Tuesday, January 8, 2008

Rhabdoid tumors, a sui generis class in the Neoplasm Classification

Rhabdoid tumors occur in just a few dozen children each year in the U.S. These aggressive tumors arise from brain (class Neuroectoderm in the Neoplasm Classification) and from kidney (class Mesoderm in the Neoplasm Classification) and contain morphologically distinctive cells (so-called rhabdoid cells, named for their superficial similarity to muscle cells).

Not long ago, the rhabdoid tumors that arose in the kidney were thought to be different from the rhabdoid tumors that arose from the brain. The common rhabdoid cell was considered to be a peculiar morphologic variant that just happened to occur in both types of tumors. The kidney tumor was called MRT (malignant rhabdoid tumor). MRT was considered, by many pathologists, to be a variant form of nephroblastoma. The rhabdoid brain tumor was called AT/RT (Atypical teratoid rhabdoid tumor), and some pathologists classified AT/RT among the PNETs.

The perceived distinction between MRT and AT/RT started to disappear apart when it was found that about 10% of patients with MRT also developed AT/RT or so-called primitive neuroectodermal neoplasm of brain. Recently, a characteristic genetic abnormality has been found in rhabdoid tumors of CNS or renal origin: bi-allelic loss of INI1 gene expression. Immunostaining for the protein produced by the INI1 gene is absent in almost all reported cases of rhabdoid tumor cells.

Rhabdoid cells are large cells with an eosinophilic cytoplasm. Ultrastructural examination of rhabdoid cells shows characteristic whorls of intermediate filaments. Intermediate filaments are proteins contribute to the the structure of cells and provide resistance to deformity. Normal cells contain intermediate filaments that are specific for their developmental lineage. Cells of endodermal or ectodermal origin contain cytokeratin filaments. Cell of Neuroectodermal origin contain neurofilaments filaments. Cells of mesenchymal origin contain desmin filaments. Rhabdoid cells contain all these different types of intermediate filaments.

Rhabdoid tumor apparently disobey some of the rules of neoplastic development.

-Rhabdoid tumors are lineage non-specific and can arise from neuroectodermal cells or mesodermal cells. All other tumors of somatic cells (non-germ 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 totipotent 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 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.

-Rhabdoid tumors seem to be caused by bi-allelic loss of the tumor suppressor gene, INI1. Tumor suppressor genes are normally associated with different types of tumors. INI1 gene loss seems to be exclusively associated with rhabdoid tumors or with rhabdoid tumor cell subpopulations developing within other types of tumors. 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 RrobbR. haploid. 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.

How is this possible? How can a tumor suppressor gene mutation in a non-germ cell produce tumors that arise from tissues of different developmental lineage and contain a common tumor cell that contains intermediate filaments specific for multiple cell lineages?

The INI1 gene codes a subunit of the SWI/SNF chromatin remodelling complex. The study of SWI/SNF complexes in mammals, flies and plants suggests that they strongly influence many developmental pathways RkwoaR. This suggests two possible mechanisms for the action of the INI1 tumor suppressor gene in rhabdoid tumors

-1. The cell of origin of rhabdoid tumors is a primitive, pluripotent somatic stem cell with a lineage position that precedes the development of germ layers.

-2. Loss of INI1 gene expression produces a pluripotent stem cell when it occurs in cells of several different lineages (e.g., neuroectodermal or endodermal or mesodermal cells).

Of these two possibilities, the first seems unlikely because subpopulations of INI1-negative rhabdoid cells occur secondarily within adult tumors, and this would not be expected to occur if the INI1 mutation only produced rhabdoid tumors derived from primitive cells. Also, if there were a very primitive cell (with a lineage that precedes the development of the germ layers), why would the INI1 mutation be the only mutation that could produce tumors of these cells?

The second possibility, if true, might explain the odd biological features of rhabdoid tumors. The idea of mutations in differentiated cells conferring pluripotentiality is not unprecedented. In recent work, Yamanaka and coworkers successfully created pluripotent stem cells from differentiated fibroblasts by introducing (with retroviruses) several chosen genes (Oct3/4, Sox2, c-Myc and Klf4) and subsequent selection for Fbx15 RokiaR.

See: Okita K, Ichisaka T, Yamanaka S. Generation of germline-competent induced pluripotent stem cells. Nature 448:313-317 2007.

These experiments demonstrated that differentiated cells could be altered to become stem cells and provides researchers with a source of stem cells other than embryos.

It would seem that regardless of the lineage of origin, INI1 biallelic loss creates tumors of a unique phenotype.

As a result, I'm changing the class for rhabdoid tumors within the Neoplasms Classification. It is now a one-of-a-kind tumor in its own class, placed under the Neoplasm superclass.

The updated Neoplasm Classification is available as a gzipped XML file at:


An early paper on the Neoplasm Clasification is available as an open source document.

In June, 2014, my book, entitled Rare Diseases and Orphan Drugs: Keys to Understanding and Treating the Common Diseases was published by Elsevier. The book builds the argument that our best chance of curing the common diseases will come from studying and curing the rare diseases.

I urge you to read more about my book. There's a generous preview of the book at the Google Books site. If you like the book, please request your librarian to purchase a copy of this book for your library or reading room.

- Jules J. Berman, Ph.D., M.D. tags: common disease, orphan disease, orphan drugs, rare disease, disease genetics, medical terminology, rare cancers,