Combined small cell lung carcinoma
Encyclopedia
Combined small cell lung carcinoma (c-SCLC) is a form of multiphasic 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).
(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 98% of lung cancers are carcinoma
, a term for malignant neoplasms derived from cells of epithelial lineage, and/or that exhibit cytological or tissue architectural features characteristically found in epithelial cells. Under WHO-2004, lung carcinomas are divided into 8 major taxa:
SCLC is generally considered to be the most aggressive form of lung cancer, with the worst long term prognosis and survival rates. Therefore, all tumor(s) containing SCLC cells are classified as c-SCLC, and not as combined forms of any other components(s) present, regardless of their relative proportions. The only exception occurs in cases where anaplastic large cell lung carcinoma (LCLC) is the second component. In these instances, a minimum of 10% of the malignant cells must be identified as LCLC before the tumor is considered a c-SCLC. Under WHO-2004, c-SCLC is the only recognized variant of SCLC.
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 examined. In contrast, Nicholson et al. found 28 c-SCLC (28%) in a series of 100 consecutive resected SCLC cases. It appears likely, then, that the c-SCLC variant comprises 25% to 30% of all SCLC cases.
As the incidence of SCLC has declined somewhat in the U.S. in recent decades, 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%. With 220,000 cases of newly diagnosed lung cancer in the U.S. each year, it can be estimated that between 8,800 and 13,200 of these are c-SCLC.
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 component.
However, as patients with tumors containing mixtures of histological subtypes are usually excluded from clinical trials, the properties of multiphasic tumors like c-SCLC are much less well understood than those of monophasic tumors. 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.Simon GR, Turrisi A, American College of Chest Physicians. Management of small cell lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 2007; 132(3 Suppl):324S-39S.
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.
Approximately 98% of lung cancers are carcinoma
, a term which implies that the tumor derives from transformed epithelial cells, or consists of cells that have acquired epithelial characteristics as a result of cell differentiation
. 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.
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. 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 therapy.Brambilla E, Moro D, Gazzeri S, Brichon PY, Nagy-Mignotte H, Morel F, Jacrot M, Brambilla C. Cytotoxic chemotherapy induces cell differentiation in small cell lung carcinoma. J Clin Oncol 1991;9:50-61.
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. 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.
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.
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 amirubicin 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.
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.Rossi A, Galetta D, Gridelli C. Biological prognostic and predictive factors in lung cancer. Oncology 2009;77 (Suppl 1):90-6. 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.Spiro SG, Tanner NT, Silvestri GA, Janes SM, Lim E, Vansteenkiste JF, Pirker R. Lung cancer: progress in diagnosis, staging and therapy. Respirology 2010;15:44-50.
EGFR-TKI's have been found to be active against variants exhibiting certain mutations in the EGFR gene
. While EGFR mutations are very rare (<5%) in "pure" SCLC, they are considerably more common (about 15%-20%) in c-SCLC, 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. EGFR-targeted agents appear particularly effective in papillary adenocarcinoma
, non-mucinous bronchioloalveolar carcinoma, and adenocarcinoma with mixed subtypes.
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 patients and in some non-squamous cell variants of NSCLC.
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 carcinoma.
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. However, it is at present unknown whether blockade of these receptors affects the growth of c-SCLC.
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 diagnosis.
Given proper multimodality treatment, SCLC patients with limited disease have median survival rates of between 16 and 24 months, and about 20% will be cured. 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 months.
Some evidence suggests that c-SCLC patients who continue to smoke may have much worse outcomes after treatment than those who quit.
Lung cancer
Lung cancer is a disease characterized by uncontrolled cell growth in tissues of the lung. If left untreated, this growth can spread beyond the lung in a process called metastasis into nearby tissue and, eventually, into other parts of the body. Most cancers that start in lung, known as primary...
that is diagnosed when a malignant
Malignant
Malignancy is the tendency of a medical condition, especially tumors, to become progressively worse and to potentially result in death. Malignancy in cancers is characterized by anaplasia, invasiveness, and metastasis...
tumor
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
arising from lung
Lung
The lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...
tissue
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
contains a component of small cell lung carcinoma (SCLC) admixed with one (or more) components of non-small cell lung carcinoma (NSCLC).
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 OrganizationWorld Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
(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 98% of lung cancers are carcinoma
Carcinoma
Carcinoma is the medical term for the most common type of cancer occurring in humans. Put simply, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that generally arises from cells originating in the endodermal or ectodermal germ layer during...
, a term for malignant neoplasms derived from cells of epithelial lineage, and/or that exhibit cytological or tissue architectural features characteristically found in epithelial cells. Under WHO-2004, lung carcinomas are divided into 8 major taxa:
- Squamous cell carcinomaSquamous cell carcinomaSquamous cell carcinoma , occasionally rendered as "squamous-cell carcinoma", is a histologically distinct form of cancer. It arises from the uncontrolled multiplication of malignant cells deriving from epithelium, or showing particular cytological or tissue architectural characteristics of...
- Small cell carcinomaSmall cell carcinomaSmall cell carcinoma is a type of highly malignant cancer that most commonly arises within the lung, although it can occasionally arise in other body sites, such as the cervix and prostate....
- AdenocarcinomaAdenocarcinomaAdenocarcinoma is a cancer of an epithelium that originates in glandular tissue. Epithelial tissue includes, but is not limited to, the surface layer of skin, glands and a variety of other tissue that lines the cavities and organs of the body. Epithelium can be derived embryologically from...
- Large cell carcinomaLarge cell carcinomaLarge-cell lung carcinoma is a heterogeneous group of undifferentiated malignant neoplasms originating from transformed epithelial cells in the lung.-Incidence:In most series, LCLC's comprise between 5% and 10% of all lung cancers....
- Adenosquamous carcinomaAdenosquamous carcinomaAdenosquamous carcinoma is a type of cancer that contains two types of cells: squamous cells and gland-like cells.- External links :* entry in the public domain NCI Dictionary of Cancer Terms...
- Sarcomatoid carcinomaSarcomatoid carcinomaSarcomatoid carcinoma is a relatively uncommon form of cancer whose malignant cells have histological, cytological, or molecular properties of both epithelial tumors and mesenchymal tumors .-Sarcomatoid Carcinomas of the Lung:...
- Carcinoid tumor
- Salivary gland-like carcinoma
SCLC is generally considered to be the most aggressive form of lung cancer, with the worst long term prognosis and survival rates. Therefore, all tumor(s) containing SCLC cells are classified as c-SCLC, and not as combined forms of any other components(s) present, regardless of their relative proportions. The only exception occurs in cases where anaplastic large cell lung carcinoma (LCLC) is the second component. In these instances, a minimum of 10% of the malignant cells must be identified as LCLC before the tumor is considered a c-SCLC. Under WHO-2004, c-SCLC is the only recognized variant of SCLC.
Incidence
Reliable comprehensive incidenceIncidence
Incidence may refer to:* Incidence , a measure of the risk of developing some new condition within a specified period of time* Incidence , the binary relations describing how subsets meet...
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
Segmental resection
Segmental resection is a surgical procedure to remove part of an organ or gland. It may also be used to remove a tumor and normal tissue around it. In lung cancer surgery, segmental resection refers to removing a section of a lobe of the lung.- External links :* entry in the public domain NCI...
specimens are examined, and lower when diagnoses are based on small cytology
Cytology
Cytology means "the study of cells".Cytology is that branch of life science, which deals with the study of cells in terms of structure, function and chemistry.Based on usage it can refer to:...
and/or biopsy
Biopsy
A biopsy is a medical test involving sampling of cells or tissues for examination. It is the medical removal of tissue from a living subject to determine the presence or extent of a disease. The tissue is generally examined under a microscope by a pathologist, and can also be analyzed chemically...
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 contrast, Nicholson et al. found 28 c-SCLC (28%) in a series of 100 consecutive resected SCLC cases. It appears likely, then, that the c-SCLC variant comprises 25% to 30% of all SCLC cases.
As the incidence of SCLC has declined somewhat in the U.S. in recent decades, 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%. With 220,000 cases of newly diagnosed lung cancer in the U.S. each year, it can be estimated that between 8,800 and 13,200 of these are c-SCLC.
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 component.
Significance
In terms of case numbers, the estimated 8,800 to 13,200 c-SCLC cases occurring annually in the U.S. 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 (12,300). 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, (see Prognosis and survival) it is arguably critical to better understand these aggressive lesions so specific strategies for their management can be rationally designed.However, as patients with tumors containing mixtures of histological subtypes are usually excluded from clinical trials, the properties of multiphasic tumors like c-SCLC are much less well understood than those of monophasic tumors. 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.Simon GR, Turrisi A, American College of Chest Physicians. Management of small cell lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 2007; 132(3 Suppl):324S-39S.
Histogenesis
In most cases, lung cancers probably result from the malignant transformationMalignant transformation
Malignant transformation is the process by which cells acquire the properties of cancer. This may occur as a primary process in normal tissue, or secondarily as malignant degeneration of a previously existing benign tumor....
of a single multipotent cell
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
. This newly formed cancer stem cell
Cancer stem cell
Cancer stem cells are cancer cells that possess characteristics associated with normal stem cells, specifically the ability to give rise to all cell types found in a particular cancer sample. CSCs are therefore tumorigenic , perhaps in contrast to other non-tumorigenic cancer cells...
then begins to divide uncontrollably, giving rise to new daughter cancer cells in an exponential
Exponential growth
Exponential growth occurs when the growth rate of a mathematical function is proportional to the function's current value...
(or near exponential) fashion. Unless this runaway cell division
Cell division
Cell division is the process by which a parent cell divides into two or more daughter cells . Cell division is usually a small segment of a larger cell cycle. This type of cell division in eukaryotes is known as mitosis, and leaves the daughter cell capable of dividing again. The corresponding sort...
process is checked, a clinically apparent tumor will eventually form.
Approximately 98% of lung cancers are carcinoma
Carcinoma
Carcinoma is the medical term for the most common type of cancer occurring in humans. Put simply, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that generally arises from cells originating in the endodermal or ectodermal germ layer during...
, a term which implies that the tumor derives from transformed epithelial cells, or consists of cells that have acquired epithelial characteristics as a result of cell differentiation
Differentiation
Differentiation may refer to:* Differentiation , the process of finding a derivative* Differentiated instruction in education* Cellular differentiation in biology* Planetary differentiation in planetary science...
. In most cases of c-SCLC, genomic and immunohistochemical studies suggest that the morphological
Morphology (biology)
In biology, morphology is a branch of bioscience dealing with the study of the form and structure of organisms and their specific structural features....
divergence
Divergence
In vector calculus, divergence is a vector operator that measures the magnitude of a vector field's source or sink at a given point, in terms of a signed scalar. More technically, the divergence represents the volume density of the outward flux of a vector field from an infinitesimal volume around...
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
Progression
Progression may refer to:In mathematics:* Arithmetic progression, sequence of numbers such that the difference of any two successive members of the sequence is a constant...
. The end result is that the tumor acquires specific cytologic and architectural features suggesting a mixture of SCLC and NSCLC.
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. 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
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
and/or radiation
Radiation
In physics, radiation is a process in which energetic particles or energetic waves travel through a medium or space. There are two distinct types of radiation; ionizing and non-ionizing...
, probably as a result of a combination of tumor genome-specific "progressional" mutations, stochastic
Stochastic
Stochastic refers to systems whose behaviour is intrinsically non-deterministic. A stochastic process is one whose behavior is non-deterministic, in that a system's subsequent state is determined both by the process's predictable actions and by a random element. However, according to M. Kac and E...
genomic phenomena, and additional mutations induced by the cytotoxic therapy.Brambilla E, Moro D, Gazzeri S, Brichon PY, Nagy-Mignotte H, Morel F, Jacrot M, Brambilla C. Cytotoxic chemotherapy induces cell differentiation in small cell lung carcinoma. J Clin Oncol 1991;9:50-61.
The most common forms of NSCLC identified as components within c-SCLC are large cell carcinoma
Large cell carcinoma
Large-cell lung carcinoma is a heterogeneous group of undifferentiated malignant neoplasms originating from transformed epithelial cells in the lung.-Incidence:In most series, LCLC's comprise between 5% and 10% of all lung cancers....
, adenocarcinoma
Adenocarcinoma
Adenocarcinoma is a cancer of an epithelium that originates in glandular tissue. Epithelial tissue includes, but is not limited to, the surface layer of skin, glands and a variety of other tissue that lines the cavities and organs of the body. Epithelium can be derived embryologically from...
, and squamous cell carcinoma
Squamous cell carcinoma
Squamous cell carcinoma , occasionally rendered as "squamous-cell carcinoma", is a histologically distinct form of cancer. It arises from the uncontrolled multiplication of malignant cells deriving from epithelium, or showing particular cytological or tissue architectural characteristics of...
. Rarer variants of NSCLC are seen less commonly, such as combinations with carcinoids
Carcinoid
Carcinoid is a slow-growing type of neuroendocrine tumor, originating in the cells of the neuroendocrine system.In 2000, the World Health Organization redefined "carcinoid", but this new definition has not been accepted by all practitioners. This has led to some complexity in distinguishing...
, spindle cell carcinoma, and giant cell carcinoma
Giant cell carcinoma of the lung
Giant cell carcinoma of the lung is a rare histological type of undifferentiated lung cancer containing extremely large, bizarre, mono- and multinucleated malignant cells microscopically resembling pleomorphic cells found in some forms of sarcoma....
. Giant cell carcinoma
Giant cell carcinoma of the lung
Giant cell carcinoma of the lung is a rare histological type of undifferentiated lung cancer containing extremely large, bizarre, mono- and multinucleated malignant cells microscopically resembling pleomorphic cells found in some forms of sarcoma....
components are seen much more commonly in patients who have undergone radiation. 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
StagingStaging
Staging may refer to:* Staging , a chef works briefly and without pay in another chef's kitchen to learn to new techniques and cuisines* Staging , the use of multiple engines and propellant to launch a rocket...
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
Supraclavicular lymph nodes
Supraclavicular lymph nodes are lymph nodes found superior to the clavicle, palpable in the supraclavicular fossa.The most notable supraclavicular lymph node is Virchow's node.-External links:* * http://www.med.mun.ca/anatomyts/head/hnl3a.htm...
. 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
Pericardium
The pericardium is a double-walled sac that contains the heart and the roots of the great vessels.-Layers:...
, 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
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
.
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
Diagnosis
Diagnosis is the identification of the nature and cause of anything. Diagnosis is used in many different disciplines with variations in the use of logics, analytics, and experience to determine the cause and effect relationships...
. 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
Cisplatin
Cisplatin, cisplatinum, or cis-diamminedichloroplatinum is a chemotherapy drug. It is used to treat various types of cancers, including sarcomas, some carcinomas , lymphomas, and germ cell tumors...
or carboplatin
Carboplatin
Carboplatin, or cis-Diammineplatinum is a chemotherapy drug used against some forms of cancer...
plus etoposide
Etoposide
Etoposide phosphate is an anti-cancer agent. It is known in the laboratory as a topoisomerase poison. Etoposide is often incorrectly referred to as a topoisomerase inhibitor in order to avoid using the term "poison" in a clinical setting...
or irinotecan
Irinotecan
Irinotecan is a drug used for the treatment of cancer.Irinotecan prevents DNA from unwinding by inhibition of topoisomerase 1. In chemical terms, it is a semisynthetic analogue of the natural alkaloid camptothecin....
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
Topotecan
Topotecan hydrochloride is a chemotherapy agent that is a topoisomerase I inhibitor. It is the water-soluble derivative of camptothecin...
is the only agent which has been definitively shown to offer increased survival over best supportive care (BSC), although in Japan amirubicin is considered effective as salvage therapy
Salvage therapy
Salvage therapy is a form of treatment given after an ailment does not respond to standard treatment. The most common diseases that require salvage therapy are HIV and various tumors...
.
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 receptorEpidermal growth factor receptorThe epidermal growth factor receptor is the cell-surface receptor for members of the epidermal growth factor family of extracellular protein ligands...
(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.Rossi A, Galetta D, Gridelli C. Biological prognostic and predictive factors in lung cancer. Oncology 2009;77 (Suppl 1):90-6. 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.Spiro SG, Tanner NT, Silvestri GA, Janes SM, Lim E, Vansteenkiste JF, Pirker R. Lung cancer: progress in diagnosis, staging and therapy. Respirology 2010;15:44-50.
EGFR-TKI's have been found to be active against variants exhibiting certain mutations in the EGFR gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. While EGFR mutations are very rare (<5%) in "pure" SCLC, they are considerably more common (about 15%-20%) in c-SCLC, 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. EGFR-targeted agents appear particularly effective in papillary adenocarcinoma
Papillary adenocarcinoma
Papillary adenocarcinoma is a histological form of lung cancer that is diagnosed when the malignant cells of the tumor form complex papillary structures and exhibit compressive, destructive growth that replaces the normal lung tissue.- External links :...
, non-mucinous bronchioloalveolar carcinoma, and adenocarcinoma with mixed subtypes.
The role of VEGF inhibition and bevacizumab
Bevacizumab
Bevacizumab is a drug that blocks angiogenesis, the growth of new blood vessels. It is commonly used to treat various cancers, including colorectal, lung, breast, kidney, and glioblastomas....
in treating SCLC remains unknown. Some studies suggest it may, when combined with other agents, improve some measures of survival in SCLC patients and in some non-squamous cell variants of NSCLC.
Pemetrexed
Pemetrexed
Pemetrexed is a chemotherapy drug manufactured and marketed by Eli Lilly and Company. Its indications are the treatment of Pleural Mesothelioma as well as non-small cell lung cancer.-History:...
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 carcinoma.
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. However, it is at present unknown whether blockade of these receptors affects the growth of c-SCLC.
Prognosis and survival
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 cancer. Although data on c-SCLC is very sparse, some studies suggest that survival rates in c-SCLC may be even worse than that of pure SCLC, likely due to the lower rate of complete response to chemoradiation in c-SCLC, although not all studies have shown a significant difference in survival.Untreated "pure" SCLC patients have a median
Median
In probability theory and statistics, a median is described as the numerical value separating the higher half of a sample, a population, or a probability distribution, from the lower half. The median of a finite list of numbers can be found by arranging all the observations from lowest value to...
survival time of between 4 weeks and 4 months, depending on stage and performance status at the time of diagnosis.
Given proper multimodality treatment, SCLC patients with limited disease have median survival rates of between 16 and 24 months, and about 20% will be cured. 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 months.
Some evidence suggests that c-SCLC patients who continue to smoke may have much worse outcomes after treatment than those who quit.
External links
- Lung Cancer Home Page. The National Cancer InstituteNational Cancer InstituteThe National Cancer Institute is part of the National Institutes of Health , which is one of 11 agencies that are part of the U.S. Department of Health and Human Services. The NCI coordinates the U.S...
site containing further reading and resources about lung cancer. - http://www.iarc.fr/en/publications/pdfs-online/pat-gen/bb10/BB10.pdf. World Health Organization Histological Classification of Lung and Pleural Tumours. 4th Edition.