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An Atypical Teratoid Rhabdoid Tumor (AT/RT) is a rare and highly malignant childhood brain tumor with a high mortality rate. In the United States 3 children per 1,000,000 or around 30 new AT/RT cases are diagnosed each year. Each year there are 2,500 to 3,000 new Pediatric cancers of the central nervous system (CNS) and only around 3% are diagnosed with AT/RT.  Around 17% of all Pediatric Cancers involve the CNS; it is the most common childhood solid tumour. The survival rate for CNS tumors is around 60%; with AT/RT it is around 10%. Pediatric Brain cancer is the second leading cause of childhood death, just after Leukemia. Recent trends suggest that the rate of overall CNS tumor diagnosis is increasing by about 2.7% per year. As diagnostic techniques using genetic markers improve (e.g., better differentiation between PNET/medulloblastoma and AT/RTs) and are used more often, the proportion of AT/RT diagnoses is expected to increase.
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% (See: Figure 1). 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.
Additional recommended knowledge
AT/RT of the central nervous system (CNS) was first described in 1987 Rorke and her associates at the Children’s Hospital of Philadelphia. Early subsequent reports called this kind of CNS tumor either atypical teratoid rhaboid tumor or malignant rhabdoid tumor (MRT) of the CNS. Between 1978 and 1987, AT/RT likely was misdiagnosed as rhabdoid tumor. Before 1978, when rhabdoid tumor was described, AT/RT likely was misdiagnosed as medulloblastoma. However, both AT/RT and non-CNS MRT have a worse prognosis and are resistant to the standard treatment protocols for medulloblastoma.
By 1995, AT/RT had become regarded as a newly defined aggressive, biologically unique class of primarily brain and spinal tumors, primarily affecting infants and young children. In January 2001, the U.S. National Cancer Institute and 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. The workshop's 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.
AT/RT and rhabdoid tumor share the term "rhabdoid" because under a microscope both tumors resemble rhabdomyosarcoma.
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.
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.
An estimated 3% of pediatric brain tumors are AT/RTs although this percentage may increase with better differentiation between PNET/medulloblastoma tumors and AT/RTs.
A 2005 survey of AR/TR patients at St. Jude Children's Hospital showed a 11% survival rate for patients < 3 years old and an over 70% survival rate for patients > 3 years old. This is based on 37 AT/RT patients treated at Saint Jude's from 1984 to 2003.
Appearance on radiologic exam
AT/RTs can occur at any sites within the Central Nervous System (CNS), however approximately 60% are located in the posterior fossa area/Cerebellum area. An ASCO study by Dr. Kieran showed 52% posterior fossa (PF); 39% sPNET (supratentorial primitive neuroectodermal tumors); 5% pineal; 2% spinal, and 2% multi-focal.
The tumors’ appearance on CT and MRI are nonspecific tending towards large size, calcifications, necrosis (tissue death),and hemorrhage (bleeding). Radiological studies alone cannot identify AT/RT. A pathologist almost always has to evaluate a brain tissue sample.
Technical Information- CT Scans- The increased cellularity of the tumor may make the appearance on an uncontrasted CT to have increased attenuation. Solid parts of the tumor often enhance with contrast MRI Scans- Finding on T1 and T2 weighted images are variable. Pre-contrast T2 weighted images may show an iso-signal or slightly hyper-signal. Solid components of the tumor may enhance with contrast but do not always. MRI studies appear to be more able to pick up metastatic foci in other intracranial locations as well as intraspinal locations.
Preoperative and followup studies are needed to detect metastatic disease.
This is a tumor primarily of young children and infants. A Pediatric Oncology Group study reported the average age at diagnosis to be 17 months. The ASCO study of the 188 documented AT/RT cases prior to 2004 showed 173 cases < 5 years and 15 cases > 5 years. It should be noted that children older than three have been diagnosed with this tumor. In addition, a med-line search revealed four adults between the ages of 20 and 30 whose brain tumors have been classified as atypical/teratoid rhabdoid tumors.
The clinical presentation depends on the locations of the tumor. Since many of the tumors occur in the posterior fossa they present like other posterior fossa tumors- headache, vomitting, lethargy, and ataxia (unsteady gait). There is a case report by Tamiya and associates of a 7 month old child with a primarily spinal tumor that presented with progressive paraplegia and abnormal feeling in the legs. 
The tumors can be located anywhere within the CNS including the spinal cord. Approximately 60% will be in the posterior fossa/cerebellar area. The ASCO study by Dr. Kieran showed 52% posterior fossa (PF); 39% sPNET (supratentorial primitive neuroectodermal tumors); 5% pineal; 2% spinal, and 2% multi-focal.
Male to female ratio
As with other CNS tumors, slightly more males are affected than females (ratio 1.6:1). Mark Kieran's summary of the 188 documented AT/RT cases (all prior to 2004) showed a 1.4:1 male to female ratio.
The standard Work-up for AT/RT includes the following procedures:
The initial diagnosis of a tumor is made with a radiographic study (MRI or CT-). If CT was performed first, a MRI is usually performed as the images are often more detailed and may reveal previously undetected metastatic tumors in other locations of the brain. In addition, a MRI of the spine is usually performed. The AT/RT tumor often spreads to the spine. It is difficult to diagnosis AT/RT only from radiographic study. Usually a pathologist must perform a cytological or genetic analysis.
Examination of the cerebral spinal fluid is important as 1/3 of these patients will have intracranial dissemination with involvement of the CSF (cerebral spinal fluid). Lu reported the most consistent finding were large tumor cells, eccentricity of the nuclei and prominent nucleoli. Interestingly usually only a minority of AT/RT biopsies have Rhabdoid cells. This makes diagnosis more difficult. Increasingly deletions in INI1/hSNF5 gene are looked for.
Spread is noted in approximately 1/3 of the AT/RT cases at the time of diagnosis and tumors can occur anywhere throughout the Central Nervous System(CNS). In the ASCO study by Dr. Kieran of the 188 documented AT/RT cases prior to 2004; he found 30% of the cases had mets (metastasis) at diagnosis. Metastatic spread to the Meninges (leptomenigeal spread sometimes referred to as sugar coating) is very common both initially and with relapse. Average survival times decline when there is metastasis. Primary CNS tumors metastasize only within the CNS.
One case of metastatic disease to the abdomen via ventriculoperitoneal shunt has been reported with AT/RT . It should be noted that metastatic dissemination via this mechanism has been reported with other brain tumors including germinomas, medulloblastomas, astrocytomas, glioblastomas, endymomas and endodermal sinus tumors. Guler and Sugita separately reported cases of lung metastasis without a shunt.
As of 2006 the prognosis for AT/RT remains very poor. Although there are some indications that an IRSIII-based therapy can produce long-term survival (60 to 72 months):
Cancer Treatment Effects on Long-Term Survivors
Surgery plays a critical role in obtaining tissue to make an accurate diagnosis. Surgery alone is not curative. In addition, 30% of the AT/RT tumors are located supratentorially and there is a predilection for the cerebello-pontine angle which makes surgical resection difficult. Unfortunately 1/3 or more children will have disseminated disease at the time of diagnosis. Total or near-total resections are often not possible. A range new treatments are emerging for Brain Tumors.
Approximately 50% of the AT/RT tumors will transiently respond. Chemotherapy by itself is rarely curative. There is no standard treatment for AT/RT. Various chemotherapeutic agents have been used against AT/RTs which are also used against other CNS tumors including cisplatinum, carboplatinum, cyclophosphamide, vincristine and eptoposide. Some Chemotherapy protocols are listed below:
The traditional dogma for childhood brain tumors has been to use chemotherapy in order to defer radiation until a child is older than 3 years. This strategy is based upon observations that children under 3 have significant long term complications as a result of brain irradiation. However, the long term outcomes of AT/RT are so poor that current protocols are calling for upfront radiation therapy, often in spite of young age. 
The dose and volume of radiation had not been standardized, however, radiation does appear to improve survival. The use of radiation has been limited in children younger than three because of the risk of severe neurocognitive deficits. There are protocols using conformal, local radiation in the young child to try to cure this tumor (see clinical trial information).
Conformal radiation uses several fields that beam intersects at the tumor location. In this way, the normal brain tissue receives less radiation and hopefully is at less impact on cognitive function.
In 2002 this type of therapy was only offered in Massachusetts General Hospital in Boston and Loma Linda, California. The Northeast Proton Therapy Center claims that proton beam therapy offers “some theoretical advantages over other types of sterotactic radiosurgery because it uses the quantum wave properties of protons to reduce the doses to the surrounding tissue beyond the target to a theoretical minimum of zero. It is also advantageous in the treatment of unusually shaped brain tumors.” An overview articlenotes that it provides better effective treatment with fewer side effects in pediatric cases. Since 2003 three or four more proton therapy centers have opened in the United States.
Chromatin re-modeling agents
This protocol is still in pre-clinical evaluation. Information on HDAC inhibitors, a new class of anticancer agents targeted directly at chromatin remodeling, was presented on the Workshop on Atypical Teratoid Rhabdoid Tumors of the CNS. These agents have been used in acute promyelocytic leukemia and have been found to affect the HDAC-mediated transcriptional repression. The participants in the workshop concluded that there was too little understanding of the INI1 deficiency to predict whether HDAC inhibitors will be effective against AT/RTs. Although, there are some laboratory results that indicate it is effective against certain AT/RT cell lines.
Proteomics Lab to Study Pediatric Brain Tumours
There is not a treatment protocol yet, but in June, 2006 Children's National Medical Center opened the first proteomics Lab. This Center treats around 10% of CNS pediatric cancers in the United States. Proteomics, an innovative method that allows research scientists to study thousands of complex proteins at once, will be used to analyze brain tumors using samples of spinal fluid. Until recently, scientists were only able to study a few proteins at a time, leaving behind the information contained in the thousands of other proteins that make up the complete picture.
By sampling the spinal fluid, one can see a snapshot of the tumor at a given time, which may help doctors create a “protein fingerprint” of the tumor to help track the tumor’s status. Brain tumors are biologically interrelated with the surrounding tissue environment and the patient’s spinal fluid circulates through this environment. Thus, CSF be used to identify a tumor’s characteristics and whether it is changing at different time points. This could eventually side-step the invasiveness of brain surgery and assess a tumor’s behavior in real-time, particular its response to drugs. The technology could be used to match drugs to target the tumor’s specific “protein fingerprint” and to see whether the drugs are working the way they are intended.
Atypical teratoid rhabdoid tumor is rare and no therapy has been proven to deliver long term survival, nor is there a set of standard protocols. Thus, most children with AT/RT are enrolled in clinical trials to try to find an effective cure. A clinical trial is not a treatment standard; it is research. Some clinical trials compare an experimental treatment to a standard treatment, but only if there exists a standard treatment.
Search clinical trial registeries for open trials that may be appropriate for a child with AT/RT.
Are there options in alternative or complementary medicine?
Especially because the prognosis for this tumor is dismal, many parents may consider alternative medicine. Before committing to an alternative therapy a parent might want to review information on quackwatch site. Other sites to investigate are:
What are the risk for siblings and other members of the family?
Atypical teratoid rhabdoid tumors are very rare tumors and absolute risk to siblings is not reported in the literature. However, there have been some reports of AT/RTs presenting in two members of the same family, or one family member with a AT/RT and another with a renal rhabdoid tumor or other CNS tumor. These are thought to arise from Germ-line genetic mutations.
Recent research includes:
A site maintained by a child’s grandfather since 1998. On this site there is a listing of kids fighting this tumor including pictures, email addresses and many personal websites. There also is a similar angel page. There is also a discussion board regarding rhabdoid tumors.
Emily’s Rhabdoid Page
A web site dedicated to Emily who died of an AT/RT in 2000. The journal is complete from initial symptoms to the end of life. There is a variety of other interesting information including:
The Childhood Oncology Group Registry started as an official registry run by Dr. Joanne Hilden, Dr. Jackie Biegel, and Jan Watterson in 1995 at Saint Paul's Hospital. They are very interested in hearing from any rhabdoid parent whose child is not already listed in their registry. The registry, which will be made available to medical professionals, hopes to document as many rhabdoid cases as possible, an important step in finding the most effective treatment for rhabdoid. The registry started at Children’s Hospital in St. Paul. The main center for registry data collection is now at the Cleveland Clinic Foundation due to Dr. Hilden’s relocation to Chair of the Department of Pediatric Hematology/Oncology.
If your child is diagnosed with rhabdoid one should consider adding his case to the registry. Dr. Hilden can be contacted at 216-444-8407.The Rhabdoid Registry now operates at Cleveland Clinic. This AT/RT Registry is still run by Dr. Joanne Hilden, Chair of Pediatric Hematology/Oncology. It provides a voluntary, free, confidential, central database of information and outcomes on Central Nervous System Atypical Teratoid/Rhabdoid tumors. Below is an 2004 article written on the 42 complete AT/RT cases they have stored.
Joanne M. Hilden, M.D. (Principal Investigator) Chair, Department of Pediatric Hematology/Oncology/Desk S20 Medical Director, Pediatric Palliative Care Cleveland Clinic Children's Hospital 9500 Euclid Avenue Cleveland OH 44195 Phone: 216-444-8407 Fax: 216-444-5925 E-Mail: email@example.com
Workshop on Childhood Atypical Teratoid Rhadoid Tumors of the CNS
This is a listing of the abstract on and participants in a major AT/RT workshop held in January 2001 by the National Cancer Institute and the Office of Rare Disease Abstract. The citation (paper is online) is provided below:
|This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "ATRT". A list of authors is available in Wikipedia.|