Malignant Rhabdoid Tumor
- Author: James I Geller, MD; Chief Editor: Max J Coppes, MD, PhD, MBA more...
Malignant rhabdoid tumor (MRT) is one of the most aggressive and lethal malignancies in pediatric oncology. Malignant rhabdoid tumor was initially described in 1978 as a rhabdomyosarcomatoid variant of a Wilms tumor because of its occurrence in the kidney and because of the resemblance of its cells to rhabdomyoblasts. The absence of muscular differentiation led Haas and colleagues to coin the term rhabdoid tumor of the kidney in 1981.
Although renal malignant rhabdoid tumor was historically included in treatment protocols of the National Wilms Tumor Study (NWTS) Group, this tumor is now recognized as an entity separate from a Wilms tumor. In contrast to a Wilms tumor, a malignant rhabdoid tumor of the kidney is characterized by the early onset of local and distant metastases and resistance to chemotherapy. Whereas the overall survival rate for Wilms tumors exceeds 85%, the survival rate for renal malignant rhabdoid tumors is only 20-25%.
Because rhabdoid tumor of the kidney was originally described, malignant rhabdoid tumors have been reported in practically every location in the body, including the brain, liver, soft tissues, lung, skin, and heart. This article focuses on renal and extrarenal rhabdoid tumors that arise outside the CNS.
Cytogenetic, fluorescence in situ hybridization (FISH), and loss-of-heterozygosity (LOH) studies have revealed that malignant rhabdoid tumors frequently contain deletions at chromosome locus 22q11.1. Positional cloning efforts revealed that this locus contains the SWI/SNF related, matrix-associated, actin-dependent regulator of chromatin, subfamily B, member 1 (SMARCB1) gene, also known as human sucrose nonfermenting gene number 5 (hSNF5), integrase interactor 1 (INI1) , or 47-Kd Brg1/Bam– associated factor (BAF47). SMARCB1 encodes a member of the human SWI/SNF complex.
Combined analyses including FISH, coding sequence analysis, high-density single nucleotide polymorphism–based oligonucleotide arrays, and multiplex ligation-dependent probe amplification enable the identification of biallelic, inactivating perturbations of SMARCB1 in nearly all malignant rhabdoid tumors, consistent with the 2-hit model of tumor formation. Thus, SMARCB1 is presumed to function as a classic tumor suppressor and the primary gene responsible for malignant rhabdoid tumor development.
Homozygous inactivation of SMARCB1 in mice demonstrates embryonic lethality, whereas heterozygous SMARCB1 mice demonstrate a normal phenotype at birth, with 20% developing sarcomas at a median age of 1 year. Similar to human malignant rhabdoid tumors, murine tumors in these mice acquire a second hit to the SMARCB1 locus. All mice harboring a conditional biallelic inactivation of SMARCB1 develop cancer with a median onset of 11 weeks, revealing one of the most aggressive cancer predisposition genotype-phenotype correlations known.
Unexpectedly, despite an aggressive clinical pattern of behavior, malignant rhabdoid tumors are generally diploid and genomically stable, without recurrent gene amplifications or deletions. The mechanism by which SMARCB1 perturbation leads to aggressive neoplasia therefore likely relates to its role in epigenetic modification. The SWI/SNF complex acts in an adenosine triphosphate (ATP)–dependent manner to remodel chromatin, which regulates gene transcription and DNA repair. Reports to date have demonstrated that SMARCB1 loss can promote cell cycle progression resulting from upregulation of targets of the p16INK4a-Rb-E2F pathway. Rb family loss has been shown to increase malignant rhabdoid tumor tumorigenesis and progression, whereas ablation of CyclinD1 abrogates malignant rhabdoid tumor evolution in mouse models.
Similarly, tumor development in SMARCB1 -deficient mice is greatly accelerated in the absence of functional p53 protein. These findings suggest a cooperative effect between SMARCB1 and the pRB, CyclinD1, and p53 pathways.
The histogenetic origin of rhabdoid tumor of the kidney (RTK) remains obscure. Rhabdoid tumor cells are polyphenotypic, with an immunostaining pattern that shows evidence of mesenchymal, epithelial, and neural differentiation. Polyantigenic expression suggests that RTK arises from a pluripotent cell capable of differentiating along several lines.
Considerable debate has been focused on whether extrarenal malignant rhabdoid tumors are the same as RTK. The recent recognition that CNS atypical teratoid/rhabdoid tumors (AT/RT) have deletions of the SMARCB1 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. Moreover, 10-15% of patients with malignant rhabdoid tumors have synchronous or metachronous brain tumors, many of which are second primary malignant rhabdoid tumors. Germline SMARCB1 mutations were detected in some of these patients.
Conversely, the spectrum of tumors characterized by mutations in the SMARCB1 gene has also been expanded beyond tumors with a rhabdoid histologic phenotype to include hereditary schwannomas, extraskeletal myxoid chondrosarcoma, proximal-type epithelioid sarcoma, epithelioid malignant peripheral nerve sheath tumor, renal medullary carcinoma, and pediatric undifferentiated sarcoma lacking rhabdoid features. Inactivation of SMARCB1 has also been identified in small cell undifferentiated variant of hepatoblastoma.[7, 8] Whether extrarenal or extracranial rhabdoid tumors have the same histogenetic origin as that of their renal counterparts is unclear. Although some extrarenal or extracranial rhabdoid tumors are considered to be undifferentiated sarcomas or carcinomas with rhabdoid features, others represent true rhabdoid tumors because they have documented SMARCB1 mutations.
The Children's Oncology Group (COG) has initiated an effort to prospectively screen all types of malignant rhabdoid tumor for SMARCB1 mutations and protein expression, which should improve the classification and prognostication of tumors with rhabdoid features. As molecular-based targeted therapies emerge, the distinction between true and pseudorhabdoid tumors may prove to have important therapeutic implications.
For details about the gross and histologic features of malignant rhabdoid tumors, see Histologic Findings below.
Malignant rhabdoid tumor is a rare tumor. According to registration data from NWTS 1-5, malignant rhabdoid tumor accounts for only 158 (1.6%) of 10,031 registrants with childhood renal tumors. Likewise, only 26 (0.9%) of 3000 participants in the Intergroup Rhabdomyosarcoma Studies I-III had tumors consistent with malignant rhabdoid tumor. About 15 cases of extrarenal or non-CNS malignant rhabdoid tumors are diagnosed each year in the North America.
The incidence of malignant rhabdoid tumor in most countries has not been reported. Between 1984 and 1999, approximately 6 patients per year diagnosed with malignant rhabdoid tumor were enrolled onto various national registries or protocols in Germany.
The overall survival rate for patients with malignant rhabdoid tumor enrolled in NWTS 1-5 was 23.2%.
Malignant rhabdoid tumor is a rapidly progressive tumor, with most deaths occurring within 12 months of presentation. The most common sites of metastasis at presentation are the lungs, abdominal lymph nodes, liver, brain and bone.
A young age at diagnosis is strongly associated with an adverse outcome. Four-year event-free survival rates according to age at diagnosis were 8.8% for patients aged 0-5 months, 17.2% for patients aged 6-11 months, 28.6% for patients aged 12-23 months, and 41.1% for patients aged 24 months or older (p < 0.0001).
High-stage (stage III/IV) disease is correlated with an adverse outcome (p=0.014), and most patients present with stage III or IV disease.
The survival of patients with malignant rhabdoid tumor in NWTS was as follows:
Stage I - 15 patients (33.3%)
Stage II - 25 patients (46.9%)
Stage III - 58 patients (21.8%)
Stage IV - 41 patients (8.4%)
Stage V - 3 patients (0%)
In a smaller study of 70 patients with malignant rhabdoid tumor and AT/RT from Germany, metastatic disease at diagnosis maintains prognostic value, although age does not. Additional preliminary data suggest that patients with germline mutations of SMARCB1 likely manifest disease at an earlier age, with a high risk of progression and inferior prognosis.
Malignant rhabdoid tumor has no apparent racial predilection.
Malignant rhabdoid tumor occurs slightly more frequently in male individuals than in female individuals, with male-to-female ratio of 1.4:1.
The median age at presentation is 10.6 months, with a mean age of 15 months. Most patients are younger than 2 years. Malignant rhabdoid tumor has been reported in children older than this and in adults, but whether these patients have true rhabdoid tumors or other poorly differentiated tumors with rhabdoid features is unclear.
Haas JE, Palmer NF, Weinberg AG, Beckwith JB. Ultrastructure of malignant rhabdoid tumor of the kidney. A distinctive renal tumor of children. Hum Pathol. 1981 Jul. 12(7):646-57. [Medline].
Jackson EM, Sievert AJ, Gai X, et al. Genomic analysis using high-density single nucleotide polymorphism-based oligonucleotide arrays and multiplex ligation-dependent probe amplification provides a comprehensive analysis of INI1/SMARCB1 in malignant rhabdoid tumors. Clin Cancer Res. Mar 2009. 15:1923-30. [Medline]. [Full Text].
Kohashi K, Oda Y, Yamamoto H, et al. SMARCB1/INI1 protein expression in round cell soft tissue sarcomas associated with chromosomal translocations involving EWS: a special reference to SMARCB1/INI1 negative variant extraskeletal myxoid chondrosarcoma. Am J Surg Pathol. Aug 2008. 32:1168-74. [Medline].
Cheng JX, Tretiakova M, Gong C, Mandal S, Krausz T, Taxy JB. Renal medullary carcinoma: rhabdoid features and the absence of INI1 expression as markers of aggressive behavior. Mod Pathol. Jun 2008. 21:647-52. [Medline].
Kreiger PA, Judkins AR, Russo PA, et al. Loss of INI1 expression defines a unique subset of pediatric undifferentiated soft tissue sarcomas. Mod Pathol. Jan 2009. 22:142-50. [Medline].
Trobaugh-Lotrario AD, Tomlinson GE, Finegold MJ, Gore L, Feusner JH. Small cell undifferentiated variant of hepatoblastoma: adverse clinical and molecular features similar to rhabdoid tumors. Pediatr Blood Cancer. Mar 2009. 52:328-34. [Medline].
Russo P, Biegel JA. SMARCB1/INI1 alterations and hepatoblastoma: another extrarenal rhabdoid tumor revealed?. Pediatr Blood Cancer. Mar 2009. 52:312-3. [Medline].
Reinhard H, Reinert J, Beier R, et al. Rhabdoid tumors in children: prognostic factors in 70 patients diagnosed in Germany. Oncol Rep. Mar 2008. 19:819-23. [Medline].
Mestre-Fusco A, Trampal C, Intriago B, Wessling H, Fuertes J, Suárez-Piñera M, et al. Assessment of rhabdoid brain tumor by F-18 FDG PET, C-11 methionine PET and MRI. Clin Nucl Med. 2012 Feb. 37(2):e33-5. [Medline].
Hilden JM, Meerbaum S, Burger P, et al. Central nervous system atypical teratoid/rhabdoid tumor: results of therapy in children enrolled in a registry. J Clin Oncol. 2004 Jul 15. 22(14):2877-84. [Medline].
Tekautz TM, Fuller CE, Blaney S, et al. Atypical teratoid/rhabdoid tumors (ATRT): improved survival in children 3 years of age and older with radiation therapy and high-dose alkylator-based chemotherapy. J Clin Oncol. 2005 Mar 1. 23(7):1491-9. [Medline].
Koga Y, Matsuzaki A, Suminoe A, et al. Long-term survival after autologous peripheral blood stem cell transplantation in two patients with malignant rhabdoid tumor of the kidney. Pediatr Blood Cancer. Jul 2009. 52:888-90. [Medline].
Furtwängler R, Nourkami-Tutdibi N, Leuschner I, Vokuhl C, Niggli F, Kager L, et al. Malignant rhabdoid tumor of the kidney: significantly improved response to pre-operative treatment intensified with doxorubicin. Cancer Genet. 2014 Jul 18. [Medline].
Agarwala S. Primary Malignant Liver Tumors in Children. Indian J Pediatr. 2012 Mar 1. [Medline].
Agrons GA, Kingsman KD, Wagner BJ, Sotelo-Avila C. Rhabdoid tumor of the kidney in children: a comparative study of 21 cases. AJR Am J Roentgenol. 1997 Feb. 168(2):447-51. [Medline].
Amar AM, Tomlinson G, Green DM, et al. Clinical presentation of rhabdoid tumors of the kidney. J Pediatr Hematol Oncol. 2001 Feb. 23(2):105-8. [Medline].
Biegel JA, Fogelgren B, Wainwright LM, et al. Germline INI1 mutation in a patient with a central nervous system atypical teratoid tumor and renal rhabdoid tumor. Genes Chromosomes Cancer. 2000 May. 28(1):31-7. [Medline].
Biegel JA, Zhou JY, Rorke LB, et al. Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Cancer Res. 1999 Jan 1. 59(1):74-9. [Medline].
Bruch LA, Hill DA, Cai DX, et al. A role for fluorescence in situ hybridization detection of chromosome 22q dosage in distinguishing atypical teratoid/rhabdoid tumors from medulloblastoma/central primitive neuroectodermal tumors. Hum Pathol. 2001 Feb. 32(2):156-62. [Medline].
Burger PC, Yu IT, Tihan T, et al. 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. Am J Surg Pathol. 1998 Sep. 22(9):1083-92. [Medline].
Chai J, Charboneau AL, Betz BL, Weissman BE. Loss of the hSNF5 gene concomitantly inactivates p21CIP/WAF1 and p16INK4a activity associated with replicative senescence in A204 rhabdoid tumor cells. Cancer Res. 2005 Nov 15. 65(22):10192-8. [Medline].
Chai J, Lu X, Godfrey V, et al. Tumor-specific cooperation of retinoblastoma protein family and Snf5 inactivation. Cancer Res. Apr 2007. 67:3002-9. [Medline].
Chung CJ, Lorenzo R, Rayder S, et al. Rhabdoid tumors of the kidney in children: CT findings. AJR Am J Roentgenol. 1995 Mar. 164(3):697-700. [Medline].
D'Angio GJ, Breslow N, Beckwith JB, et al. Treatment of Wilms' tumor. Results of the Third National Wilms' Tumor Study. Cancer. 1989 Jul 15. 64(2):349-60. [Medline].
Fruhwald MC, Hasselblatt M, Wirth S, et al. Non-linkage of familial rhabdoid tumors to SMARCB1 implies a second locus for the rhabdoid tumor predisposition syndrome. Pediatr Blood Cancer. 2006 Sep. 47(3):273-8. [Medline].
Fujisawa H, Misaki K, Takabatake Y, et al. Cyclin D1 is overexpressed in atypical teratoid/rhabdoid tumor with hSNF5/INI1 gene inactivation. J Neurooncol. 2005 Jun. 73(2):117-24. [Medline].
Gururangan S, Bowman LC, Parham DM, et al. Primary extracranial rhabdoid tumors. Clinicopathologic features and response to ifosfamide. Cancer. 1993 Apr 15. 71(8):2653-9. [Medline].
Han TI, Kim MJ, Yoon HK, et al. Rhabdoid tumour of the kidney: imaging findings. Pediatr Radiol. 2001 Apr. 31(4):233-7. [Medline].
Hoot AC, Russo P, Judkins AR, et al. Immunohistochemical analysis of hSNF5/INI1 distinguishes renal and extra-renal malignant rhabdoid tumors from other pediatric soft tissue tumors. Am J Surg Pathol. 2004 Nov. 28(11):1485-91. [Medline].
Isakoff MS, Sansam CG, Tamayo P, et al. Inactivation of the Snf5 tumor suppressor stimulates cell cycle progression and cooperates with p53 loss in oncogenic transformation. Proc Natl Acad Sci U S A. 2005 Dec 6. 102(49):17745-50. [Medline].
Jafri SZ, Freeman JL, Rosenberg BF, et al. Clinical and imaging features of rhabdoid tumor of the kidney. Urol Radiol. 1991. 13(2):94-7. [Medline].
Janson K, Nedzi LA, David O, et al. Predisposition to atypical teratoid/rhabdoid tumor due to an inherited INI1 mutation. Pediatr Blood Cancer. 2006 Sep. 47(3):279-84. [Medline].
Kordes U, Gesk S, Fruhwald MC, et al. Clinical and molecular features in patients with atypical teratoid rhabdoid tumor or malignant rhabdoid tumor. Genes Chromosomes Cancer. 2010 Feb. 49(2):176-81. [Medline].
Madigan CE, Armenian SH, Malogolowkin MH, Mascarenhas L. Extracranial malignant rhabdoid tumors in childhood: the Childrens Hospital Los Angeles experience. Cancer. Nov 2007. 110:2061-6. [Medline].
Parham DM, Weeks DA, Beckwith JB. The clinicopathologic spectrum of putative extrarenal rhabdoid tumors. An analysis of 42 cases studied with immunohistochemistry or electron microscopy. [published erratum appears in Am J Surg Pathol. 1995;19(4):488-9.]. Am J Surg Pathol. 1994 Oct. 18(10):1010-29. [Medline].
Puri DR, Meyers PA, Kraus DH, Laquaglia MP, Wexler LH, Wolden SL. Radiotherapy in the multimodal treatment of extrarenal extracranial malignant rhabdoid tumors. Pediatr Blood Cancer. Jan 2008. 50:167-9. [Medline].
Reddy AT. Atypical teratoid/rhabdoid tumors of the central nervous system. J Neurooncol. 2005 Dec. 75(3):309-13. [Medline].
Roberts CW, Galusha SA, McMenamin ME, et al. Haploinsufficiency of Snf5 (integrase interactor 1) predisposes to malignant rhabdoid tumors in mice. Proc Natl Acad Sci U S A. 2000 Dec 5. 97(25):13796-800. [Medline].
Roberts CW, Leroux MM, Fleming MD, Orkin SH. Highly penetrant, rapid tumorigenesis through conditional inversion of the tumor suppressor gene Snf5. Cancer Cell. 2002 Nov. 2(5):415-25. [Medline].
Rorke LB, Packer RJ, Biegel JA. Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood: definition of an entity. J Neurosurg. 1996 Jul. 85(1):56-65. [Medline].
Rousseau-Merck MF, Fiette L, Klochendler-Yeivin A, et al. Chromosome mechanisms and INI1 inactivation in human and mouse rhabdoid tumors. Cancer Genet Cytogenet. 2005 Mar. 157(2):127-33. [Medline].
Rousseau-Merck MF, Versteege I, Legrand I, et al. hSNF5/INI1 inactivation is mainly associated with homozygous deletions and mitotic recombinations in rhabdoid tumors. Cancer Res. 1999 Jul 1. 59(13):3152-6. [Medline].
Sigauke E, Rakheja D, Maddox DL, et al. Absence of expression of SMARCB1/INI1 in malignant rhabdoid tumors of the central nervous system, kidneys and soft tissue: an immunohistochemical study with implications for diagnosis. Mod Pathol. 2006 May. 19(5):717-25. [Medline].
Sisler CL, Siegel MJ. Malignant rhabdoid tumor of the kidney: radiologic features. Radiology. 1989 Jul. 172(1):211-2. [Medline].
Tomlinson GE, Breslow NE, Dome J, et al. Rhabdoid tumor of the kidney in the National Wilms' Tumor Study: age at diagnosis as a prognostic factor. J Clin Oncol. 2005 Oct 20. 23(30):7641-5. [Medline].
Tsikitis M, Zhang Z, Edelman W, et al. Genetic ablation of Cyclin D1 abrogates genesis of rhabdoid tumors resulting from Ini1 loss. Proc Natl Acad Sci U S A. 2005 Aug 23. 102(34):12129-34. [Medline].
Versteege I, Sevenet N, Lange J, et al. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature. 1998 Jul 9. 394(6689):203-6. [Medline].
Wagner L, Hill DA, Fuller C, et al. Treatment of metastatic rhabdoid tumor of the kidney. J Pediatr Hematol Oncol. 2002 Jun-Jul. 24(5):385-8. [Medline].
Waldron PE, Rodgers BM, Kelly MD, Womer RB. Successful treatment of a patient with stage IV rhabdoid tumor of the kidney: case report and review. J Pediatr Hematol Oncol. 1999 Jan-Feb. 21(1):53-7. [Medline].
Weeks DA, Beckwith JB, Mierau GW, Luckey DW. Rhabdoid tumor of kidney. A report of 111 cases from the National Wilms' Tumor Study Pathology Center. Am J Surg Pathol. 1989 Jun. 13(6):439-58. [Medline].
Weeks DA, Beckwith JB, Mierau GW, Zuppan CW. Renal neoplasms mimicking rhabdoid tumor of kidney. A report from the National Wilms' Tumor Study Pathology Center. Am J Surg Pathol. 1991 Nov. 15(11):1042-54. [Medline].
Winger DI, Buyuk A, Bohrer S, et al. Radiology-Pathology Conference: rhabdoid tumor of the kidney. Clin Imaging. 2006 Mar-Apr. 30(2):132-6. [Medline].
Yamamoto M, Suzuki N, Hatakeyama N, et al. Treatment of stage IV malignant rhabdoid tumor of the kidney (MRTK) with ICE and VDCy: a case report. J Pediatr Hematol Oncol. May 2006. 28:286-9. [Medline].
Zhang ZK, Davies KP, Allen J, et al. Cell cycle arrest and repression of cyclin D1 transcription by INI1/hSNF5. Mol Cell Biol. 2002 Aug. 22(16):5975-88. [Medline].
|Carboplatin||Target dose to the AUC of 6 mg/mL/min by using the Calvert equation||IV||Day 1|
|Etoposide||3.3 mg/kg/dose or 100 mg/m2/dose||IV||Days 1, 2, and 3|
|Ifosfamide||65 mg/kg/dose or 2 g/m2/dose||IV||Days 1, 2, and 3|
|Mesna||16 mg/kg/dose or 500 mg/m2/dose||IV||Start immediately after and at 3 h, 6 h, and 9 h after ifosfamide|
|Filgrastim G-CSF||5 mcg/kg/dose||SC||Start 24 h after chemotherapy and continue until ANC recovers|
|Vincristine||0.05 mg/kg/dose or 1.5 mg/m2/dose; not to exceed 2 mg/dose||IV||Days 1, 8, and 15|
|Doxorubicin||1.2 mg/kg/dose or 37.5 mg/m2/dose||IV||Days 1 and 2|
|Cyclophosphamide||60 mg/kg/dose or 1.8 g/m2/dose||IV||Day 1|
|Mesna||15 mg/kg/dose or 450 mg/m2/dose||IV||Start immediately after and at 3, 6, and 9 h after cyclophosphamide|
|Filgrastim G-CSF||5 mcg/kg/dose||SC||Start 24 h after chemotherapy and continue until ANC recovers|