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Atypical Teratoid Rhabdoid Tumors (AT/RT) Information for Parents, Relative, Friends and other interested parties What is the history of atypical teratoid rhabdoid Tumors of the central nervous system? Atypical teratoid rhaboid tumors of the central nervous system (CNS) were first described by Rorke and her associates at the Children’s Hopsital of Philadelphia in 1987. Early literature called these tumors both atypical teratoid rhaboid tumors or malignant rabdoid tumors (MRT) of the CNS. By 1995 AT/RTs had become regarded as an aggressive, newly defined, biologically unique class of primarily brain and spinal tumors predominately affecting infants and young children. In January 2001, the National Cancer Institute and the Office of Rare Disease hosted a Workshop on Childhood Atypical Teratoid/Rhabdoid Tumors of the Central Nervous System. Twenty-two participants from 14 different institutions came together to discuss the biology, treatments and new strategies for these tumors. The consensus paper on the biology of the tumor was published in Clinical Research. The consensus paper is still in progress at this time. Given the rare nature of this tumor, there have only been a few dozen papers in the literature since it was initially reported. Lefkowitz JB, Rorke LB, Packer RJ. Atypical teratoid tumors of infancy: definition of an entity. Ann Neurol 1988 22:448-489. Rorke LB, Packer R, Biegel J. Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood. J Neurooncol 2995 24:21-8. Beigel J, Kalpana G, Knudsen E, etal. 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. Cancer Research 2002 63:323-328. What is the pathology of AT/RT tumors? The pathology of the tumor is highly technical only relevant to the new brain tumor parent to show the difficulty in pathologically diagnosis to highlight the basic science research that is underway to understand this tumor. The technical information is included for those that have a background and interest in this. For all others- skip to the next section. Technical Information • Histology- Histology is the way the tumor looks under the microscope. The tumor’s architecture is jumbled small and large cells. The tissue of this tumor contains many different types of cells including the presence of rhabdoid cells, large spindled cell, epithelial and mesencymal components and focal areas resembling a primative neruectodermal tumor. As much as 70% of the tumor may be made up of PNET cells. Ultrastructure characteristic whorls of intermediate filaments in the rhabdoid tumors (as with rhabdoid tumors in any area of the body). Ho and associates reported a previously unrecognized component of sickled shaped embracing cells that were present in all eleven cases atypical teratoid/rhadboid tumors that were reviewed.
• Immunohistochemistry Vimentin-positive Cytokeratin-positive Neuron specific enolase-positive Epitelial membrane antigen-positive Glial fiibrillary acidic protien- positive Synaptophysin Chromogranin Smooth muscle actin Desmin, Carcinoembrionary antigen CD99 s100 neurofilaments AFP- not found HCG – negative • Cytogenetic Studies- Cytogenetics is the study of the tumor’s genetic make-up. A technique called fluoroscence 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. Bruch LA, Hill DA, Cai Dx, etal. A role for flouresence is situ hybidization detection of chromosomal 22q dosage in distinguishing atypical teratoid/rhabdoid tumors from medulloblastoma.central primitive neurectodermal tumors. Hum Pathol 2001 32:156-62. This paper reports a comparasion of 8 AT/RT, 12 MB/PNETs and 4 central nervous system PNETs using fluoresecene in situ bybridization (FISH). None of the MB/PNET had a deletion of 22q, whereas 75% of the AT/RTs had deletion of 22q. The authors highlight the diagnositic potential of this technique in assisting in making the correct diagnosis. Morley E. FISH as a Diagnostic Tool on Childhood Cancer. www.sas.upenn.edu/~emorley This paper discussing the utilization of FISH as a diagnostic tool has a very good introduction into childhood cancer and brain tumors.
A case of central nervous system atypical teratoid.rhabdoid tumor (Hungarian). Hauser P, Slowik F. Babosa M. etal Magy Onkol 2000 44:285-288. Abstract reviewed on medline as article is in Hungarian. Oka H, Scheithauer BW. Clinicopathologic characteristics of atypical teratoid/rhabdoid tumor/ Neurol Med Chir (Tokyo) 1999 39:510-7. A meta-anaylsis of 133 cases (15 new and 118 from the literature) which reviews the distingishing clinicopathologic features of this tumor. Ho DM, Hsu CY, Wong TT. Atypical teratoid/rhabdoid tumors of the central nervous system: a compariative study with primitive neurectodermal tumors/medulloblastoma. Acta Neuropathol (Berl) 2000 99; 482-8. A comparison of 11 AT/RTs and 121 PNET/medulloblastomas through histopathologic and immunohistochemical studies. What other type of tumors can AT/RT tumors be mistaken for? The critical step in treatment planning is an accurate pathologic diagnosis. Atypical teratoid rhaboid tumors are very rare tumors which may be mistaken for medulloblastomas, primitive neurectodermal tumors, choroid plexus carcinomas or germ cell tumors. Atypical teratoid rhaboid tumors may have areas that are identical to other CNS neoplasms as rhabdoid characteristics are not the sole component of these tumors. The rhabdoid aspect may be located only in focal areas or less pronounced. It is important to consider AT/RT, particularly when a medulloblastoma or PNET diagnosis is entertained in the child under the age of one as these children are at the highest risk. Cytogenetic studies can assist in differentiating MB/PNETs from AT/RTs. Germ cell markers in tumor tissues and serum can guide an accurate diagnosis of germ cell tumors as AT/RTs lack these markers. Misclassification of the tumor’s pathology can lead to errors in treatment and prognosis. On study revealed an 8.8% major disagreement in neuropathologic cases. Thus, the American Cancer Society and the American Society of Clinical Pathologist recommend a second opinion on all cancer diagnoses. Shmooker BM, Successful cancer treatment begins with an accurate pathologic diagnosis. http://www.childhoodbraintumor.org/diagnosis.html Beigel JA. Cytogenetics and molecular genetics of childhood brain tumors. Neuro-oncol. 1999 1:139-51. This is a review articl of cytogentetic and molectular genetic changes which have been idenfied in childhood brain tumors to date. Biegel JA, Fogelgren B, Zhoe Jy, etal. Mutations of the INI1 rhabdoid tumor suppressor gene in medulloblastomas and primitive neurectodermal tumors of the central nervous system. Clin Cancer Res 2000. 6(2759-63. The frequency of deletions and mutations of INI1 was determined in 52 children whose diagnosis was MB or PNET of the CNS. Mutations were detected in four tumors. Recommendations are made that all children less than 1 year of age diagnosed with an MB/PNET should have the tumor tissue analyzed for chromosome 22 deletion and INI1 mutation.
Burger PC, Yu I, Tihan T, etal. Atypical teratoid rhaboid tumors of the central nervous system: a highly malignant tumor of infancy and childhood frequently mistaken for medulloblatoma: a Pediatric Oncology Group Study. Am J Surg Pathol 1998 22:1083-92. This is a review of 55 patients diagnosed with AT/RTs to define this disease both clinically and pathologically. Cuesta MT, deLeon Bojorge B, Rivas H, etal. Atypical rhabdoid/teratoid tumors: a presentation of three cases and a review of the literature. Rev Neurol 2001 32:618-624. This paper reporst the clinical, radiological,cytohistopathological and immunohistopathological aspects of three cases of AT/RTs. How are AT/RT related to other rhabdoid tumors of the body? Malignant rhabdoid tumors were first described as a variant of Wilms tumors of the kidney in 1978. Later rhaboid tumors outside the kidney were reported in many tissues including the liver, soft tissue, and central nervous system. Although the cell of origin is not know, cytogenetic studies have suggested a common genetic basis for rhabdoid tumors regardless of location with abnormalities in chromosome 22 commonly occurring. Regardless of location, all rhabdoid tumors are highly aggressive and tend to occur in children less than two years of age. It should be noted that there have been reported cases of a child having both atypical teratoid rhaboid tumors in the brain as well as rhabdoid tumors of the kidney. Weeks and associates reported on 111 renal rhabdoid cases of which 13.5% also had a central nervous system malignancy. It has been hypothesized that a germline INI mutation may predispose a child to these tumors. There have been some references in the literature alluding to a new diagnosis called rhabdoid predispostion syndrome related to the gene hSNF5/INI.. Weeks DA, Beckwith JB, Mierau GW, Luckery DW. Rhabdoid tumors of the kideny: a report of 111 cases form the National Wilms Tumor Study Pathology Center Am J Surg Path 1989 13:439-458. Beigel JA, Fogelgren B, Wainwright LM, etal. Germ-line INI1 mutations in a patient with a central nervous system atypical teratoid tumor and renal rhabdoid tumor. Genes Chromosomes Cancer 2000 1:31-7. A case report of a infant that developed both tumors that were identical in histoligic and immunophenotypic features. Huret J, Sevenet N. Rhabdoid predispostion syndrome. Atalas of Genetics and Cytogenetics in Oncology and Haematology. http://www.infobiogen.fr/services/chromcancer/Kprones/rhabdKpronID10051.html What is the cause of these tumors? The cause is unknown. Technical information However, genetic similarities have been found within these tumors. In particular the chromosomal 22 deletion is very common in AT/RTs. This chromosomal area contains the NSNF5/INI gene that appears to function as a classic tumor suppressor gene. This mutation is viewed as the “first hit” which predisposes these children to malignancies. 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.
Beigel J, Kalpana G, Knudsen E, etal. 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. Cancer Research 2002 63:323-328. Morley E. FISH as a Diagnostic Tool on Childhood Cancer. www.sas.upenn.edu/~emorley This paper discussing the utilization of FISH as a diagnostic tool has a very good introduction into childhood cancer and brain tumors. How common are AT/RTs? Approximately 2.76 children per 100,000 will be affected by a CNS tumor in the United States each year. This is approximately 2500-3000 pediatric brain tumors a year in the US. It has been estimated that 3% are AT/RTs although this percentage may increase as there is better differentiation between PNET/medulloblastoma tumors and AT/RTs. It should be noted that the tumor incidence is increasing by about 2.7% per year. Morley E. FISH as a Diagnostic Tool on Childhood Cancer. www.sas.upenn.edu/~emorley This paper discussing the utilization of FISH as a diagnostic tool has a very good introduction into childhood cancer and brain tumors. How do AT/RT tumors look on radiologic exam? • Location AT/RTs can occur at any sites within the CNS, however approximately 60% are located in the posterior fossa area/cerebellar area. • Appearance The tumors’ appearance on CT and MRI are nonspecific tending towards large size, calcifications, necrosis (tissue death),and hemorrhage (bleeding). 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. Zuccoli G, Izzi G, Baccinin E, etal. Cental nervous system atypical teratodi/rhabdoid tumors of infancy. CT and MR finding. Clinical Imaging 1999 23:356-60. Yoon CS, Chuang S. Jay V. Primarly malignant rhabdoid tumors of the brain: CT and MRI findings. Yonsei Med J 2000 4:8-16. A restrospective evaluation of the radiologic appearance of 5 tumors. Howelett DC, King, AP, Jarosz JM, eta. Imaging and patholoigc features of primary malignant rhabdoid tumors of the brain and spine. Neuroradiaology 1997 39:719-23. A description of two cases.
What are the clinical features of AT/RT? • 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. However, 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 classifed as atypical/teratoid rhabdoid tumors. Burger PC, Yu I, Tihan T, etal. Atypical teratoid rhaboid tumors of the central nervous system: a highly malignant tumor of infancy and childhood frequently mistaken for medulloblatoma: a Pediatric Oncology Group Study. Am J Surg Pathol 1998 22:1083-92. This is a review of 55 patients diagnosed with AT/RTs to define this disease both clinically and pathologically Chang HK. Kim JH. Classical malignant rhabodid tumors of central nervous system in 9-year-old Korean. Yonsei Med J 2001 42:142-6. Ashraf R, Bently RC, Awan AN. Implantation metstasis of primary malignant rhabdoid tumors of the brain in an adult (one case report). Med Pediatr Oncol. 1997 28:223-7. Arrazola J, Pedrosa I, Mendez R etal. Primary malignant rhabdoid tumour of the brain in an adult. Neuroradiology 2000 42:363-7. Lutterbach J, Liegibel J, Koch D. Atypical teratodi/rhabdoid tumors in adult patients: case report and a review of the literature. J Neurooncol 2001 52:49-56. Sugita Y, Takahashi Y, Hayashi I. Pineal malignant rhabdoid tumor with chondroid formation in an adult. Path Int 1999 49:1114-8. • 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. Tamiya T, Nakashima H, Ono Y, etal. Spinal atypical teratoid/rhabdoid tumor in an infant. Pediatr Neurosurg 2000 32:145-9 • Location The tumors can be located anywhere within the CNS including the spinal cord. Approximately 60% will be in the posterior fossa/cerebellar area. • Male to Female Ratio- As with other CNS tumors, slightly more males are affected than females (ratio 1.6:1) Morley E. FISH as a Diagnostic Tool on Childhood Cancer. www.sas.upenn.edu/~emorley This paper discussing the utilization of FISH as a diagnostic tool has a very good introduction into childhood cancer and brain tumors.
• Diagnostic Workup The initial diagnosis of tumor is made with a radiographic study (MRI or CT). If CT was preformed 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 tumor often spread to the spine. Examination of the cerebral spinal fluid is important as 1/3 of these patients will have intracranial dissemination with involvement of the CSF. Lu reported the most consistent finding were large tumor cells, ecentricity of the nucei and prominent neucleoli. Lu L, Wilkinson EJ, Yachinis AT. CSF cytology of atypical teratoid/rhaboid tumors of the brain in a two-year-old girl: a case report. Diagn Cytopathol 2000 23:329-32. • Metastasis Spread is noted in approximately 1/3 of the cases at the time of diagnosis and can occur anywhere throughout the CNS. Metastatic spread to the meninges (leptomenigeal spread sometimes referred to as sugar coating) is very common both initially and with relapse. 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, ependymomas and endodermal sinus tumors. Guler and Sugita separately reported cases of lung metastasis without a shunt. Rickett CH.Abdominal metastases of pediatric brain tumors via ventriculo-peritoneal shunts. Childs Nerv Syst. 1998 ;14:10-4. A review of the literature which discusses the clinical aspects of 35 cases. Newton HB, Rosenblum MK, Walker RW. Extraneural metastases of infratentorial glioblastoma multiforme to the peritoneal cavity.Cancer. 1992 69:2149-53. Two cases reported with spread to the abdomen. Cranston PE, Matten MT, Smith EE. Metastatic pineoblastoma via a ventriculoperitoneal shunt: CT demonstration. Comput Med Imaging Graph. 1992 16:349-51. A single case is reviewed. Pallini R, Bozzini V, Scerrati M, etal.Bone metastasis associated with shunt-related peritoneal deposits from a pineal germinoma. Case report and review of the literature. Acta Neurochir (Wien). 1991;109:78-83. A case report of a 15 year old boy with metastatic spread by the blood and the shunt detected two months after surgery. There is a review of the literature. Iwamuro Y, Seo S, Hirose Y etal.Intrathecal and intraperitoneal germinomas occurring 20 years after total removal of a pineal teratoma. Case report.J Neurosurg. 2002 96:364-7. Altundage OO, Celik I, Kars A. Pineal germ cell tumor metastasis via ventriculoperitoneal shunt.Am J Clin Oncol. 2002 ;25:104-5. Thambidorai DR, Azmi A, Rahman AJ, etal. Spermatic cord metastasis from a medulloblastoma. Pediatr Surg Int. 2001 ;17:654-6.
Fiorillo A, Maggi G, Martone A, Migliorati R, etal. Shunt-related abdominal metastases in an infant with medulloblastoma: long-term remission by systemic chemotherapy and surgery. J Neurooncol. 2001;52:273-6. Kornoes DN, Meyers SP, Rubin A, etal. A 4-year-old girl with a ventriculperitoneal shunt metastasis of a central nervous system atypical teratoid/rhabdoid tumor. Med Tediat Oncol 1999 32:389-91. Guler, E, Varan A, Soylemezoglu F. etal. Extraneural metastasis in a child with atypical teratoid rhabdoid tumors of the central nervous system. J Neurooncology 2001 54:53-56. • Prognosis

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