ATRT

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. ^[1] 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.

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History

AT/RT of the central nervous system (CNS) was first described in 1987 Rorke and her associates at the Children’s Hospital of Philadelphia.^[2] 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.^[3] 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.^[4] 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.

Pathology

AT/RT and rhabdoid tumor share the term "rhabdoid" because under a microscope both tumors resemble rhabdomyosarcoma.

Histology

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^{[citation needed]} found sickle shaped embracing cells, previously unreported, in all of 11 cases of AT/RT.

Immunohistochemistry

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.

• Vimentin-positive
• Cytokeratin-positive
• Neuron specific enolase-positive
• Epitelial membrane antigen-positive
• Glial fibrillary acidic protein- positive
• Synaptophysin
• Chromogranin
• Smooth muscle actin
• Desmin
• Carcinoembrionary antigen
• CD99 antigen; 2nd CD99 link
• S-100
• neurofilaments
• AFP- not found
• HCG – negative

Cytogenetic studies

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.

Differential diagnosis

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,^[5] 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.^{[citation needed]}

Misclassification of the tumor’s pathology can lead to errors in treatment and prognosis.^[6]

One study revealed an 8.8% major disagreement in neuropathologic cases.^[7] Thus, the American Cancer Society and the American Society of Clinical Pathologist recommend a second opinion on all cancer diagnoses.^{[citation needed]}

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.

Causes

The cause is unknown.

Genetics

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.

Incidence/prevalence

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.^[8] This is based on 37 AT/RT patients treated at Saint Jude's from 1984 to 2003.

Appearance on radiologic exam

• Location

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.^[9]

• Appearance

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.

• Follow-up

Preoperative and followup studies are needed to detect metastatic disease.

Clinical features

Age

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.^[9] 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.^{[10][11][12][13]}

Presentation

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. ^[14]

Location

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.^[9]

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.^[9]

Diagnostic workup

The standard Work-up for AT/RT includes the following procedures:

• MRI Magnetic resonance imaging of the brain and spine

• LP (Lumbar puncture) to look for M1 Disease

• CT (Computed tomography) of Chest and abdomen, in order to check for a Tumor

• BMA (Bone Marrow Asperant) to check for bone tumors. Often a doctor will want perform a Stem Cell Transplant. More specifically, he will harvest the patient's stem cells, prescribe an intense chemotherapy (that kills most stem cells) and then performs a subsequent transplant of the patient's previously harvested Stem Cells.

• BX Bone Marrow Biopsy

• Bone scan

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.^[15] 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.

Metastasis

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.^[9] 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.^[16][17]

Prognosis

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):

• Two year survival- less than 20%

• Average survival postoperatively- 11 months

• Many doctors recommend pallative care, especially with younger children because of the poor outcomes

• The longest term survivals reported in the literature are:
  • (a) Hilden and associates reported a child who was still free from disease at 46 months from diagnosis.^[18]
  • (b) Olson and associates reported a child who was disease free at 5 years from diagnosis based on the IRS III protocol. ^[19]
  • (c) In 2003 Hirth reported a case who had been disease free for over six years.^[20]
  • (d) More recently (2005) Zimmerman at DFCI (Dana-Farber Cancer Institute) reports 50-to-72 month survial rates on four patients using an IRS III based protocol. Interestingly two of these LT survivors had been treated after an AT/RT reoccurance.^[21]
  • (f) Based on this IRS III (Rhabdomyosarcoma Study Group (IRS III) parameningeal) protocol (Janas, Rorke et al. 2004) Philadelphia Children's Hospital updated this treatment (DFCI 02-294 protocol - see Kieran presentation) and is executing a NCI funded clinical trial.^[22] Zimmerman is expected to update this study soon.
  • (g) A NYU study (Gardner 2004) has 4 of 12 longer term AT/RT survivors. The oldest was alive at 46 months after diagnosis.^[23]
  • (h) A small German study had a 94% survival rate at two years (Peters 2006).^[24]
  • (i) The Rhabdoid Kids web site has a 84+ month survivor - he is called Connor Titmarsh.
  • (j) Finally, (Aurélie Fabre 2004) reported a 16 year survivor of a soft-tissue rhabdoid tumor.^[25]

• Patients with Metastasis (Disseminated tumor), larger tumours, tumours that could not be fully removed, tumor reoccurance, and were younger than 36 months had the worse outcomes (i.e., shorter survival times).

• Based on a retrospective survey from 36 AT/RT St. Jude Children's Hospital patients from 1984 to 2004 a <10% survival rate in children under 3 was found, but a 70% survival rate in older children.^[26] The survival rates by age are shown in Figure 1. in this reference. The full Saint Jude article citation (Atypical Teratoid/Rhabdoid Tumors (ATRT)) is shown below:

• Based on a retrospective Register at the Cleveland Children's hospital on 42 AT/RT patients. Median survival time is 16.25 months. The survival rate is currently around 33%. 25% of these cases did not show the mutation in the INI1/hSNF5 gene. The full article citation (CNS AT/RT Tumor: Results of Therapy in Children Enrolled in a Registry) is shown below.

• COG CNS Committee Studies 2003-2007 by Ian Pollack See: Slide No. 30-32 on protocol ACNS033 in Study Management of MO Infant Medulloblastomas (P9934). This treatment is based on surgical resection; chemotherapy, stem cell replacement with intense chemotherapy, and radiation for older patients. This P9934 study^[27] is another AT/RT prospective study; it is a Phase III AT/RT study. The DFCI 02-294 protocol and the ACNS033 should be non-randomly compared as to their respective outcomes.

• Increasingly it is recommended that a genetic analysis be performed on the brain tumor, especially to find if a deletion in the INI1/hSNF5 gene is involved (appears to account for over 80% of the cases). The correct diagnosis of the tumour is critical to any protocol. Studies have shown that 8% to over 50% of AT/RT tumors are diagnosed incorrectly.

Cancer Treatment Effects on Long-Term Survivors

Cancer treatments in long-term survivors who are children usually cause a series of negative effects on physical well being, fertility, cognition, and learning.^{[28][29][30][31]}

Treatment options

Surgical option

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.

Chemotherapy options

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:

• CCG clinical trial CCG-9921 was activated in 1993 and published its results in 2005. The proposed treatments did not have different outcomes and were not an improvement on prior treatments.^[32] Geyer published a review of chemotherapy on 299 infants (< 3 years old) with CNS Tumors. It evaluates response rate, event-free survival (EFS), and toxicity of two chemotherapeutic regimens for treatment of children younger than 36 months with malignant brain tumors. Patients were randomly assigned to one of two regimens of induction chemotherapy (vincristine, cisplatin, cyclophosphamide, and etoposide v vincristine, carboplatin, ifosfamide, and etoposide Intensified induction chemotherapy resulted in a high response rate of malignant brain tumors in infants. Survival was comparable to that of previous studies, and most patients who survived did not receive radiation therapy.^[32]

• More recently (2005) Zimmerman at DFCI (Dana Farber Cancer Institute) reports 50-to-72 month survial rates on four patients using an IRSIII based protocol. Zimmerman is expected to update this study soon. The Philadelphia Children's Hospital is using this new DFCI 02-294 protocol (see Dr. Kieran ASCO presentation).

• In addition, the COG CNS Committee Studies 2003-2007 by Ian Pollack See: Slide No. 30-32 on protocol ^[33] in Study Management of MO Infant Medulloblastomas (P9934). The P9934 study^[34] study is the first prospective study; it is also a Phase III AT/RT study. It is expected to make a preliminary report in 2007. The DFCI 02-294 and the ACNS033 chemotherapy protocols should be compared as to their respective outcomes.

• Sarcoma protocols. There has been at least one report in the literature of malignant rhabdoid tumors of the CNS being treated in as a high-grade intracranial sarcoma. These three cases were treated with surgery, chemotherapy, radiotherapy and triple intrathecal chemotherapy similar to the Intergroup Rhadbdomyoscarcoma Study III guidelines.^[35]

• Intrathecal protocols. One of the difficulties with brain and spinal tumors is that there is a blood brain barrier that needs to be crossed so that the drug can get to the tumor. One mechanism to deliver the drug is through a device called an Ommaya reservoir. This is a device which shares some similarities to a shunt in which a tube a surgically placed in the fluid surrounding the brain and a bulb shaped reservoir attached to the tubing is placed under the skin of the scalp. When the child is to receive intrathecal chemotherapy, the drug is administered into this bulb reservoir. At other times intrathecal chemotherapeutic agents are delivered through a lumbar puncture (spinal tap). A current Pediatric Brain Tumor Consortium Protocol uses intrathecal mafosfamide, a pre-activated cyclophosphamidederivative, in addition to other modalities to try to effect this tumor.^[36]

• High dose chemotherapy with stem cell rescue. This therapy uses chemotherapy at doses high enough to completely suppress the bone marrow. Prior to instituting this therapy, the child has a central line placed and stem cells are gathered. After therapy these cells are given back to the child to regrow the bone marrow. Stem cell rescue or autologous bone marrow transplantation, was initially thought to be of benefit to a wide group of patients, but has declined over the history of chemotherapy protocols. A general description of stem cell rescue is available.^[37] In addition, there are some reports that it is effective with select cancers and this includes AT/RT.^[38]

Radiation options

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. ^[39]

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).

• External beam (conformal)

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.

• Proton Beam Radiation

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.

• • Massachusetts General Hospital- Northeast Proton Therapy Center
    • Principles of Proton Beam Therapy
    • Proton Beam RadioTheraphy at Mass. General
    • Proton Beam Therapy Article
    • Proton Beam Therapy - BJC Abstract
  • Loma Linda Medical Center Proton Treatment Center - Overview
    • Loma Linda overview of Childhood Brain Tumors

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.^[40]

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.

Clinical trials

Main article: clinical trial

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.

Examples:

• Pilot Study of Systemic and Intrathecal Chemotherapy followed by Conformal Radiation for Infants with Embryonal Intracranial Central Nervous System Tumors, A Pediatric Brain Tumor Consortium Protocol. This study (PBTC-001) is run out of the nine institutions associated with the Pediatric Brain Tumor consortium and uses combined modalities including intrathecal mafosfamide, systemic chemotherapy (vincristine, cyclophosphamide, cisplatinum and oral etoposide) and possibly the use of craniospinal or conformal radiation.

• Head Start Chemotherapy Protocol. This chemotherapy protocol is for children <10 years old with newly diagnosed high grade primary brain tumors with intent to eliminate irradiation and shorten the treatment time to 6 months. The therapy consists of 3-5 cycles of intensive chemotherapy followed by a single myeloblative chemotherapy with stem cell rescue. Dr. Jonathan Finlay of New York University Medical Center is the contact person although run at a few hospitals in the county (contact information is listed on the site).

• Phase I Pilot Study of Intensive Chemotherapy with Peripheral Blood Stem Cell Rescue in Infants with Malignant Brain or Spinal Cord Tumors This study uses cisplatinum, cycophosphamide, vincristine and etoposide followed by carboplatinum and thiopeta and then stem cell rescue. There are to be three cycles of carboplatinum and thiopeta with stem cell rescue.

• Intrathecal and Systemic Chemotherapy Combined With Radiation Therapy in Treating Young Patients With Newly Diagnosed Central Nervous System Atypical Teratoid/Rhabdoid Tumors Children's Hospital of Philadelphia

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:

• Complementary and Alternative Medicine on ACOR’s Ped-Onc

• National Center for Complementary and Alternative Medicine (NIH site)

• Complementary/Intergrative Medicine Educational Resource at MD Anderson Site

• Steve Dunn’s Cancer Guide

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:

• The authors identified a three-generation family in which two half-brothers were diagnosed with central nervous system atypical teratoid/rhabdoid tumors (AT/RT). The two boys, diagnosed at 2 months and 17 months of age, had a germline insertion mutation in exon 4 of the INI1 gene that was inherited from their healthy mother. A maternal uncle died in childhood from a brain tumor and a malignant rhabdoid tumor of the kidney. The identification of two unaffected carriers in a family segregating a germline mutation and rhabdoid tumor supports the hypothesis that there may be variable risks of development of rhabdoid tumor in the context of a germline mutation. There may be a developmental window in which most rhabdoid tumors occur. This family highlights the importance of mutation analysis in all patients with a suspected rhabdoid tumor.^[41]

• This is the first case report of monozygotic twin both with brain tumors having similar genertic alterations of both tumors. The authors suggest a common genetic pathway.^[42]

• The Atlas of Genetics and Cytogenetics in Oncology and Haematology is a peer reviewed on-line journal and database in free access on internet devoted to genes, cytogenetics, and clinical entities in cancer, and cancer-prone diseases. This particular article was last updated in 2002 and references five (5) papers.^[43]

• A case report of an infant that developed both AT/RT and renal rhabdoid tumors that were identical in histoligic and immunophenotypic features.^[44]

• This article reviews a family that has had multiple generations of posterior fossa tumors including rhabdoid tumors and choroid plexus carcinoma. There seemed to be a germ-line mutation (SMARCB1) seen in both affected and some unaffected family members.^[45]

• Two sisters were diagnosed with AT/RTs 15 days apart. This case report stated there were no karyotypic anomalies noted.^[46]

• Three siblings had a mutation of the SMARCB1 gene and one had a plexus carcinoma and two had a AT/RT. Although the mother had a normal DNA it appears that the mutation was inherited from the mother due to a mutation during oogenesis.^[47]

Rhabdoid Resources

• Rhabdoid Kids and Angels Home Page-

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:

• AT/RT Case Summaries
• Journal Articles
• AT/RT, Brain, and Cancer websites

Rhabdoid Registry

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.

• Contact:

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: hildenj@ccf.org

• Hilden, Joanne M.; Sharon Meerbaum, Peter Burger, Jonathan Finlay, Anna Janss, Bernd W. Scheithauer, Andrew W. Walter, Lucy B. Rorke, Jaclyn A. Biegel ((July 15)). "Central Nervous System Atypical Teratoid/Rhabdoid Tumor: Results of Therapy in Children Enrolled in a Registry". Journal of Clinical Oncology 22 (14): 2877-2884. doi:10.1200/JCO.2004.07.073. Retrieved on May 23, 2007.As of 2004 they had complete data on 42 patients.
  

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:

• Beigel J; Kalpana G, Knudsen E, et al. (2002). "The role of INI and the SWI/SNF complex in the development of rhabdoid tumors: Meeting Summary from the workshop on childhood atypical teratoid rhabdoid tumors" (in English). Cancer Research 2002 (63:): 323-328.
  

References