eMedicine Specialties > Pediatrics: General Medicine > Oncology

Malignant Rhabdoid Tumor

James I Geller, MD, Assistant Professor of Clinical Pediatrics, Division of Hematology/Oncology, Cincinnati Children's Hospital Medical Center
Nancy D. Leslie MD, Professor of Clinical Pediatrics, Cincinnati Children's Hospital Research Foundation; Hong Yin, MD, Assistant Professor, Department of Pathology and Laboratory Medicine, University of Cincinnati School of Medicine; Staff Pathologist, Department of Pathology, Cincinnati Children's Hospital

Updated: Dec 18, 2009

Introduction

Background

Introduction

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.^{[1 ]}

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.

Molecular genetics

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).^{[2 ]} 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.^{[3 ]}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.

Pathophysiology

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,^{[4 ]}proximal-type epithelioid sarcoma, epithelioid malignant peripheral nerve sheath tumor, renal medullary carcinoma,^{[5 ]}and pediatric undifferentiated sarcoma lacking rhabdoid features.^{[6 ]}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.

Frequency

United States

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.

International

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.^{[9 ]}

Mortality/Morbidity

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.^{[9 ]}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.

Race

Malignant rhabdoid tumor has no apparent racial predilection.

Sex

Malignant rhabdoid tumor occurs slightly more frequently in male individuals than in female individuals, with male-to-female ratio of 1.4:1.

Age

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.

Clinical

History

Children with rhabdoid tumor of the kidney (RTK) present with signs and symptoms related to an intrarenal mass.

• Pain is difficult to assess because the median age at presentation is about 11 months. However, fussiness is reported in most patients.
• Gross hematuria is a presenting feature in approximately 60% of patients. By contrast, only 20% of patients with Wilms tumor have gross hematuria.
• Fever is a presenting symptom in 50% of patients with a rhabdoid tumor of the kidney, compared with 25% of patients with a Wilms tumor.
• As many as 20% of patients with a rhabdoid tumor of the kidney have synchronous or metachronous CNS lesions, including both metastases and second primary cancers.

A detailed family cancer history should be obtained.

Physical

The physical findings of patients with malignant rhabdoid tumor (MRT) depend on the site of origin of the tumor.

• For rhabdoid tumor of the kidney, the physical examination is most remarkable for a large intra-abdominal mass.
• Hypertension, defined as blood pressure greater than the 95th percentile, is observed in up to 70% of patients.
• In contrast to a Wilms tumor, an malignant rhabdoid tumor is not associated with the WAGR syndrome, which consists of a Wilms tumor, aniridia, genitourinary anomalies, and mental retardation, or with Beckwith-Wiedemann syndrome, which is organomegaly, large birth weight, macroglossia, and hemihypertrophy.
• Evidence of focal neurologic signs or increased intracranial pressure should be evaluated in light of the prevalence of synchronous CNS tumors.

Causes

• Although mutations or deletions of the SMARCB1/INI1 gene play a role in the development of malignant rhabdoid tumor, the events that incite these genetic alterations are unknown.
• Several cases of familial malignant rhabdoid tumor are reported.
• No environmental or infectious associations with malignant rhabdoid tumor have been established.

Differential Diagnoses

Clear Cell Sarcoma of the Kidney
Congenital Mesoblastic Nephroma
Rhabdomyosarcoma
Wilms Tumor

Other Problems to Be Considered

• For malignant rhabdoid tumor (MRT) of the kidney
  • Wilms tumor
  • Congenital mesoblastic nephroma
  • Renal cell carcinoma
  • Clear cell sarcoma of the kidney
  • Primitive neuroectodermal tumor of the kidney
  • Renal medullary carcinoma
• For extrarenal malignant rhabdoid tumor
  • Rhabdomyosarcoma
  • Nonrhabdomyosarcoma soft tissue sarcomas
  • Hepatoblastoma/small cell undifferentiated tumor

Workup

Laboratory Studies

• Although malignant rhabdoid tumor (MRT) is definitively diagnosed by means of histologic analysis (see Histologic Findings below), laboratory studies can help in distinguishing a rhabdoid tumor of the kidney from a Wilms tumor.
• The following tests may be helpful:
  • CBC count: Approximately 55% of patients with malignant rhabdoid tumor present with a hemoglobin level of less than 9 g/dL. Only 25% of patients with Wilms tumor are anemic at presentation.
  • Urinalysis: Microscopic hematuria is seen in 75% of patients with malignant rhabdoid tumor. Approximately 25% of patients with malignant rhabdoid tumors have proteinuria; this prevalence is similar to that of patients with Wilms tumors.
  • Serum calcium measurement: As many as 25% of patients with malignant rhabdoid tumor present with hypercalcemia. This finding is attributed to the ectopic production of parathyroid hormone-related protein by the tumor. Hypercalcemia is uncommon in Wilms tumor but is associated with congenital mesoblastic nephroma.
• Liver function test results may be abnormal in infants and children with primary hepatic malignant rhabdoid tumor or in the case of hepatic metastases from a renal or soft tissue primary malignant rhabdoid tumor.

Imaging Studies

• No pathognomonic imaging feature aids in distinguishing malignant rhabdoid tumor from the other renal tumors of childhood. However, several features may raise the suspicion for malignant rhabdoid tumor.
• The following imaging studies are suggested for the diagnosis and staging of malignant rhabdoid tumor:
  • Abdominal CT: Malignant rhabdoid tumor typically appears as a large, lobulated mass in the center or periphery of the kidney. The margins of the tumor may be sharply defined from the adjacent renal parenchyma, or they may be indistinct. Tumoral lobules are often separated by hypoattenuating areas of hemorrhage or necrosis.
    • Calcification, seen in about 10% of Wilms tumors and rarely seen in clear cell sarcoma or congenital mesoblastic nephroma, occurs frequently in malignant rhabdoid tumor. Malignant rhabdoid tumor–associated calcifications are often linear or curvilinear, and they may outline tumor lobules, as is shown in the image below.
    • 
      

      

      Nonenhanced CT scan demonstrates linear and curvilinear calcifications outlining tumor lobules in a malignant rhabdoid tumor (MRT) (arrows). A hypoattenuating fluid collection surrounds and separates the lobules. These imaging features are seen with MRT more often than with other childhood renal neoplasms.

      
      
    • A peripheral, subcapsular, crescent-shaped fluid collection is often seen in association with malignant rhabdoid tumor, as is shown in the image below.
    • 
      

      

      Contrast-enhanced CT scan demonstrates a subcapsular fluid collection (arrow) and the lobulated nature of a malignant rhabdoid tumor (MRT). Subcapsular fluid collections are more common with MRTs than with the other renal neoplasms that occur in children.

      
      
    • In one study, this finding was present in 15 of 21 patients (71%) with malignant rhabdoid tumor but was present in only 8 of 93 patients (9%) with Wilms tumors, 6 of 44 patients (14%) with congenital mesoblastic nephromas, and 3 of 12 patients (25%) with clear cell sarcomas. These subcapsular fluid collections may be due either to hemorrhage or tumor necrosis.
  • Chest CT: Lungs remain the most common site of metastatic disease from non-CNS malignant rhabdoid tumor; the lungs are involved in 83% of infants and children with metastatic malignant rhabdoid tumor at diagnosis. When present, lung disease tends to be bilateral and unresectable.
  • Abdominal ultrasonography: Tumoral invasion of the renal vein and/or the inferior vena cava is sometimes seen with malignant rhabdoid tumor and is best diagnosed with Doppler ultrasonography or magnetic resonance angiography.
  • MRI or CT of the brain: Imaging of the head is indicated to exclude the possibility of a synchronous primary or metastatic brain tumor.
  • Bone Scan: Bone metastases are present in 5% of infants and children with metastatic malignant rhabdoid tumor at diagnosis. As such, the COG's current malignant rhabdoid tumor research protocol now requires bone scan at diagnosis. Whether all children with malignant rhabdoid tumor require a bone scan at diagnosis is unclear.

Other Tests

• The finding of germline perturbations in SMARCB1, assessed via genetic study of patient lymphocyte DNA, confirms a rhabdoid tumor predisposition and is estimated to occur in approximately 15-30% of patients with malignant rhabdoid tumor.

Procedures

• Tumor tissue sampling is required to make the diagnosis of malignant rhabdoid tumor and assists in defining the genetic background.
• Bone marrow aspiration and biopsy are not routinely necessary in the workup of malignant rhabdoid tumor because malignant rhabdoid tumor rarely metastasizes to the bone marrow.
• Lumbar puncture is not routinely indicated unless a CNS tumor is diagnosed.

Histologic Findings

• On gross examination, MRTs are heterogeneous, bulky, lobulated, friable, solid, gray-tan masses with areas of necrosis and hemorrhage.
• On microscopic examination, malignant rhabdoid tumors are characterized by sheets or solid trabeculae of large tumor cells with vesicular chromatin, nuclei with prominent cherry-red nucleoli, moderate amounts of eccentric eosinophilic cytoplasm, and a distinctive, globoid, hyaline pink intracytoplasmic inclusion, as is shown in the image below.
• 
  

  

  Histology of malignant rhabdoid tumors (MRTs). This photomicrograph shows the typical large malignant cells with large, vesicular nuclei, prominent red nucleoli, and abundant eosinophilic cytoplasm. Many tumor cells have a distinct, pale, rhabdoid inclusion in the cytoplasm. (Hematoxylin and eosin stain, original magnification x400).

  
  
• Mitoses are frequent and necrosis is common. A subset of tumors may be composed predominantly of primitive undifferentiated small round blue cells, but, upon closer inspection, small foci of cells with diagnostic cytologic features can be identified. Other patterns described as sclerosing (including chondroid), epithelioid, spindled, lymphomatoid or histiocytoid, and vascular may coexist with the classic pattern. Unlike a Wilms tumor, malignant rhabdoid tumor of the kidney typically has an infiltrative border with the surrounding nonneoplastic cortex and renal medulla.
• The most useful ultrastructural finding is a large whorl of intermediate filaments in the cytoplasm with a diameter of 8-10 nm, correlating with the rhabdoid inclusions seen with light microscopy. Dilated rough endoplasmic reticulum, rudimentary cell junctions, and cytoplasmic tonofilamentlike bundles are other characteristic features. The cells do not have external lamina or evidence of myogenic differentiation.
• On immunohistochemical examination, the tumor cells are polyphenotypic with consistent staining for vimentin, and most are positive for epithelial membrane antigen and/or cytokeratin. Positivity for glial fibrillary acidic protein, neuron-specific enolase, smooth muscle actin, desmin, CD99, and other markers has been seen in malignant rhabdoid tumor. Malignant rhabdoid tumor lacks INI1 immunohistochemical staining, as is seen in the image below, whereas most other tumors have detectable INI1 protein.
• 
  

  

  INI1 immunohistochemistry stain shows diffuse loss of INI1 expression in tumor nuclei, with appropriate staining of intratumoral endothelial cells serving as the internal control (original magnification x400).

  
  
• Loss of INI1 protein expression correlates closely with biallelic SMARCB1 gene perturbation, assessed via molecular genetic testing. Therefore, INI1 immunohistochemical studies can be used in conjunction with other studies to confirm the histologic diagnosis of malignant rhabdoid tumor.

Staging

• In North America, malignant rhabdoid tumors are staged according to the staging system of the NWTS Group, which the COG has modified.
• The COG staging system is as follows:
  • Stage I: Tumor is limited to the kidney and completely excised. The renal capsule is intact. The tumor is not ruptured or sampled for biopsy before it is removed. (Fine-needle aspiration is excluded from this restriction.) The vessels of the renal sinus are not involved. No evidence suggests tumor at or beyond the margins of resection.
  • Stage II: The tumor extended beyond the kidney, but it was completely excised. The tumor may regionally extend into the renal sinus or penetrate the renal capsule. Blood vessels outside the renal sinus may contain tumor, but the tumor must be removed en bloc with the tumor. No evidence of tumor at or beyond the margins of resection is present.
  • Stage III: Residual nonhematogenous tumor is confined to the abdomen. Any of the following may occur: (1) Tumor involves abdominal lymph nodes. (2) The tumor has penetrated the peritoneal surface. (3) Tumor implants are found on the peritoneal surface. (4) Gross or microscopic tumor remains after surgery. (5) The tumor is not completely resectable because of local infiltration of vital structures. (6) Tumoral spillage occurs before or during surgery. (7) Tumor biopsy was performed before resection.
  • Stage IV: Hematogenous metastases or lymph node metastases are present outside the abdominal and/or pelvic cavity.
  • Stage V: Tumors are bilateral.

Treatment

Medical Care

After the primary tumor is surgically removed, chemotherapy is indicated as adjuvant treatment for malignant rhabdoid tumor (MRT). Chemotherapy for malignant rhabdoid tumor was historically based on therapy for a Wilms tumor, which included vincristine, actinomycin, and doxorubicin with or without cyclophosphamide. With these agents, the estimated survival rate for patients with malignant rhabdoid tumor was only 23%.

To try to improve these results, investigators in NWTS 5 used a regimen consisting of carboplatin-etoposide alternating with cyclophosphamide. However, this strategy, did not improve outcomes. Recent case reports have documented successful outcomes in patients with metastatic malignant rhabdoid tumor treated with ifosfamide-carboplatin-etoposide (ICE) or ifosfamide-etoposide (IE) alternating with vincristine-doxorubicin-cyclophosphamide (VDC). On the basis of these reports, cyclophosphamide-carboplatin-etoposide (CCE) alternating with VDC is the main treatment in the current COG study.

Insights into the treatment of malignant rhabdoid tumor may be derived from the experience with atypical teratoid/rhabdoid tumors (AT/RT) of the CNS. Like its extra-CNS counterparts, AT/RT results in an unfavorable prognosis and is characterized by resistance to chemotherapy. A review of the AT/RT registry by Hilden and colleagues revealed that 14 (33%) of 42 patients with AT/RT survived disease-free over 9.5-month to 96-month follow-up.^{[10 ]}Survivors were treated with surgery, radiation therapy, and various chemotherapy regimens that typically included cisplatin, etoposide, vincristine, ifosfamide, doxorubicin, actinomycin, cyclophosphamide, and intrathecal agents. Some survivors received high-dose therapy with autologous stem-cell rescue.

In a separate review by Tekautz et al, AT/RT presenting in older patients demonstrated a 2 year event-free survival of 78% when treated with a combination of radiation and high-dose alkylating therapy.^{[11 ]}More recently, a multisite study of a multimodal therapy plan incorporating surgery, radiation, and a systemic and intrathecal conventional chemotherapeutic regimen based on a modified IRS-III regimen demonstrated a 2 year progression-free survival of 58%. This later study includes infants younger than 3 years. Considering all data, the COG AT/RT protocol is currently testing a regimen incorporating surgery, conventional chemotherapy, radiation, and tandem high dose chemotherapy with stem cell rescue.

Two reports describe the successful use of high dose chemotherapy with stem cell rescue to treat non-CNS malignant rhabdoid tumor.^{[12 ]}However, in combination, none of the 4 children described had metastatic disease at presentation. Based on the limited data available at this time, whether high-dose chemotherapy with stem cell rescue is of any added benefit for non-CNS malignant rhabdoid tumor is unclear.

Similarly, anecdotal reports suggest a benefit from the use of radiotherapy as part of multimodal therapy for malignant rhabdoid tumor. However, the lack of treatment uniformity among reported patients makes it difficult to determine if radiotherapy is effective for malignant rhabdoid tumor. In NWTS 1-5, radiation therapy was given to the flank or abdomen at total doses of 1080-3500 cGy. However, the optimal dose remains to be determined. Radiation therapy is a cornerstone of treatment for CNS AT/RT, and some suggest that the high doses delivered to the posterior fossa improve patients' outcomes.

Surgical Care

Children with a renal tumor or soft tissue mass should be referred to a pediatric surgeon with experience in oncologic surgery.

For renal tumors, a large transabdominal, transperitoneal incision is recommended for adequate exposure. If the mass is unilateral, a radical nephrectomy with subtotal ureterectomy should be performed. The tumor should be removed en bloc to avoid tumoral spillage into the peritoneal cavity because this spillage increases the stage of the tumor. If the mass involves the upper pole of the kidney, the adrenal gland should be removed.

Lymph nodes from the iliac, para-aortic, and celiac areas should be sampled, even if they do not appear abnormal. Lymph node dissection is not indicated. If the tumor is bilateral or unresectable, biopsy should be performed. If a bilateral or unresectable Wilms tumor is diagnosed, preoperative chemotherapy is recommended to shrink the tumor and facilitate subsequent resection. If malignant rhabdoid tumor is diagnosed, complete removal of the tumor is advised.

For extrarenal tumors, the surgical approach depends on the site of disease. Complete resection should be attempted if feasible. If not initially feasible, a preoperative course of chemotherapy is advised.

Consultations

Therapy for malignant rhabdoid tumor is intensive and requires a multidisciplinary effort.

Practitioners who should be consulted include the following:

• Pediatric oncologist
• Pediatric surgeon or urologist
• Radiation oncologist
• Pediatric clinical geneticist or genetics counselor
• Social worker
• Nutritionist

Diet

No dietary restrictions are necessary. The patient's nutritional status should be closely monitored to ensure adequate caloric intake during the intensive chemotherapy. Parenteral nutrition may be required at some point during treatment.

Activity

No restrictions on activity are necessary except during periods of thrombocytopenia. Standard neutropenic precautions should be employed when appropriate.

Medication

The treatment for malignant rhabdoid tumor (MRT) remains investigational. No accepted standard therapy has been established for this disease. Enrollment of patients on clinical trials is strongly encouraged. The following regimen of ifosfamide-carboplatin-etoposide (ICE) alternating with vincristine-doxorubicin-cyclophosphamide (VDC) has been used to successfully treat malignant rhabdoid tumor.

Due to excessive toxicity in affected infants and young children, chemotherapeutic doses in the current COG protocol, which uses CyCE (rather than ICE) alternating with VDC, have been decreased, and in general, infants and children undergoing intensive chemotherapy for malignant rhabdoid tumor, either VDC/CyCE or VDC/ICE, must be carefully monitored for toxicity, and doses of chemotherapeutic agents must be adjusted as necessary.

Table 1. One Ifosfamide-Carboplatin-Etoposide regimen for Malignant Rhabdoid Tumor

Note.—AUC = area under the concentration-time curve; IV = intravenous; G-CSF = granulocyte colony-stimulating factor; SC = subcutaneous; ANC = absolute neutrophil count.

Table 2. One Vincristine-Doxorubicin-Cyclophosphamide Regimen for Malignant Rhabdoid Tumor

Antineoplastic agents

For children older than 12 months and more than 10 kg, chemotherapy drugs should be dosed according to the child's body surface area. The total number of cycles of ICE or VDC necessary to treat malignant rhabdoid tumor is unknown. Some investigators have advocated for between 8-10 cycles of chemotherapy total. The current COG malignant rhabdoid tumor protocol is exploring the use of VDC and CyCE (5 cycles of each = 10 cycles total).

Ifosfamide (Ifex)

Inhibits DNA and protein synthesis and, therefore, cellular proliferation by causing DNA cross-linking and denaturation of double helix.

Dosing

Adult

Pediatric

Dosages and schedules vary

Interactions

Drugs that affect the cytochrome P450 (CYP) hepatic microsomal enzymes (eg, barbiturates, phenytoin, azole antifungals) may alter the metabolism of ifosfamide and potentially increase toxicity or decrease serum levels

Contraindications

Documented hypersensitivity; severely depressed bone marrow function

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Because of association with renal insufficiency and renal tubular disease (Fanconi syndrome), caution in patients with a single kidney, though series of patients with single kidneys who were treated with ifosfamide indicated that the drug can be administered without clinically significant renal toxicity; limit possibility of ifosfamide-induced nephrotoxicity, renal function, and electrolytes by closely monitoring and limiting cumulative exposure; protect against hemorrhagic cystitis with hydration and mesna; monitor for CNS effects (eg, somnolence, hallucinations, coma); monitor blood counts for myelosuppression

Carboplatin (Paraplatin)

Analog of cisplatin. Heavy-metal coordination complex that exerts cytotoxic effect by platinating DNA; mechanism analogous to alkylation, leading to interstrand and intrastrand DNA cross-linking and inhibited DNA replication. Binds to protein and other compounds containing SH group. Cytotoxicity can occur at any stage of cell cycle, but cell most vulnerable in G1 and S phases. Same efficacy as cisplatin but improved toxicity profile. Main advantages over cisplatin include decreased nephrotoxicity and ototoxicity not requiring extensive prehydration and reduced risk of nausea and vomiting, but more likely than cisplatin to induce myelotoxicity.

Dosing

Adult

Pediatric

Dosages and schedules vary

Interactions

Nephrotoxicity increases with aminoglycosides and other nephrotoxic drugs

Contraindications

Documented hypersensitivity to carboplatin or other platinum-containing compounds; severely depressed bone marrow function

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Caution in patients with single kidney, though associated nephrotoxicity not as pronounced as that associated with cisplatin; adjust dosage according to renal function; monitor electrolyte (including calcium and magnesium) levels; monitor blood counts for myelosuppression, particularly thrombocytopenia; ototoxicity, severe hypersensitivity reactions, and hepatotoxicity may occur

Etoposide (VePesid, Toposar, VP-16)

Glycosidic derivative of podophyllotoxin that exerts cytotoxic effect by stabilizing normally transient covalent intermediates formed between DNA substrate and topoisomerase II, leading to single- and double-strand DNA breaks. This arrests cell proliferation in late S or early G2 portion of cell cycle.

Dosing

Adult

Pediatric

Dosages and schedules vary

Interactions

P-glycoprotein modulators (eg, cyclosporine, verapamil) can increase active metabolite concentrations and increase toxicity; azole antifungals and other CYP inhibitors may increase toxicity; anticonvulsants and other CYP inducers (eg, phenytoin) can increase clearance; high doses of platinum compounds can decrease clearance; may prolong the effects of warfarin and increase clearance of methotrexate

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Severe allergic reactions with anaphylaxis may occur; myelosuppression and hepatotoxicity may occur; risk for secondary acute myeloid leukemia (AML)

Vincristine (Oncovin, Vincasar PFS)

Inhibits cellular mitosis by inhibiting intracellular tubulin function, binding to microtubule and spindle proteins in S phase.

Dosing

Adult

Pediatric

1.5 mg/m²/dose or 0.05 mg/kg/dose; not to exceed 2 mg/dose

Interactions

Acute pulmonary reaction may occur with concurrent mitomycin-C; asparaginase, CYP3A4 inhibitors (eg, itraconazole, quinupristin-dalfopristin, sertraline, ritonavir), granulocyte-macrophage colony-stimulating factor (GM-CSF, eg, sargramostim, filgrastim), or nifedipine increase toxicity, particularly neurologic effects; CYP3A4 inducers (eg, carbamazepine, phenytoin, phenobarbital, rifampin) may decrease effects

Contraindications

Documented hypersensitivity; demyelinating form of Charcot-Marie-Tooth syndrome; intrathecal use

Precautions

Pregnancy

D - Unsafe in pregnancy

Precautions

For IV use only; intrathecal administration may result in death; monitor for peripheral neuropathy manifesting as constipation, ileus, foot drop, ptosis, jaw pain, abdominal pain, and vocal cord paralysis; reduce dose in severe peripheral neuropathy; extravasation may cause severe local tissue damage; reduce dose with hepatic dysfunction; monitor for syndrome of inappropriate antidiuretic hormone secretion (SIADH), hyponatremia, and seizures; caution in severe cardiopulmonary disease or preexisting neuromuscular dysfunction

Doxorubicin (Adriamycin)

Cytotoxic anthracycline antibiotic isolated from cultures of Streptomyces peucetius var. caesius. Blocks DNA and RNA synthesis by inserting between adjacent base pairs and binding to sugar-phosphate backbone of DNA, inhibiting DNA polymerase. Binds to nucleic acids presumably by specific intercalation of anthracycline nucleus with DNA double helix.
Also powerful iron chelator. Iron-doxorubicin complex induces production of free radicals that can destroy DNA and cancer cells. Can also cause breakage of DNA strands by means of effects on topoisomerase II. Maximum toxicity occurs during S phase of cell cycle.
Multiphasic disappearance curve, with half-lives as long as 30 h. Does not cross blood-brain barrier but taken up rapidly by heart, lungs, liver, kidney, and spleen. Mutagenic and carcinogenic.

Dosing

Adult

Pediatric

Dosages and schedules vary

Interactions

Azole antifungal drugs and other CYP inhibitors may increase toxicity; may decrease phenytoin and digoxin plasma levels; phenobarbital may decrease plasma levels; P-glycoprotein modulators (eg, cyclosporine, verapamil) may induce coma or seizures; mercaptopurine increases toxicity; cyclophosphamide increases cardiac toxicity

Contraindications

Documented hypersensitivity to the drug; severe congestive heart failure, cardiomyopathy, arrhythmias; severe myelosuppression

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Assess baseline cardiac function before treatment and monitor throughout treatment; decrease dose with hepatic dysfunction; extravasation may cause severe local tissue damage; myelosuppression may occur

Cyclophosphamide (Cytoxan)

Chemically related to nitrogen mustards. Activated in liver to active metabolite 4-hydroxycyclophosphamide, which alkylates target sites in susceptible cells in all-or-none reaction. As alkylating agent, mechanism of action of active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

Dosing

Adult

Pediatric

Doses and schedules vary

Interactions

Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; toxicity may increase with chloramphenicol; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia; coadministration with succinylcholine may increase neuromuscular blockade by inhibiting cholinesterase activity; chloroquine, imipramine, phenothiazines, potassium iodide, azole antifungals, or vitamin A could alter metabolism and potentially increase toxicity

Contraindications

Documented hypersensitivity; severely depressed bone marrow function

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Protect against hemorrhagic cystitis with adequate hydration and mesna; monitor blood counts for myelosuppression; monitor electrolytes for hyponatremia related to SIADH; with high doses, monitor for cardiotoxicity; may cause infertility, secondary malignancies, and pulmonary fibrosis; regularly examine urine for RBCs, which may precede hemorrhagic cystitis

Uroprotective antidote

Mesna is a prophylactic detoxifying agent used to inhibit hemorrhagic cystitis caused by ifosfamide and cyclophosphamide. In the kidney, mesna disulfide is reduced to free mesna. Free mesna has thiol groups that react with acrolein, which is the ifosfamide and cyclophosphamide metabolite considered responsible for urotoxicity.

Mesna (Mesnex)

Inactivates acrolein and prevents urothelial toxicity without affecting cytostatic activity.

Dosing

Adult

Pediatric

Dose depends on dose of ifosfamide or cyclophosphamide and is typically 60-100% of the dosage of antineoplastic agent used; may be administered as initial bolus followed by continuous or intermittent IV infusions before and after chemotherapy regimen

Interactions

May increase warfarin effects; adjust dose according to INR target

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Usually safe but benefits must outweigh the risks.

Precautions

Monitor morning urine for hematuria before ifosfamide or cyclophosphamide dose; common adverse effects include hypotension, headache, GI toxicity, and limb pain

Follow-up

Further Inpatient Care

• Treatment for malignant rhabdoid tumor (MRT) requires frequent inpatient admissions to administer chemotherapy and to manage complications of treatment, such as febrile neutropenia.
• The duration of therapy is approximately 6-12 months.

Further Outpatient Care

• The myelosuppressive effects of the chemotherapy used to treat malignant rhabdoid tumor necessitate frequent monitoring of blood counts on an outpatient basis.
• In addition, serum electrolyte levels and renal function must be observed closely because patients have a single kidney and often receive nephrotoxic chemotherapeutic agents. Electrolyte supplementation is not uncommonly required.

Inpatient & Outpatient Medications

• Chemotherapy regimens for malignant rhabdoid tumor are immunosuppressive.
• As such, prophylaxis for Pneumocystis carinii pneumonia (PCP) is recommended. Trimethoprim-sulfamethoxazole or pentamidine are the first choices for PCP prophylaxis.

Transfer

• Initial transfer to the care of a pediatric oncologist, preferably one at a center that participates in clinical trials, is recommended.

Deterrence/Prevention

• In most cases, the cause of malignant rhabdoid tumor is unknown; thus, no preventive measures can be prescribed. 
• With advancements in genetic testing and counseling, families, including neonates, with rhabdoid tumor predisposition can be identified.
  • Recommendations for surveillance of individuals found to carry a constitutional SMARCB1 mutation are not based on evidence.
  • Unclear penetrance, gonadal mosaicism, and risk of multiple primary tumors confound assessing an individual's cancer risk. However, infants and young children with germline SMARCB1 mutation develop the most aggressive forms of malignant rhabdoid tumor within the first two years of life; therefore, screening such infants with noninvasive radiological techniques might enable cancer detection at an earlier cancer stage, and an earlier diagnosis can be hypothesized to impact overall prognosis.
  • As such, a preliminary screening plan under consideration proposed to the COG Rhabdoid Tumor Working Group includes the use of serial abdominal and transcranial ultrasonography (monthly for 1 y) with more detailed MRI performed every 3 months during the first year of life, with continued surveillance into the second and third year of life.
  • The risk of cancer development in late childhood and beyond in affected patients with constitutional SMARCB1 mutations remains even less predictable, making it challenging to prescribe a screening plan at this time.

Complications

• Complications related to tumoral progression: Malignant rhabdoid tumors in the abdomen can rapidly progress, as can those at metastatic sites, including the lungs, liver, and brain. Malignant rhabdoid tumors can be associated with tumoral hemorrhage and organ failure.
• Complications related to treatment
  • Hematologic complications: The major acute complication of chemotherapy for malignant rhabdoid tumors is myelosuppression, which places patients at risk for serious infections. Patients require frequent RBC and platelet transfusions.
  • Renal complications: Patients may have renal tubular dysfunction, with wasting of protein, phosphorous, bicarbonate, and other electrolytes if platinum drugs or ifosfamide are used. The long-term prevalence of renal failure is unknown because malignant rhabdoid tumors is rare and the survival rate is low. Renal failure is uncommon in patients with unilateral Wilms tumor; however, patients with malignant rhabdoid tumors are treated intensively and with additional nephrotoxic drugs.
  • Cardiac complications: Some treatment regimens for malignant rhabdoid tumors include anthracyclines, which can cause arrhythmias and congestive heart failure. Cardiac function should be monitored periodically.
  • Gonadal complications: Ifosfamide and cyclophosphamide are associated with a risk of infertility.
  • Secondary cancers: The risk of secondary cancers from chemotherapy and/or radiation, particularly in patients with a genetic rhabdoid cancer predisposition, remain unknown.

Prognosis

• The prognosis for children with malignant rhabdoid tumors remains fair to poor, depending on the stage of the tumor at presentation, the patient's age at diagnosis, and possibly the genetic background.
• The hope is that new multi-institutional clinical trials will help in identifying novel therapies that improve the outcome of patients with this disease.

Patient Education

• Patients and families should be educated about malignant rhabdoid tumor and its aggressive biologic behavior.
• Although families must be given hope for a cure, they must also be made aware of the unfavorable prognosis associated with malignant rhabdoid tumors. Families must also understand the risks of intensive chemotherapy and the signs and symptoms that require immediate medical attention.

Genetic counseling

• Genetic counseling is highly recommended for all malignant rhabdoid tumor affected families.
• The incidence of germline deletions or missense mutations of SMARCB1 in infants and children with malignant rhabdoid tumor approximates 15-30%. Families with more than one affected child have been reported; in 2 families, evidence of germline mosaicism was suggested because neither parent had a mutation in their own peripheral blood. The incidence and age distribution of cancer in individuals with inherited SMARCB1 mutations has not been formally studied, but adults without cancer have been shown to transmit the abnormal allele in at least 3 families, and individuals with germline perturbations of SMARCB1 are predisposed to malignant rhabdoid tumors of the kidney, soft tissues, and brain and may, in fact, present with more than one primary tumor.
• Accumulating evidence suggests that individuals with a confirmed malignant rhabdoid tumor should be evaluated for SMARCB1 expression in the tumor. Direct evaluation of the tumor by karyotyping, fluorescence in situ hybridization (FISH), or genomic microarray, with high-density single nucleotide polymorphism-based oligonucleotide arrays and multiplex ligation-dependent probe amplification as necessary, should be pursued to detect the mechanisms for biallelic silencing of SMARCB1 expression. Direct sequencing of SMARCB1 for missense mutations is recommended if abnormalities are not seen in both alleles. Evaluation of peripheral blood should follow tumor analysis. The finding of a chromosomal abnormality involving 22q or SMARCB1 missense mutation in the germline of an affected individual would then be followed by testing both parents. Because sibling recurrence is known to occur, testing of siblings, particularly those younger than 5 years, should be considered, even if bothparents are healthy.
• Surveillance of individuals found to carry a constitutional SMARCB1 mutation for the development of CNS or abdominal malignant rhabdoid tumor may be advisable (see Deterrence/Prevention).

Miscellaneous

Medicolegal Pitfalls

• The diagnosis of malignant rhabdoid tumor (MRT) is not straightforward, and this tumor may be confused with other renal malignancies of childhood.
• A correct diagnosis must be made early because the treatment and clinical course of malignant rhabdoid tumor and those of other renal or soft tissue neoplasms are tremendously disparate.
• Because of the rarity of these tumors, experienced pediatric oncologists, surgeons, and pathologists should become involved early in the treatment of affected patients.

Special Concerns

• In recognition of the unique challenges and need for scientific and clinical advancement for infants and children affected by malignant rhabdoid tumors, the Rhabdoid Tumor Working Group has been formed within the COG, comprising representation from multiple disease committees and disease disciplines. The working group aims to centralize biological interrogation and clinical strategy for new drug discovery. One success of this group is the advancement of phase II strata for infants and children with relapsed rhabdoid tumor, independent of primary cancer organ location within the body, within COG Phase II study planning.
• Through a consolidation of resources and through appropriate patient advocacy, the Rhabdoid Working Group efforts, as well as additional efforts ongoing internationally, hold promise to identify new therapeutic agents active against malignant rhabdoid tumors, critically necessary for this patient subgroup.

Multimedia

Media file 1: Nonenhanced CT scan demonstrates linear and curvilinear calcifications outlining tumor lobules in a malignant rhabdoid tumor (MRT) (arrows). A hypoattenuating fluid collection surrounds and separates the lobules. These imaging features are seen with MRT more often than with other childhood renal neoplasms.

Media file 2: Contrast-enhanced CT scan demonstrates a subcapsular fluid collection (arrow) and the lobulated nature of a malignant rhabdoid tumor (MRT). Subcapsular fluid collections are more common with MRTs than with the other renal neoplasms that occur in children.

Media file 3: Histology of malignant rhabdoid tumors (MRTs). This photomicrograph shows the typical large malignant cells with large, vesicular nuclei, prominent red nucleoli, and abundant eosinophilic cytoplasm. Many tumor cells have a distinct, pale, rhabdoid inclusion in the cytoplasm. (Hematoxylin and eosin stain, original magnification x400).

Media file 4: INI1 immunohistochemistry stain shows diffuse loss of INI1 expression in tumor nuclei, with appropriate staining of intratumoral endothelial cells serving as the internal control (original magnification x400).

References

1. Haas JE, Palmer NF, Weinberg AG, Beckwith JB. Ultrastructure of malignant rhabdoid tumor of the kidney. A distinctive renal tumor of children. Hum Pathol. Jul 1981;12(7):646-57. [Medline].

2. Roberts CW, Biegel JA. The role of SMARCB1/INI1 in development of rhabdoid tumor. Cancer Biol Ther. Mar 2009;8:412-6. [Medline].

3. 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].

4. 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].

5. 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].

6. 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].

7. 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].

8. Russo P, Biegel JA. SMARCB1/INI1 alterations and hepatoblastoma: another extrarenal rhabdoid tumor revealed?. Pediatr Blood Cancer. Mar 2009;52:312-3. [Medline].

9. 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].

10. 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. Jul 15 2004;22(14):2877-84. [Medline].

11. 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. Mar 1 2005;23(7):1491-9. [Medline].

12. 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].

13. 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. Feb 1997;168(2):447-51. [Medline].

14. Amar AM, Tomlinson G, Green DM, et al. Clinical presentation of rhabdoid tumors of the kidney. J Pediatr Hematol Oncol. Feb 2001;23(2):105-8. [Medline].

15. 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. May 2000;28(1):31-7. [Medline].

16. Biegel JA, Zhou JY, Rorke LB, et al. Germ-line and acquired mutations of INI1 in atypical teratoid and rhabdoid tumors. Cancer Res. Jan 1 1999;59(1):74-9. [Medline].

17. 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. Feb 2001;32(2):156-62. [Medline].

18. 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. Sep 1998;22(9):1083-92. [Medline].

19. 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. Nov 15 2005;65(22):10192-8. [Medline].

20. 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].

21. Chi SN, Zimmerman MA, Yao X, et al. Intensive multimodality treatment for children with newly diagnosed CNS atypical teratoid rhabdoid tumor. J Clin Oncol. Jan 2009;27:385-9. [Medline].

22. Chung CJ, Lorenzo R, Rayder S, et al. Rhabdoid tumors of the kidney in children: CT findings. AJR Am J Roentgenol. Mar 1995;164(3):697-700. [Medline].

23. D'Angio GJ, Breslow N, Beckwith JB, et al. Treatment of Wilms' tumor. Results of the Third National Wilms' Tumor Study. Cancer. Jul 15 1989;64(2):349-60. [Medline].

24. 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. Sep 2006;47(3):273-8. [Medline].

25. Fujisawa H, Misaki K, Takabatake Y, et al. Cyclin D1 is overexpressed in atypical teratoid/rhabdoid tumor with hSNF5/INI1 gene inactivation. J Neurooncol. Jun 2005;73(2):117-24. [Medline].

26. Gururangan S, Bowman LC, Parham DM, et al. Primary extracranial rhabdoid tumors. Clinicopathologic features and response to ifosfamide. Cancer. Apr 15 1993;71(8):2653-9. [Medline].

27. Han TI, Kim MJ, Yoon HK, et al. Rhabdoid tumour of the kidney: imaging findings. Pediatr Radiol. Apr 2001;31(4):233-7. [Medline].

28. 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. Nov 2004;28(11):1485-91. [Medline].

29. 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. Dec 6 2005;102(49):17745-50. [Medline].

30. 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].

31. Janson K, Nedzi LA, David O, et al. Predisposition to atypical teratoid/rhabdoid tumor due to an inherited INI1 mutation. Pediatr Blood Cancer. Sep 2006;47(3):279-84. [Medline].

32. 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. Feb 2010;49(2):176-81. [Medline].

33. 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].

34. McKenna ES, Sansam CG, Cho YJ, et al. Loss of the epigenetic tumor suppressor SNF5 leads to cancer without genomic instability. Mol Cell Biol. Oct 2008;28:5223-33. [Medline].

35. 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. Oct 1994;18(10):1010-29. [Medline].

36. 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].

37. Reddy AT. Atypical teratoid/rhabdoid tumors of the central nervous system. J Neurooncol. Dec 2005;75(3):309-13. [Medline].

38. 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. Dec 5 2000;97(25):13796-800. [Medline].

39. Roberts CW, Leroux MM, Fleming MD, Orkin SH. Highly penetrant, rapid tumorigenesis through conditional inversion of the tumor suppressor gene Snf5. Cancer Cell. Nov 2002;2(5):415-25. [Medline].

40. Rorke LB, Packer RJ, Biegel JA. Central nervous system atypical teratoid/rhabdoid tumors of infancy and childhood: definition of an entity. J Neurosurg. Jul 1996;85(1):56-65. [Medline].

41. Rousseau-Merck MF, Fiette L, Klochendler-Yeivin A, et al. Chromosome mechanisms and INI1 inactivation in human and mouse rhabdoid tumors. Cancer Genet Cytogenet. Mar 2005;157(2):127-33. [Medline].

42. 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. Jul 1 1999;59(13):3152-6. [Medline].

43. 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. May 2006;19(5):717-25. [Medline].

44. Sisler CL, Siegel MJ. Malignant rhabdoid tumor of the kidney: radiologic features. Radiology. Jul 1989;172(1):211-2. [Medline].

45. [Best Evidence] 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. Oct 20 2005;23(30):7641-5. [Medline].

46. 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. Aug 23 2005;102(34):12129-34. [Medline].

47. Versteege I, Sevenet N, Lange J, et al. Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature. Jul 9 1998;394(6689):203-6. [Medline].

48. Wagner L, Hill DA, Fuller C, et al. Treatment of metastatic rhabdoid tumor of the kidney. J Pediatr Hematol Oncol. Jun-Jul 2002;24(5):385-8. [Medline].

49. 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. Jan-Feb 1999;21(1):53-7. [Medline].

50. 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. Jun 1989;13(6):439-58. [Medline].

51. 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. Nov 1991;15(11):1042-54. [Medline].

52. Winger DI, Buyuk A, Bohrer S, et al. Radiology-Pathology Conference: rhabdoid tumor of the kidney. Clin Imaging. Mar-Apr 2006;30(2):132-6. [Medline].

53. 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].

54. Zhang ZK, Davies KP, Allen J, et al. Cell cycle arrest and repression of cyclin D1 transcription by INI1/hSNF5. Mol Cell Biol. Aug 2002;22(16):5975-88. [Medline].

Keywords

malignant rhabdoid tumor, MRT, rhabdoid tumor of the kidney, RTK, kidney tumor, kidney malignancy, kidney carcinoma, kidney cancer, rhabdoid kidney tumor, Wilms tumor, treatment, diagnosis, symptoms

Contributor Information and Disclosures

Author

James I Geller, MD, Assistant Professor of Clinical Pediatrics, Division of Hematology/Oncology, Cincinnati Children's Hospital Medical Center
James I Geller, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Clinical Oncology, American Society of Pediatric Hematology/Oncology, and Children's Oncology Group
Disclosure: Nothing to disclose.

Coauthor(s)

Nancy D. Leslie MD, Professor of Clinical Pediatrics, Cincinnati Children's Hospital Research Foundation
Disclosure: Nothing to disclose.

Hong Yin, MD, Assistant Professor, Department of Pathology and Laboratory Medicine, University of Cincinnati School of Medicine; Staff Pathologist, Department of Pathology, Cincinnati Children's Hospital
Hong Yin, MD is a member of the following medical societies: American Medical Association, Children's Oncology Group, College of American Pathologists, Society for Pediatric Pathology, and United States and Canadian Academy of Pathology
Disclosure: Nothing to disclose.

Medical Editor

Stephan A Grupp, MD, PhD, Director, Stem Cell Biology Program, Department of Pediatrics, Division of Oncology, Children's Hospital of Philadelphia; Associate Professor of Pediatrics, University of Pennsylvania
Stephan A Grupp, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Society for Blood and Marrow Transplantation, American Society of Hematology, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Steven K Bergstrom, MD, Assistant to the Chairman, Department of Pediatrics, Division of Hematology-Oncology, Kaiser Permanente Medical Center of Oakland
Steven K Bergstrom, MD is a member of the following medical societies: Alpha Omega Alpha, American Society of Clinical Oncology, American Society of Hematology, American Society of Pediatric Hematology/Oncology, Children's Oncology Group, and International Society for Experimental Hematology
Disclosure: Nothing to disclose.

CME Editor

Helen SL Chan, MBBS, FRCP(C), FAAP, Senior Scientist, Research Institute; Professor, Division of Hematology/Oncology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Canada
Helen SL Chan, MBBS, FRCP(C), FAAP is a member of the following medical societies: American Academy of Pediatrics, American Association for Cancer Research, American Society of Hematology, and Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

Chief Editor

Max J Coppes, MD, PhD, MBA, Senior Vice President, Children's National Medical Center (Center for Cancer and Blood Disorders); Director, Center for Cancer and Immunology Research, Children's Research Institute, Children's National Medical Center; Professor of Medicine, Oncology, and Pediatrics, Georgetown University
Max J Coppes, MD, PhD, MBA is a member of the following medical societies: American Association for Cancer Research, American Society of Pediatric Hematology/Oncology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Jeffrey Dome, MD, to the original writing and development of this article.

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