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Large Cell Lung Carcinoma With Rhabdoid Phenotype Information

Large Cell Lung Carcinoma with Rhabdoid Phenotype (LCLC-RP) is a rare histological variant of large cell lung carcinoma (LCLC), wherein at least 10% of the cells contain distinctive eosinophilic whorled perinuclear inclusions composed of intermediate filaments,[1][2] giving the cells a general microscopic resemblance to rhabdomyosarcoma, an unrelated highly malignant tumor of skeletal muscle.[3]

Contents

Classification

Lung cancers are an extremely heterogeneous family of malignant neoplasms[4], with well over 50 different histological variants recognized under the 2004 revision of the World Health Organization ("WHO-2004") typing system, currently the most widely used lung cancer classification scheme.[2] Because these variants can have widely 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]

Approximately 98% of lung cancers are carcinoma, which are tumors composed of cells with epithelial characteristics.[7] LCLC's are one of 8 major groups of lung carcinomas recognized in WHO-2004:[2]

Colby and colleagues were the first to report a primary lung cancer with a rhabdoid phenotype in a paper published in 1995.[8] LCLC-RP were first recognized as a distinct entity under the 3rd WHO classification system, published in 1999.[9]

Diagnosis

While occasional scattered rhabdoid cell formation occurs with considerable frequency in lung carcinomas, this is not considered to be of any clinical significance.[10][11] 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.[12]

Microscopic characteristics of rhabdoid cells include[2][10][13]:

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, mesothelioma, and plasmacytoma.[10][11][13][14] 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.[15] 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.[16]

Results of immunohistochemistry staining in rhabdoid lung cancers tends to reflect the multiphasic nature of these tumors. Typical expressed markers include those of "generic" NSCLC's, such as epithelial membrane antigen (61%)and various cytokeratins (80%), as well as those of the underlying "parent" pulmonary carcinoma. These markers are also often expressed in the rhabdoid cells too, although they may be weaker and more diffuse.[10][13] They also frequently express "non-carcinomatous" markers, some of which are associated with "dedifferentiated" neoplasms. Interestingly, expression of thyroid transcription factor-1 (TTF-1), a commonly used marker for primary lung cancers, appears to be infrequent in rhabdoid carcinomas.[17]

Vimentin, an intermediate filament usually found in sarcoma, is ubiquitously (100%) expressed - often intermingled with cytokeratins - in the whorled inclusions and diffusely throughout the cytoplasm. Neuroendocrine-related markers, such as neuron-specific enolase, neural cell adhesion molecule, chromogranin, and synaptophysin, are also quite frequently expressed to some degree in a significant proportion of rhabdoid cells.[10][11][13]

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.[2] Election microscopic studies, however, have shown that many LCLC do have ultrastructural characteristics of other tumor types (i.e. adenocarcinoma, squamous cell carcinoma).[18], and that rhabdoid carcinomas often show similar features.[19]

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.[14][16][19] Missense mutations occurring in the cytokeratin 8 gene (RTK 8)[20] 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.[21] 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[22] and stochastic genomic phenomena.[23][24]

Rhabdoid cells often express protein products suggestive of aggressive, dedifferentiated cells, including neuroendocrine tumor-related products[11] and granulocyte-macrophage colony stimulating factor (GM-CSF).[19][25] Vimentin, which is an intermediate filament protein usually associated with non-carcinomatous tumors (i.e. sarcoma), is ubiquitous in rhabdoid cells.[26]. Co-expression of cytokeratins and vimentin are associated with cells undergoing epithelial-mesenchymal transition (EMT).[27][28]

While undifferentiated large cell lung carcinoma is the most common parent lung tumor from which a rhabdoid phenotype evolves,[10] malignant cells with a rhabdoid phenotype are known to occur in many different histological variants of lung cancer, including adenocarcinoma[17], sarcomatoid carcinoma,[13][17], squamous cell carcinoma,[29], combined large cell neuroencrine carcinoma,[29] and mucinous bronchioloalveolar carcinoma [30] and combined small cell lung carcinoma.[29]

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 is the primary treatment of choice in 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.[31]

In numerous clinical trials of (generic) NSCLC, several different platinum-based chemotherapy regimens have been shown to be more-or-less equally effective.[31] 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.[5][6] Pemetrexed, in particular, has shown significant reduction in the hazard ratio for death when used in patients with LCLC.[32] 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.[10]

There have also been reports of rhabdoid carcinomas expressing vascular endothelial growth factor (VEGF),[16] suggesting that targeted molecular therapy with VEGF blocking monoclonal antibodies such as bevacizumab may be active in these variants.[33][34][35] 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.[33]

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.[25]

Prognosis

LCLC-RP are considered to be especially aggressive tumors with a dismal prognosis.[5][17][24] Many published cases have shown short survival times after diagnosis.[11][36] Some studies suggest that, as the proportion of rhabdoid cells in the tumor increases, the prognosis tends to worsen,[11] although this is most pronounced when the proportion of rhabdoid cells exceeds 5%.[11] With regard to "parent" neoplasms other than LCLC, adenocarcinomas with rhabdoid features have been reported to have worse prognoses than adenocarcinomas without rhabdoid features,[37] although an "adenocarcinoma with rhabdoid phenotype" tumor variant has not been specifically recognized as a distinct entity under the WHO-2004 classification system.[2]

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.[16] 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.[13]

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.[10][18] LCLC's make up about 10% of all lung cancers in most series,[2][7][38][39] equating to approximately 22,000 cases per year in the U.S.[40] Of these, it is estimated that approximately 1% eventually develop the rhabdoid phenotype during tumor evolution.[18] 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.[11] 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.[17]

References

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