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| {{DiseaseDisorder infobox |
| | __NOTOC__ |
| Name = Atypical teratoid rhabdoid tumor |
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| ICD10 = {{ICD10|C|70||c|69}}-{{ICD10|C|72||c|69}} |
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| ICD9 = {{ICD9|191}}-{{ICD9|192}} |
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| Image = ATRT-MRI.jpg|
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| Caption = [[Magnetic resonance imaging|MRI]] of an AT/RT|
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| ICDO = 9508/3 |
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| OMIM = 609322|
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| DiseasesDB = 30780|
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| MedlinePlus = 000768 |
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| MeshID = D016543 |
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| }}
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| {{Atypical teratoid rhabdoid tumor}} | | {{Atypical teratoid rhabdoid tumor}} |
| {{CMG}} | | '''For patient information click [[{{PAGENAME}} (patient information)|here]]''' |
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| | {{CMG}}{{AE}}{{SR}}{{Sab}} |
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| ==Overview==
| | {{SK}} ATRT; AT/RT; Atypical teratoid rhabdoid tumour; Atypical teratoid/Rhabdoid tumor; Atypical teratoid/Rhabdoid tumour; Primary brain tumor; Brain tumour |
| '''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 (PF), 39% sPNET ([[supratentorial]] [[primitive neuroectodermal tumor| primitive neuroectodermal tumors]]), 5% [[pineal gland|pineal]], 2% [[Spinal tumor|spinal]], and 2% multi-focal.<ref name="Kieran">{{cite journal
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| | author = Kieran MW
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| | title = An Update on Germ Cell Tumors, Atypical Teratoid/Rhaboid Tumors, and Choroid Plexus Tumors Rare Tumors 3: Brain Tumors---Germ Cell Tumors, Atypical Teratoid/Rhabdoid Tumors, and Choroid Plexus Tumors
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| | journal = American Society of Clinical Oncology
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| | volume = Education Book
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| | year = 2006
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| | url = http://www.asco.org/portal/site/ASCO/menuitem.64cfbd0f85cb37b2eda2be0aee37a01d/?vgnextoid=09f8201eb61a7010VgnVCM100000ed730ad1RCRD&vmview=vm_session_presentations_view&confID=40&sessionID=295
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| | accessdate = 2007-05-20 }}
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| </ref>
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| ==Genetics== | | ==[[Atypical teratoid rhabdoid tumor overview|Overview]]== |
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| | == [[Atypical teratoid rhabdoid tumor historical perspective|Historical Perspective]] == |
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| | == [[Atypical teratoid rhabdoid tumor classification|Classification]]== |
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| === Risk for siblings and other members of the family=== | | == [[Atypical teratoid rhabdoid tumor pathophysiology|Pathophysiology]] == |
| 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 [[Germline|germ-line]] genetic mutations in a parent shared by affected siblings. | |
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| *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.<ref>{{cite journal |author=Janson K, Nedzi LA, David O, ''et al'' |title=Predisposition to atypical teratoid/rhabdoid tumor due to an inherited INI1 mutation |journal=Pediatr Blood Cancer |volume=47 |issue=3 |pages=279–84 |year=2006 |pmid=16261613 |doi=10.1002/pbc.20622}}</ref>
| | == [[Atypical teratoid rhabdoid tumor causes|Causes]] == |
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| *In the first case report of [[monozygotic]] twins, both with brain tumors having similar genetic alterations, authors suggest a common genetic pathway.<ref>{{cite journal
| | == [[Atypical teratoid rhabdoid tumor differential diagnosis|Differentiating Atypical Teratoid Rhabdoid Tumor from other Diseases]] == |
| | last = Fernandez C, Bouvier C, Sevent N.
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| | title = Congenital disseminated malignant rhabdoid tumor and cerebellar tumor mimicking medulloblastoma in monozygotic twins: pathologic and molecular diagnosis
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| | journal = Am J Surg Pathol
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| | pmid = 11812951
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| | year = 2002
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| | issue = 26:
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| | pages = 266–70 }}</ref>
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| *A case reported on an infant that developed both AT/RT and renal rhabdoid tumors that were identical in gross and immunologic histology.<ref>{{cite journal
| | == [[Atypical teratoid rhabdoid tumor epidemiology and demographics|Epidemiology and Demographics]] == |
| | author = Beigel, JA, Fogelgren B, Wainwright LM, et al
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| | title = Germ-line INI1 mutations in a patient with a central nervous system atypical teratoid tumor and renal rhabdoid tumor
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| | journal = Genes Chromosomes Cancer
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| | volume =
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| | year = 2000
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| | issue = 1
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| | pages = 31–7 }}</ref>
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| * A family has had multiple generations of posterior fossa tumors including rhabdoid tumors and [[choroid plexus]] [[carcinoma]]. A germ-line mutation (SMARCB1) was found in both affected and some unaffected family members.<ref>{{cite journal
| | == [[Atypical teratoid rhabdoid tumor risk factors|Risk Factors]] == |
| |author=Taylor MD, Gokgoz N, Andrulis IL, Mainprize TG, Drake JM, Rutka JT
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| |title=Familial posterior fossa brain tumors of infancy secondary to germline mutation of the hSNF5 gene
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| |journal=Am. J. Hum. Genet.
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| |volume=66
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| |issue=4
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| |pages=1403–6
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| |year=2000
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| |pmid=10739763
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| |doi=10.1086/302833
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| |url=
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| }}</ref>
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| *Two sisters were diagnosed with AT/RTs fifteen days apart. A case report stated there were no [[Karyotype|karyotypic]] anomalies noted.<ref>{{cite journal
| | == [[Atypical teratoid rhabdoid tumor screening|Screening]] == |
| |author=Proust F, Laquerriere A, Constantin B, Ruchoux MM, Vannier JP, Fréger P
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| |title=Simultaneous presentation of atypical teratoid/rhabdoid tumor in siblings
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| |journal=J. Neurooncol. | |
| |volume=43
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| |issue=1
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| |pages=63–70
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| |year=1999
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| |pmid=10448873
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| |doi=
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| |url=http://www.kluweronline.com/art.pdf?issn=0167-594X&volume=43&page=63
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| }}</ref>
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| *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 it appears that the mutation was inherited from the mother's germline due to a mutation during [[oogenesis]].<ref>{{cite journal
| | == [[Atypical teratoid rhabdoid tumor natural history, complications and prognosis|Natural History, Complications and Prognosis]] == |
| | author = Sevent N, Sheridan E, Amran D, et al
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| | title = Constitutional mutations of the hSNF/INI1 gene predispose to a variety of cancers
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| | journal = Am J Hum Genet
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| | year = 1999
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| | issue = 65
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| | pages = 1343–48 }}</ref>
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| *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|FISH]] analysis showed significant genetic differences in the specimens which suggest that the occurrence of these virulent CNS malignancies within a single family was coincidental.<ref>{{cite
| | == Diagnosis == |
| | author = Ewa Izycka-Swieszewska, Maria Debiec-Rychter, Bartosz Wasag, et al.
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| | title = A unique occurrence of a cerebral atypical teratoid/rhabdoid tumor in an infant and a spinal canal primitive neuroectodermal tumor in her father
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| | journal = Journal of Neuro-Oncology
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| | year = February 2003
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| | issue = 3
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| | pages = 219-225
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| | doi = 10.1023/A:1022532727436 }}</ref>
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| ==Pathology==
| | [[Atypical teratoid rhabdoid tumor diagnostic criteria|Diagnostic Criteria]] | [[Atypical teratoid rhabdoid tumor staging|Staging]] | [[Atypical teratoid rhabdoid tumor history and symptoms|History and Symptoms]] | [[Atypical teratoid rhabdoid tumor physical examination|Physical Examination]] | [[Atypical teratoid rhabdoid tumor laboratory findings|Laboratory Findings]] | [[Atypical teratoid rhabdoid tumor CT|CT]] | [[Atypical teratoid rhabdoid tumor MRI|MRI]] | [[Atypical teratoid rhabdoid tumor echocardiography or ultrasound|Ultrasound]] | [[Atypical teratoid rhabdoid tumor other imaging findings|Other Imaging Findings]] | [[Atypical teratoid rhabdoid tumor other diagnostic studies|Other Diagnostic Studies]] |
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| AT/RT and rhabdoid tumor share the term "rhabdoid" because under a microscope both tumors resemble [[rhabdomyosarcoma]].
| | == Treatment == |
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| ===Histology===
| | [[Atypical teratoid rhabdoid tumor medical therapy|Medical Therapy]] | [[Atypical teratoid rhabdoid tumor surgery|Surgery]] | [[Atypical teratoid rhabdoid tumor prevention|Prevention]] | [[Atypical teratoid rhabdoid tumor cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Atypical teratoid rhabdoid tumor future or investigational therapies|Future or Investigational Therapies]] |
| The tumor histology is jumbled small and large cells. The [[Tissue (biology)|tissue]] of this tumor contains many different types of cells including the rhabdoid cells, large spindled cell, [[Epithelial reticular 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 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.<ref name="pmid10805090">{{cite journal |author=Ho DM, Hsu CY, Wong TT, Ting LT, Chiang H |title=Atypical teratoid/rhabdoid tumor of the central nervous system: a comparative study with primitive neuroectodermal tumor/medulloblastoma |journal=Acta Neuropathol. |volume=99 |issue=5 |pages=482–8 |year=2000 |pmid=10805090 |doi= |url=}}</ref>
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| ===Immunohistochemistry=== | | == Case Studies == |
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| [[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: | | [[Atypical teratoid rhabdoid tumor case study one|Case #1]] |
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| *[[Vimentin]]-positive
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| *[[Cytokeratin]]-positive
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| *Neuron specific enolase-positive
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| *Epitelial membrane antigen-positive
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| *[[Glial fibrillary acidic protein]]- positive
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| *[[Synaptophysin]]
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| *[[Chromogranin]]
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| *[[Smooth muscle]] [[actin]]
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| *[[Desmin]]
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| *Carcinoembrionary [[antigen]]
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| *CD99 [[antigen]];<ref>[http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=4267 CD99]</ref><ref>[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=313470 2nd CD99 link]</ref>
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| *[[S-100 protein|S-100]]
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| *[[neurofilament]]s
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| *[[Alpha-fetoprotein|AFP]] – not found
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| *[[Human chorionic gonadotropin|HCG]] – negative
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| ====Cytogenetic studies====
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| [[Cytogenetic]]s is the study of a tumor’s genetic make-up. A technique called [[fluorescent in situ hybridization|FISH]] may be able to help locate a mutation or abnormality that may be allowing tumor growth.<ref name="pmid11230702">{{cite journal
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| |author=Bruch LA, Hill DA, Cai DX, Levy BK, Dehner LP, Perry A |title=A role for fluorescence in situ hybridization detection of chromosome 22q dosage in distinguishing atypical teratoid/rhabdoid tumors from medulloblastoma/central primitive neuroectodermal tumors |journal=Hum. Pathol. |volume=32 |issue=2 |pages=156–62 |year=2001 |pmid=11230702 |doi=10.1053/hupa.2001.21572
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| |url=http://linkinghub.elsevier.com/retrieve/pii/S0046-8177(01)87801-1}}</ref> 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.
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| 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.
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| ==Diagnosis==
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| The standard work-up for AT/RT includes:
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| * MRI [[Magnetic resonance imaging]] of the brain and spine
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| * LP ([[Lumbar puncture]]) to look for M1 disease
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| * CT ([[Computed tomography]]) of chest and abdomen to check for a tumor
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| * BMA ([[Bone marrow examination|Bone Marrow Asperant]]) to check for bone tumors. Often a doctor will want perform a [[Hematopoietic stem cell transplantation|stem cell transplant]]
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| * BX [[Bone marrow examination|Bone marrow biopsy]]
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| * [[Bone scan]]
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| The initial diagnosis of a tumor is made with a [[Medical radiography|radiographic]] study ([[Magnetic Resonance Imaging|MRI]]<ref>
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| {{cite journal |author=Meyers SP, Khademianc ZP, Biegeld JA, Chuange SH, Koronesb DN, Zimmerman RA |title=Primary Intracranial Atypical Teratoid/Rhabdoid Tumors of Infancy and Childhood: MRI Features and Patient Outcomes |journal=American Journal of Neuroradiology |volume=27 |issue=5 |pages=962-971 |year=2006 |month=May |url=http://www.ajnr.org/cgi/content/full/27/5/962 | accessdate = 2008-05-05 }}</ref> or [[Computed Tomography|CT]]-). If CT was performed first, a MRI is usually performed as the images are often more detailed and may reveal previously undetected [[Metastasis|metastatic]] tumors in other locations of the brain. In addition, an MRI of the [[Vertebral column|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.
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| 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.<ref>{{cite journal
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| |author=Lu L, Wilkinson EJ, Yachnis AT
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| |title=CSF cytology of atypical teratoid/rhabdoid tumor of the brain in a two-year-old girl: a case report
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| |journal=Diagn. Cytopathol.
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| |volume=23
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| |issue=5
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| |pages=329–32
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| |year=2000
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| |pmid=11074628
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| }}</ref> 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.
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| ===Differential diagnosis===
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| 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.<ref> {{cite journal
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| |author=Jay V, Edwards V, Halliday W, Rutka J, Lau R
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| |title="Polyphenotypic" tumors in the central nervous system: problems in nosology and classification
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| |journal=Pediatr Pathol Lab Med
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| |volume=17
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| |issue=3
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| |pages=369–89
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| |year=1997
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| |pmid=9185218
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| |doi=
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| |url=
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| }}</ref>
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| Atypical teratoid/rhaboid tumor closely resembles medulloblastoma,<ref>
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| {{cite journal |author=Burger PC, Yu IT, Tihan T, ''et al'' |title=Atypical teratoid/rhabdoid tumor of the central nervous system: a highly malignant tumor of infancy and childhood frequently mistaken for medulloblastoma: a Pediatric Oncology Group study |journal=Am. J. Surg. Pathol. |volume=22 |issue=9 |pages=1083–92 |year=1998 |pmid=9737241 |doi=}}
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| </ref> [[primitive neuroectodermal tumor]], [[choroid plexus]] [[carcinoma]], and some kinds of [[germ cell tumor]].<!-- which kinds of germ cell tumor? --> Because rhabdoid characteristics<!-- defined above? --> 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.
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| It is important to consider AT/RT when a medulloblastoma or PNET is suspected, particularly in a child under the age of one. [[Cytogenetics|Cytogenetic]] studies can assist in differentiating MB/PNETs from AT/RTs. Some kinds of [[germ cell tumor]] secrete [[tumor marker]]s [[Alpha-fetoprotein|AFP]] or [[bHCG]]; AT/RTs do not.
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| <!-- move this paragraph to Prognosis? -->
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| 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.
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| ===Appearance on radiologic exam===
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| 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 (PF); 39% sPNET ([[supratentorial]] primitive neuroectodermal tumors); 5% [[Pineal gland|pineal]]; 2% [[Spinal tumor|spinal]], and 2% multi-focal.<ref name="Kieran"/>
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| The tumors' appearance on CT and MRI are nonspecific, tending towards large size, [[Metastatic calcification|calcifications]], [[Necrosis|necrosis (tissue death)]],and hemorrhage (bleeding). Radiological studies alone cannot identify AT/RT; a pathologist almost always has to evaluate a brain tissue sample.
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| 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 [[Relaxation (NMR)|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. [[Magnetic Resonance Imaging|MRI]] studies appear to be more able to pick up metastatic foci in other intracranial locations as well as intraspinal locations.
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| Preoperative and followup studies are needed to detect metastatic disease.
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| ==Treatment==
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| ===Surgical option===
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| [[Surgery]] plays a critical role in obtaining [[Tissue (biology)|tissue]] to make an accurate [[diagnosis]]. Surgery alone is not curative. In addition, 30% of the AT/RTs are located supratentorially and there is a predilection for the cerebello-pontine angle<ref>[http://www.utmb.edu/otoref/Grnds/Mass-CPA-040602/Mass-CPA-slides-040602.pdf PDF</ref> 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.
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| ===Chemotherapy options===
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| Approximately 50% of the AT/RTs will transiently respond, but [[Chemotherapy]] by itself is rarely curative. There is no standard treatment for AT/RT. Various chemotherapeutic agents have been used against AT/RTs which are also used against other CNS tumors including [[cisplatin]]um, [[carboplatinum]], [[cyclophosphamide]], [[vincristine]] and [[etoposide]]. Some [[chemotherapy regimens|Chemotherapy protocols]] are listed below:
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| * 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.<ref name="Geyer">{{cite journal |author=Geyer JR, Sposto R, Jennings M, ''et al'' |title=Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: a report from the Children's Cancer Group |journal=J. Clin. Oncol. |volume=23 |issue=30 |pages=7621–31 |year=2005 |pmid=16234523 |doi=10.1200/JCO.2005.09.095 |url=http://jco.ascopubs.org/cgi/content/abstract/23/30/7621}}</ref> 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.<ref name="Geyer" />
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| *[[Sarcoma]] protocols. There has been at least one report in the literature of malignant rhabdoid tumors of the CNS being treated in as a high-grade intracranial [[sarcoma]]. These three cases were treated with surgery, chemotherapy, radiotherapy and triple [[intrathecal]] chemotherapy similar to the Intergroup Rhadbdomyoscarcoma Study III guidelines.<ref>{{cite web |url=http://www.cancer.gov/cancertopics/pdq/treatment/childrhabdomyosarcoma/healthprofessional/ |title=Childhood Rhabdomyosarcoma Treatment|publisher= National Cancer Institute |accessdate=2007-07-09 }}</ref>
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| * [[Intrathecal]] 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 reservoir]]. 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 [[intrathecal]] [[chemotherapy]], the drug is administered into this bulb reservoir. At other times intrathecal chemotherapeutic agents are delivered through a [[lumbar puncture]] (spinal tap). A current Pediatric Brain Tumor Consortium [[Chemotherapy regimens|Protocol]] uses intrathecal [[mafosfamide]], a pre-activated [[cyclophosphamide]]derivative, in addition to other modalities to try to effect this tumor.<ref>{{cite journal |author=Poussaint TY, Phillips PC, Vajapeyam S, ''et al'' |title=The Neuroimaging Center of the Pediatric Brain Tumor Consortium-collaborative neuroimaging in pediatric brain tumor research: a work in progress |journal=AJNR. American journal of neuroradiology |volume=28 |issue=4 |pages=603–7 |year=2007 |pmid=17416804 |doi=}}</ref>
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| * High dose chemotherapy with stem cell rescue. This therapy uses chemotherapy at doses high enough to completely suppress the [[bone marrow]]. Prior to instituting this therapy, the child has a [[Central venous catheter|central line]] placed and [[stem cell|stem cells]] are gathered. After therapy these cells are given back to the child to [[Hematopoietic stem cell transplantation|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 cancer chemotherapy|history of chemotherapy]] protocols. A general description of stem cell rescue is available.<ref>{{cite web |url=http://www.cancerbackup.org.uk/Treatments/Stemcellbonemarrowtransplants/Generalinformation |title=Stem cell and bone marrow transplants|publisher= Cancerbackup |accessdate=2007-07-09 }}</ref> In addition, there are some reports that it is effective with select cancers and this includes AT/RT.<ref>{{cite web |url=http://content.nejm.org/cgi/content/abstract/348/19/1875 |publisher=NEJM|title= High-Dose Chemotherapy with Hematopoietic Stem-Cell Rescue for Multiple Myeloma |accessdate=2007-07-09}}</ref>
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| ===Radiation options===
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| The traditional practice for childhood brain tumors has been to use chemotherapy to defer [[radiation therapy]] 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 protocols call for upfront radiation therapy, often in spite of young age.<ref>{{cite journal |author=Squire SE, Chan MD, Marcus KJ |title=Atypical teratoid/rhabdoid tumor: the controversy behind radiation therapy |journal=J. Neurooncol. |volume=81 |issue=1 |pages=97–111 |year=2007 |pmid=16855864 |doi=10.1007/s11060-006-9196-z}}</ref>
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| 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.
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| [[External beam radiotherapy|External beam]] (conformal) radiation uses several fields that beam intersects at the tumor location; the normal brain tissue receives less radiation and hopefully is at less impact on cognitive function.
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| [[Proton therapy|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.<ref>[http://www.massgeneral.org/cancer/about/providers/radiation/proton/principles.asp Principles of Proton Beam Therapy]</ref><ref>[http://neurosurgery.mgh.harvard.edu/ProtonBeam/ Proton Beam RadioTheraphy at Mass. General]</ref><ref>[http://www.ihf-publications.org/html/images/pdfs_ref2/107-117.pdf Proton Beam Therapy Article]</ref><ref>[http://www.nature.com/bjc/journal/v93/n8/abs/6602754a.html Proton Beam Therapy - BJC Abstract]</ref><ref>[http://www.llu.edu/proton/patient/index.html Loma Linda Medical Center Proton Treatment Center - Overview]</ref><ref>[http://www.llu.edu/proton/patient/sites.html#BRAIN Loma Linda overview of Childhood Brain Tumors]</ref>
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|
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| ===Chromatin re-modeling agents===
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| This protocol is still in pre-clinical evaluation. [[HDAC inhibitors]] 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 [[Histone deacetylase|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.<ref>{{cite journal |author=Zhang ZK, Davies KP, Allen J, ''et al'' |title=Cell cycle arrest and repression of cyclin D1 transcription by INI1/hSNF5 |journal=Mol. Cell. Biol. |volume=22 |issue=16 |pages=5975–88 |year=2002 |pmid=12138206 |doi=}}</ref>
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|
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| ==Prognosis==
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|
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| The prognosis for AT/RT is 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 recommend palliative care, especially with younger children because of the poor outcomes.
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|
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| Patients with metastasis (disseminated tumor), larger tumors, tumors that could not be fully removed, tumor reoccurrence, and were younger than 36 months had the worse outcomes (i.e., shorter survival times).
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|
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| A retrospective survey from 36 AT/RT St. Jude Children's Hospital patients from 1984 to 2004 found a less than 10% survival rate in children under three, but a 70% survival rate in older children.<ref>{{cite web |url=http://www.stjude.org/disease-summaries/0,2557,449_2160_7267,00.html |title=Atypical Teratoid / Rhabdoid Tumor (ATRT) |accessdate=2007-07-10 |publisher=St Jude's Hospital}}</ref> 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 [[SWI/SNF|INI1/hSNF5]] gene.
| |
|
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| The longest term survivals reported in the literature are:
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| * (a) Hilden and associates reported a child who was still free from disease at 46 months from diagnosis.<ref> {{cite journal
| |
| |author=Hilden JM, Meerbaum S, Burger P, ''et al''
| |
| |title=Central nervous system atypical teratoid/rhabdoid tumor: results of therapy in children enrolled in a registry
| |
| |journal=J. Clin. Oncol.
| |
| |volume=22
| |
| |issue=14
| |
| |pages=2877–84
| |
| |year=2004
| |
| |pmid=15254056
| |
| |doi=10.1200/JCO.2004.07.073
| |
| |url= http://jco.ascopubs.org/cgi/content/full/22/14/2877?ck=nck
| |
| | accessdate = 2007-05-23}}</ref>
| |
| * (b) Olson and associates reported a child who was disease free at five years from diagnosis based on the IRS III protocol. <ref> {{cite journal
| |
| | author = Olson TA, Bayar E, Kosnic E
| |
| | title = Successful treatment of disseminated central nervous system malignant rhabdoid tumors
| |
| | journal = J Pediatr Hematol Oncol
| |
| | volume = 17
| |
| | pages = 71–75
| |
| | pmid = 7743242
| |
| | year = 1995 }}</ref>
| |
| * (c) In 2003 Hirth reported a case who had been disease free for over six years.<ref>{{cite journal
| |
| | author = Hirth A, Pedersen P-H, Wester K, et al
| |
| | year = 2003
| |
| | title = Cerebral Atypical Teratoid/Rhabdoid Tumor of Infancy: Long-Term Survival after Multimodal Treatment, also Including Triple Intrathecal Chemotherapy and Gamma Knife Radiosurgery--Case Report (Abstract)
| |
| | journal = Pediatric Hematology and Oncology 2003
| |
| | volume = 20
| |
| | issue = 4
| |
| | pages = 327–332
| |
| |DOI = 10.1080/713842315
| |
| | url = http://www.informaworld.com/smpp/content~content=a713842315~db=all
| |
| }} </ref>
| |
| * (d) Zimmerman in 2005 reported 50-to-72 month survival rates on four patients using an IRS III-based protocol. Two of these LT survivors had been treated after an AT/RT reoccurrence.<ref>{{cite journal
| |
| |author=Zimmerman MA, Goumnerova LC, Proctor M, ''et al''
| |
| |title=Continuous remission of newly diagnosed and relapsed central nervous system atypical teratoid/rhabdoid tumor
| |
| |journal=J. Neurooncol.
| |
| |volume=72
| |
| |issue=1
| |
| |pages=77–84
| |
| |year=2005
| |
| |pmid=15803379
| |
| |doi=10.1007/s11060-004-3115-y
| |
| |url= http://www.ingentaconnect.com/content/klu/neon/2005/00000072/00000001/00003115
| |
| | accessdate = 2007-05-20}}</ref>
| |
| * (e) A NYU study (Gardner 2004) has 4 of 12 longer term AT/RT survivors; the oldest was alive at 46 months after diagnosis.<ref>{{cite journal
| |
| | author = Gardner S, Diez B, Green A, et al
| |
| | title = THER 27. INTENSIVE INDUCTION CHEMOTHERAPY FOLLOWED BY HIGH-DOSE CHEMOTHERAPY WITH AUTOLOGOUS STEM CELL RESCUE (ASCR) IN YOUNG CHILDREN NEWLY DIAGNOSED WITH CENTRAL NERVOUS SYSTEM (CNS) ATYPICAL TERATOID RHABDOID TUMORS (ATT/RT)—THE “HEAD START” REGIMENS
| |
| | journal = Abstracts from the Eleventh International Symposium on Pediatric Neuro-Oncology
| |
| | year = 2004
| |
| | date=June 13–16
| |
| | url = http://neuro-oncology.dukejournals.org/cgi/reprint/6/4/401.pdf
| |
| | accessdate = 2007-06-03}}</ref>
| |
| * (f) Aurélie Fabre, 2004, reported a 16-year survivor of a soft-tissue rhabdoid tumor.<ref>{{cite journal
| |
| | author = Fabre A, Eyden B, Ali HH
| |
| | title = Soft-Tissue Extrarenal Rhabdoid Tumor with a Unique Long-Term Survival
| |
| | journal = Ultrastructural Pathology
| |
| | volume = 28
| |
| | issue = 1
| |
| | date= January 2004
| |
| | year = 2004
| |
| | pages = 49–52
| |
| | DOI = 10.1080/01913120490275259
| |
| | url = http://www.informaworld.com/smpp/content~content=a714860453~db=all
| |
| | accessdate = 2007-05-28}}</ref>
| |
|
| |
| Cancer treatments in long-term survivors who are children usually cause a series of negative effects on physical well being, fertility, cognition, and [[Learning problems in childhood cancer|learning]].<ref>
| |
| {{cite journal
| |
| | author = Fouladi M, Gilger E, Kocak M, et al
| |
| | title = Intellectual and Functional Outcome of Children 3 Years Old or Younger Who Have CNS Malignancies
| |
| | journal = Journal of Clinical Oncology
| |
| | volume = 23
| |
| | number = 28
| |
| | date= [[October 1]], [[2005]]
| |
| | pages = 7152–60
| |
| | DOI = 10.1200/JCO.2005.01.214
| |
| | url = http://jco.ascopubs.org/cgi/content/full/23/28/7152}}</ref><ref>
| |
| {{cite journal
| |
| | author = Monteleone P, Meadows AT
| |
| | title = Late Effects of Childhood Cancer and Treatment
| |
| | journal = eMedicine from WebMD
| |
| | date= [[June 6]], [[2006]]
| |
| | year = 2006
| |
| | url = http://www.emedicine.com/ped/topic2591.htm}}</ref><ref>
| |
| {{cite journal
| |
| | author = Foreman NK, Faestel PM, Pearson J, et al
| |
| | title = Health Status in 52 Long-term Survivors of Pediatric Brain Tumors
| |
| | journal = Journal of Neuro-Oncology
| |
| | date= January 1999
| |
| | year = 1999
| |
| | volume = 41
| |
| | number = 1
| |
| | pages = 47–52
| |
| | DOI = 10.1023/A:1006145724500
| |
| | url = http://www.springerlink.com/content/n651371xh3q8g42t/}}
| |
| </ref><ref>
| |
| {{cite journal
| |
| |author = Meyers EA, Kieran MW
| |
| |title = Brief Report Psychological adjustment of surgery-only pediatric neuro-oncology patients: a retrospective analysis
| |
| |journal = Psycho-Oncology
| |
| |publisher = John Wiley & Sons, Ltd.
| |
| |year = 2002
| |
| |volume = 11
| |
| |number = 1
| |
| |pages = 74–79
| |
| |DOI = 10.1002/pon.553
| |
| |url = http://www3.interscience.wiley.com/cgi-bin/abstract/89016824/ABSTRACT?CRETRY=1&SRETRY=0}}
| |
| </ref>
| |
|
| |
| === 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.<ref name="Kieran" /> Metastatic spread to the [[meninges]] (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 metastasize only within the CNS.
| |
|
| |
| One case of metastatic disease to the abdomen via ventriculoperitoneal [[shunt (medical)|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, [[Glioma|glioblastomas]], [[Ependymoma|ependymomas]] and [[endodermal sinus tumor]]s. Guler and Sugita separately reported cases of lung metastasis without a shunt.<ref>{{cite journal
| |
| |author=Güler E, Varan A, Söylemezoglu F, ''et al''
| |
| |title=Extraneural metastasis in a child with atypical teratoid rhabdoid tumor of the central nervous system
| |
| |journal=J. Neurooncol.
| |
| |volume=54
| |
| |issue=1
| |
| |pages=53–6
| |
| |year=2001
| |
| |pmid=11763423
| |
| |doi=
| |
| |url=http://www.kluweronline.com/art.pdf?issn=0167-594X&volume=54&page=53
| |
| }}</ref><ref>{{cite journal
| |
| |author=Sugita Y, Takahashi Y, Hayashi I, Morimatsu M, Okamoto K, Shigemori M
| |
| |title=Pineal malignant rhabdoid tumor with chondroid formation in an adult
| |
| |journal=Pathol. Int.
| |
| |volume=49
| |
| |issue=12
| |
| |pages=1114–8
| |
| |year=1999
| |
| |pmid=10632935
| |
| |doi=
| |
| |url=http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=1320-5463&date=1999&volume=49&issue=12&spage=1114
| |
| }}</ref>
| |
|
| |
| ==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.<ref name="Kieran" />
| |
|
| |
| ==History==
| |
|
| |
| Atypical teratoid/rhabdoid tumor was first described as a distinct entity in 1987.<ref>
| |
| {{cite journal
| |
| |author=Rorke LB, Packer RJ, Biegel JA
| |
| |title=Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood: definition of an entity
| |
| |journal=J. Neurosurg.
| |
| |volume=85
| |
| |issue=1
| |
| |pages=56–65
| |
| |year=1996
| |
| |pmid=8683283
| |
| }}</ref><!-- cite 1987 description --> In some early subsequent reports the tumor was known also as '''malignant rhabdoid tumor (MRT) of the CNS'''. Between 1978 and 1987, AT/RT likely was misdiagnosed as [[rhabdoid tumor]]. Before 1978, when rhabdoid tumor was described, AT/RT likely was misdiagnosed as [[medulloblastoma]]. However, both AT/RT and non-CNS MRT have a worse prognosis 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.<ref>{{cite journal
| |
| |author=Rorke LB, Packer R, Biegel J
| |
| |title=Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood
| |
| |journal=J. Neurooncol.
| |
| |volume=24
| |
| |issue=1
| |
| |pages=21–8
| |
| |year=1995
| |
| |pmid=8523069
| |
| |doi=
| |
| |url=
| |
| }}</ref> 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.<ref>{{cite journal |author=Biegel JA, Kalpana G, Knudsen ES, ''et al'' |title=The role of INI1 and the SWI/SNF complex in the development of rhabdoid tumors: meeting summary from the workshop on childhood atypical teratoid/rhabdoid tumors |journal=Cancer Res. |volume=62 |issue=1 |pages=323–8 |year=2002 |pmid=11782395 |doi= |url=http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=11782395}}</ref>
| |
| 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 trial|clinical trials]] 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.
| |
| *[http://www.pbtc.org/public/PBTC001_patient_abstract.htm Pilot Study of Systemic and Intrathecal Chemotherapy followed by Conformal Radiation for Infants with Embryonal Intracranial Central Nervous System Tumors, A Pediatric Brain Tumor Consortium Protocol]. This [http://www.pbtc.org/public/PBTC001_HP_abstract.htm study (PBTC-001)] is run out of the nine institutions associated with the Pediatric Brain Tumor consortium and uses combined modalities including intrathecal mafosfamide, systemic chemotherapy (vincristine, cyclophosphamide, cisplatinum and oral etoposide) and possibly the use of craniospinal or conformal radiation.
| |
| *[http://www.virtualtrials.com/trialdetails.cfm?id=9600209 Head Start Chemotherapy Protocol]. This chemotherapy protocol is for children <10 years old with newly diagnosed high grade primary brain tumors with intent to eliminate irradiation and shorten the treatment time to 6 months. The therapy consists of 3-5 cycles of intensive chemotherapy followed by a single myeloblative chemotherapy with stem cell rescue. Dr. Jonathan Finlay of New York University Medical Center is the contact person although run at a few hospitals in the county (contact information is listed on the site).
| |
| *[http://clinicaltrials.gov/show/NCT00003141 Phase I Pilot Study of Intensive Chemotherapy with Peripheral Blood Stem Cell Rescue in Infants with Malignant Brain or Spinal Cord Tumors] This study uses cisplatinum, cycophosphamide, vincristine and etoposide followed by carboplatinum and thiopeta and then stem cell rescue. There are to be three cycles of carboplatinum and thiopeta with stem cell rescue.
| |
| *[http://www.clinicaltrials.gov/show/NCT00084838 Intrathecal and Systemic Chemotherapy Combined With Radiation Therapy in Treating Young Patients With Newly Diagnosed Central Nervous System Atypical Teratoid/Rhabdoid Tumors] Children's Hospital of Philadelphia
| |
|
| |
| ==References==
| |
| {{reflist|2}}
| |
|
| |
| ==External links==
| |
| * [http://cms.clevelandclinic.org/childrenshospital/body.cfm?id=471 The Rhabdoid Registry]
| |
| * {{cite journal
| |
| | authors = Hilden JM, Meerbaum S, Burger P, et al
| |
| | title = Central Nervous System Atypical Teratoid/Rhabdoid Tumor: Results of Therapy in Children Enrolled in a Registry
| |
| | journal = Journal of Clinical Oncology
| |
| | volume = 22
| |
| | issue = 14
| |
| | pages = 2877–84
| |
| | date = [[2004-07-15]]
| |
| | url = http://jco.ascopubs.org/cgi/content/full/22/14/2877?ck=nck
| |
| | doi = 10.1200/JCO.2004.07.073
| |
| | accessdate = 2007-05-23}}
| |
| *{{cite journal
| |
| | authors = Beigel J, Kalpana G, Knudsen E, et al.
| |
| | year = 2002
| |
| | title = 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
| |
| | journal = Cancer Research 2002
| |
| | issue = 63:
| |
| | pages = 323–28
| |
| | url = http://cancerres.aacrjournals.org/cgi/content/abstract/62/1/323
| |
| }}
| |
| *{{cite journal
| |
| | author = Huret J, Sevenet N
| |
| | title = Rhabdoid predisposition syndrome
| |
| | year = 2002
| |
| | journal = Atlas of Genetics and Cytogenetics in Oncology and Haematology
| |
| | url = http://www.infobiogen.fr/services/chromcancer/Kprones/rhabdKpronID10051.html
| |
| }}
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| {{Nervous tissue tumors}} | | {{Nervous tissue tumors}} |
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| [[pl:Atypowy nowotwór teratoidny (rabdoidny)]] | | [[pl:Atypowy nowotwór teratoidny (rabdoidny)]] |
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