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Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Lung Cancer Center, Tianjin Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin, People's Republic of ChinaGeorgetown University, Washington, District of Columbia
Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Lung Cancer Center, Tianjin Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin, People's Republic of China
Department of Lung Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Lung Cancer Center, Tianjin Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin, People's Republic of China
Corresponding author. Address for correspondence: Giuseppe Giaccone, MD, PhD, Lombardi Comprehensive Cancer Center, Georgetown University, 3970 Reservoir Rd., Washington, DC 20007.
SCLC accounts for 15% and 20% of all lung cancers, with combined SCLC (CSCLC) comprising 2% to 5%. Little is known about the clinical characteristics and molecular changes associated with the various histologic components.
Methods
A total of 205 SCLC cases were resected between 2005 and 2015. Clinical and pathologic features were analyzed. All CSCLC cases were confirmed by histologic examination and immunohistochemistry. The individual components were microdissected using a novel automated dissection system, and DNA was extracted and subjected to targeted exome sequencing.
Results
A total of 10 cases of CSCLC were identified out of 170 cases with adequate histologic material; squamous cell carcinoma comprised the second component in half of these (n = 5). There were no significant differences between CSCLC and pure SCLC with respect to clinical features. The median follow-up time was 36 months. The median survival times of patients with pure SCLC and CSCLC were 58 months and 26 months, respectively (p = 0.030). The different components of three cases of CSCLC were deemed adequate for microdissection and sequencing. Approximately 75% of the identified somatic mutations were present in both components. There were also 15 gene mutations or six amplifications unique to only one of the components.
Conclusions
We identified no significant clinical or pathologic differences between pure SCLC and CSCLC; CSCLC was associated with decreased overall survival compared with pure SCLC. The histologic components of CSCLC had high genetic concordance but also showed divergent genotypes. These findings may suggest a common precursor with subsequent acquisition of oncogenic changes in CSCLC.
Combined SCLC (CSCLC) is a rare subtype of SCLC, defined by the combination of SCLC and NSCLC components. The NSCLC component is typically composed of adenocarcinoma, squamous cell carcinoma, or large cell carcinoma, but it can also rarely involve sarcomatoid or giant cell carcinoma.
Furthermore, more than two components can also be observed.
To date, the cell of origin of CSCLC remains unclear and the literature thus far has been based on limited but older techniques such as loss of heterozygosity (LOH), immunophenotype, or comparative genomic hybridization analysis.
A few studies have concluded that the different components in CSCLC may have a common cellular origin, and that tumor stem cells undergo divergent differentiation during proliferation or, rather, one of the two components arises by random genetic mutations in the other component.
Exposure to tyrosine kinase inhibitors (TKIs) against the EGFR may lead to the transformation from EGFR-mutant adenocarcinoma to SCLC in less than 10% of EGFR TKI–resistant cases, suggesting plasticity between the different histologic subtypes.
A prospective randomized trial to determine the benefit of surgical resection of residual disease following response of small cell lung cancer to combination chemotherapy.
This variation may reflect ongoing changes in the classification of SCLC, as well as the nature of the specimen obtained (e.g., resection versus small biopsy versus fine-needle aspiration specimen). There are few studies assessing the clinical and prognostic features of CSCLC after surgery. Furthermore, few studies have addressed the molecular changes in the different histologic components. Here, we have investigated the clinicopathologic features of a large series of resected SCLCs and performed next-generation sequencing (NGS) on the different components in three CSCLC cases.
Materials and Methods
This study included a total of 170 patients with resected SCLC at the Tianjin Medical University Cancer Institute and Hospital between 2005 and 2015 for which adequate material was available. Details of this series are described elsewhere (X. Zhao, Tianjin Medical University Cancer Institute and Hospital, personal/written communication, 2017). All specimens were reviewed and independently confirmed by two board-certified pathologists. Ten cases of CSCLC were identified, accounting for 5.9% of the SCLC in this series (Table 1). All cases were restaged according to the seventh edition of American Joint Committee on Cancer TNM staging system for lung cancer.
The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours.
Clinical data on all patients were extracted from medical records and follow-up (as of March 2017) was obtained. Overall survival (OS) was defined as the interval between the date of the operation and the time of death or the date of the last follow-up.
Table 1Clinicopathologic Characteristics of CSCLC (n = 10)
Case
Age
Sex
Smoking index
Location
pStage
Surgery Type
R Resection
Diameter, cm
Adjuvant chemotherapy
1
74
M
0
RL
IA
Wedge
R1
2
Yes
2
63
M
1600
RL
IIA
Lobectomy
R0
7
Yes
3
70
F
0
RM
IV
Lobectomy
R0
6
No
4
59
M
1200
LU
IIIA
Lobectomy
R0
5
Yes
5
63
M
3200
RL
IA
Lobectomy
R0
2
Yes
6
60
M
800
LU
IA
Lobectomy
R0
2
No
7
62
M
800
LU
IIIA
Wedge
R1
2.2
No
8
58
M
1200
LL
IIIA
Lobectomy
R0
3
Yes
9
44
M
40
RL
IIIA
Lobectomy
R0
5
Yes
10
49
M
400
LU
IIIB
Lobectomy
R0
3.5
No
Note: Smoking index is cigarettes per day multiplied by years smoked.
CSCLC, combined SCLC; M, male; F, female; LLL, left lower lobe; RLL, right lower lobe; RUL, right upper lobe; LUL, left upper lobe; RML, right middle lobe.
All samples were formalin-fixed and paraffin-embedded (FFPE); 4-μm tissue sections were stained with hematoxylin and eosin (HE) and analyzed using a select panel of immunohistochemical (IHC) markers. Pretreatment of the FFPE sections with heat-induced epitope retrieval was performed. Optimal results were obtained by pretreating tissues with heat-induced epitope retrieval using diluted Envision FLEX Target Retrieval Solution, HIGH pH (50×) (Agilent Technologies, Santa Clara, CA). Deparaffinization, rehydration, and epitope retrieval were performed in DAKO PT Link (PT100/PT101) (Agilent Technologies). The following parameters were used for PT Link: preheat temperature, 65°C; epitope retrieval temperature and time, 97°C for 20 minutes; and cool down to 65°C. Racks were placed in diluted Envision Flex Wash Buffer (20×) (Agilent Technologies) for 5 minutes.
Slides were treated with Flex Peroxidase Blocking solution for 5 minutes and then with the first antibody with an incubation time of 20 minutes, Flex Mouse Linker for 15 minutes, Flex HRP for 20 minutes, Flex DAB with Substrate-Chromogen for 10 minutes, and Flex hematoxylin for 5 minutes. Wash buffer was applied before the addition of each reagent for 5 minutes to guarantee that no residual remains of any reagent were left on the slide.
All the antibodies were run on the Dako/Agilent Autostainers Link 48, and the antigen retrieval for all the antibodies was performed on the Dako/Agilent PT Links.
The following prediluted antibodies were used: CD56 (123C3), synaptophysin (DAK-SYNAP [Agilent]), thyroid transcription factor 1 (8G7G3/1), cytokeratin 7 (OV-TL12/30), Ki-67 (MIB-1), chromogranin A (1:50 dilution, Clone LK2H10, Cell Marque, Rocklin, CA), Napsin A (Pre-Diluted, Cell Marque), p63 (Pre-Diluted, Clone 4A4, Ventana Medical Systems, Tucson, AZ) and GNAS complex locus (GNAS) (1:200 dilution, Clone PA5-22261, Invitrogen, Carlsbad, CA) (see Supplementary Table 6 for details on the antibodies).
Tumor Enrichment and DNA Extraction
All CSCLC cases were carefully reviewed using HE staining and IHC markers. Only cases with a clear morphologic boundary between the SCLC and NSCLC components were selected for microdissection. CSCLC samples with highly mixed components that could not be confidently separated by the dissection method were not included.
Tumor enrichment was achieved using a prototype novel software-guided dissection system from Roche Sequencing Solutions (Avenio Millisect System, Roche, Pleasanton, CA) that utilizes an automated platform to guide tissue dissection, and is capable of dissecting areas of interest as small as 200 μm in diameter. Serial 5-μm sections were cut from FFPE tissue blocks. Reference HE and IHC stains were used to assist with accurate demarcation of selected tumor regions to accurately separate and enrich for the different tumor components. The reference slides were converted to whole slide images using an Aperio Scanscope XT (Leica Biosystems Imaging, Buffalo Grove, IL) scanned at ×40 magnification. Areas of interest were digitally annotated using Imagescope (Leica Biosystems) to designate the dissection regions. The annotated reference images were imported to the Millisect instrument and overlayed with live images of unstained slides situated on an automated stage. Annotated tumor areas were then dissected using 200-μm, 400-μm, or 800-μm Millisect Milling tips directly into ATL (lysis) buffer (Qiagen, Valencia, CA), and DNA was extracted using the QIAamp DNA FFPE Tissue Kit (Q). Proteinase K was added to the excised tissue lysis buffer mixture, and the samples were incubated at 56°C on a heater/shaker for 3 hours or until the tissue was completely digested. After incubation, the tubes were heated to 90°C and then brought back to room temperature. The samples were centrifuged to eliminate particulate undigested material, after which the supernatants were processed on a QIAcube robotic workstation (Qiagen) and the DNA was eluted in a volume of 40 μL. Optical density was measured using a NanoDrop microvolume spectrophotometer (ThermoFisher Scientific, Waltham, MA, USA), to determine DNA concentration and quality for subsequent analysis.
NGS Library Construction and MiSeq Sequencing
Before NGS library construction, DNA quality and quantity were analyzed using the NanoDrop 2000 spectrophotometer (Thermo Fisher Scientific) and the Quantifluor ONE dsDNA system (Promega, Madison,WI), respectively. Briefly, 200 to 300 ng of each DNA sample was sheared to a target size of 200 base pairs on the Covaris M220 focused ultrasonicator (Covaris, Woburn, MA). The sheared DNA fragments were repaired using the NEBNext End Repair Module (New England Biolabs, Ipswish, MA) and purified with Agencourt AMPure XP beads (Beckman Coulter, Indianapolis, IN). Libraries were constructed by ligating Illumina adapters and unique indexes (Personal Genome Diagnostics, PGDx, Baltimore, MD) to the DNA fragments with the NEB Next Quick Ligation Module (New England Biolabs). Library amplification was performed by a 12-cycle polymerase chain reaction protocol with primers complimentary to the Illumina adapters. Each sample was hybridized to custom RNA baits from our PGDx custom gene panel (PGDx) for 24 hours and captured using streptavidin C1 beads (ThermoFisher Scientific). A final 16-cycle polymerase chain reaction amplification was performed to enrich for the indexed libraries. Quantity and quality of the libraries were assessed after each step by using either the DNA 1000 kit or the High Sensitivity DNA kit on the Bioanalyzer (Agilent Technologies). The indexed libraries were combined into a 4-nM equimolar pool for MiSeq (Illumina, San Diego, CA) sequencing preparation. The 4-nM library pool was diluted further to 8-pM with HT1 buffer (Illumina), and 5% of 12.5 nM PhiX v3 control (Illumina) was spiked into the diluted library pool. Six hundred microliters of the 8-pM pooled library with 5% PhiX control was loaded into the MiSeq Reagent Kit v2 (300 cycle) cartridge (Illumina). A 1 × 150 -base pair paired-end read was executed on the MiSeq sequencer (Illumina) according to the manufacturer’s user guide.
MiSeq Sequencing Data Analysis
The PGDx custom gene panel (1.3–megabase pair region size) targets the exons of 206 cancer genes and interrogates microsatellite instability (MSI) and specific genes for copy number variation and translocations (Supplementary Table 1). Alignment to the human reference genome 19 (UCSC hg19), adapter trimming, and variant calling were automatically executed by the MiSeq Reporter software (version 2.6.2, Illumina). The MSI, copy number variation, and translocation analysis was completed by our PGDx custom analysis pipeline. The VariantStudio software (version 2.2.1, Illumina) was used to annotate and filter all the variants. The databases used to annotate the variants included SIFT, PolyPhen, Catalogue of Somatic Mutations in Cancer (COSMIC), dbSNP v137, and RefSeq. The variants were filtered on the basis of their passing score (not flagged with low genotyping, low quality, or strand bias), mapping quality score (Q score >30), read depth (>30), and consequence (only nonsynonymous mutations). The samples were analyzed by examining both the SCLC and NSCLC components together to report common mutations between both components in the same patient and by examining each component separately to reveal mutations unique to their SCLC or NSCLC component. All mutations were visually inspected in the Integrative Genomics Viewer (Broad Institute, Cambridge, MA). Variants could not be validated using Sanger sequencing because of limitations of tissue and lack of high quality DNA. However, there is high confidence in the variant calling from the quality scoring, coverage with a read depth greater than 30, and evidence of clean surrounding reads in Integrative Genomics Viewer.
Statistical Analysis
SPSS 19.0 software (IBM Corp., Armonk, NY) was adopted for statistical analysis of the data. OS was estimated by the Kaplan-Meier method and the log-rank test was used to compare survival curves. All tests were two sided, and p values less than 0.05 were considered statistically significant.
Results
Patient Demographics and Survival
All patients with SCLC were followed up for 2 to 139 months, with a median follow-up period of 36 months. The median age was 61 years (range 25–78), with 133 male and 37 female patients. The distribution of clinicopathologic features was not statistically different between patients with pure SCLC and those with CSCLC (p > 0.05) (Table 2). The 1-, 3-, and 5-year survival rates of patients with pure SCLC and those with CSCLC were 85.6%, 59.2%, and 49.3% and 70%, 17.5%, and 17.5%, respectively. The OS of CSCLC was significantly shorter than that of pure SCLC: pure SCLC median OS was 58 months (95% confidence interval: 32.86–83.14), versus 26 months for CSCLC (95% confidence interval: 17.65–34.36) (log-rank χ2 = 4.729, p = 0.030) (Fig. 1).
Table 2Distribution of Clinical and Pathologic Factors in Pure and Combined SCLC
IHC Characteristics of Different Components of CSCLC
Among the 10 CSCLC cases, squamous cell carcinoma was the most common NSCLC component (five of 10 [50%]), followed by large cell neuroendocrine carcinoma (LCNEC) (three of 10 [30%]), and adenocarcinoma (two of 10 [20%]). The SCLC and NSCLC components were clearly demarcated in six cases (five SCCs and one adenocarcinoma), whereas in the remaining four cases the two different components were highly mixed, without obvious tumor boundaries (Fig. 2 and Supplementary Fig. 1). CD56 staining was positive in all SCLC components and was negative in all NSCLC components except LCNEC. The SCC component was consistently positive for p63. Thyroid transcription factor 1 staining was positive in 30% of the SCLC component and almost completely negative in the NSCLC component, except for one LCNEC that was positive. The proliferation index (Ki-67) was higher in the SCLC component, with an average of 80% compared with 50% in the NSCLC component. LCNEC as the NSCLC component had a proliferation index similar to that of the SCLC component (Table 3).
Figure 2Immunohistochemical characteristics and boundary areas of different components in four selected cases of combined SCLC. Syn, synaptophysin; TTF-1, thyroid transcription factor 1.
A targeted exome sequencing approach with a custom 206–cancer gene panel on the Illumina MiSeq platform was used to investigate the mutation profiles of CSCLC tumors. The MiSeq sequencing run yielded 5.17 gigabase pairs, with 95.4% greater than Q30 (5.0 gigabase pairs), and it produced 33,872,774 passing filter reads, with a mean total coverage and distinct coverage of 206 and 77, respectively. Six samples were microdissected and DNA successfully extracted (Fig. 2 and Supplementary Fig. 1); however, only three cases passed quality control and were sequenced successfully. The NSCLC component of these three cases was squamous carcinoma in each of them. A total of 81 mutations were found in all samples: most (77% [n = 62]) were missense mutations, whereas the remaining mutations (23% [n = 19]), were frameshift indels, stop gain, or splicing mutations. Moreover, of the 81 mutations, 23% (n = 19) were flagged as deleterious or damaging and 14% (n =11) were found in the COSMIC database. Of those mutations found in COSMIC, 64% (n = 7) were predicted as pathogenic according to the FATHMM predictor.
Subsequently, all missense mutations were retrieved in he Exome Aggregation Consortium database; 22 mutations and 9 mutations were found as common SNPs and rare SNPs, respectively. Excluding the common SNPs, common gene mutations found in both the SCLC and NSCLC components, represented approximately 75% of all mutations and were found in all samples: case 1 (n = 24), case 2 (n = 12), and case 3 (n = 8). Unique mutations found only in one component were identified in five out of the six samples: case 1-SCLC (n = 6), case 1-NSCLC (n = 2), case 2-SCLC (n = 2), case 2-NSCLC (n = 4), case 3-SCLC (n = 1) (Supplementary Tables 2 and 3 and Fig. 3A). Different tumor protein p53 gene (TP53) mutations were present in all three cases, but both histologic components shared the same mutation. Amplifications of GATA binding protein 2 gene (GATA2) and ret proto-oncogene gene (RET) were identified in both components in sample case 3. Amplifications of five genes (fibroblast growth factor receptor 3 gene [FGFR3], GNAS complex locus gene [GNAS], NK2 homeobox 1 gene [NKX2-1], H3 family member histone 3A gene [H3F3A], and nuclear receptor coactivator 3 gene [NCOA3]) were found in only one component of the tumor in samples case 3-SCLC (n = 2), case 1-NSCLC (n = 1), case 2-NSCLC (n = 1), and case 2-SCLC (n = 2) (Supplementary Tables 4 and 5 and Fig. 3B). There were 2 cases (cases 2 and 3) showing a unique GNAS amplification in only the SCLC components. We used IHC to verify the expression of GNAS in these two cases. Higher expression of GNAS with a diffuse pattern of distribution could be seen in the SCLC components than in the NSCLC components (Supplementary Fig. 2). Furthermore, the SCLC component of sample case 3 was flagged as MSI-positive with the microsatellite marker MONO27 with 30% of the reads being shorter than normal, indicating damage to the mismatch repair pathway. It should be noted that the components in case 3 had a lower number of mutations because of the low quality of input DNA and the low-quality sequencing reads and coverage. Case 3 showed a lower unique mutation percentage (19% [one of nine]) compared with case 1 (25% [eight of 32]) and case 2 (33% [six of 18]).
Figure 3(A) The number of mutations in common, unique mutations in the SCLC component and unique mutations in the NSCLC component in three cases of combined SCLC. (B) The number of gene amplifications in common, SCLC component unique amplifications and unique amplifications in the NSCLC component in three cases of combined SCLC.
As an entity, SCLC has undergone significant changes in classification over the past 40 years. SCLC was initially divided into the four types of lymphocyte-like, polygonal, fusiform, and others. Later, the classification of SCLC was revised as oat cell, intermediate, and combined types by the WHO.
Following recommendations of the International Association for the Study of Lung Cancer in 1998, the oat cell type was changed to pure SCLC, CSCLC was retained, the intermediate type was removed, and mixed with large cell components changed to mixed type. Last revised in 1999, SCLC was divided into two types, pure SCLC and CSCLC, which could be a mixed tumor with any NSCLC components.
On the basis of morphologic features, spindle cell carcinoma, which is initially regarded as an NSCLC component, was reclassified to a subtype of SCLC. The change in CSCLC definitions is a potential reason for the variability in the proportion of CSCLC reported in older series. Furthermore, studies have shown that the diagnostic rate for CSCLC reflects the size of the biopsy specimen, the presence of crush artifacts, and the low frequency of cases. The material commonly used for diagnosis of SCLC is limited (fine-needle aspiration or bronchoscopic biopsy), and previous studies showed that CSLC accounts for approximately 14.3% in postmortem material, 8.6% in cytologic or biopsy specimens, and as high as 12% to 28% in surgical resection specimens.
To our knowledge, our series is the largest series of resected SCLC from a single institution. In the current study, the incidence of CSCLC was low at around 6%.
To our knowledge, this is the first study utilizing NGS to investigate potential the various components of CSCLC. As previously mentioned, prior studies have utilized less sensitive and/or specific methods (e.g., IHC, LOH, comparative genomic hybridization).
The most frequently identified mutation was of TP53 (92%), followed by mutation of the retinoblastoma 1 gene (RB1) (76%), and inactivating mutations in NOTCH family genes (25%); common genomic rearrangements of tumor protein p73 gene (TP73), SRY-box 2 gene (SOX2) (27%) and MYC family (16%) amplification were also documented. Like SCLC, squamous cell carcinoma is a smoking-related disease and shows a high frequency of TP53 mutations (91%),
Our sequencing results indicate that TP53 was the only gene that was mutated in all components of the three CSCLCs that were subjected to microdissection and sequencing. Nearly 75% of all mutations identified were present in both components of the CSCLC samples analyzed. In our study we found mutations in cyclin-dependent kinase inhibitor 2 gene (CDKN2A) and F-box and WD repeat domain containing 7 gene (FBXW7), aberrations that are more commonly reported in SCC.
We also identified mutations in insulin-like growth factor 2 receptor gene (IGF2R) in both components; these mutations have been more frequently reported in SCLC than in SCC.
In contrast, type II alveolar cells and club cells of the bronchoalveolar duct, and basal cells in the proximal airway are reported cells of origin for lung adenocarcinoma and squamous carcinoma, respectively.
Murase et al. suggested that SCLC and SCC components of CSCLC are more closely related than adenocarcinoma, which is more likely to be derived from a different clone or from the same stem cell at a much earlier stage before occurrence of mutations in p53.
It has also been suggested that SCLC is derived from neuroendocrine cells (Kulchitsky cells) but less frequently may also derive from type II alveolar epithelial cells.
It has also been proposed that CSCLC is more closely related to pure SCLC than to NSCLC. Other investigators have suggested that the SCLC component originates through chromosomal changes in squamous cell carcinoma in early stages of development.
suggesting that both histologic forms may coexist, independent of transformation to SCLC observed as a mechanism of resistance to EGFR TKIs. Studies about the complexities of the SCLC metastases in mice have indicated that multiple metastases with different genomic profiles are driven by intratumoral heterogeneity.
In spite of the small number of CSCLC cases analyzed, our results may indicate that CSCLC components are derived from common precursors. The different components shared nearly 50% of target gene mutations and amplifications. We hypothesize that poly-subclones of tumor stem cells may undergo different genetic mutations or amplifications under the influence of the tumor microenvironment, influencing the differentiation of tumor cells. Swanton et al. have pioneered the field of cancer heterogeneity and demonstrated the evolutionary process of polyclonal seeding of metastases from a primary tumor in adenocarcinoma of the lung.
They suggest that the early clonal mutational events, such as TP53 mutations and EGFR-activating mutations, that drive tumorigenesis occur at the very early time points, early in the trunk of the evolutionary tree. Subclonal driver events such as phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PI3KCA) mutations may occur later, in the branches of the evolutionary tree of the tumor. In our study, the different components of CSCLC shared nearly 75% common mutations, and we hypothesize that the different components have the same stem cell of origin because they had a similar genetic background, such as TP53 mutation. One component of CSCLC arises from the other component at a relatively late time point in the presence of a different microenvironment.
The National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology (National Comprehensive Cancer Network guidelines) do not make a distinction in the treatment recommendations for CSCLC and SCLC.
However, the NSCLC component of CSCLC shows decreased responsiveness to chemotherapy, which is a commonly used modality for pure SCLC (etoposide and cisplatin [EP]).
Attempts to supplement standard EP regimens by adding agents that are more active in NSCLC (such as paclitaxel or vinorelbine) to them have not been successful, with overall response rate, progression-free survival, and OS not significantly improved and side effects greater than those of the EP regimen.
Comparison of vinorelbine, ifosfamide and cisplatin (NIP) and etoposide and cisplatin (EP) for treatment of advanced combined small cell lung cancer (cSCLC) patients: a retrospective study.
Paclitaxel-etoposide-carboplatin/cisplatin versus etoposide-carboplatin/cisplatin as first-line treatment for combined small-cell lung cancer: a retrospective analysis of 62 cases.
Etoposide-cisplatin alternating with vinorelbine-cisplatin versus etoposide-cisplatin alone in patients with extensive disease combined with small cell lung cancer.
In a report of 10 patients with CSCLC who underwent surgical treatment, OS was found to be longer in the patients with CSCLC than in those with pure SCLC.
Furthermore, the postoperative 5-year survival rate was 100% for patients with stage I and II disease. Whether survival of CSCLC is any different from survival of SCLC remains controversial. Evidence, including that presented here, indicates that CSCLC has a shorter OS and is less responsive to chemotherapy than pure SCLC.
In conclusion, the results presented here indicate that CSCLC has a poorer OS compared with pure SCLC. There were no significant differences in clinicopathologic features between pure SCLC and CSCLC. The different histologic components of CSCLC had a similar mutational profile but also demonstrated divergent genotypes. The different components of CSCLC may share a similar cellular precursor. Further research involving larger numbers of dissected cases will be needed to confirm our findings.
Acknowledgments
This study was supported by the National Key R&D Program of China (grant) 2016YFC0905501 and National Institutes of Health grant P30 CA51008.
A prospective randomized trial to determine the benefit of surgical resection of residual disease following response of small cell lung cancer to combination chemotherapy.
The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM Classification of malignant tumours.
Comparison of vinorelbine, ifosfamide and cisplatin (NIP) and etoposide and cisplatin (EP) for treatment of advanced combined small cell lung cancer (cSCLC) patients: a retrospective study.
Paclitaxel-etoposide-carboplatin/cisplatin versus etoposide-carboplatin/cisplatin as first-line treatment for combined small-cell lung cancer: a retrospective analysis of 62 cases.
Etoposide-cisplatin alternating with vinorelbine-cisplatin versus etoposide-cisplatin alone in patients with extensive disease combined with small cell lung cancer.
SCLC is a deadly, recalcitrant form of lung cancer that is strongly associated with tobacco exposure. Inactivation of the tumor protein p53 gene (TP53) and retinoblastoma 1 gene (RB1) genes in SCLC is almost universal and is believed to be the initiating molecular event.1,2 The WHO classification of lung cancers recognizes only one major morphologic form of SCLC, although elements of NSCLC cancers may be present (combined SCLC [CSCLC]).3 Historically, SCLC has been regarded as a “homogenous” disease (with little documented intertumor or intratumor heterogeneity with respect to histologic characteristics or molecular biology).
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