Large cell lung carcinoma with rhabdoid phenotype
Encyclopedia
Large-cell lung carcinoma with rhabdoid phenotype (LCLC-RP), sometimes referred to simply as "rhabdoid carcinoma", is a rare histological variant of large-cell lung carcinoma (LCLC), wherein at least 10% of the malignant cells making up the tumor contain distinctive eosinophilic whorled perinuclear inclusions composed of aggregates of intermediate filaments, giving the cells a microscopic resemblance to rhabdomyosarcoma
, an unrelated malignant tumor of skeletal muscle
.
classification systems divide lung cancers into groups based on medical criteria, particularly their response to different treatment regimens.
Before the mid-1900s, lung cancer was considered to be a single disease entity, with all forms treated similarly. In the 1960s, small cell lung carcinoma (SCLC) was recognized as a unique form of lung cancer, based both on its appearance (histology
) and its clinical
properties, including much greater susceptibility to chemotherapy
and radiation
, more rapid growth rate, and its propensity to metastasize widely early on in its course. Since then, most oncologists have based patient treatment decisions on a dichotomous division of lung cancers into SCLC and non small cell lung carcinomas (NSCLC), with the former being treated primarily with chemoradiation, and the latter with surgery.
An explosion of new knowledge, accumulated mainly over the last 20 years, has proved that lung cancers should be considered an extremely heterogeneous family of neoplasms with widely varying genetic, biological, and clinical characteristics, particularly their responsiveness to the large number of newer treatment protocols. Well over 50 different histological variants are now recognized under the 2004 revision of the World Health Organization
("WHO-2004") typing system, currently the most widely used lung cancer classification scheme. Recent studies have shown beyond doubt that the old clinical classification paradigm of "SCLC vs. NSCLC" is now obsolete, and that correct "subclassification" of lung cancer cases is necessary to assure that lung cancer patients receive optimum management.
Approximately 98% of lung cancers are carcinoma
, which are tumors composed of cells with epithelial characteristics. LCLC's are one of 8 major groups of lung carcinomas recognized in WHO-2004:
Microscopic characteristics of rhabdoid cells include:
The differential diagnosis of LCLC-RP includes secondary metastatic lesions, melignant melanoma
of the lung with rhabdoid phenotype
, mucinous adenocarcinomas (particularly those featuring signet-ring cells), rhabdomyosarcoma
, epitheloid angiosarcoma, pleural mesothelioma, and plasmacytoma
.
On radiological imaging, most cases of LCLC-RP are single "coin lesions" or discrete masses, but cases presenting as multiple nodules throughout the lung have also been noted. LCLC-RP may also be a tumor variant that is particularly susceptible to massive central necrosis and cavitation, with rhabdoid cells flourishing and progressing only in a "rim" remaining at the edge of the necrotic tumor mass.
Results of immunohistochemistry
staining in rhabdoid lung cancers tends to reflect the multiphasic nature of these tumors. Typically, markers expressed in LCLC-RP include those seen in "generic" NSCLC's, such as epithelial membrane antigen (EMA, 61%) and various cytokeratins (CK's, 80%), and markers associates with the underlying "parent" pulmonary carcinoma. Expression of immunomarkers in the rhabdoid cells, however, have often been noted to be weaker and more diffuse than those in the more differentiated tumor cells. They also more frequently express "non-carcinomatous" markers typically associated with "dedifferentiated" neoplasms. Interestingly, expression of thyroid transcription factor-1 (TTF-1), a commonly used marker for primary lung cancers, appears to be less frequent in rhabdoid carcinomas than in most other histotypes of pulmonary cancers.
Vimentin, an intermediate filament protein usually found in sarcoma
, is ubiquitously (nearly 100%) expressed diffusely throughout the cytoplasm
of the rhabdoid cells, and is often intermingled with CK's in their whorled inclusions. Neuroendocrine-related markers (i.e. neuron-specific enolase (NSE), neural cell adhesion molecule (NCAM), chromogranin A (CgA), and synaptophysin, are also quite frequently expressed in a significant proportion of rhabdoid cells.
Some evidence suggests that cells with the rhabdoid phenotype result from further mutations occurring in some cells of the "parent" tumor, which leads to "emergence" of distinct cells with the rhabdoid phenotype within the parent neoplasm, often in the peripheral part of the tumor. Missense mutations occurring in the cytokeratin 8 gene (RTK 8) at specific codons affects the way the protein products of this gene assume their normal shape and undergo assembly into filamentous structures within the cytoplasm. These defective "protofilament" products apparently accumulate to form the distinctive whorled paranuclear inclusions of the rhabdoid cell. It seems likely that mutations (and possibly post-tranlational modifications) affecting cytokeratins 8 and 18, and possibly vimentin, protofilaments are intimately involved in the genesis of the characteristic inclusions, and therefore, the rhabdoid phenotype. The particulars of this process are poorly understood, but depend in part on the origin of the tumor and stochastic genomic phenomena.
Rhabdoid cells often express protein products suggestive of aggressive, dedifferentiated cells, including neuroendocrine tumor-related products and granulocyte-macrophage colony stimulating factor (GM-CSF). Vimentin
, which is an intermediate filament protein usually associated with non-carcinomatous tumors (i.e. sarcoma
), is ubiquitous in rhabdoid cells. Co-expression of cytokeratins and vimentin are associated with cells undergoing epithelial-mesenchymal transition
(EMT).
While undifferentiated large-cell lung carcinoma is the most common parent lung tumor from which a rhabdoid phenotype evolves, malignant cells with a rhabdoid phenotype are known to occur in many different histological variants of lung cancer, including adenocarcinoma, sarcomatoid carcinoma, squamous cell carcinoma, combined large-cell neuroencrine carcinoma, and mucinous bronchioloalveolar carcinoma and combined small-cell lung carcinoma.
In numerous clinical trials conducted in NSCLC, several different platinum-based chemotherapy regimens have been shown to be more-or-less equally effective. LCLC's, as a subtype of NSCLC, have traditionally been included in many of these clinical trials, and have been treated like other NSCLC's. More recent trials, however, have shown that some newer agents may have particular effectiveness in prolonging survival of LCLC patients. Pemetrexed, in particular, has shown significant reduction in the hazard ratio for death when used in patients with LCLC. Taxane-based (paclitaxel
, docetaxel) chemotherapy was shown to induce a complete and sustained response in a liver metastasis in a case of LCC-RP. A later-appearing metastasis within mediastinal lymph nodes in the same case also showed a durable response to a taxane alone.
There have also been reports of rhabdoid carcinomas expressing vascular endothelial growth factor (VEGF), suggesting that targeted molecular therapy with VEGF blocking monoclonal antibodies such as bevacizumab
may be active in these variants. However, evidence suggests that caution must be used when treating a cavitated rhabdoid tumor, one that contains significant components of squamous cell differentiation, or large tumors with containing major blood vessels, due to the potential high risk of life-threatening pulmonary hemorrhage.
A recent study reported a case wherein 2 courses of adjuvant therapy with cisplatin and paclitaxel, followed by oral gefitinib, were used after complete resection. The patient had had no recurrence 34 months later.
Interestingly, there are case reports of rhabdoid carcinomas recurring after unusually long periods, which is unusual for a fast growing, aggressive tumor type. One report described a very early stage patient whose tumor recurred 6 years after initial treatment. Although rapidly progressive, fulminant courses seem to be the rule in this entity, long term survival has also been noted, even post-metastectomy in late stage, distant metastatic disease.
LCLC with rhabdoid phenotype appears to be highly related to tobacco smoking, and to be more common in males than in females.
Rhabdomyosarcoma
A rhabdomyosarcoma is a type of cancer, specifically a sarcoma , in which the cancer cells are thought to arise from skeletal muscle progenitors. It can also be found attached to muscle tissue, wrapped around intestines, or in any anatomic location...
, an unrelated malignant tumor of skeletal muscle
Muscle
Muscle is a contractile tissue of animals and is derived from the mesodermal layer of embryonic germ cells. Muscle cells contain contractile filaments that move past each other and change the size of the cell. They are classified as skeletal, cardiac, or smooth muscles. Their function is to...
.
Classification
Lung cancers have been historically classified using two major paradigms. Histological classification systems group lung cancers according to the appearance of the cells and surrounding tissues when they are viewed under a microscope. ClinicalIllness
Illness is a state of poor health. Illness is sometimes considered another word for disease. Others maintain that fine distinctions exist...
classification systems divide lung cancers into groups based on medical criteria, particularly their response to different treatment regimens.
Before the mid-1900s, lung cancer was considered to be a single disease entity, with all forms treated similarly. In the 1960s, small cell lung carcinoma (SCLC) was recognized as a unique form of lung cancer, based both on its appearance (histology
Histology
Histology is the study of the microscopic anatomy of cells and tissues of plants and animals. It is performed by examining cells and tissues commonly by sectioning and staining; followed by examination under a light microscope or electron microscope...
) and its clinical
Illness
Illness is a state of poor health. Illness is sometimes considered another word for disease. Others maintain that fine distinctions exist...
properties, including much greater susceptibility to 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 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...
, more rapid growth rate, and its propensity to metastasize widely early on in its course. Since then, most oncologists have based patient treatment decisions on a dichotomous division of lung cancers into SCLC and non small cell lung carcinomas (NSCLC), with the former being treated primarily with chemoradiation, and the latter with surgery.
An explosion of new knowledge, accumulated mainly over the last 20 years, has proved that lung cancers should be considered an extremely heterogeneous family of neoplasms with widely varying genetic, biological, and clinical characteristics, particularly their responsiveness to the large number of newer treatment protocols. Well over 50 different histological variants are now recognized under the 2004 revision of the World Health Organization
World 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-2004") typing system, currently the most widely used lung cancer classification scheme. Recent studies have shown beyond doubt that the old clinical classification paradigm of "SCLC vs. NSCLC" is now obsolete, and that correct "subclassification" of lung cancer cases is necessary to assure that lung cancer patients 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...
, which are tumors composed of cells with epithelial characteristics. LCLC's are one of 8 major groups of lung carcinomas recognized in WHO-2004:
- Squamous cell carcinoma
- Small cell carcinoma
- Adenocarcinoma
- Large cell carcinoma
- Adenosquamous carcinoma
- Sarcomatoid carcinoma
- Carcinoid tumor
- Salivary gland like carcinoma
The Rhabdoid Phenotype
Colby and colleagues were the first to report a primary lung cancer with a rhabdoid phenotype in a paper published in 1995. LCLC-RP were first recognized as a distinct entity under the 3rd WHO classification system, published in 1999.Diagnosis
While occasional scattered rhabdoid cell formation occurs with considerable frequency in lung carcinomas, this is not considered to be of clinical significance. According to current classification criteria, a tumor can only be diagnosed as LCLC-RP when an undifferentiated large-cell lung carcinoma contains a rhabdoid cell component that makes up at least 10% of the tumor mass.Microscopic characteristics of rhabdoid cells include:
- Oval to polygonal cell shape
- Eosinophilic, hyaline-like perinuclear agglomerations of intermediate filaments
- Compressed, eccentric nuclei
- Prominent central macronucleoli (one or two)
- Abundant eosinophilic cytoplasm
- Reticular chromatin pattern
The differential diagnosis of LCLC-RP includes secondary metastatic lesions, melignant melanoma
Melanoma
Melanoma is a malignant tumor of melanocytes. Melanocytes are cells that produce the dark pigment, melanin, which is responsible for the color of skin. They predominantly occur in skin, but are also found in other parts of the body, including the bowel and the eye...
of the lung with rhabdoid phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
, mucinous adenocarcinomas (particularly those featuring signet-ring cells), rhabdomyosarcoma
Rhabdomyosarcoma
A rhabdomyosarcoma is a type of cancer, specifically a sarcoma , in which the cancer cells are thought to arise from skeletal muscle progenitors. It can also be found attached to muscle tissue, wrapped around intestines, or in any anatomic location...
, epitheloid angiosarcoma, pleural mesothelioma, and plasmacytoma
Plasmacytoma
Plasmacytoma refers to a malignant plasma cell tumor growing within soft tissue or within the skeleton. The skeletal forms usually have other occult tumors and frequently disseminate to multiple myeloma over the course of 5–10 years. The soft tissue forms most often occur in the upper respiratory...
.
On radiological imaging, most cases of LCLC-RP are single "coin lesions" or discrete masses, but cases presenting as multiple nodules throughout the lung have also been noted. LCLC-RP may also be a tumor variant that is particularly susceptible to massive central necrosis and cavitation, with rhabdoid cells flourishing and progressing only in a "rim" remaining at the edge of the necrotic tumor mass.
Results of immunohistochemistry
Immunohistochemistry
Immunohistochemistry or IHC refers to the process of detecting antigens in cells of a tissue section by exploiting the principle of antibodies binding specifically to antigens in biological tissues. IHC takes its name from the roots "immuno," in reference to antibodies used in the procedure, and...
staining in rhabdoid lung cancers tends to reflect the multiphasic nature of these tumors. Typically, markers expressed in LCLC-RP include those seen in "generic" NSCLC's, such as epithelial membrane antigen (EMA, 61%) and various cytokeratins (CK's, 80%), and markers associates with the underlying "parent" pulmonary carcinoma. Expression of immunomarkers in the rhabdoid cells, however, have often been noted to be weaker and more diffuse than those in the more differentiated tumor cells. They also more frequently express "non-carcinomatous" markers typically associated with "dedifferentiated" neoplasms. Interestingly, expression of thyroid transcription factor-1 (TTF-1), a commonly used marker for primary lung cancers, appears to be less frequent in rhabdoid carcinomas than in most other histotypes of pulmonary cancers.
Vimentin, an intermediate filament protein usually found in sarcoma
Sarcoma
A sarcoma is a cancer that arises from transformed cells in one of a number of tissues that develop from embryonic mesoderm. Thus, sarcomas include tumors of bone, cartilage, fat, muscle, vascular, and hematopoietic tissues...
, is ubiquitously (nearly 100%) expressed diffusely throughout the cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
of the rhabdoid cells, and is often intermingled with CK's in their whorled inclusions. Neuroendocrine-related markers (i.e. neuron-specific enolase (NSE), neural cell adhesion molecule (NCAM), chromogranin A (CgA), and synaptophysin, are also quite frequently expressed in a significant proportion of rhabdoid cells.
Histogenesis and genetics
The histogenesis of most lung cancers is not well understood. Carcinomas of the lung are thought to arise from the uncontrolled growth of mutated, transformed multipotent "cancer stem cells" with epithelial characteristics. When viewed under a light microscope, the transformed cancer cells in LCLC are undifferentiated, lacking the specific cytological and tissue architectural characteristics of other types, subtypes, and variants of lung cancer. Election microscopic studies, however, have shown that many LCLC do have ultrastructural characteristics of other tumor types (i.e. adenocarcinoma, squamous cell carcinoma)., and that rhabdoid carcinomas often show similar features.Some evidence suggests that cells with the rhabdoid phenotype result from further mutations occurring in some cells of the "parent" tumor, which leads to "emergence" of distinct cells with the rhabdoid phenotype within the parent neoplasm, often in the peripheral part of the tumor. Missense mutations occurring in the cytokeratin 8 gene (RTK 8) at specific codons affects the way the protein products of this gene assume their normal shape and undergo assembly into filamentous structures within the cytoplasm. These defective "protofilament" products apparently accumulate to form the distinctive whorled paranuclear inclusions of the rhabdoid cell. It seems likely that mutations (and possibly post-tranlational modifications) affecting cytokeratins 8 and 18, and possibly vimentin, protofilaments are intimately involved in the genesis of the characteristic inclusions, and therefore, the rhabdoid phenotype. The particulars of this process are poorly understood, but depend in part on the origin of the tumor and stochastic genomic phenomena.
Rhabdoid cells often express protein products suggestive of aggressive, dedifferentiated cells, including neuroendocrine tumor-related products and granulocyte-macrophage colony stimulating factor (GM-CSF). Vimentin
Vimentin
Vimentin is a type III intermediate filament protein that is expressed in mesenchymal cells. IF proteins are found in all metazoan cells as well as bacteria. IF, along with tubulin-based microtubules and actin-based microfilaments, comprise the cytoskeleton...
, which is an intermediate filament protein usually associated with non-carcinomatous tumors (i.e. sarcoma
Sarcoma
A sarcoma is a cancer that arises from transformed cells in one of a number of tissues that develop from embryonic mesoderm. Thus, sarcomas include tumors of bone, cartilage, fat, muscle, vascular, and hematopoietic tissues...
), is ubiquitous in rhabdoid cells. Co-expression of cytokeratins and vimentin are associated with cells undergoing epithelial-mesenchymal transition
Epithelial-mesenchymal transition
Epithelial-mesenchymal transition or transformation is a hypothesized program of development of biological cells characterized by loss of cell adhesion, repression of E-cadherin expression, and increased cell mobility...
(EMT).
While undifferentiated large-cell lung carcinoma is the most common parent lung tumor from which a rhabdoid phenotype evolves, malignant cells with a rhabdoid phenotype are known to occur in many different histological variants of lung cancer, including adenocarcinoma, sarcomatoid carcinoma, squamous cell carcinoma, combined large-cell neuroencrine carcinoma, and mucinous bronchioloalveolar carcinoma and combined small-cell lung carcinoma.
Treatment
Because LCLC-RP is so rare, no clinical trials have ever been conducted that specifically address treatment of this lung cancer variant. Because LCLC-RP is considered a form of non-small cell lung carcinoma (NSCLC), most physicians adhere to published NSCLC treatment guidelines in rhabdoid carcinoma cases. When possible, radical surgical resection with curative intent is the primary treatment of choice in nearly all NSCLC's (with or without adjuvant, neoadjuvant, or palliative chemotherapy and/or radiotherapy, depending on the disease stage and performance status of the individual patient).In numerous clinical trials conducted in NSCLC, several different platinum-based chemotherapy regimens have been shown to be more-or-less equally effective. LCLC's, as a subtype of NSCLC, have traditionally been included in many of these clinical trials, and have been treated like other NSCLC's. More recent trials, however, have shown that some newer agents may have particular effectiveness in prolonging survival of LCLC patients. Pemetrexed, in particular, has shown significant reduction in the hazard ratio for death when used in patients with LCLC. Taxane-based (paclitaxel
Paclitaxel
Paclitaxel is a mitotic inhibitor used in cancer chemotherapy. It was discovered in a U.S. National Cancer Institute program at the Research Triangle Institute in 1967 when Monroe E. Wall and Mansukh C. Wani isolated it from the bark of the Pacific yew tree, Taxus brevifolia and named it taxol...
, docetaxel) chemotherapy was shown to induce a complete and sustained response in a liver metastasis in a case of LCC-RP. A later-appearing metastasis within mediastinal lymph nodes in the same case also showed a durable response to a taxane alone.
There have also been reports of rhabdoid carcinomas expressing vascular endothelial growth factor (VEGF), suggesting that targeted molecular therapy with VEGF blocking monoclonal antibodies such as 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....
may be active in these variants. However, evidence suggests that caution must be used when treating a cavitated rhabdoid tumor, one that contains significant components of squamous cell differentiation, or large tumors with containing major blood vessels, due to the potential high risk of life-threatening pulmonary hemorrhage.
A recent study reported a case wherein 2 courses of adjuvant therapy with cisplatin and paclitaxel, followed by oral gefitinib, were used after complete resection. The patient had had no recurrence 34 months later.
Prognosis
LCLC-RP are considered to be especially aggressive tumors with a dismal prognosis. Many published cases have shown short survival times after diagnosis. Some studies suggest that, as the proportion of rhabdoid cells in the tumor increases, the prognosis tends to worsen, although this is most pronounced when the proportion of rhabdoid cells exceeds 5%. With regard to "parent" neoplasms other than LCLC, adenocarcinomas with rhabdoid features have been reported to have worse prognoses than adenocarcinomas without rhabdoid features, although an "adenocarcinoma with rhabdoid phenotype" tumor variant has not been specifically recognized as a distinct entity under the WHO-2004 classification system.Interestingly, there are case reports of rhabdoid carcinomas recurring after unusually long periods, which is unusual for a fast growing, aggressive tumor type. One report described a very early stage patient whose tumor recurred 6 years after initial treatment. Although rapidly progressive, fulminant courses seem to be the rule in this entity, long term survival has also been noted, even post-metastectomy in late stage, distant metastatic disease.
Epidemiology
Although reliable and comprehensive incidence statistics are nonexistent, LCLC-RP is known to be a rare tumor, with only a few hundred cases reported in the scientific literature to date. LCLC's make up about 10% of all lung cancers in most series, equating to approximately 22,000 cases per year in the U.S. Of these, it is estimated that approximately 1% eventually develop the rhabdoid phenotype during tumor evolution. In one large series of 902 surgically resected lung cancers, only 3 cases (0.3%) were diagnosed as LCLC-RP. In another highly selected series of large-cell lung carcinoma cases, 4 of 45 tumors (9%) were diagnosed as the rhabdoid phenotype using the 10% criterion, while another 10 (22%) had at least some rhabdoid cell formation. It appears, therefore, that LCLC-RP probably comprises between 0.1% and 1.0% of all lung malignancies.LCLC with rhabdoid phenotype appears to be highly related to tobacco smoking, and to be more common in males than in females.
External links
- http://www.iarc.fr/en/publications/pdfs-online/pat-gen/index.php World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Lung, Pleura, Thymus and Heart (Download Page).
- http://www.cancer.gov/cancertopics/types/lung Lung cancer page at the National Cancer Institute.