Atypical teratoid rhabdoid tumor
Encyclopedia
Atypical teratoid rhabdoid tumor (AT/RT) is a rare tumor
usually diagnosed in childhood. Although usually a brain tumor
, AT/RT can occur anywhere in the central nervous system
(CNS) including the spinal cord
. About 60% will be in the posterior cranial fossa
(particularly the cerebellum
). One review estimated 52% posterior fossa, 39% sPNET (supratentorial
primitive neuroectodermal tumor
s), 5% pineal
, 2% spinal
, and 2% multi-focal.
In the United States, three children per 1,000,000 or around 30 new AT/RT cases are diagnosed each year. AT/RT represents around 3% of pediatric cancer
s of the CNS.
Around 17% of all pediatric cancers involve the CNS; it is the most common childhood solid tumor. 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 and are used more often, the proportion of AT/RT diagnoses is expected to increase.
Because it is highly malignant
, AT/RT has a high mortality rate
. A survey of 36 AT/RT patients at St. Jude Children's Research Hospital
from 1984 to 2003 showed that the two-year event-free survival for children under three was 11%, the overall survival rate was 17%. For children aged 3 years or older the event-free survival was 78% and the overall survival 89%. Because most patients with AT/RT are less than three years old (71% in St Jude Study), 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.
(MRT), which occurs outside the CNS, usually in the kidney. The finding 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 also have similar histology
and similar clinical and demographic features. Moreover, 10–15% of MRT patients have simultaneous or subsequent brain tumors, many of which are secondary or primary MRT.
Since many of the tumors occur in the posterior fossa
they present like other posterior fossa tumors, often with headache, vomiting, lethargy, and ataxia
(unsteady gait). There is a case report of a seven-month-old child with a primarily spinal tumor
that presented with progressive paraplegia
and abnormal feeling in the legs.
similarities have been found within rhabdoid tumors. In particular the chromosomal
22 deletion is very common in AT/RTs. The 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 they occur in the CNS, kidney or elsewhere. This mutation
is viewed as the "first hit" which predisposes 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 chromosome 22 deletion. This is mainly point mutations on the hSNF5/INI1 gene (i.e., one can diagnosis AT/RT without a chromosome 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 all of the AT/RT cancers are not associated with the hSNF5/INI1 gene is that there are 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. 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.
genetic mutations in a parent shared by affected siblings.
is the study and diagnosis
of disease
through examination of organs
, tissues
, bodily fluid
s and whole bodies (Autopsy
). AT/RT and rhabdoid tumor share the term "rhabdoid" because under a microscope both tumors resemble rhabdomyosarcoma
.
is the study of the microscopic anatomy
of cells
and tissues
of plant
s and animal
s. It is performed by examining a thin slice of tissue under a light microscope. The tumor histopathology
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 mesenchymal cells and areas resembling primitive neuroectodermal tumor
(PNET). As much as 70% of the tumor may be made up of PNET-like cells. Ultrastructure
characteristic whorls of intermediate filament
s 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. Proteins found in an Atypical Teratoid Rhaboid Tumor are:
may be able to help locate a mutation or abnormality that may be allowing tumor growth. 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 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, an 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 cerebrospinal fluid
is important as one-third of patients will have intracranial dissemination with involvement of the cerebrospinal fluid (CSF). Large tumor cells, eccentricity of the nuclei and prominent nucleoli are consistent findings. Usually only a minority of AT/RT biopsies have Rhabdoid cells, making diagnosis more difficult. 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 tumor is critical to any protocol. Studies have shown that 8% to over 50% of AT/RT tumors are diagnosed incorrectly.
Atypical teratoid/rhaboid tumor closely resembles medulloblastoma, primitive neuroectodermal tumor
, choroid plexus carcinoma
, and some kinds of germ cell tumor
. Because rhabdoid characteristics are not the only component of AT/RT, some sections of an AT/RT may resemble other tumors. These characteristics may be present 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 marker
s AFP
or bHCG; AT/RTs do not.
Compared to medulloblastoma, AT/RT has a significantly worse prognosis. AT/RT occurs in young children (often younger than three years) who are difficult to evaluate, it is resistant to many current therapies, and its recurrence is fast.
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.
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 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.
plays a critical role in obtaining tissue
to make an accurate diagnosis
. Surgery alone is curative. In addition, 30% of the AT/RTs are located supratentorially and there is a predilection for the cerebello-pontine angle which makes surgical resection difficult. One-third or more children will have disseminated disease
at the time of diagnosis. Total or near-total resections are often not possible.
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 cisplatin
um, carboplatinum, cyclophosphamide
, vincristine
and etoposide
. Some Chemotherapy protocols
are listed below:
until a child is older than three years. This strategy is based upon observations that children under three have significant long term complications as a result of brain irradiation. However, the long term outcomes of AT/RT are so poor that some protocols call 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.
External beam
(conformal) radiation uses several beams that intersect at the tumor location; the normal brain tissue receives less radiation and cognitive function is thereby less affected.
Proton beam radiation
was only offered at Massachusetts General Hospital
in Boston and at Loma Linda, California as of 2002. Since 2003 three or four more proton therapy centers have opened in the United States.Some centres have since opened in Europe. (Germany, Switzerland and France).
are a new class of anticancer agents targeted directly at chromatin remodeling
. These agents have been used in acute promyelocytic leukemia and have been found to affect the HDAC
-mediated transcriptional repression. There is too little understanding of the INI1 deficiency to predict whether HDAC inhibitors will be effective against AT/RTs. There are some laboratory results that indicate it is effective against certain AT/RT cell lines.
Patients with metastasis (disseminated tumor), larger tumors, tumors that could not be fully removed, or tumor recurrence, and who were younger than 36 months had the worst outcomes (i.e., shorter survival times).
A retrospective survey from 36 AT/RT St. Jude Children's Hospital patients from 1984 to 2003 showed that the Two-year event-free survival (EFS) for children under three was 11%, the overall survival (OS) rate was 17%. For children aged 3 years or older the EFS was 78% and the OS 89%. A retrospective register at the Cleveland Children's hospital on 42 AT/RT patients found median survival time is 16.25 months and a survival rate around 33%. One-quarter of these cases did not show the mutation in the INI1/hSNF5
gene.
The longest term survivals reported in the literature are:
Cancer treatments in long-term survivors who are children usually cause a series of negative effects on physical well being, fertility, cognition, and learning
.
(leptomenigeal spread sometimes referred to as sugar coating) is common both initially and with relapse. Average survival times decline with the presence of metastasis. Primary CNS tumors generally metastasize only within the CNS.
One case of metastatic disease to the abdomen via ventriculoperitoneal shunt
has been reported with AT/RT . Metastatic dissemination via this mechanism has been reported with other brain tumors including germinoma
s, medulloblastoma
s, astrocytoma
s, glioblastomas
, ependymoma
s and endodermal sinus tumor
s. Guler and Sugita separately reported cases of lung metastasis without a shunt.
As with other CNS tumors, slightly more males are affected than females (ratio 1.6:1). The ASCO study showed a 1.4:1 male to female ratio.
. In some early reports the tumor was known also as malignant rhabdoid tumor
(MRT) of the CNS. Between 1978 and 1987, AT/RT was usually misdiagnosed as rhabdoid tumor. However, both AT/RT and non-CNS MRT have a worse prognosis than medulloblastoma 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, usually 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 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.
s to attempt 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 such a standard treatment exists.
There is an ongoing research into stem cell transplant surgeries.
Tumor
A tumor or tumour is commonly used as a synonym for a neoplasm that appears enlarged in size. Tumor is not synonymous with cancer...
usually diagnosed in childhood. Although usually a brain tumor
Brain tumor
A brain tumor is an intracranial solid neoplasm, a tumor within the brain or the central spinal canal.Brain tumors include all tumors inside the cranium or in the central spinal canal...
, AT/RT can occur anywhere in the central nervous system
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
(CNS) including the spinal cord
Spinal cord
The spinal cord is a long, thin, tubular bundle of nervous tissue and support cells that extends from the brain . The brain and spinal cord together make up the central nervous system...
. About 60% will be in the posterior cranial fossa
Posterior cranial fossa
The posterior cranial fossa is part of the intracranial cavity, located between the foramen magnum and tentorium cerebelli. It contains the brainstem and cerebellum.This is the most inferior of the fossae. It houses the cerebellum, medulla and pons....
(particularly the cerebellum
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...
). One review estimated 52% posterior fossa, 39% sPNET (supratentorial
Supratentorial
In anatomy, the supratentorial region of the brain is the area located above the tentorium cerebelli. The area of the brain below the tentorium cerebelli is the infratentorial region. The supratentorial region contains the cerebrum, while the infratentorial region contains the cerebellum....
primitive neuroectodermal tumor
Primitive neuroectodermal tumor
Primitive neuroectodermal tumor is a neural crest tumor. It is a rare tumor, usually occurring in children and young adults under 25 years of age...
s), 5% pineal
Pineal gland
The pineal gland is a small endocrine gland in the vertebrate brain. It produces the serotonin derivative melatonin, a hormone that affects the modulation of wake/sleep patterns and seasonal functions...
, 2% spinal
Spinal tumor
Spinal tumors are neoplasms located in the spinal cord. They are mostly metastases from primary cancers elsewhere . Primary tumors may be benign Spinal tumors are neoplasms located in the spinal cord. They are mostly metastases from primary cancers elsewhere (commonly breast, prostate and lung...
, and 2% multi-focal.
In the United States, three children per 1,000,000 or around 30 new AT/RT cases are diagnosed each year. AT/RT represents around 3% of pediatric cancer
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
s of the CNS.
Around 17% of all pediatric cancers involve the CNS; it is the most common childhood solid tumor. 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
Leukemia
Leukemia or leukaemia is a type of cancer of the blood or bone marrow characterized by an abnormal increase of immature white blood cells called "blasts". Leukemia is a broad term covering a spectrum of diseases...
. 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 and are used more often, the proportion of AT/RT diagnoses is expected to increase.
Because it is highly malignant
Cancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
, AT/RT has a high mortality rate
Mortality rate
Mortality rate is a measure of the number of deaths in a population, scaled to the size of that population, per unit time...
. A survey of 36 AT/RT patients at St. Jude Children's Research Hospital
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital, founded in 1962, is a leading pediatric treatment and research facility focused on children's catastrophic diseases. It is located in Memphis, Tennessee. It is a nonprofit medical corporation chartered as a 501 tax-exempt organization under IRS regulations.In...
from 1984 to 2003 showed that the two-year event-free survival for children under three was 11%, the overall survival rate was 17%. For children aged 3 years or older the event-free survival was 78% and the overall survival 89%. Because most patients with AT/RT are less than three years old (71% in St Jude Study), the overall prognosis for AT/RT is very poor.
Current research is focusing on using chemotherapy
Chemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
protocols that are effective against rhabdomyosarcoma
Rhabdomyosarcoma
A rhabdomyosarcoma is a type of cancer, specifically a sarcoma , in which the cancer cells are thought to arise from skeletal muscle progenitors. It can also be found attached to muscle tissue, wrapped around intestines, or in any anatomic location...
in combination with surgery and radiation therapy.
Classification
AT/RT may be related to malignant rhabdoid tumorRhabdoid tumour
Malignant rhabdoid tumour is a very aggressive form of tumour originally described as a variant of Wilms' tumour, which is primarily a kidney tumour that occurs mainly in children....
(MRT), which occurs outside the CNS, usually in the kidney. The finding 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 also have similar histology
Histology
Histology is the study of the microscopic anatomy of cells and tissues of plants and animals. It is performed by examining cells and tissues commonly by sectioning and staining; followed by examination under a light microscope or electron microscope...
and similar clinical and demographic features. Moreover, 10–15% of MRT patients have simultaneous or subsequent brain tumors, many of which are secondary or primary MRT.
Signs and symptoms
Clinical signs and symptoms depend on the location of the tumor.Since many of the tumors occur in the posterior fossa
Posterior cranial fossa
The posterior cranial fossa is part of the intracranial cavity, located between the foramen magnum and tentorium cerebelli. It contains the brainstem and cerebellum.This is the most inferior of the fossae. It houses the cerebellum, medulla and pons....
they present like other posterior fossa tumors, often with headache, vomiting, lethargy, and ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
(unsteady gait). There is a case report of a seven-month-old child with a primarily spinal tumor
Spinal tumor
Spinal tumors are neoplasms located in the spinal cord. They are mostly metastases from primary cancers elsewhere . Primary tumors may be benign Spinal tumors are neoplasms located in the spinal cord. They are mostly metastases from primary cancers elsewhere (commonly breast, prostate and lung...
that presented with progressive paraplegia
Paraplegia
Paraplegia is an impairment in motor or sensory function of the lower extremities. The word comes from Ionic Greek: παραπληγίη "half-striking". It is usually the result of spinal cord injury or a congenital condition such as spina bifida that affects the neural elements of the spinal canal...
and abnormal feeling in the legs.
Genetics
GeneticGenetics
Genetics , a discipline of biology, is the science of genes, heredity, and variation in living organisms....
similarities have been found within rhabdoid tumors. In particular the chromosomal
Chromosome
A chromosome is an organized structure of DNA and protein found in cells. It is a single piece of coiled DNA containing many genes, regulatory elements and other nucleotide sequences. Chromosomes also contain DNA-bound proteins, which serve to package the DNA and control its functions.Chromosomes...
22 deletion is very common in AT/RTs. The chromosome 22 area contains the hSNF5/INI1 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
that appears to function as a classic tumor suppressor gene. Most rhabdoid tumors have INI1 deletions whether they occur in the CNS, kidney or elsewhere. This mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
is viewed as the "first hit" which predisposes children to malignancies. INI1/hSNF5, a component of the chromatin
Chromatin
Chromatin is the combination of DNA and proteins that make up the contents of the nucleus of a cell. The primary functions of chromatin are; to package DNA into a smaller volume to fit in the cell, to strengthen the DNA to allow mitosis and meiosis and prevent DNA damage, and to control gene...
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
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
for SWI/SNF and HDAC
Histone deacetylase
Histone deacetylases are a class of enzymes that remove acetyl groups from an ε-N-acetyl lysine amino acid on a histone. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. Its action is opposite to that of histone...
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 chromosome 22 deletion. This is mainly point mutations on the hSNF5/INI1 gene (i.e., one can diagnosis AT/RT without a chromosome 22 deletion elsewhere). The hSNF5/INI1
SWI/SNF
SWI/SNF is a yeast nucleosome remodeling complex composed of several proteins – products of the SWI and SNF genes as well as several other polypeptides...
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 all of the AT/RT cancers are not associated with the hSNF5/INI1 gene is that there are 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. 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
SWI/SNF
SWI/SNF is a yeast nucleosome remodeling complex composed of several proteins – products of the SWI and SNF genes as well as several other polypeptides...
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.
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 suspected to arise from germ-lineGermline
In biology and genetics, the germline of a mature or developing individual is the line of germ cells that have genetic material that may be passed to a child.For example, gametes such as the sperm or the egg, are part of the germline...
genetic mutations in a parent shared by affected siblings.
- A three-generation family is known 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.
- In the first case report of monozygotic twins, both with brain tumors having similar genetic alterations, authors suggest a common genetic pathway.
- A case reported on an infant that developed both AT/RT and renal rhabdoid tumors that were identical in gross and immunologic histology.
- A family has had multiple generations of posterior fossa tumors including rhabdoid tumors and choroid plexus carcinomaChoroid plexus carcinoma-Signs and symptoms:the symptoms of choroid plexus carcinoma are similar to those of other brain tumors,and include:*Persistent or new onset headaches*Macrocephaly or bulging fontanels in infants.*Loss of appetite...
. A germ-line mutation (SMARCB1) was found in both affected and some unaffected family members.
- Two sisters were diagnosed with AT/RTs fifteen days apart. A case report stated there were no karyotypicKaryotypeA karyotype is the number and appearance of chromosomes in the nucleus of an eukaryotic cell. The term is also used for the complete set of chromosomes in a species, or an individual organism.p28...
anomalies noted.
- Three siblings had a mutation of the SMARCB1 gene and one had a choroid plexusChoroid plexusThe choroid plexus is a structure in the ventricles of the brain where cerebrospinal fluid is produced...
carcinomaCarcinomaCarcinoma is the medical term for the most common type of cancer occurring in humans. Put simply, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that generally arises from cells originating in the endodermal or ectodermal germ layer during...
and two had an AT/RT. Although the mother had a normal somatic DNA it appears that the mutation was inherited from the mother's germline due to a mutation during oogenesisOogenesisOogenesis, ovogenesis or oögenesis is the creation of an ovum . It is the female form of gametogenesis. The male equivalent is spermatogenesis...
.
- Izycka-Swieszewska et al. describe a five month-old child with an AT/RT, whose father was diagnosed with a primitive neuroectodermal tumor (PNET) of the spinal canal. FISHFluorescent in situ hybridizationFISH is a cytogenetic technique developed by biomedical researchers in the early 1980s that is used to detect and localize the presence or absence of specific DNA sequences on chromosomes. FISH uses fluorescent probes that bind to only those parts of the chromosome with which they show a high...
analysis showed significant genetic differences in the specimens which suggest that the occurrence of these virulent CNS malignancies within a single family was coincidental.
Pathology
PathologyPathology
Pathology is the precise study and diagnosis of disease. The word pathology is from Ancient Greek , pathos, "feeling, suffering"; and , -logia, "the study of". Pathologization, to pathologize, refers to the process of defining a condition or behavior as pathological, e.g. pathological gambling....
is the study and diagnosis
Diagnosis
Diagnosis is the identification of the nature and cause of anything. Diagnosis is used in many different disciplines with variations in the use of logics, analytics, and experience to determine the cause and effect relationships...
of disease
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
through examination of organs
Organ (anatomy)
In biology, an organ is a collection of tissues joined in structural unit to serve a common function. Usually there is a main tissue and sporadic tissues . The main tissue is the one that is unique for the specific organ. For example, main tissue in the heart is the myocardium, while sporadic are...
, tissues
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
, bodily fluid
Bodily fluid
Body fluid or bodily fluids are liquids originating from inside the bodies of living people. They include fluids that are excreted or secreted from the body as well as body water that normally is not.Body fluids include:-Body fluids and health:...
s and whole bodies (Autopsy
Autopsy
An autopsy—also known as a post-mortem examination, necropsy , autopsia cadaverum, or obduction—is a highly specialized surgical procedure that consists of a thorough examination of a corpse to determine the cause and manner of death and to evaluate any disease or injury that may be present...
). AT/RT and rhabdoid tumor share the term "rhabdoid" because under a microscope both tumors resemble rhabdomyosarcoma
Rhabdomyosarcoma
A rhabdomyosarcoma is a type of cancer, specifically a sarcoma , in which the cancer cells are thought to arise from skeletal muscle progenitors. It can also be found attached to muscle tissue, wrapped around intestines, or in any anatomic location...
.
Histology
HistologyHistology
Histology is the study of the microscopic anatomy of cells and tissues of plants and animals. It is performed by examining cells and tissues commonly by sectioning and staining; followed by examination under a light microscope or electron microscope...
is the study of the microscopic anatomy
Anatomy
Anatomy is a branch of biology and medicine that is the consideration of the structure of living things. It is a general term that includes human anatomy, animal anatomy , and plant anatomy...
of cells
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
and tissues
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
of plant
Plant
Plants are living organisms belonging to the kingdom Plantae. Precise definitions of the kingdom vary, but as the term is used here, plants include familiar organisms such as trees, flowers, herbs, bushes, grasses, vines, ferns, mosses, and green algae. The group is also called green plants or...
s and animal
Animal
Animals are a major group of multicellular, eukaryotic organisms of the kingdom Animalia or Metazoa. Their body plan eventually becomes fixed as they develop, although some undergo a process of metamorphosis later on in their life. Most animals are motile, meaning they can move spontaneously and...
s. It is performed by examining a thin slice of tissue under a light microscope. The tumor histopathology
Histopathology
Histopathology refers to the microscopic examination of tissue in order to study the manifestations of disease...
is jumbled small and large cells. The tissue
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
of this tumor contains many different types of cells including the rhabdoid cells, large spindled cell, epithelial and mesenchymal cells and areas resembling primitive neuroectodermal tumor
Primitive neuroectodermal tumor
Primitive neuroectodermal tumor is a neural crest tumor. It is a rare tumor, usually occurring in children and young adults under 25 years of age...
(PNET). As much as 70% of the tumor may be made up of PNET-like cells. Ultrastructure
Ultrastructure
Ultrastructure is the detailed structure of a biological specimen, such as a cell, tissue, or organ, that can be observed by electron microscopy...
characteristic whorls of intermediate filament
Intermediate filament
Intermediate filaments are a family of related proteins that share common structural and sequence features. Intermediate filaments have an average diameter of 10 nanometers, which is between that of 7 nm actin , and that of 25 nm microtubules, although they were initially designated...
s 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
Immunohistochemistry
Immunohistochemistry or IHC refers to the process of detecting antigens in cells of a tissue section by exploiting the principle of antibodies binding specifically to antigens in biological tissues. IHC takes its name from the roots "immuno," in reference to antibodies used in the procedure, and...
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. Proteins found in an Atypical Teratoid Rhaboid Tumor are:
- VimentinVimentinVimentin is a type III intermediate filament protein that is expressed in mesenchymal cells. IF proteins are found in all metazoan cells as well as bacteria. IF, along with tubulin-based microtubules and actin-based microfilaments, comprise the cytoskeleton...
-positive - CytokeratinCytokeratinCytokeratins are proteins of keratin-containing intermediate filaments found in the intracytoplasmic cytoskeleton of epithelial tissue. The term "cytokeratin" began to be used in the late 1970s when the protein subunits of keratin intermediate filaments inside cells were first being identified and...
-positive - Neuron specific enolase-positive
- Epitelial membrane antigen-positive
- Glial fibrillary acidic proteinGlial fibrillary acidic proteinGlial fibrillary acidic protein is an intermediate filament protein that was thought to be specific for astrocytes in the central nervous system . Later, it was shown that GFAP is also expressed by other cell types in CNS, including ependymal cells...
- positive - SynaptophysinSynaptophysinSynaptophysin also known as the major synaptic vesicle protein p38 is a protein that in humans is encoded by the SYP gene.-Genomics:...
- ChromograninChromograninGranin is a protein family of regulated secretory proteins ubiquitously found in the cores of amine and peptide hormone and neurotransmitter dense-core secretory vesicles.- Function :...
- Smooth muscleSmooth muscleSmooth muscle is an involuntary non-striated muscle. It is divided into two sub-groups; the single-unit and multiunit smooth muscle. Within single-unit smooth muscle tissues, the autonomic nervous system innervates a single cell within a sheet or bundle and the action potential is propagated by...
actinActinActin is a globular, roughly 42-kDa moonlighting protein found in all eukaryotic cells where it may be present at concentrations of over 100 μM. It is also one of the most highly-conserved proteins, differing by no more than 20% in species as diverse as algae and humans... - DesminDesminDesmin is a protein that in humans is encoded by the DES gene.Desmin is a type III intermediate filament found near the Z line in sarcomeres. It was first described in 1976, first purified in 1977, the gene was cloned in 1989, and the first knock-out mouse was created in 1996. Desmin is only...
- Carcinoembrionary antigenAntigenAn antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
- CD99 antigenAntigenAn antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
; - S-100S-100 proteinS-100 protein is a family of low molecular weight protein found in vertebrates characterized by two calcium binding sites of the helix-loop-helix conformation. There are at least 21 different types of S100 proteins...
- neurofilamentNeurofilamentNeurofilaments are the 10 nanometer intermediate filaments found specifically in neurons. They are a major component of the cell's cytoskeleton, and provide support for normal axonal radial growth...
s - AFPAlpha-fetoproteinAlpha-fetoprotein is a protein that in humans is encoded by the AFP gene....
– not found - HCGHuman chorionic gonadotropinHuman chorionic gonadotropin or human chorionic gonadotrophin is a glycoprotein hormone produced during pregnancy that is made by the developing embryo after conception and later by the syncytiotrophoblast .. Some tumors make this hormone; measured elevated levels when the patient is not...
– negative
Cytogenetic studies
Cytogenetics is the study of a tumor’s genetic make-up. A technique called FISHFluorescent in situ hybridization
FISH is a cytogenetic technique developed by biomedical researchers in the early 1980s that is used to detect and localize the presence or absence of specific DNA sequences on chromosomes. FISH uses fluorescent probes that bind to only those parts of the chromosome with which they show a high...
may be able to help locate a mutation or abnormality that may be allowing tumor growth. 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.
Diagnosis
The standard work-up for AT/RT includes:- MRI Magnetic resonance imagingMagnetic resonance imagingMagnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
of the brain and spine - Lumbar punctureLumbar punctureA lumbar puncture is a diagnostic and at times therapeutic procedure that is performed in order to collect a sample of cerebrospinal fluid for biochemical, microbiological, and cytological analysis, or very rarely as a treatment to relieve increased intracranial pressure.-Indications:The...
to look for M1 disease - CT (Computed tomographyComputed tomographyX-ray computed tomography or Computer tomography , is a medical imaging method employing tomography created by computer processing...
) of chest and abdomen to check for a tumor - Bone Marrow Asperant to check for bone tumors. Often a doctor will want to perform a stem cell transplant
- Bone marrow biopsy
- Bone scanBone scanA bone scan or bone scintigraphy is a nuclear scanning test to find certain abnormalities in bone which are triggering the bone's attempts to heal. It is primarily used to help diagnose a number of conditions relating to bones, including: cancer of the bone or cancers that have spread to the bone,...
The initial diagnosis of a tumor is made with a radiographic
Medical radiography
Radiography is the use of ionizing electromagnetic radiation such as X-rays to view objects. Although not technically radiographic techniques, imaging modalities such as PET and MRI are sometimes grouped in radiography because the radiology department of hospitals handle all forms of imaging...
study (MRI
Magnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
or CT
Computed tomography
X-ray computed tomography or Computer tomography , is a medical imaging method employing tomography created by computer processing...
-). If CT was performed first, a MRI is usually performed as the images are often more detailed and may reveal previously undetected metastatic
Metastasis
Metastasis, or metastatic disease , is the spread of a disease from one organ or part to another non-adjacent organ or part. It was previously thought that only malignant tumor cells and infections have the capacity to metastasize; however, this is being reconsidered due to new research...
tumors in other locations of the brain. In addition, an MRI of the spine
Vertebral column
In human anatomy, the vertebral column is a column usually consisting of 24 articulating vertebrae, and 9 fused vertebrae in the sacrum and the coccyx. It is situated in the dorsal aspect of the torso, separated by intervertebral discs...
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 cerebrospinal fluid
Cerebrospinal fluid
Cerebrospinal fluid , Liquor cerebrospinalis, is a clear, colorless, bodily fluid, that occupies the subarachnoid space and the ventricular system around and inside the brain and spinal cord...
is important as one-third of patients will have intracranial dissemination with involvement of the cerebrospinal fluid (CSF). Large tumor cells, eccentricity of the nuclei and prominent nucleoli are consistent findings. Usually only a minority of AT/RT biopsies have Rhabdoid cells, making diagnosis more difficult. 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 tumor is critical to any protocol. Studies have shown that 8% to over 50% of AT/RT tumors are diagnosed incorrectly.
Differential diagnosis
The critical step in treatment planning is to determine the correct histology of the tumor. Misidentification of the tumor histology can lead to errors in treatment and prognosis.Atypical teratoid/rhaboid tumor closely resembles medulloblastoma, primitive neuroectodermal tumor
Primitive neuroectodermal tumor
Primitive neuroectodermal tumor is a neural crest tumor. It is a rare tumor, usually occurring in children and young adults under 25 years of age...
, choroid plexus carcinoma
Choroid plexus carcinoma
-Signs and symptoms:the symptoms of choroid plexus carcinoma are similar to those of other brain tumors,and include:*Persistent or new onset headaches*Macrocephaly or bulging fontanels in infants.*Loss of appetite...
, and some kinds of germ cell tumor
Germ cell tumor
A germ cell tumor is a neoplasm derived from germ cells. Germ cell tumors can be cancerous or non-cancerous tumors. Germ cells normally occur inside the gonads...
. Because rhabdoid characteristics are not the only component of AT/RT, some sections of an AT/RT may resemble other tumors. These characteristics may be present 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
Cytogenetics
Cytogenetics is a branch of genetics that is concerned with the study of the structure and function of the cell, especially the chromosomes. It includes routine analysis of G-Banded chromosomes, other cytogenetic banding techniques, as well as molecular cytogenetics such as fluorescent in situ...
studies can assist in differentiating MB/PNETs from AT/RTs. Some kinds of germ cell tumor
Germ cell tumor
A germ cell tumor is a neoplasm derived from germ cells. Germ cell tumors can be cancerous or non-cancerous tumors. Germ cells normally occur inside the gonads...
secrete tumor marker
Tumor marker
A tumor marker is a substance found in the blood, urine, or body tissues that can be elevated in cancer, among other tissue types. There are many different tumor markers, each indicative of a particular disease process, and they are used in oncology to help detect the presence of cancer...
s AFP
Alpha-fetoprotein
Alpha-fetoprotein is a protein that in humans is encoded by the AFP gene....
or bHCG; AT/RTs do not.
Compared to medulloblastoma, AT/RT has a significantly worse prognosis. AT/RT occurs in young children (often younger than three years) who are difficult to evaluate, it is resistant to many current therapies, and its recurrence is fast.
Appearance on radiologic exam
AT/RTs can occur at any sites within the CNS, however, approximately 60% are located in the posterior fossa or cerebellar area. The ASCO study showed 52% posterior fossa; 39% sPNET (supratentorialSupratentorial
In anatomy, the supratentorial region of the brain is the area located above the tentorium cerebelli. The area of the brain below the tentorium cerebelli is the infratentorial region. The supratentorial region contains the cerebrum, while the infratentorial region contains the cerebellum....
primitive neuroectodermal tumors); 5% pineal
Pineal gland
The pineal gland is a small endocrine gland in the vertebrate brain. It produces the serotonin derivative melatonin, a hormone that affects the modulation of wake/sleep patterns and seasonal functions...
; 2% spinal
Spinal tumor
Spinal tumors are neoplasms located in the spinal cord. They are mostly metastases from primary cancers elsewhere . Primary tumors may be benign Spinal tumors are neoplasms located in the spinal cord. They are mostly metastases from primary cancers elsewhere (commonly breast, prostate and lung...
, and 2% multi-focal.
The tumors' appearance on CT and MRI are nonspecific, tending towards large size, calcifications
Metastatic calcification
Metastatic calcification is deposition of calcium salts in otherwise normal tissue, because of elevated serum levels of calcium in blood, which can occur because of deranged metabolism as well as increased absorption or decreased excretion of calcium and related minerals.It occurs as opposed to...
, necrosis (tissue death)
Necrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...
,and hemorrhage (bleeding). Radiological studies alone cannot identify AT/RT; a pathologist almost always has to evaluate a brain tissue sample.
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 finding on T1 and T2
Relaxation (NMR)
In nuclear magnetic resonance spectroscopy and magnetic resonance imaging the term relaxation describes several processes by which nuclear magnetization prepared in a non-equilibrium state return to the equilibrium distribution. In other words, relaxation describes how fast spins "forget" the...
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
Magnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
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.
Surgery
SurgerySurgery
Surgery is an ancient medical specialty that uses operative manual and instrumental techniques on a patient to investigate and/or treat a pathological condition such as disease or injury, or to help improve bodily function or appearance.An act of performing surgery may be called a surgical...
plays a critical role in obtaining tissue
Tissue (biology)
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
to make an accurate diagnosis
Diagnosis
Diagnosis is the identification of the nature and cause of anything. Diagnosis is used in many different disciplines with variations in the use of logics, analytics, and experience to determine the cause and effect relationships...
. Surgery alone is curative. In addition, 30% of the AT/RTs are located supratentorially and there is a predilection for the cerebello-pontine angle which makes surgical resection difficult. One-third or more children will have disseminated disease
Disseminated disease
Disseminated disease refers to a diffuse disease process, generally either infectious or neoplastic, but sometimes also referring to connective tissue disease....
at the time of diagnosis. Total or near-total resections are often not possible.
Chemotherapy
Approximately 50% of the AT/RTs will transiently respond, but ChemotherapyChemotherapy
Chemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
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 cisplatin
Cisplatin
Cisplatin, cisplatinum, or cis-diamminedichloroplatinum is a chemotherapy drug. It is used to treat various types of cancers, including sarcomas, some carcinomas , lymphomas, and germ cell tumors...
um, carboplatinum, cyclophosphamide
Cyclophosphamide
Cyclophosphamide , also known as cytophosphane, is a nitrogen mustard alkylating agent, from the oxazophorines group....
, vincristine
Vincristine
Vincristine , formally known as leurocristine, sometimes abbreviated "VCR", is a vinca alkaloid from the Catharanthus roseus , formerly Vinca rosea and hence its name. It is a mitotic inhibitor, and is used in cancer chemotherapy.-Mechanism:Tubulin is a structural protein that polymerizes to...
and etoposide
Etoposide
Etoposide phosphate is an anti-cancer agent. It is known in the laboratory as a topoisomerase poison. Etoposide is often incorrectly referred to as a topoisomerase inhibitor in order to avoid using the term "poison" in a clinical setting...
. Some Chemotherapy protocols
Chemotherapy regimens
A fundamental philosophy of combination cancer therapy is that different drugs work through different cytotoxic mechanisms. Because they have different dose-limiting adverse effects, they can be given together at full doses in chemotherapy regimens....
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. Geyer published a review of chemotherapy on 299 infants with CNS tumors that evaluated 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.
- SarcomaSarcomaA sarcoma is a cancer that arises from transformed cells in one of a number of tissues that develop from embryonic mesoderm. Thus, sarcomas include tumors of bone, cartilage, fat, muscle, vascular, and hematopoietic tissues...
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 sarcomaSarcomaA sarcoma is a cancer that arises from transformed cells in one of a number of tissues that develop from embryonic mesoderm. Thus, sarcomas include tumors of bone, cartilage, fat, muscle, vascular, and hematopoietic tissues...
. These three cases were treated with surgery, chemotherapy, radiotherapy and triple intrathecalIntrathecalIntrathecal is an adjective that refers to something introduced into or occurring in the space under the arachnoid membrane of the brain or spinal cord...
chemotherapy similar to the Intergroup Rhabdomyosarcoma Study III guidelines.
- IntrathecalIntrathecalIntrathecal is an adjective that refers to something introduced into or occurring in the space under the arachnoid membrane of the brain or spinal cord...
protocols. One of the difficulties with brain and spinal tumors is that the blood brain barrier 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 reservoirOmmaya reservoirAn Ommaya reservoir is an intraventricular catheter system that can be used for the aspiration of cerebrospinal fluid or for the delivery of drugs into the cerebrospinal fluid. It consists of a catheter in one lateral ventricle attached to a reservoir implanted under the scalp...
. This is a device which shares some characteristics with 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 intrathecalIntrathecalIntrathecal is an adjective that refers to something introduced into or occurring in the space under the arachnoid membrane of the brain or spinal cord...
chemotherapyChemotherapyChemotherapy is the treatment of cancer with an antineoplastic drug or with a combination of such drugs into a standardized treatment regimen....
, the drug is administered into this bulb reservoir. At other times intrathecal chemotherapeutic agents are delivered through a lumbar punctureLumbar punctureA lumbar puncture is a diagnostic and at times therapeutic procedure that is performed in order to collect a sample of cerebrospinal fluid for biochemical, microbiological, and cytological analysis, or very rarely as a treatment to relieve increased intracranial pressure.-Indications:The...
(spinal tap). A current Pediatric Brain Tumor Consortium ProtocolChemotherapy regimensA fundamental philosophy of combination cancer therapy is that different drugs work through different cytotoxic mechanisms. Because they have different dose-limiting adverse effects, they can be given together at full doses in chemotherapy regimens....
uses intrathecal mafosfamideMafosfamideMafosfamide is an oxazaphosphorine alkylating agent under investigation as a chemotherapeutic. Several Phase I trials have been completed....
, a pre-activated cyclophosphamideCyclophosphamideCyclophosphamide , also known as cytophosphane, is a nitrogen mustard alkylating agent, from the oxazophorines group....
derivative, in addition to other modalities to try to effect this tumor.
- High dose chemotherapy with stem cell rescue. This therapy uses chemotherapy at doses high enough to completely suppress the bone marrowBone marrowBone marrow is the flexible tissue found in the interior of bones. In humans, bone marrow in large bones produces new blood cells. On average, bone marrow constitutes 4% of the total body mass of humans; in adults weighing 65 kg , bone marrow accounts for approximately 2.6 kg...
. Prior to instituting this therapy, the child has a central lineCentral venous catheterIn medicine, a central venous catheter is a catheter placed into a large vein in the neck , chest or groin...
placed and stem cellStem cellThis article is about the cell type. For the medical therapy, see Stem Cell TreatmentsStem cells are biological cells found in all multicellular organisms, that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells...
s 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 chemotherapyHistory of cancer chemotherapyThe era of cancer chemotherapy began in the 1940s with the first use of nitrogen mustards and folic acid antagonist drugs. Cancer drug development has exploded since then into a multi-billion dollar industry...
protocols.
Radiation therapy
The traditional practice for childhood brain tumors has been to use chemotherapy and to defer radiation therapyRadiation therapy
Radiation therapy , radiation oncology, or radiotherapy , sometimes abbreviated to XRT or DXT, is the medical use of ionizing radiation, generally as part of cancer treatment to control malignant cells.Radiation therapy is commonly applied to the cancerous tumor because of its ability to control...
until a child is older than three years. This strategy is based upon observations that children under three have significant long term complications as a result of brain irradiation. However, the long term outcomes of AT/RT are so poor that some protocols call 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.
External beam
External beam radiotherapy
External beam radiotherapy or teletherapy is the most common form of radiotherapy. The patient sits or lies on a couch and an external source of radiation is pointed at a particular part of the body...
(conformal) radiation uses several beams that intersect at the tumor location; the normal brain tissue receives less radiation and cognitive function is thereby less affected.
Proton beam radiation
Proton therapy
Proton therapy is a type of particle therapy which uses a beam of protons to irradiate diseased tissue, most often in the treatment of cancer. The chief advantage of proton therapy is the ability to more precisely localize the radiation dosage when compared with other types of external beam...
was only offered at Massachusetts General Hospital
Massachusetts General Hospital
Massachusetts General Hospital is a teaching hospital and biomedical research facility in the West End neighborhood of Boston, Massachusetts...
in Boston and at Loma Linda, California as of 2002. Since 2003 three or four more proton therapy centers have opened in the United States.Some centres have since opened in Europe. (Germany, Switzerland and France).
Chromatin re-modeling agents
This protocol is still in pre-clinical evaluation. HDAC inhibitorsHistone deacetylase inhibitor
Histone deacetylase inhibitors are a class of compounds that interfere with the function of histone deacetylase.HDIs have a long history of use in psychiatry and neurology as mood stabilzers and anti-epileptics...
are a new class of anticancer agents targeted directly at chromatin remodeling
Chromatin remodeling
Chromatin remodeling is the enzyme-assisted movement of nucleosomes on DNA.This is performed by chromatin remodeling complexes like SWI/SNF , RSC and Imitation SWI complexes ....
. These agents have been used in acute promyelocytic leukemia and have been found to affect the HDAC
Histone deacetylase
Histone deacetylases are a class of enzymes that remove acetyl groups from an ε-N-acetyl lysine amino acid on a histone. This is important because DNA is wrapped around histones, and DNA expression is regulated by acetylation and de-acetylation. Its action is opposite to that of histone...
-mediated transcriptional repression. There is too little understanding of the INI1 deficiency to predict whether HDAC inhibitors will be effective against AT/RTs. There are some laboratory results that indicate it is effective against certain AT/RT cell lines.
Prognosis
The prognosis for AT/RT has been very poor, although there are some indications that an IRSIII-based therapy can produce long-term survival (60 to 72 months). Two-year survival is less than 20%, average survival postoperatively is 11 months, and doctors often recommend palliative care, especially with younger children because of the poor outcomes. Recently a protocol utilized by a multicenter trial reported in the Journal of Clinical Oncology resulted in a 70% survival rate at 2–3 years, with most relapses occurring within months, leading to hope that there is a point beyond which patients can be considered cured.Patients with metastasis (disseminated tumor), larger tumors, tumors that could not be fully removed, or tumor recurrence, and who were younger than 36 months had the worst outcomes (i.e., shorter survival times).
A retrospective survey from 36 AT/RT St. Jude Children's Hospital patients from 1984 to 2003 showed that the Two-year event-free survival (EFS) for children under three was 11%, the overall survival (OS) rate was 17%. For children aged 3 years or older the EFS was 78% and the OS 89%. A retrospective register at the Cleveland Children's hospital on 42 AT/RT patients found median survival time is 16.25 months and a survival rate around 33%. One-quarter of these cases did not show the mutation in the INI1/hSNF5
SWI/SNF
SWI/SNF is a yeast nucleosome remodeling complex composed of several proteins – products of the SWI and SNF genes as well as several other polypeptides...
gene.
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.
- (b) Olson and associates reported a child who was disease free at five years from diagnosis based on the IRS III protocol.
- (c) In 2003 Hirth reported a case who had been disease free for over six years.
- (d) Zimmerman in 2005 reported 50-to-72 month survival rates on four patients using an IRS III-based protocol. Two of these long term survivors had been treated after an AT/RT recurrence.
- (e) A NYU study (Gardner 2004) has 4 of 12 longer term AT/RT survivors; the oldest was alive at 46 months after diagnosis.
- (f) Aurélie Fabre, 2004, reported a 16-year survivor of a soft-tissue rhabdoid tumor.
Cancer treatments in long-term survivors who are children usually cause a series of negative effects on physical well being, fertility, cognition, and learning
Learning problems in childhood cancer
According to the National Cancer Institute, the incidence of childhood cancers has increased over the past 20 years. New medical treatments and technologies are improving the survival rate of childhood cancers however, late effects of cancer and its treatments, particularly those involving...
.
Metastasis
Metastatic spread is noted in approximately one-third of the AT/RT cases at the time of diagnosis and tumors can occur anywhere throughout the CNS. The ASCO study of the 188 documented AT/RT cases prior to 2004 found 30% of the cases had metastasis at diagnosis. Metastatic spread to the meningesMeninges
The meninges is the system of membranes which envelopes the central nervous system. The meninges consist of three layers: the dura mater, the arachnoid mater, and the pia mater. The primary function of the meninges and of the cerebrospinal fluid is to protect the central nervous system.-Dura...
(leptomenigeal spread sometimes referred to as sugar coating) is common both initially and with relapse. Average survival times decline with the presence of metastasis. Primary CNS tumors generally metastasize only within the CNS.
One case of metastatic disease to the abdomen via ventriculoperitoneal shunt
Shunt (medical)
In medicine, a shunt is a hole or a small passage which moves, or allows movement of fluid from one part of the body to another. The term may describe either congenital or acquired shunts; and acquired shunts may be either biological or mechanical.* Cardiac shunts may be described as...
has been reported with AT/RT . Metastatic dissemination via this mechanism has been reported with other brain tumors including germinoma
Germinoma
A germinoma is a type of germ cell tumor which is not differentiated upon examination. It may be benign or malignant.-Classification:The term germinoma most often has referred to a tumor in the brain that has a histology identical to two other tumors: dysgerminoma in the ovary and seminoma in the...
s, medulloblastoma
Medulloblastoma
Medulloblastoma is a highly malignant primary brain tumor that originates in the cerebellum or posterior fossa.Previously, medulloblastomas were thought to represent a subset of primitive neuroectodermal tumor of the posterior fossa...
s, astrocytoma
Astrocytoma
Astrocytomas are a type of neoplasm of the brain. They originate in a particular kind of glial-cells, star-shaped brain cells in the cerebrum called astrocytes. This type of tumor does not usually spread outside the brain and spinal cord and it does not usually affect other organs...
s, glioblastomas
Glioma
A glioma is a type of tumor that starts in the brain or spine. It is called a glioma because it arises from glial cells. The most common site of gliomas is the brain.-By type of cell:...
, ependymoma
Ependymoma
Ependymoma is a tumor that arises from the ependyma, a tissue of the central nervous system. Usually, in pediatric cases the location is intracranial, while in adults it is spinal. The common location of intracranial ependymoma is the fourth ventricle...
s and endodermal sinus tumor
Endodermal sinus tumor
Endodermal sinus tumor , also known as yolk sac tumor , is a member of the germ cell tumor group of cancers. It is the most common testicular tumor in children under 3, and is also known as infantile embryonal carcinoma. This age group has a very good prognosis...
s. Guler and Sugita separately reported cases of lung metastasis without a shunt.
Epidemiology
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.As with other CNS tumors, slightly more males are affected than females (ratio 1.6:1). The ASCO study showed a 1.4:1 male to female ratio.
History
Atypical teratoid/rhabdoid tumor was first described as a distinct entity in 1987. Before 1978, when rhabdoid tumor was described, AT/RT likely was misdiagnosed as medulloblastomaMedulloblastoma
Medulloblastoma is a highly malignant primary brain tumor that originates in the cerebellum or posterior fossa.Previously, medulloblastomas were thought to represent a subset of primitive neuroectodermal tumor of the posterior fossa...
. In some early reports the tumor was known also as malignant rhabdoid tumor
Rhabdoid tumour
Malignant rhabdoid tumour is a very aggressive form of tumour originally described as a variant of Wilms' tumour, which is primarily a kidney tumour that occurs mainly in children....
(MRT) of the CNS. Between 1978 and 1987, AT/RT was usually misdiagnosed as rhabdoid tumor. However, both AT/RT and non-CNS MRT have a worse prognosis than medulloblastoma 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, usually affecting infants and young children. In January 2001, the U.S. National Cancer Institute
National Cancer Institute
The National Cancer Institute is part of the National Institutes of Health , which is one of 11 agencies that are part of the U.S. Department of Health and Human Services. The NCI coordinates the U.S...
and Office of Rare Diseases hosted a Workshop on Childhood Atypical Teratoid/Rhabdoid Tumors of the Central Nervous System. Twenty-two participants from 14 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.
Research directions
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 trialClinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s to attempt 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 such a standard treatment exists.
There is an ongoing research into stem cell transplant surgeries.