Combined Small Cell Carcinoma of the Lung: Is It a Single Entity?

Zhao, Xiaoliang; McCutcheon, Justine N.; Kallakury, Bhaskar; Chahine, Joeffrey J.; Pratt, Drew; Raffeld, Mark; Chen, Yulong; Wang, Changli; Giaccone, Giuseppe

doi:10.1016/j.jtho.2017.10.010

Cited by 47 publications

(81 citation statements)

References 39 publications

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“…When another NSCLC histological subtype, such as adenocarcinoma, squamous cell carcinoma, or sarcomatoid carcinoma, coexists with SCLC, C‐SCLC is diagnosed irrespective of cell amounts . In addition, more than two components can coexist within C‐SCLC …”

Section: Introductionmentioning

confidence: 99%

Effect of histological subtype and treatment modalities on T1–2 N0–1 small cell lung cancer: A population‐based study

et al. 2019

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Background Combined small cell lung cancer (C‐SCLC) is rare and its clinical features, appropriate treatment, and prognosis are poorly understood. Reports conflict over the prognosis of C‐SCLCs compared to pure small cell lung cancer. Methods The records of patients diagnosed with primary SCLC from 1988 to 2014 were extracted from the Surveillance, Epidemiology, and End Results database. The general features of C‐SCLCs were compared to those of SCLCs. T1–2 N0–1 data was extracted and the effects of the histological subtype, treatment modality, and other prognostic factors on lung cancer‐specific survival (CSS) was analyzed in a 3:1 matched dataset. Analysis was performed using the 8th edition tumor node metastasis staging system and previous staging systems adjunctively. Results C‐SCLCs comprised 1.5% of all SCLCs (1486/98 667); 184 cases of C‐SCLCs and 2681 cases of non‐combined SCLCs (NC‐SCLCs) were included in this study. C‐SCLCs were more likely to be of a higher grade and to occur in the upper lobe than NC‐SCLCs. Before matching, C‐SCLCs showed better CSS (hazard ratio 0.69; P < 0.001). However, stratified Cox proportional hazards analysis in the matched dataset revealed that only treatment modality and age at diagnosis were associated with CSS; the histological subtype had no effect on survival. Of all treatment modalities, surgery with chemoradiation showed the best CSS in T1–2 N0–1 SCLC. Conclusion In early SCLC, surgery with chemoradiation shows the best CSS. C‐SCLC patients might benefit more from multimodal treatments, including surgery, than SCLC patients.

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Section: Introductionmentioning

confidence: 99%

Effect of histological subtype and treatment modalities on T1–2 N0–1 small cell lung cancer: A population‐based study

et al. 2019

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“…Although our histological and immunohistochemical findings suggest that SCLC gave rise to the SLC, which in turn gave rise to the SpCC, this could not be confirmed with the molecular study. To date, there have been several molecular studies of cSCLCs . Most suggested that the SCLC and non‐SCLC components of cSCLCs had the same origin: they had identical mutations in the p53 and EGFR (exon 21) genes, as well as common LOH at 3p .…”

Section: Discussionmentioning

confidence: 99%

“…Most suggested that the SCLC and non‐SCLC components of cSCLCs had the same origin: they had identical mutations in the p53 and EGFR (exon 21) genes, as well as common LOH at 3p . In a study by Zhao et al ., approximately 75% of the mutations examined by next‐generation sequencing were shared between SCLC and non‐SCLC components . So far, there have been no reports of an intermingling‐pattern cSCLC with an additional separate area of pure SCLC, nor any discussion about the genetics of pure SCLC and cSCLC components.…”

Section: Discussionmentioning

confidence: 99%

“…The reported incidence of cSCLC is low but variable: 0.2% to 1.6% among surgically‐resected primary lung cancers and 14.6% to 28% when both surgical and biopsied cases are included . Non‐SCLC elements in cSCLCs include large cell neuroendocrine carcinomas, adenocarcinomas, SCCs, spindle cell carcinomas (SpCCs), and giant cell carcinomas …”

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confidence: 99%

“…When pure SCLC and cSCLC areas are both present, is the pure SCLC a more advanced state of cSCLC (or vice versa)? Several studies have examined cSCLC tumorigenesis via molecular analyses . However, to date, none have examined this process by comparing cSCLC and pure SCLC areas.…”

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confidence: 99%

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A case of combined small cell lung carcinoma with unique morphology: Investigation of tumorigenesis

Asahina

Fukumura

Osman

et al. 2018

Pathology International

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Small cell lung carcinoma (SCLC) usually grows in a pure form with no other associated histological components. However, combined small cell lung carcinoma (cSCLC), which is accompanied by other histological components (cSCLCs) may sometimes occur. Herein, we analyzed the tumorigenesis of cSCLC containing a demarcated area of pure SCLC. A 76‐year‐old man had a 25‐mm mass in the perihilar portion of his right upper lung. Histologically, the cSCLC contained two relatively demarcated areas: one area composed of pure SCLC cells and another area of SCLC, squamous‐like component (SLC), and spindle cell carcinoma (SpCC) cells. Loss of heterozygosity (LOH) was observed at allele 3p in all tumor components and at 22q in the pure SCLC component. Histological and immunohistochemical analysis and LOH study suggested that all components were likely to be monoclonal in origin and revealed that the pure SCLC component was not the precursor of the cSCLC. In the tumorigenesis of this case, the pure SCLC and the cSCLC may have originated from a common pluripotent tumor cell and then diverged, although we cannot state this conclusively. Further studies with more cases are necessary to test this theory.

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Identification of RUNX1T1 as a potential epigenetic modifier in small‐cell lung cancer

et al. 2020

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Small cell lung cancer (SCLC) can be sub-grouped into common 'pure' and rare 'combined' SCLC (c-SCLC). c-SCLC features a mixed tumor histology of both SCLC and non-small cell lung cancer (NSCLC). We performed targeted exon sequencing on 90 SCLC patients, including two with c-SCLC, and discovered RUNX1T1 amplification specific to small cell tumors of both c-SCLC patients, but in only 2 of 88 'pure' SCLC patients. RUNX1T1 was first identified in the fusion transcript AML1/ETO, which occurs in 12%-15% of acute myelogenous leukemia (AML). We further show higher expression of RUNX1T1 in the SCLC component of another c-SCLC tumor by in situ hybridization. RUNX1T1 expression was enriched in SCLC compared to all other cancers, including NSCLC, in both cell lines and tumor specimens, as shown by mRNA level and western blotting. Transcriptomic analysis of hallmark genes decreased by stable RUNX1T1 overexpression revealed a significant change in E2F targets. Validation experiments in multiple lung cancer cell lines showed that RUNX1T1 overexpression consistently decreased CDKN1A (p21) expression and increased E2F transcriptional activity, which is commonly altered in SCLC. Chromatin immunoprecipitation (ChIP) in these overexpressing cells demonstrated that RUNX1T1 interacts with the CDKN1A (p21) promoter region, which displayed parallel reductions in histone 3 acetylation. Furthermore, reduced p21 expression could be dramatically restored by HDAC inhibition using Trischostatin A. Reanalysis of ChIP-seq data in Kasumi-1 AML cells showed that knockdown of the RUNX1T1 fusion protein was associated with increased global acetylation, including the CDKN1A (p21) promoter. Thus, our study identifies RUNX1T1 as a biomarker and potential epigenetic regulator of SCLC.

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Combined Small Cell Carcinoma of the Lung: Is It a Single Entity?

Cited by 47 publications

References 39 publications

Effect of histological subtype and treatment modalities on T1–2 N0–1 small cell lung cancer: A population‐based study

Effect of histological subtype and treatment modalities on T1–2 N0–1 small cell lung cancer: A population‐based study

A case of combined small cell lung carcinoma with unique morphology: Investigation of tumorigenesis

Identification of RUNX1T1 as a potential epigenetic modifier in small‐cell lung cancer

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