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Combined small-cell lung carcinoma

Combined small cell lung carcinoma or c-SCLC, and rarely rendered as "small-cell lung carcinoma" is a form of multiphasic lung cancer that is diagnosed by a pathologist when a malignant tumor arising from transformed cells originating in lung tissue contains a component of small cell lung carcinoma SCLC admixed with one or more components of non-small cell lung carcinoma NSCLC123


  • 1 Classification
  • 2 Incidence
  • 3 Significance
  • 4 Histogenesis
  • 5 Staging
  • 6 Treatment
    • 61 Targeted agents
  • 7 Prognosis and survival
  • 8 References
  • 9 External links


Lung cancer is a large and exceptionally heterogeneous family of malignancies4 Over 50 different histological variants are explicitly recognized within the 2004 revision of the World Health Organization WHO typing system "WHO-2004", currently the most widely used lung cancer classification scheme1 Many of these entities are rare, recently described, and poorly understood5 However, since different forms of malignant tumors generally exhibit diverse genetic, biological, and clinical properties — including response to treatment — accurate classification of lung cancer cases are critical to assuring that patients with lung cancer receive optimum management67

Approximately 99% of lung cancers are carcinoma, a term that indicates that the malignant neoplasm is composed of, or descended from, cells of epithelial lineage ie derived from embryonic endoderm, as is the case in lung carcinomas, or from ectoderm, and/or that the malignant cells exhibit tissue architectural, cytological, or molecular features characteristically found in epithelial cells8 Under WHO-2004, lung carcinomas are divided into 8 major taxa:1

  • Squamous cell carcinoma
  • Small cell carcinoma
  • Adenocarcinoma
  • Large cell carcinoma
  • Adenosquamous carcinoma
  • Sarcomatoid carcinoma
  • Carcinoid tumor
  • Salivary gland-like carcinoma

SCLC is generally considered to be the most aggressive of these major forms of lung cancer, with the worst long term prognosis and survival rates8 As a result, it is recommended that all multiphasic malignant lung tumors ie those with more than one histological pattern that are found to contain any proportion of SCLC cells should be classified as c-SCLC, and not as combined forms of any of the other histological variants present in the tumor1 Currently, the only exception to this recommendation occurs in cases where anaplastic large cell lung carcinoma LCLC is the second histological component In these instances, a minimum of 10% of the viable malignant cells present must be identified as LCLC before the tumor is considered to be a c-SCLC19 Under the WHO-2004 classification scheme, c-SCLC is the only recognized variant of SCLC1


Reliable comprehensive incidence statistics for c-SCLC are unavailable In the literature, the frequency with which the c-SCLC variant is diagnosed largely depends on the size of tumor samples, tending to be higher in series where large surgical resection specimens are examined, and lower when diagnoses are based on small cytology and/or biopsy samples Tatematsu et al reported 15 cases of c-SCLC 12% in their series of 122 consecutive SCLC patients, but only 20 resection specimens were examined10 In contrast, Nicholson et al found 28 c-SCLC 28% in a series of 100 consecutive resected SCLC cases9 It appears likely, then, that the c-SCLC variant comprises 25% to 30% of all SCLC cases1112

As the incidence of SCLC has declined somewhat in the US in recent decades,13 it is likely that c-SCLC has also decreased in incidence Nevertheless, small cell carcinomas including the c-SCLC variant still comprise 15–20% of all lung cancers, with c-SCLC probably accounting for 4–6%14 With 220,000 cases of newly diagnosed lung cancer in the US each year, it can be estimated that between 8,800 and 13,200 of these are c-SCLC15

In a study of 408 consecutive patients with SCLC, Quoix and colleagues found that presentation as a solitary pulmonary nodule SPN is particularly indicative of a c-SCLC — about 2/3 of their SPN's were pathologically confirmed to be c-SCLC's containing a large cell carcinoma component16


In terms of case numbers, the estimated 8,800 to 13,200 c-SCLC cases occurring annually in the US makes this disease roughly comparable in incidence to Hodgkin's Disease 8,500, testicular cancer 8,400, cervical cancer 11,300, and cancers of the larynx 12,30015 However, these four "better-known" cancers all have exceptionally high 85%-95% cure rates In contrast, less than 10% of c-SCLC patients will be cured, and thus the number of annual cases of c-SCLC is a reasonable approximation of the annual number of deaths Therefore, given the significant incidence and mortality attributable to this malignancy,17 see Prognosis and survival it is arguably critical to better understand these aggressive lesions so specific strategies for their management can be rationally designed6718

However, as patients with tumors containing mixtures of histological subtypes are usually excluded from clinical trials,19 the properties of multiphasic tumors like c-SCLC are much less well understood than those of monophasic tumors20 C-SCLC contains both SCLC and NSCLC by definition, and since patients with SCLC and NSCLC are usually treated differently, the lack of good data on c-SCLC means there is little evidence available with which to form consensus about whether c-SCLC should be treated like SCLC, NSCLC, or uniquely21


The exact mechanisms and histogenesis of lung cancers are topics of intense interest and research It is currently thought that most cases of lung cancer probably occur after damage to genomic DNA causes malignant transformation of a single multipotent cell This newly formed entity, sometimes referred to as a cancer stem cell, then begins to divide uncontrollably, giving rise to new daughter cancer cells in an exponential or near exponential fashion Unless this runaway cell division process is checked, a clinically apparent tumor will eventually form as the mass reaches sufficient size to be detected clinically, or begins to cause signs or symptoms22 Approximately 98% of lung cancers are eventually diagnosed as a histological variant of carcinoma, a term that signifies that the tumor derives from transformed epithelial cells, or cells that have acquired epithelial characteristics as a result of cell differentiation8

The histogenesis of c-SCLC and other multiphasic forms of lung cancer appear to be complex and varied phenomena In most cases of c-SCLC, genomic and immunohistochemical studies suggest that the morphological divergence of the separate components occurs when a SCLC-like cell is transformed into a cell with the potential to develop NSCLC variant characteristics, and not vice versa Daughter cells of this transdifferentiated SCLC-like cell then repeatedly divide and, under both intrinsic genomic and extrinsic environmental influences, acquire additional mutations a process known as tumor progression The end result is that the tumor acquires specific cytologic and architectural features suggesting a mixture of SCLC and NSCLC12

Other analyses suggest that, in at least in some cases, more highly differentiated variants of NSCLC ie adenocarcinoma can "progress" to give rise to areas within the primary original tumor or its metastases that develop histological and molecular characteristics of SCLC23

Other molecular studies, however, suggest that — in at least a minority of cases — independent development of the components in c-SCLC occurs via mutation and transformation in two different cells in close spatial proximity to each other, due to field cancerization In these cases, repeated division and mutational progression in both cancer stem cells generate a biclonal "collision tumor"2425

Regardless of which of these mechanisms give rise to the tumor, recent studies suggest that, in the later stages of c-SCLC oncogenesis, continued mutational progression within each tumor component results in the cells of the combined tumor developing molecular profiles that more closely resemble each other than they do cells of the "pure" forms of the individual morphological variants26 This molecular oncogenetic convergence likely has important implications for treatment of these lesions, given the differences between standard therapeutic regimens for SCLC and NSCLC

C-SCLC also occurs quite commonly after treatment of "pure" SCLC with chemotherapy and/or radiation, probably as a result of a combination of tumor genome-specific "progressional" mutations, stochastic genomic phenomena, and additional mutations induced by the cytotoxic therapy27282930

The most common forms of NSCLC identified as components within c-SCLC are large cell carcinoma, adenocarcinoma, and squamous cell carcinoma2420 Rarer variants of NSCLC are seen less commonly, such as combinations with carcinoids,20 spindle cell carcinoma,23 and giant cell carcinoma9 Giant cell carcinoma components are seen much more commonly in patients who have undergone radiation313233 With the approval and use of newer "molecularly targeted" agents revealing differential efficacies in specific subtypes and variants of NSCLC, it is becoming more important for pathologists to correctly subclassify NSCLC's as distinct tumor entities, or as components of c-SCLC's


Staging of c-SCLC patients is usually performed in an analogous fashion to patients with "pure" small cell lung carcinoma

For several decades, SCLC has been staged according to a dichotomous distinction of "limited disease" LD vs "extensive disease" ED tumor burdens3435 Nearly all clinical trials have been conducted on SCLC patients staged dichotomously in this fashion36 LD is roughly defined as a locoregional tumor burden confined to one hemithorax that can be encompassed within a single, tolerable radiation field, and without detectable distant metastases beyond the chest or supraclavicular lymph nodes A patient is assigned an ED stage when the tumor burden is greater than that defined under LD criteria — either far advanced locoregional disease, malignant effusions from the pleura or pericardium, or distant metastases37

However, more recent data reviewing outcomes in very large numbers of SCLC patients suggests that the TNM staging system used for NSCLC is also reliable and valid when applied to SCLC patients, and that more current versions may allow better treatment decisionmaking and prognostication in SCLC than with the old dichotomous staging protocol343839


A very large number of clinical trials have been conducted in "pure" SCLC over the past several decades36 As a result, evidence-based sets of guidelines for treating monophasic SCLC are available1121 While the current set of SCLC treatment guidelines recommend that c-SCLC be treated in the same manner as "pure" SCLC, they also note that the evidence supporting their recommendation is quite weak21 It is likely, then, that the optimum treatment for patients with c-SCLC remains unknown20

The current generally accepted standard of care for all forms of SCLC is concurrent chemotherapy CT and thoracic radiation therapy TRT in LD, and CT only in ED For complete responders patients in whom all evidence of disease disappears, prophylactic cranial irradiation PCI is also given TRT serves to increase the probability of total eradication of residual locoregional disease, while PCI aims to eliminate any micrometastases to the brain21

Surgery is not often considered as a treatment option in SCLC including c-SCLC due to the high probability of distant metastases at the time of diagnosis40 This paradigm was driven by early studies showing that the administration of systemic therapies resulted in improved survival as compared to patients undergoing surgical resection414243 Recent studies, however, have suggested that surgery for highly selected, very early-stage c-SCLC patients may indeed improve outcomes44 Other experts recommend resection for residual masses of NSCLC components after complete local tumor response to chemotherapy and/or radiotherapy in c-SCLC45

Although other combinations of drugs have occasionally been shown to be noninferior at various endpoints and in some subgroups of patients, the combination of cisplatin or carboplatin plus etoposide or irinotecan are considered comparable first-line regimens for SCLC2146 For patients who do not respond to first line therapy, or who relapse after complete remission, topotecan is the only agent which has been definitively shown to offer increased survival over best supportive care BSC,2147 although in Japan amirubicin is considered effective as salvage therapy47

Importantly, c-SCLC is usually much more resistant to CT and RT than "pure" SCLC122830484950 While the mechanisms for this increased resistance of c-SCLC to conventional cytotoxic treatments highly active in "pure" SCLC remain mostly unknown, recent studies suggest that the earlier in its biological history that a c-SCLC is treated, the more likely it is to resemble "pure" SCLC in its response to CT and RT26272829

Targeted agentsedit

In recent years, several new types of "molecularly targeted" agents have been developed and used to treat lung cancer While a very large number of agents targeting various molecular pathways are being developed and tested, the main classes and agents that are now being used in lung cancer treatment include:51

  • Epidermal growth factor receptor EGFR tyrosine kinase inhibitors TKIs:52
    • Erlotinib Tarceva53
    • Gefitinib Iressa54
    • Cetuximab Erbitux55
  • Inhibitors of vascular endothelial growth factor VEGF56
    • Bevacizumab Avastin57
  • Inhibitors of folate metabolism58
    • Pemetrexed Alimta59

To date, most clinical trials of targeted agents, alone and in combination with previously tested treatment regimens, have either been ineffective in SCLC or no more effective than standard platinum-based doublets60616263 While there have been no randomized clinical trials of targeted agents in c-SCLC,64 some small case series suggest that some may be useful in c-SCLC Many targeted agents appear more active in certain NSCLC variants Given that c-SCLC contains components of NSCLC, and that the chemoradioresistance of NSCLC components impact the effectiveness of c-SCLC treatment, these agents may permit the design of more rational treatment regimens for c-SCLC6765

EGFR-TKI's have been found to be active against variants exhibiting certain mutations in the EGFR gene66676869 While EGFR mutations are very rare <5% in "pure" SCLC, they are considerably more common about 15–20% in c-SCLC,1070 particularly in non-smoking females whose c-SCLC tumors contain an adenocarcinoma component These patients are much more likely to have classical EGFR mutations in the small cell component of their tumors as well, and their tumors seem to be more likely to respond to treatment with EGFR-TKI's707172 EGFR-targeted agents appear particularly effective in papillary adenocarcinoma,7374 non-mucinous bronchioloalveolar carcinoma,75 and adenocarcinoma with mixed subtypes74

The role of VEGF inhibition and bevacizumab in treating SCLC remains unknown Some studies suggest it may, when combined with other agents, improve some measures of survival in SCLC patients7677 and in some non-squamous cell variants of NSCLC77665

Pemetrexed has been shown to improve survival in non-squamous cell NSCLC, and is the first drug to reveal differential survival benefit in large cell lung carcinoma778

Interestingly, c-SCLC appear to express female hormone ie estrogen and/or progesterone receptors in a high 50–67% proportion of cases, similar to breast carcinomas79 However, it is at present unknown whether blockade of these receptors affects the growth of c-SCLC

Prognosis and survivaledit

Current consensus is that the long-term prognosis of c-SCLC patients is determined by the SCLC component of their tumor, given that "pure" SCLC seems to have the worst long-term prognosis of all forms of lung cancer8 Although data on c-SCLC is very sparse,20 some studies suggest that survival rates in c-SCLC may be even worse than that of pure SCLC,8081 likely due to the lower rate of complete response to chemoradiation in c-SCLC, although not all studies have shown a significant difference in survival82

Untreated "pure" SCLC patients have a median survival time of between 4 weeks and 4 months, depending on stage and performance status at the time of diagnosis2143

Given proper multimodality treatment, SCLC patients with limited disease have median survival rates of between 16 and 24 months, and about 20% will be cured21438384 In patients with extensive disease SCLC, although 60% to 70% will have good-to-complete responses to treatment, very few will be cured, with a median survival of only 6 to 10 months2184

Some evidence suggests that c-SCLC patients who continue to smoke may have much worse outcomes after treatment than those who quit85


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External linksedit

  • Lung Cancer Home Page The National Cancer Institute site containing further reading and resources about lung cancer
  • 1 World Health Organization Histological Classification of Lung and Pleural Tumours 4th Edition

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