Large-cell lung carcinoma with rhabdoid phenotype

Large Cell Lung Carcinoma with Rhabdoid Phenotype
Specialty	Oncology

Large cell lung carcinoma with rhabdoid phenotype (LCLC-RP) is a rare

• Squamous cell lung carcinoma
• Small cell lung carcinoma
• Adenocarcinoma of the lung
• Large cell lung carcinoma
• Adenosquamous carcinoma
• Sarcomatoid carcinoma
• Carcinoid tumor
• Salivary gland-like carcinoma of the lung

LCLC-RP are considered variants of

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 or lineage. When viewed under a light microscope, the transformed cancer cells in LCLC are undifferentiated, lacking 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).,^[8] and that rhabdoid carcinomas often show similar features.^[9]

Some evidence suggests that cells with the rhabdoid phenotype result from mutations occurring in some of the cells descending from the "parent" tumor, leading to the "emergence" of distinct populations of characteristic cells with the rhabdoid phenotype within the parent neoplasm, often in the peripheral part of the tumor.^[10][11][9] Missense mutations occurring in the cytokeratin 8 (CK-8) gene (RTK 8)^[12] at specific codons affects the way the protein products of this gene assume their normal two- and three-dimensional shapes, and may well affect the way the mutant proteins undergo assembly into filamentous structures within the cytoplasm. The defective "protofilament" products apparently accumulate aberrantly, and thus form the distinctive whorled paranuclear inclusions that are characteristic of the rhabdoid cell.^[13]

It seems likely that mutations and post-translational modifications affecting cytokeratin 8, cytokeratin 18, and vimentin protofilaments are intimately involved in the genesis of the characteristic inclusions and, therefore, of the rhabdoid phenotype. The particulars of this process are poorly understood, but depend in part on the origin of the tumor^[14] and stochastic genomic phenomena.^[15][16]

Rhabdoid cells often express protein products suggestive of aggressive, dedifferentiated cells, including neuroendocrine tumor-related products

LCLC-RP is generally considered to be an especially aggressive malignancy that metastasizes widely early on in its clinical course. Similar to most other forms of lung carcinoma, LCLC-RP may spread ("metastasize") in three major ways — by local extension and infiltration into surrounding tissues, by lymphatic spread to regional lymph nodes, and through the bloodstream (hematogeneous metastasis) to distant organs and tissues such as the liver, brain, and skeleton.^[citation needed]

It has been reported recently

While occasional scattered rhabdoid cell formation occurs with considerable frequency in lung carcinomas, this is not considered to be of clinical significance.[21]^[17] 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.^[27]

Microscopic characteristics of rhabdoid cells include:^[2][21][23]

• Oval to polygonal cell shape
• Eosinophilic,
  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, malignant

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.[28] Cases with inhomogeneous-appearing consolidation on CT have been reported, as well as aerogenous, lepidic-type spread.^[26] Some large, centrally located LCLC-RP have been noted to show signs of gross necrosis and cavitation on imaging studies,^[11] as well as being associated with the presence of large bullae.^[26]

Immunohistochemistry is an important factor in diagnosis.

In numerous clinical trials conducted in NSCLC, several different platinum-based chemotherapy regimens have been shown to be more-or-less equally effective.[30] 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.^[31] 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.^[21]

There have also been reports of rhabdoid carcinomas expressing vascular endothelial growth factor (VEGF),^[11] suggesting that targeted molecular therapy with VEGF blocking monoclonal antibodies such as bevacizumab may be active in these variants.^[32][33][34] 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.^[32]

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.^[18]

As large-volume LCLC-RP may show significant central necrosis and cavitation, prudence dictates that oncologists use extreme caution if contemplating the therapeutic use of bevacizumab, other anti-VEGF compounds, or anti-angiogenesis agents in general, which have been associated with a greatly increased risk of severe hemorrhage and hemoptysis that may be quickly fatal in cavatated pulmonary squamous cell carcinomas. Similar elevated risks have also been noted in tumors located near, or containing, large blood vessels.,^[11]

LCLC-RP are considered to be especially aggressive tumors with a dismal prognosis.^[5][22][16] Many published cases have shown short survival times after diagnosis.^[17][35] Some studies suggest that, as the proportion of rhabdoid cells in the tumor increases, the prognosis tends to worsen,^[17] although this is most pronounced when the proportion of rhabdoid cells exceeds 5%.^[17] With regard to "parent" neoplasms other than LCLC, adenocarcinomas with rhabdoid features have been reported to have worse prognoses than adenocarcinomas without rhabdoid features,^[36] although an "adenocarcinoma with rhabdoid phenotype" tumor variant has not been specifically recognized as a distinct entity under the WHO-2004 classification system.^[2]

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.^[11] 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.^[23]

Although reliable and comprehensive incidence statistics are nonexistent, LCLC-RP is a rare tumor, with only a few hundred cases described in the scientific literature to date.^[21][8] LCLC's made up about 10% of lung cancers in most historical series,^{[2][7][37][38]} equating to approximately 22,000 cases per year in the U.S.^[39] Of these LCLC cases, it is estimated that about 1% will eventually develop the rhabdoid phenotype during tumor evolution and progression.^[8] 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, only 4 of 45 tumors (9%) were diagnosed as the rhabdoid phenotype using the 10% criterion, but another 10 (22%) had at least some rhabdoid cell formation.^[17] It appears likely, therefore, that LCLC-RP probably comprises between 0.1% and 1.0% of all lung malignancies.

Similar to nearly all variants of lung carcinoma, large cell lung carcinoma with rhabdoid phenotype appears to be highly related to tobacco smoking. It also appears to be significantly more common in males than in females.^[22]

As the rhabdoid phenotype may exclusively be associated with certain missense mutations in the CK-8 gene (or, possibly, the vimentin gene — see above), it may prove possible to develop specific monoclonal antibodies against certain peptides in these aberrant gene products that may target only rhabdoid cells with these specific mutations. Recent reports suggest that antibodies may be easier to get into the interior of cells than previously thought.^{[citation needed]}

Although Colby and colleagues were the first to report a primary lung cancer with a rhabdoid

LCLC-RP were first recognized as a distinct entity under the 3rd (published in 1999) revision of the World Health Organization (WHO) lung tumor histological typing scheme.^[41] Its placement in the classification schema went unchanged during the 2004 revision.^[2]