The basic premise of modern tumor classification is that each type of tumor derives from a progenitor cell that belongs to a specific developmental lineage (e.g., mesoderm, endoderm, ectoderm, etc.). The resulting tumor usually looks and behaves somewhat like a normal differentiated cell type. Hence, we have tumor names like fibroscarcoma, adenocarcinoma, squamous cell carcinoma, etc. These tumors arise from the same tissues that produce normal cells (e.g., epidermis gives rise to normal squamous cells and can also be the site of squamous cell carcinoma; glandular tissues give rise to adenocarcinoma). We would not expect to see adenocarcinomas arising from muscle or pheochromocytomas arising from epidermis.
But there is one notable exception to this rule: the rhabdoid tumor.
Rhabdoid tumors are very rare tumors, that occur in children. Only a few dozen occur in the United States, each year. These aggressive tumors can arise from brain (neuroectoderm), or from kidney (mesoderm), thus breaking the one-tumor one-lineage rule of tumor development. This dual origin of the rhabdoid tumors was so unusual, that it was formerly believed that rhabdoid tumors arising in the brain must be fundamentally different from rhabdoid tumors arising in the kidneys. The biological divide between brain and kidney rhabdoid tumors began to disintegrate when it was found that 10% of patients with rhabdoid tumors of the kidney also developed rhabdoid tumors of the brain. More recently, biallelic loss of the tumor suppressor INI1 was found in both tumors. This more or less clinched the idea that rhabdoid tumors arising from the brain are the same tumor as those arising in the kidney.
Here is a list of summarizing the biological oddities of rhabdoid tumors.
- Rhabdoid tumors are lineage nonspecific and can arise from neuroectodermal cells or mesodermal cells. All other tumors of somatic cells (nongerm cells) arise from a single germ lineage.
- Cells within a single rhabdoid tumor seem to have differentiated along several developmental lineages (ectodermal, endodermal, neuroectodermal, and mesodermal). This phenomenon is otherwise restricted to pluripotent germ cell tumors.
- Cells within a single rhabdoid tumor may include primitive cells indistinguishable from PNET tumors (primitive neuroectodermal tumors). PNET tumors are typically monomorphic tumors.
- Rhabdoid tumors are all associated with a specific phenotypic cell (the rhabdoid cell) regardless of the developmental origin of the tumor (neuroectoderm or mesoderm).
- The rhabdoid cells contain several different intermediate filaments. In normal cells, only one type of intermediate filaments is found in any single cell, and that filament is specific for the lineage of the cell.
- Almost all tumors (other than rhabdoid tumors) arise from cells that resemble an observable normal cell. For example, a squamous cell carcinoma is composed of cells that resemble normal squamous cells biochemically, ultrastructurally, and by light microscopic examination. The rhabdoid cell has no known counterpart in any adult tissue or in any stage of development.
- Currently, there is no other known genetic mutation that produces a specific phenotype akin to the association between INI1 and rhabdoid cells. INI1 loss produces rhabdoid tumors in mice. Eight of 125 mice with germline haploid complement of INI (Snf5+/– mice) developed INI1-negative tumors of soft tissue origin and rhabdoid cell morphology. The mouse tumor is morphologically and genetically identical to the human tumor. Despite the phenotype and genotypic similarities between murine and human rhabdoid tumors, the mouse tumor arises from the branchial arch soft tissue, a tissue of origin not observed in human rhabdoid tumors.
Is the rhabdoid tumor just an example of tumor trivia? No. When you have a rare tumor that seems to break the rules of tumor classification, you can bet that the explanation will have fundamental importance in our understanding of tumor biology. It might even lead to a new and effective approach toward eradicating cancers.
There is an answer to the mysteries of rhabdoid tumors, and we'll approach that answer in the next few blog entries.
- Roberts CW, Galusha SA, McMenamin ME, Fletcher CD, Orkin SH. Haploinsufficiency of Snf5 (integrase interactor 1)predisposes to malignant rhabdoid tumors in mice. Proc Natl Acad Sci USA 97:13796-13800, 2000.
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-© 2010 Jules J. Berman
key words: cancer, neoplasia, neoplasms, precancer, tumor biology, tumour biology, carcinogenesis, cancer development, pre-cancer, precancerous lesions, pre-malignant lesions, gene synonyms: Snf5 Ini1 Baf47 SmarcB1, atypical teratoid tumor, malignant rhabdoid atypical teratoid tumor