Combined small cell lung carcinoma (or c-SCLC) 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) mixed with one or more components of any histological variant of non-small cell lung carcinoma (NSCLC) in any relative proportion.
In order to ensure that patients receive the proper treatment, it is critical that the pathologist, when making a diagnosis of lung cancer, reports the finding of small cell carcinoma, regardless of other components, because small cell carcinoma is considered the most aggressive of all the lung cancer variants, and its treatment is normally radically different than the other forms of lung cancer (see below).
For epidemiological and statistical purposes, combined small cell carcinoma of the lung has been long classified as a subset of small cell carcinoma, and not as a subset of the other component carcinoma in the sample.
Classification Lung cancer is a large and exceptionally heterogeneous family of malignancies. 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 scheme. Many of these entities are rare, recently described, and poorly understood. 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 management.
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 (i.e. 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 cells. Under WHO-2004, lung carcinomas are divided into 8 major taxa: 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 rates. As a result, it is recommended that all multiphasic malignant lung tumors (i.e. 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 tumor. 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-SCLC. Under the WHO-2004 classification scheme, c-SCLC is the only recognized variant of SCLC.
Histogenesis 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 symptoms. 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 differentiation.
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 result is that the tumor acquires specific cytologic and architectural features suggesting a mixture of SCLC and NSCLC.
Other analyses suggest that, in at least in some cases, more highly differentiated variants of NSCLC (i.e. adenocarcinoma) can "progress" to give rise to areas within the primary (original) tumor (or its metastases) that develop histological and molecular characteristics of SCLC.
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".
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.
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 therapy.
The most common forms of NSCLC identified as components within c-SCLC are large cell carcinoma, adenocarcinoma, and squamous cell carcinoma. Rarer variants of NSCLC are seen less commonly, such as combinations with carcinoids, spindle cell carcinoma, and giant cell carcinoma. Giant cell carcinoma components are seen much more commonly in patients who have undergone radiation.
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. Nearly all clinical trials have been conducted on SCLC patients staged dichotomously in this fashion. 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 metastases.
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 protocol.
Treatment A very large number of clinical trials have been conducted in "pure" SCLC over the past several decades. As a result, evidence-based sets of guidelines for treating monophasic SCLC are available. 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. It is likely, then, that the optimum treatment for patients with c-SCLC remains unknown.
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 brain.
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 diagnosis. This paradigm was driven by early studies showing that the administration of systemic therapies resulted in improved survival as compared to patients undergoing surgical resection. Recent studies, however, have suggested that surgery for highly selected, very early-stage c-SCLC patients may indeed improve outcomes. Other experts recommend resection for residual masses of NSCLC components after complete local tumor response to chemotherapy and/or radiotherapy in c-SCLC.
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. 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), although in Japan amrubicin is considered effective as salvage therapy.
Importantly, c-SCLC is usually much more resistant to CT and RT than "pure" SCLC. 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.
Targeted agents 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: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs): Erlotinib (Tarceva) Gefitinib (Iressa) Cetuximab (Erbitux) Inhibitors of vascular endothelial growth factor (VEGF) Bevacizumab (Avastin) Inhibitors of folate metabolism Pemetrexed (Alimta)
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 doublets. While there have been no randomized clinical trials of targeted agents in c-SCLC, 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-SCLC.