Before its description in 1978, AT/RT likely was misdiagnosed as medulloblastoma. However, AT/RT has a worse prognosis and is resistant to the standard treatment protocols for medulloblastoma. AT/RT may be related to rhabdoid tumor, which occurs outside the central nervous system. Considerable debate has been focused on whether AT/RT is the same as rhabdoid tumor of the kidney (i.e., just extra-renal malignant rhabdoid tumor (MRT). The recent recognition that AT/RT and MRT both have deletions of the INI1 gene indicates that rhabdoid tumors of the kidney and brain are at least closely related. AT/RT and MRT additionally possess similar histologic, clinical, and demographic features. Moreover, 10-15% of patients with MRT have synchronous or metachronous brain tumors, many of which are secondary or primary malignant rhabdoid tumors.
A survey of 36 AT/RT patients at St. Jude Children's Hospital from 1984 to 2003 showed the survival rate for children under 3 is < 10%, whereas for older children, the survival rate is potentially over 70% . Because most patients with AT/RT are less than 3 years old, the overall prognosis for AT/RT is very poor. Current research is focusing on using chemotherapy protocols that are effective against rhabdomyosarcoma in combination with surgery and radiation therapy.
Malignant rhabdoid tumor (MRT) was initially described in 1978 as a rhabdomyosarcomatoid variant of a Wilms tumor because of its occurrence in the kidney and because of the resemblance of its cells to rhabdomyoblasts. The absence of muscular differentiation led Haas and colleagues to coin the term "rhabdoid tumor of the kidney" in 1981. Although renal MRT was historically included in treatment protocols of the National Wilms Tumor Study (NWTS) Group, this tumor is now recognized as separate from a Wilms tumor. In contrast to a Wilms tumor, an MRT of the kidney is characterized by early onset of local and distant metastases and by resistance to chemotherapy. Whereas the overall survival rate for Wilms tumors exceeds 85%, the survival rate for renal MRTs is only 20-25%. MRT is one of the most aggressive and lethal malignancies in pediatric oncology. Since rhabdoid tumor of the kidney was originally described, malignant rhabdoid tumors have been reported in practically every location in the body, including the brain, liver, soft tissues, lung, skin, and heart.
Atypical teratoid rhaboid tumors of the central nervous system (CNS) were first described by Rorke and her associates at the Children’s Hospital of Philadelphia in 1987. Early literature called these tumors both atypical teratoid rhaboid tumors or malignant rabdoid tumors (MRT) of the CNS. Again, the term "rhabdoid" was used due to its similarity under the light microscope with rhabdomyosarcoma. By 1995 AT/RTs had become regarded as an aggressive, newly defined, biologically unique class of primarily Brain and Spinal tumors predominantly affecting infants and young children. In January 2001, the National Cancer Institute and the Office of Rare Diseases hosted a Workshop on Childhood Atypical Teratoid/Rhabdoid Tumors of the Central Nervous System. Twenty-two participants from 14 different institutions came together to discuss the biology, treatments and new strategies for these tumors. The consensus paper on the biology of the tumor was published in Clinical Research. Given the rare nature of this tumor, and its recent recognition, there have been less than fifty (50) AT/RT papers in the literature since it was initially reported.
The recent recognition that CNS atypical teratoid/rhabdoid tumors (AT/RT) have deletions of the INI1 gene indicates that rhabdoid tumors of the kidney and brain are identical or closely related entities. This observation is not surprising because rhabdoid tumors at both locations possess similar histologic, clinical, and demographic features.
The tumor histology is jumbled small and large cells. The tissue of this tumor contains many different types of cells including the rhabdoid cells, large spindled cell, epithelial and mesencymal cells and areas resembling primitive neuroectodermal tumor (PNET). As much as 70% of the tumor may be made up of PNET-likw cells. Ultrastructure characteristic whorls of intermediate filaments in the rhabdoid tumors (as with rhabdoid tumors in any area of the body). Ho and associates found sickle shaped embracing cells, previously unreported, in all of 11 cases of AT/RT.
Immunohistochemistry refers to the process of localizing proteins in cells of a tissue section exploiting the principle of antibodies binding specifically to antigens in biological tissues. A tissue sample is stained to identify specific cellular proteins. Immunohistochemical staining is widely used in the diagnosis and treatment of cancer. Specific molecular markers are characteristic of particular cancer types. Immunohistochemistry is also widely used in basic research to understand the distribution and localization of biomarkers in different parts of a tissue. Below are proteins found in an Atypical Teratoid Rhaboid Tumor.
* Neuron specific enolase-positive
* Epitelial membrane antigen-positive
* Glial fibrillary acidic protein- positive
* Smooth muscle actin
* Carcinoembrionary antigen
* AFP- not found
* HCG – negative
Cytogenetics is the study of the tumor’s genetic make-up. A technique called fluoresecene in situ hybridization (FISH) has been gaining attention in the literature because it may be able to help locate a mutation or abnormality that may be allowing tumor growth. Also, this technique has been shown to be useful in identifying some tumors and distinguishing two histologically similar tumors from each other (such as AT/RTs and PNETs). In particular, medulloblastmas/PNETs may possibly be differentiated cytogenetically from AT/RTs as chromosomal deletions of 17p are relatively common with medulloblastoma and abnormalities of 22q11.2 are not seen. On the other hand, chromosomal 22 deletions are very comomon in AT/RTs.
In importance of the hSNF5/INI1 gene located on chromosomal band 22q11.2 is highlighted in the summary paper form the Workshop on Childhood Atypical Teratoid Rhabdoid Tumors as the mutation’s presence is sufficient to change the diagnosis from a medulloblastoma or PNET to the more aggressive AT/RT classification. However, it should be noted that this mutation is not present in 100% of cases. Therefore, if the mutation is not present in an otherwise classic AT/RT immunohistochemical and morphologic pattern then the diagnosis remains an AT/RT.
The critical step in treatment planning is to determine the correct histology of the tumor. An atypical teratoid rhaboid tumor can be mistaken for a medulloblastoma, primitive neuroectodermal tumor (PNET), choroid plexus carcinoma or germ cell tumor. An atypical teratoid rhabdoid tumor may in some sections resemble other CNS neoplasms, because rhabdoid characteristics are not the sole component of these tumors. The rhabdoid aspect may be located only in focal areas or may be less pronounced.
It is important to consider AT/RT when a medulloblastoma or PNET is suspected, particularly in a child under the age of one. Cytogenetic studies can assist in differentiating MB/PNETs from AT/RTs. Some kinds of germ cell tumor secrete tumor markers AFP or bHCG; AT/RTs do not.
Misclassification of the tumor’s pathology can lead to errors in treatment and prognosis.
One study revealed an 8.8% major disagreement in neuropathologic cases. Thus, the American Cancer Society and the American Society of Clinical Pathologist recommend a second opinion on all cancer diagnoses.
Compared to medulloblastoma, AT/RT has a significantly worse prognosis. AT/RT occurs in young children (often younger than 3 years) who are difficult to evaluate, it is resistant to many current therapies, and its recurrence is fast.
The cause is unknown.
Genetic similarities have been found within these rhabdoid tumors. In particular the chromosomal 22 deletion is very common in AT/RTs. This Chromosome 22 area contains the hSNF5/INI1 gene that appears to function as a classic tumor suppressor gene. Most rhabdoid tumors have INI1 deletions whether the occur in the CNS, Kidney or elsewhere. This mutation is viewed as the “first hit” which predisposes these children to malignancies. INI1/hSNF5, a component of the chromatin remodeling SWI/SNF complex, is a critical tumor suppressor biallelically inactivated in rhabdoid tumors. Identification of INI1 as a tumor suppressor has facilitated accurate diagnosis of rhabdoid tumors.
The rate of transcription for SWI/SNF and HDAC complexes seem to be regulated by the INI1 gene. The SWI/SNF complex plays a role in chromatin remodeling. AT/RT is the first pediatric brain tumor for which a candidate tumor suppressor gene has been identified. A mutation or deletion in the INI1/hSNF5 gene occurs in the majority of AT/RT tumors. Up to 90% of AT/RT cases involve 22 deletion. This is mainly point mutations on the hSNF5/INI1 gene (i.e., one can diagnosis AT/RT without a chromsome 22 deletion elsewhere). The hSNF5/INI1 gene regulates 15 or so proteins in the chromintin structure. In addition, the OPN gene has a higher expression in AT/RT tumors. It is increasingly believed that the reason that 100% of the AT/RT cancers are not associated with the hSNF5/INI1 gene is that there 14 additional proteins in the chromintin structure that are controlled by other genes. There are also some emerging mouse models of the AT/RT cancer as well as experimental cell lines derived from tumors. Despite these advances, the function of the gene is not yet understood. At the present time, there is not enough known about the function of INI1, either as an independent modulator of gene expression or through its association with the SWI/SNF complex, to be able to use specific targeted biological agents for treatment. Prospective clinical and biologic trials are greatly needed to understand the efficacy of therapeutic interventions, as well as the role of the gene.