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Combined small-cell lung carcinoma

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Combined Small Cell Lung Carcinoma (c-SCLC) is a form of lung cancer that is diagnosed when a malignant tumor arising from lung tissue contains a component of small cell lung carcinoma (SCLC) admixed with one (or more) components of non-small cell lung carcinoma (NSCLC).[1][2][3]

Classification

Lung cancer is an extremely heterogeneous family of malignant neoplasms[4], with well over 50 different histological variants recognized under the 4th revision of the World Health Organization (WHO) typing system, currently the most widely used lung cancer classification scheme.[1] Because these variants have differing genetic, biological, and clinical properties, including response to treatment, correct classification of lung cancer cases are necessary to assure that lung cancer patients receive optimum management.[5][6]

Because SCLC is considered to be the most aggressive form of lung cancer, with the lowest survival rate,[7] tumors containing SCLC admixed with other histological types are classified as c-SCLC, and not as combined forms of the other types present in the tumor. C-SCLC is the only currently recognized variant of SCLC.[1]

Incidence

Reliable comprehensive incidence statistics for c-SCLC are unavailable. The frequency with which the c-SCLC variant is diagnosed largely depends on the size of the tumor sample, tending to be considerably higher in series where large surgical resection specimens are examined, and much 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 examined in their series.[8] In contrast, Nicholson et al. found 28 c-SCLC (28%) among 100 consecutive resected SCLC cases.[9] It appears likely, then, that the c-SCLC variant comprises 25% to 30% of all SCLC cases.[10]

As the incidence of SCLC has declined somewhat in the U.S. in recent decades,[11] 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%.[12]. Given a total of 220,000 cases of newly diagnosed lung cancers in the U.S. each year, it can be estimated that some 8,000 to 12,500 of these are c-SCLC.[13].

Significance

Given that 8,000 to 12,500 c-SCLC cases occur annually in the U.S., and the extreme seriousness of this type of malignancy (see Prognosis and Survival, below) it is arguably critical to better understand these aggressive lesions so specific strategies for their management can be rationally designed.[5][6][14]

However, patients with tumors containing mixtures of histological subtypes are usually excluded from clinical trials,[15] and therefore, the properties of multiphasic tumors like c-SCLC are much less well understood than those of monophasic tumors.[16] 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 uniquely.[17]

Histogenesis

In most cases, lung cancers probably result from the malignant transformation of a single multipotent cell. This newly formed 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.[18]

Approximately 98% of lung cancers are carcinoma, a term which implies that the tumor derives from transformed epithelial cells, or cells that have acquired epithelial characteristics as a result of cell differentiation.[7] In most cases of c-SCLC, genomic and immunohistochemical studies suggest that the morphological divergence of the separate components in a c-SCLC 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 NSCLC.[10]

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.[19][20]

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 variants.[21]

C-SCLC also occurs quite commonly after treatment of "pure" SCLC with chemotherapy and/or radiation, probably as a result of both progressional mutations and some additional mutations induced by the cytotoxic therapy.[22][23][24][25]

The most common forms of NSCLC identified as components within c-SCLC are large cell carcinoma, adenocarcinoma, and squamous cell carcinoma.[2][4][16] Rarer variants of NSCLC are seen less commonly, such as combinations with carcinoids,[16] spindle cell carcinoma,[2][3] and giant cell carcinoma.[9] Giant cell carcinoma components are seen much more commonly in patients who have undergone radiation.[26][27][28]

Staging

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 burdens.[29][30] Nearly all clinical trials have been conducted on SCLC patients staged dichotomously in this fashion.[31] LD is roughly defined as a locoregional tumor burden that can be encompassed within a single, tolerable radiation port, without detectable distant metastases beyond the chest or supraclavicular lymph nodes. ED is defined as a tumor burden greater than that defined as LD - either far advanced locoregional disease, distant metastases, or a pleural effusion.[32]

Recent data reviewing outcomes in very large numbers of SCLC patients suggests that the TNM staging system used for NSCLC is also applicable to SCLC patients, and indeed may allow better treatment decisionmaking and prognostication than the old dichotomous staging protocol.[29][33][34]

Treatment

A very large number of clinical trials have been conducted in SCLC over the past several decades.[31]. As a result, an evidence-based set of guidelines for treating SCLC is available.[17] The generally accepted current standard of care 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 brain.[17]

Surgery is not usually considered as a treatment option in SCLC (including c-SCLC) due to high probability of distant metastases at the time of diagnosis.[35][36][37]. Recent studies, however, have suggested that surgery for highly selected, very early-stage c-SCLC patients may indeed improve outcomes.[38]

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 SCLC.[17][39] 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), [17][40] although in Japan amirubicin is considered effective as salvage therapy.[40]

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 weak.[17] It is likely, then, that the optimum treatment for patients with c-SCLC remains unknown.[16]

Importantly, c-SCLC is usually much more resistant to CT and RT than "pure" SCLC.[23][25][41][42][43][44] 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 RT.[21][22][23][24]

Molecularly Targeted Agents and c-SCLC Treatment

In recent years, several new "molecularly targeted" and "semi-targeted" agents have been developed and used to treat lung cancer. These agents appear to be somewhat more active in, and selective for, certain histological types of lung cancer (particularly NSCLC variants) than previously developed agents, strongly suggest that treatment paradigms for c-SCLC may evolve and improve more rapidly in coming years, given that c-SCLC contains components of NSCLC, and that the chemoradioresistance of the NSCLC component can greatly impact treatment, it is logical that these agents may prove effective in improving treatment regimens in c-SCLC, particularly in certain subgroups of patients.[45].[5][6][5][6] Given that

Furthermore, the recent identification and use of new agents and combinations of older agents that are more highly active in certain histological variants of lung cancer

The most important classes and agents now being used and tested include:

  • Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI's)
  • Inhibitors of vascular endothelial growth factor (VEGF)
  • Inhibitors of folate metabolism

EGFR-TKI's have been found to be active against lung cancer variants that exhibit mutations in certain codons of the EGFR gene. While EGFR mutations are very rare (<5%) in "pure" SCLC, they are considerably more common (about 15%-20%) in c-SCLC,[46][8] 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's.[47][48][46]


including bevacizumab , a monoclonal antibody targeted against vascular endothelial growth factor (VEGF) receptor protein called cetuximab, and the angiogenesis inhibitor bevacizumab.[45] Clinical trials of these agents have shown that they are more effective and active in some histological variants of lung cancer, and some may be harmful when used in others.[6] In addition, a newer "conventional" cytotoxic drug called pemetrexed, which inhibits folate synthesis, also shows considerable histological selectivity in lung cancer.


Expand: Pemetrexed[49]



Small molecules such as erlotinib and gefitinib greatly inhibit epidermal growth factor receptor (EGFR) tyrosine kinase activity when certain mutations are present.[50][51][52][53]

EGFR-targeted agents appear particularly effective in papillary adenocarcinoma,</ref>De Oliveira Duarte Achcar R, Nikiforova MN, Yousem SA. Micropapillary lung adenocarcinoma: EGFR, K-ras, and BRAF mutational profile. Am J Clin Pathol 2009;131:694-700.</ref>[54], non-mucinous bronchioloalveolar carcinoma,[55], and adenocarcinoma with mixed subtypes.[54] While SCLC rarely

Results of early SCLC trials using erlotinib, gefitinib, cetuximab, and pemetrexed., either alone or in combination with platinum, are almost uniformly negative/inferior compared to a platinum-etoposide doublet.[56][57][58][59]

Bevacizumab is a monoclonal antibody against vascular endothelial growth factor (VEGF) that may improve some measures of survival in both SCLC.[60]

Interestingly, c-SCLC appear to express female hormone (i.e. estrogen and/or progesterone) receptors in a high (50%-67%) proportion of cases, similar to breast carcinomas[61] However, it is at present unknown whether blockade of these receptors affects the growth of c-SCLC.

Prognosis and Survival

Untreated SCLC patients have a hopeless prognosis, with a median survival time of between 4 weeks and 4 months, depending on stage and performance status.[37].[17]

Given proper multimodality treatment with curative intent, SCLC patients with limited disease have median survival rates of between 16 and 24 months, and about 20% will be cured.[62] with about 14% to 20% surviving 5 years.[37][17] In patients with extensive disease SCLC, although 60% to 70% will have good responses to treatment, very few will be cured, with median survival of only 6 to 10 months.[62][17]

Although data on c-SCLC is very sparse[16], some studies suggest that survival rates in c-SCLC may be even worse than that of pure SCLC,[63] [64] possibly due to the lower rate of response to chemoradiation in c-SCLC, although not all studies have shown a significant difference.[65]

Some evidence suggests that c-SCLC patients who continue to smoke may have much worse outcomes after treatment than those who quit.[66]

Current evidence suggests that, in most cases, the long-term prognosis of c-SCLC patients is determined by the SCLC component, given that "pure" SCLC seems to have the worst long-term prognosis of all forms of SCLC.[7]

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  • [1] World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart.
  • [2] National Library of Medicine
  • [3] Lung Cancer page at the National Cancer Institute.
  • [4] Clinical Trials for Small Cell Lung Cancer
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