atypical teratoid rhabdoid tumor atypical teratoid rhabdoid tumor an 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% in the posterior fossa, 39% are supratentorial primitive neuroectodermal tumors (spnet), 5% are in the pineal, 2% are spinal, and 2% are multifocal. atypical teratoid rhabdoid tumormri of an at/rtspecialtyneuro-oncologyusual onsetage 3 and youngerprognosisfive-year survival rate: 32.2%frequency~58 new diagnoses per year (united states) 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 cancers of the cns. around 17% of all pediatric cancers involve the cns, making these cancers the most common childhood solid tumor. the survival rate for cns tumors is around 60%. pediatric brain cancer is the second-leading cause of childhood cancer 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. at/rt was only recognized as an entity in 1996 and added to the world health organization brain tumor classification in 2000 (grade iv). the relatively recent classification and rarity has contributed to initial misdiagnosis and nonoptimal therapy. this has led to a historically poor prognosis. current research is focusing on using chemotherapy protocols that are effective against rhabdomyosarcoma in combination with surgery and radiation therapy. recent studies using multimodal therapy have shown significantly improved survival data. in 2008, the dana-farber cancer institute in boston reported two-year overall survival of 53% and event-free survival of 70% (median age at diagnosis of 26 months). in 2013, the medical university of vienna reported five-year overall survival of 100%, and event-free survival of 89% (median age at diagnosis of 24 months). survival rates can be significantly improved when the correct genetic diagnosis is made at the outset, followed with specific multimodal treatment. signs and symptoms clinical signs and symptoms depend on the location of the tumor. 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). a case of a seven-month-old child with a primarily spinal tumor that presented with progressive paraplegia and abnormal feeling in the legs was reported. genetics genetic 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 in 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 chromatin structure. in addition, the opn gene has a higher expression in at/rt tumors. all of the at/rt cancers are believed to be not associated with the hsnf5/ini1 gene, as 14 additional proteins in the chromatin structure 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. risk for siblings and other members of the family atypical teratoid/rhabdoid tumors are very rare, and absolute risk to siblings is not reported in the literature. however, some reports exist of at/rts presenting in two members of the same family, or one family member with an at/rt and another with a renal rhabdoid tumor or other cns tumor. these are suspected to arise from germline genetic mutations in a parent shared by affected siblings. a three-generation family is known in which two half-brothers were diagnosed with cns 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 variable risks of development of rhabdoid tumor in the context of a germline mutation may exist. most rhabdoid tumors may occur in a developmental window. 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 was reported of an infant who 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 carcinoma. a germline mutation (smarcb1) was found in both affected and some unaffected family members. two sisters were diagnosed with at/rts 15 days apart. a case report stated no karyotypic anomalies were noted. three siblings had a mutation of the smarcb1 gene and one had a choroid plexus carcinoma and two had an at/rt. although the mother had a normal somatic dna, the mutation apparently was inherited from the mother's germline due to a mutation during oogenesis. 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. fluorescent in situ hybridization 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 at/rt and rhabdoid tumor share the term "rhabdoid" because under a microscope, both tumors resemble rhabdomyosarcoma. at/rt histology with numerous rhabdoid tumor cells rhabdoid tumor cell - 400x magnification histology 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 cells, 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 filaments are seen 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 for ini1, the product of the smarcb1 gene typically defective in at/rt: note the loss of brown staining in the nuclei of tumor cells with defective smarcb1 as compared to retained staining of nuclei of vascular cells (internal positive control). 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 ateratoid/rt are: 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; s-100 neurofilaments afp – not found hcg – negative cytogenetic studies cytogenetics is the study of a tumor's genetic make-up. fluorescent in situ hybridization 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. however, chromosomal 22 deletions are very common in at/rts. in importance of the hsnf5/ini1 gene located on chromosomal band 22q11.2 is highlighted, as the mutation's presence is sufficient to change the diagnosis from a medulloblastoma or pnet to the more aggressive at/rt classification. however, 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: magnetic resonance imaging (mri) of the brain and spine lumbar puncture to look for m1 disease computed tomography (ct) of chest and abdomen to check for a tumor bone marrow aspiration to check for bone tumors. sometimes the physician will perform a stem cell transplant 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, an 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. at/rt is difficult to diagnose only from radiographic study; usually, a pathologist must perform a cytological or genetic analysis. examination of the cerebrospinal fluid is important (csf), as one-third of patients will have intracranial dissemination with involvement of the 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. classification at/rt may be related to malignant rhabdoid tumor (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. 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, 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. consideration of at/rt when a medulloblastoma or pnet is suspected is important, 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 tumors secrete tumor markers afp or bhcg; at/rts do not. appearance on radiologic exam at/rts can occur at any sites within the cns; however, about 60% are located in the posterior fossa or cerebellar area. the asco study showed 52% posterior fossa; 39% spnet; 5% pineal; 2% spinal, and 2% multifocal. the tumors' appearance on ct and mri are not specific,