 0.371; 95% CI, 0.180–0.769) and CSS (HR, 0.367; 95% CI, 0.162–0.892). For patients with stage II, surgery combined with radiotherapy significantly improved the OS (HR, 0.237; 95% CI, 0.063–0.890). For patients with stage III, radiotherapy alone was an independent predictor of OS (HR, 0.464; 95% CI, 0.316–0.618) and CSS (HR, 0.452; 95% CI, 0.305–0.670). For patients with stage IV, surgery combined with radiotherapy significantly improved OS (HR, 0.315; 95% CI, 0.181–0.547) and CSS (HR, 0.329; 95% CI, 0.189–0.573), and surgery alone also improved OS (HR, 0.257; 95% CI, 0.144–0.461) and CSS (HR, 0.280; 95% CI, 0.156–0.501). Undergoing chemotherapy was also an independent predictor of an improved OS (HR, 0.619; 95% CI, 0.419–0.915) in patients with stage III, and OS (HR, 0.283; 95% CI, 0.228–0.350) and CSS (HR, 0.289; 95% CI, 0.232–0.259) of patients with stage IV.ConclusionsThese findings may help to determine possible treatment choices and aid further research on this rare disease.

Analysis of Pulmonary Microbial Diversity in Patients with Advanced Lung Cancer Based on High-throughput Sequencing Technology

背景与目的肺部微生物组与肺部疾病的发生密切相关，微生物可从多方面促进肿瘤的发生与发展。既往研究证实肺癌患者肺部微生物组较健康人发生了变化，但关于不同类型肺癌患者中肺部微生物组的微生物组成尚未明确。本研究旨在探讨不同组织学类型肺癌间的微生物组相关性及差异性。方法采用Illumina HiSeq高通量测序技术对晚期肺癌患者痰样本进行细菌V3-V4区的16S rDNA测序及生物信息学分析。结果经物种分类分析发现肺癌患者痰样本中以链球菌属、奈瑟氏菌属、普雷沃氏菌属为主。腺癌（adenocarcinoma, AD）组以链球菌属及奈瑟氏菌属为主，小细胞肺癌（small cell lung cancer, SCLC）组以奈瑟氏菌属为主，鳞状细胞癌（squamous cell carcinoma, SCC）组以链球菌属为主，混合型小细胞肺癌（combined small cell lung cancer, C-SCLC）组以链球菌属为主。结论不同组织学类型肺癌的肺部细菌微生物组结构及组成存在差异性，不同组织学类型肺癌间优势菌群有所不同，本研究丰富了肺癌肺部细菌微生物组学数据。

Clinical characteristics and prognostic factors of surgically resected combined small cell lung cancer: a retrospective study

ObjectivesSmall cell lung cancer (SCLC) is the most malignant lung cancer. Some of them are mixed with non-small cell lung cancer(NSCLC, Non SCLC),which are called combined small cell lung cancer (C-SCLC).Due to the difficulty of pathological diagnosis and the complexity of treatment, studies of C-SCLC have just been rising in recent years. This study is to evaluate the clinical and pathologic characteristics of C-SCLC. MethodsStage Ⅰ-Ⅲa C-SCLC patients who received radical R0 surgery between 2009–2018 in Shanghai Chest Hospital were enrolled. Clinical characteristics and prognosis were analyzed. ResultsTotally 181 patients were included, most of them were small cell combined with large cell neuroendocrine components(SCLC/LCNEC,58.0 %,N = 105),then with adenocarcinoma(SCLC/ADC:13.8 %,N = 25),and finally with squamous cell carcinoma(SCLC/SCC:13.3 %,N = 24).Median DFS and OS of C-SCLC patients underwent radical surgery were 32.5 and 49.7 months.1,3 and 5 years DFS rates of the entire cohort were 68.5 %,32.6 % and 16.0 %,respectively. Patients with SCLC/LCNEC had longer DFS (44.1 m vs. 20.4 m, p = 0.040) and longer OS trend (62.1 m vs. 33.2 m, p = 0.122).Groups of whether tumor invaded the pleura(p = 0.028 and p = 0.050),lymph node stage(p = 0.029 and p = 0.010) and the courses of adjuvant chemotherapy(p = 0.011 and p = 0.001) had statistical differences on DFS and OS. ConclusionsSCLC/LCNEC was the most common type of C-SCLC. Patients' DFS and OS were also longer than other combined types. Adjuvant chemotherapy for SCLC is still the main treatment for surgical C-SCLC. Further studies are needed to clarify the clinical characteristics and prognosis of C-SCLC.

Primary tumor standardized uptake value (SUVmax) measured on 18F-FDG PET/CT and mixed NSCLC components predict survival in surgical-resected combined small-cell lung cancer

PurposeThe combined small-cell lung cancer (c-SCLC) is rare and has unique clinicopathological futures. The aim of this study is to investigate 18F-FDG PET/CT parameters and clinicopathological factors that influence the prognosis of c-SCLC.MethodsBetween November 2005 and October 2014, surgical-resected tumor samples from c-SCLC patients who received preoperative 18F-FDG PET/CT examination were retrospectively reviewed. The maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were used to evaluate metabolic parameters in primary tumors. The survivals were evaluated with the Kaplan–Meier method. Univariate and multivariate analyses were used to evaluate potential prognostic factors.ResultsThirty-one patients were enrolled, with a median age of 62 (range: 35 − 79) years. The most common mixed component was squamous cell carcinoma (SCC, n = 12), followed by large-cell carcinoma (LCC, n = 7), adenocarcinoma (AC, n = 6), spindle cell carcinoma (n = 4), adenosquamous carcinoma (n = 1) and atypical carcinoid (n = 1). The median follow-up period was 53.0 (11.0–142.0) months; the 5-year overall survival (OS) and progression-free survival(PFS) rate were 48.4% and 35.5%, respectively. Univariate survival analysis showed that gender, smoking history, tumor location were associated with PFS (P = 0.036, P = 0.043, P = 0.048), SUVmax and TNM stage were closely related to PFS in both Mixed SCC and non-SCC component groups (P = 0.007, P = 0.048). SUVmax, smoking history, tumor size and mixed SCC component were influencing factors of OS in patients (P = 0.040, P = 0.041, P = 0.046, P = 0.029). Multivariate survival analysis confirmed that TNM stage (HR = 2.885, 95%CI: 1.323–6.289, P = 0.008) was the most significantly influential factor for PFS. High SUVmax value (HR = 9.338, 95%CI: 2.426–35.938, P = 0.001) and mixed SCC component (HR = 0.155, 95%CI: 0.045–0.530, P = 0.003) were poor predictors for OS.ConclusionSurgical-resected c-SCLCs have a relatively good prognosis. TNM stage is the most significant factor influencing disease progression in surgical-resected c-SCLCs. SUVmax and mixed NSCLC components within c-SCLCs had a considerable influence on the survival. Both high SUVmax and mixed SCC component are poor predictors for patients with c-SCLCs.

EP1.12-09 EGFR-Mutant Adenocarcinoma Transform into Small-Cell Lung Cancer: Real or Not

Small-cell transformation is well known as one of the acquired resistance mechanism to EGFR-tyrosine kinase inhibitors (TKIs), nevertheless we recently found an interesting phenomenon that most small-cell transformations actually are combined small-cell lung cancer before TKI treatments rather than pure adenocarcinoma. We retrieved 13 patients with former pathological diagnosis of adenocarcinoma before TKI therapies from 1,082 cases with SCLC component and compared the previous biopsy results of the these cases. All the previous adenocarcinomas slides were gathered and were reviewed one by one carefully again by an advanced pathologist. All patients were stage IV EGFR-mutant adenocarcinomas and treated with EGFR-TKIs before SCLC transformation diagnosed. After their disease progress, re-biopsy were performed to identify resistance mechanism. Previous pathology showed only one patient was diagnosed with combined SCLC mixed with adenocarcinoma before TKI, the rest 12 cases were pathologically diagnosed of pure adenocarcinoma and identified as small-cell transformation. We amazingly found that 9 of 12 patients actually contained very few SCLC component when we reviewed these cases, varying from less than 1% to 5%. Dubious SCLC components were found in two patients. Only one patient was a real small-cell transformation and we didn’t find any SCLC mixture on previous adenocarcinoma sections. In conclude about 75% (9/12) of cases originally diagnosed with small-cell transformation were actually pseudo-small-cell transformation. Combined SCLC with very few SCLC components were prone to be misdiagnosed into pure adenocarcinoma. Most metastatic lung cancers were diagnosed with small biopsy, in which the potential mixture of SCLC was much more easily to miss, so the pseudo-small-cell transformation may be more common than estimate in real world. It’s worth noting that careful review again of the previous adenocarcinoma sections is essential before diagnosis of small-cell transformation.

Clinicopathological and genomic comparisons between different histologic components in combined small cell lung cancer and non-small cell lung cancer

ObjectiveHistologic transformation from adenocarcinoma to small cell lung cancer (SCLC) is one of the mechanisms of acquired resistance after epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment. Furthermore, de novo combined SCLC/non-small cell lung cancer (NSCLC) have occasionally been reported; however, their mutational statuses and clinicopathological features have not yet been elucidated. In this study, we aimed to profile the genetic backgrounds of these 2 different histologic components by investigating patients with de novo combined SCLC/NSCLC as well as those with lung adenocarcinoma who experienced SCLC transformation after TKI treatment. Materials and methodsFour patients with de novo combined SCLC/NSCLC were investigated, as were 4 other patients with lung adenocarcinoma who experienced SCLC transformation after TKI treatment. The different histologic components of the tumors in each patient were tested for thyroid transcription factor-1, p40, synaptophysin, chromogranin A, p53, retinoblastoma protein (Rb), and achaete-scute homolog 1 (ASCL1) via immunohistochemistry, and were macroscopically dissected for mutational analysis using next-generation sequencing with the Oncomine Focus Assay and Comprehensive Assay panel. ResultsThe distinct histologic components in patients with de novo combined SCLC/NSCLC and those with adenocarcinoma exhibiting small cell transformation showed high consistency in EGFR/TP53/RB1 mutations, and expression patterns of p53 and Rb. A high frequency of activating mutations involving PI3K/AKT1 signaling pathway was observed in SCLC. Nuclear ASCL1 expression was present in SCLC but absent or barely present in adenocarcinoma in 7 cases. ConclusionsOur data imply that inactivation of TP53/RB1 function is a possible early event in the histogenesis of synchronous and metachronous SCLC/NSCLC. Moreover, the non-adenocarcinoma (SCLC) component might arise from the adenocarcinoma (NSCLC) component through a mechanism that involves the activation of the ASCL1 and PI3K/AKT1 signaling pathways.

Abstract 2495: RUNX1T1 is amplified in combined small cell lung cancer

Abstract Small cell lung cancer (SCLC) is a highly aggressive malignancy that expresses neuroendocrine (NE) genes and represents approximately 15% of all lung cancers; the remaining histological subtype is non-small cell lung cancer (NSCLC). Clinically, there are two types of SCLC, termed ‘pure' and ‘combined'. Combined SCLC presents as a mixture of SCLC and NSCLC components within the same tumor mass. We analyzed 88 SCLC patient tumors by targeted exome sequencing and found that four SCLC patients demonstrated RUNX1T1 amplification. Interestingly, among these 88 SCLC patients there were two with combined SCLC and both demonstrated RUNX1T1 amplification only in the small cell component. Neither MYC (8p24) nor FGFR1 (8p11), two genes commonly amplified in SCLC that are nearby the RUNX1T1 locus (8p22), were co-amplified. RUNX1T1, also called ETO or MTG8, was first identified in the oncogenic fusion transcript AML1/ETO in acute myelogenous leukemia (AML) and was previously reported as a transcriptional co-repressor. Based on our observation we hypothesized that: 1) RUNX1T1 may be a specific marker for SCLC and may play a role in determining the SCLC phenotype, including NE expression, and 2) RUNX1T1 may play a role in transforming NSCLC to SCLC in the early stages of combined SCLC tumor formation. First we examined RUNX1T1 mRNA expression among cancer cell lines using the CCLE database and found that RUNX1T1 is highly expressed in SCLC cells compared to other cancer cells, especially NSCLC cells. This was also true in tumors using RNAseq data. Consistent with these mRNA profiles, our western blot results showed higher RUNX1T1 protein expression in SCLC compared to NSCLC cell lines. These findings validate that RUNX1T1 expression is specifically upregulated in SCLC compared to NSCLC. To investigate a role for RUNX1T1 in determining the SCLC phenotype, we overexpressed RUNX1T1 in SCLC cell lines by lentiviral transduction and observed marked growth suppression in H82, H2171, and H841 cells. Conversely, transient knock down of RUNX1T1 expression in the SCLC cell line H446 using siRNA decreased the expression of two NE proteins (NEUROD1 and TTF1). To explore a potential role of RUNX1T1 in NSCLC to SCLC transformation, we overexpressed RUNX1T1 in three NSCLC cell lines (PC-9, H1650 and A549) but observed no obvious phenotypic changes and no increase in NE gene expression. In conclusion, we have demonstrated that RUNX1T1 expression is upregulated in SCLC compared to NSCLC. Moreover, the results from RUNX1T1 overexpression and knockdown experiments in SCLC cell lines indicates a potential role of RUNX1T1 in regulating the SCLC phenotype and NE expression. Citation Format: Tian He, Karen McColl, Alyssa Savadelis, Yanwen Chen, Gary Wildey, Afshin Dowlati. RUNX1T1 is amplified in combined small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2495.

The role of prophylactic cranial irradiation in surgically resected combined small cell lung cancer: a retrospective study.

Combined small cell lung cancer (C-SCLC) is defined as small cell lung cancer (SCLC) combined with any of non-small cell lung cancer (NSCLC) histological types, such as large cell carcinoma, squamous cell carcinoma, or adenocarcinoma. Since C-SCLC is an increasingly recognized subtype of small cell carcinoma, we conducted a retrospective study in our institution to explore the value of prophylactic cranial irradiation (PCI) in patients with C-SCLC treated by surgery. Between 2005 and 2014, the records of all consecutive patients with pathologically diagnosed C-SCLC after surgery in our institution were reviewed. Overall survival (OS), disease-free survival (DFS), and brain metastasis free survival (BMFS) were estimated by Kaplan-Meier method. Survival differences were evaluated by log-rank test, while multivariate analysis was performed by a Cox proportional hazards model. Of the total 91 patients included in this analysis, 11 patients (12.1%) were in PCI group and 80 (87.9%) in non-PCI group. The 5-year cumulative incidence of brain metastasis in the whole group was 22.2% (26.3% in non-PCI group vs. 0% in PCI group), and 5-year OS rate was 44.1%. Patients treated with PCI had significantly longer OS (P=0.011) and DFS (P=0.013), also had the trend to live a longer BMFS with marginal significance (P=0.092) than non-PCI-treated patients. The multivariate analysis showed that PCI [hazard ratio (HR) =0.102, P=0.024] was one of independent prognostic factors of the OS in surgery-treated C-SCLC patients. C-SCLC patients have a relative high risk of developing brain metastases based on our study. These data showed that PCI could improve OS and DFS, as well as tend to decrease brain metastases in surgically resected C-SCLC. However, whether PCI could be part of comprehensive treatment modalities in C-SCLC should be assessed in prospective studies.

Combined small-cell lung carcinoma.

Currently, studies assessing combined small-cell lung carcinoma (C-SCLC) are relatively scarce and limited. Indeed the clinicopathological features, treatment, and prognosis of patients with C-SCLC have not been fully determined. The incidence of C-SCLC ranges from 5%–28% in different studies, which is related to the specimen types used. The clinical features of C-SCLC are characterized by the higher proportion of peripheral locations, earlier stage, and more opportunity to experience surgery. Surgery is more important for earlier stage C-SCLC. There have been no recent changes in the chemotherapy of C-SCLC, which is recommended by the treatment guidelines for SCLC, neither showing survival benefit from the 3-agent regimen. Meanwhile, the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutated C-SCLC patients remains inconclusive. This review focuses on clinical and pathologic features, prognostic factors, and optimized treatment model in C-SCLC.

Correlation between histone acetylation and expression of Notch1 in human lung carcinoma and its possible role in combined small-cell lung carcinoma

Combined small-cell lung carcinoma (cSCLC) is composed of small-cell lung carcinoma (SCLC) admixed with non-small-cell lung carcinoma (NSCLC). Evaluating the molecular differences between SCLC and NSCLC could lead to a better understanding of the pathogenesis of such neoplasms. Therefore, in this study, we investigated the correlation between histone acetylation and Notch1 expression in lung carcinoma. Using chromatin immunoprecipitation (ChIP) assay, we measured the level of acetylated histone H3 around the promoter region of Notch1 in SCLC and NSCLC cells. We then treated SCLC cells with trichostatin A (TSA) and characterized the level of histone H3 acetylation at Notch1. In addition, TSA-treated cells were injected into immune-compromised mice, for analysis of the ex vivo tumor xenograft phenotype. The level of acetylated histone H3 surrounding the Notch1 promoter was lower in lung cancer cells not expressing Notch1. Tumors originated from TSA-treated SCLC cells occasionally formed an epithelial-like glandular arrangement of cells; with Notch1 expression and decreased expression of neuroendocrine (NE) markers. Histone deacetylation around the promoter region of Notch1 inhibits Notch1 protein expression in SCLC and the restoration of Notch1 expression in SCLC leads to the concurrent appearance of epithelial-like areas within the SCLC, which could provide a possible mechanism for histogenesis of cSCLC.

The role of postoperative radiotherapy (PORT) in combined small cell lung cancer (C-SCLC).

PurposeTo explore the value of radiotherapy in C-SCLC patients, especially in those receiving a radical resection.ResultsThe differences of survivals between the postoperative radiotherapy (PORT) and non-PORT groups were not statistically significant. But analyzing the benefits in subgroups, PORT significantly improved OS (p = 0.015), DFS (p = 0.026), LRFS (p = 0.008) and DMFS (p = 0.030) in stage III patients. For the patients with N2 stage, all survivals of the PORT group were also statistically significantly higher than non-PORT group (p = 0.018, 0.032, 0.008, 0.042). Patients with more than 10% of metastatic lymph nodes could get a significant benefit survivals by receiving PORT (p = 0.033, 0.030, 0.025, 0.031). Having a systematic dissection of more than 17 lymph nodes was a subset which could get better OS and LRFS by receiving PORT (p = 0.045, 0.048).MethodsBetween Jan. 2004 to Dec. 2012, fifty-five patients diagnosed as C-SCLC after complete surgical resection in our center were retrospectively analyzed. The overall survival (OS), disease free survival (DFS), loco-regional recurrence free survival (LRFS), and distant metastasis free survival (DMFS) were calculated by Kaplan-Meier method.ConclusionsPORT can significantly improve the survival of C-SCLC patients with resected pathological pN2 stage. For the patients with a large percent of metastatic lymph nodes, PORT can also improve survivals.

Combined small cell lung carcinoma and giant cell carcinoma: a case report

BackgroundCombined small cell lung carcinoma (SCLC) is defined as SCLC combined with elements of non-small cell lung carcinoma (NSCLC), accounting for approximately 30% of cases of SCLC. However, combined SCLC and giant cell carcinoma (GC) is very rare.Case presentationA 50-year-old woman with a 45 pack-year smoking history was referred to our hospital for further investigation of an abnormal left hilar shadow. Chest computed tomography (CT) revealed a 28-mm solid pulmonary nodule in the left lower lobe and an enlarged left hilar lymph node adjacent to the left main pulmonary artery. CT-guided biopsy of the pulmonary nodule led to the diagnosis of high-grade neuroendocrine carcinoma. The preoperative clinical stage was defined as cT1bN1M0. Thus, the patient underwent left lower lobectomy with ND2a-2 lymph node dissection via thoracotomy. Pathological investigation revealed a 22-mm tumor and dense sheet-like growth of small tumor cells with scant cytoplasm and finely granular nuclear chromatin. Moreover, there was a sheet-like growth of bizarre, highly pleomorphic mono- or occasionally multinucleated giant cells, accounting for approximately 40% of the tumor. Both the small and giant cell components were thyroid transcription factor-1-positive and p40-negative and exhibited neuroendocrine differentiation, as indicated by positivity for synaptophysin and CD56 and negativity for chromogranin A. While the small cell component was E-cadherin-positive and vimentin-negative, the giant cell component was E-cadherin-negative and vimentin-positive, indicating an epithelial-to-mesenchymal transition. Only the small cell component was found within the mediastinal and hilar lymph nodes. The final pathological diagnosis was combined SCLC and GC, pT1bN2M0, and pStage IIIA. The patient received adjuvant chemotherapy with 4 cycles of cisplatin and irinotecan. No sign of recurrence has been noted for 1 year after the surgery.ConclusionsThis is the first detailed report of a unique case with combined SCLC and GC. The coexistence of SCLC and GC in the presented case might indicate several possibilities: (1) GC may arise from SCLC via epithelial-to-mesenchymal transition, (2) SCLC may arise from GC through phenotypic conversion, and (3) SCLC and GC may have derived from a common neuroendocrine origin. Further investigation is necessary to reveal the underlying pathological process.

Clinical outcomes of surgically resected combined small cell lung cancer: a two-institutional experience.

The combined small cell lung cancer (c-SCLC) was rare and its clinicopathological characteristics had not been thoroughly described. The aim of this study was to determine prognostic factors and survival in c-SCLC patients. Clinical records of patients with c-SCLC who underwent surgery between January 2009 and December 2013 in two institutions were retrospectively reviewed. Ninety-seven patients were identified. The most common pathology was combined SCLC and large cell neuroendocrine carcinoma (LCNEC, N=46), followed by combined SCLC and squamous cell carcinoma (SCC) (N=32), combined SCLC and adenocarcinoma (AC) (N=12), and combined SCLC and adenosquamous carcinoma (ASC) (N=7). The overall survival (OS) rates of the entire cohort were 42.4% and 35.2% at 3 and 5 years, respectively. Multivariate analysis identified sex [female vs. male, hazards ratio (HR) =0.38; 95% confidence interval (CI): 0.19-0.79; P=0.010], age (<53 vs. >53 years, HR =0.28; 95% CI: 0.09-0.81; P=0.019), performance status (<2 vs. >2, HR =0.08; 95% CI: 0.02-0.32; P<0.001), combined non-small cell lung cancer (NSCLC) components (LCNEC vs. non-LCNEC, HR =3.00; 95% CI: 1.03-8.76; P=0.045), adjuvant therapy (yes vs. no, HR =0.33; 95% CI: 0.17-0.67; P=0.002) as significantly prognostic factors of OS in patients with complete resection and lymphadenectomy. The mixed NSCLC components within c-SCLCs had a significant influence on the survival. Compared with surgery alone, adjuvant therapy was associated with significantly improved survival in patients with complete resection and lymphadenectomy.

Elucidating alternative pathways triggering small cell lung carcinoma tumor biology

In their recent perspective Ito et al . comprehensively reviewed the carcinogenesis of pure and combined small cell lung carcinoma (SCLC) (1) and we appreciate the explicit discussion of our article Meder et a l. “ NOTCH, ASCL1, p53 and RB alterations define an alternative pathway driving neuroendocrine and small cell lung carcinomas. ” (2).

Rare case of combined small cell lung cancer with adenocarcinoma and squamous cell carcinoma

Combined small cell lung cancer (cSCLC) is relatively unusual. We report a case of cSCLC in a 78-year-old man with no prior medical history who presented for evaluation of right upper lobe (RUL) lung mass. A CT scan showed a 3.0×2.5×2.3cm RUL lung mass with mildly prominent mediastinal and hilar lymphadenopathy. A right thoracotomy with right upper lobectomy and lymphadenectomy was performed. Histological examination and immunohistochemical stains confirmed the diagnosis of combined small cell lung carcinoma (SCLC) with adenocarcinoma (AC) and squamous cell carcinoma (SCC) components.While there are available guidelines for treating SCLC, the optimal treatment for cSCLC which will improve prognosis has not been adequately determined. We report a very rare category of primary lung malignant neoplasm to represent our institution's experience in diagnosing and managing this type of rare case.

Genetic alterations and protein expression in combined small cell lung cancers and small cell lung cancers arising from lung adenocarcinomas after therapy with tyrosine kinase inhibitors.

There are 2 hypotheses regarding the mechanism underlying the adenocarcinoma (AD) to small cell lung cancer (SCLC) transition in patients receiving Tyrosine kinase inhibitor (TKI) therapy: 1) AD gives rise to SCLC owing to the pressure of the TKI therapy, and 2) the SCLC coexists with the AD de novo, but is not detected in biopsy specimens of the heterogeneous tumor. In this study, we try to address this issue by examination the genetic alteration and protein expression profile between SCLC arising from AD, and SCLC in combined small cell lung cancers (CSCLC). In the former, the SCLC had the same genetic profile as the AD, and we strongly suggest that the transition was a consequence of TKI therapy. In the latter, genetic alterations and protein expression tended to differ between the NSCLC and SCLC components of the CSCLC. The results showed that EGFR and KRAS mutation were found in 1 but not both component of CSCLC, and the NSCLC component usually expressed the EGFR and RB1 proteins, whereas the SCLC component did not. This finding indicates that the NSCLC and SCLC components arose separately and that CSCLC are unsuitable for TKI therapy despite the presence of sensitive EGFR mutations.

Further understanding of an uncommon disease of combined small cell lung cancer: clinical features and prognostic factors of 114 cases.

ObjectiveCombined small cell lung cancer (C-SCLC) is an uncommon subgroup of small cell lung cancer (SCLC) and few clinical data can be referred. Our study is to investigate the clinical features and prognostic factors of C-SCLC, as well as the role of multimodality treatment.MethodsBetween January 2004 and December 2012, patients with histologically diagnosed C-SCLC were retrospectively analyzed. The survivals were evaluated with the Kaplan-Meier method. Univariate and multivariate analyses were used to evaluate potential prognostic factors.ResultsOne hundred and fourteen patients were enrolled, with a median age of 59 (range: 20−79) years old. The most common combined component was squamous cell carcinoma (52.6%). Among these patients, the disease was stage I, II, III and IV in 9.6%, 19.3%, 46.5% and 24.6% of the patients, respectively. Eighty patients (70.2%) received at least two of the three modalities containing chemotherapy, radiotherapy and surgery. The median follow-up was 32.5 months. The median time of overall survival (OS) was 26.2 months. On univariate analysis, smoking (P=0.029), Karnofsky performance score (KPS) <80 (P=0.000), advanced TNM stage (P=0.000), no surgery (P=0.010), positive resection margin (P=0.000), positive lymph nodes ≥4 (P=0.000), positive lymph node ratio >10% (P=0.000) and non-multimodality treatment (P=0.004) were associated with poor OS. Multivariate analysis confirmed that smoking, advanced TNM stage, positive resection margin and positive lymph nodes ratio >10% were poor prognostic features.ConclusionsC-SCLC has a relatively early stage and good prognosis, which may due to the underestimated diagnosis in non-surgical patients. Multimodality therapy is recommended, especially for limited disease. Smoking, advanced TNM stage, positive resection margin and positive lymph nodes ratio >10% are poor prognostic factors.