AUTHOR INFORMATION

Section 1 of 12

Authored by Jeffrey S Dome, MD, Chief, Division of Oncology, Center for Cancer and Blood Disorders, Children's National Medical Center

Coauthored by D Ashley Hill, MD, Assistant Professor, Department of Pathology and Immunology, Washington University School of Medicine, St Louis; Mary Elizabeth McCarville, MD, Associate Member, Department of Radiological Sciences, St Jude Children's Research Hospital

Jeffrey S Dome, MD, is a member of the following medical societies: American Association for Cancer Research, American Society of Clinical Oncology, American Society of Pediatric Hematology/Oncology, and Children's Oncology Group

Edited by Stephan A Grupp, MD, PhD, Director, Stem Cell Biology Program, Children's Hospital of Philadelphia; Assistant Professor, Department of Pediatrics, Division of Oncology, University of Pennsylvania; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Steven K Bergstrom, MD, Assistant to the Chairman, Department of Pediatrics, Division of Hematology-Oncology, Kaiser Permanente Medical Center of Oakland, CA; 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; and Max J Coppes, MD, PhD, MBA, Executive Director, Center for Cancer and Blood Disorders, Children's National Medical Center

Author's Email:	Jeffrey S Dome, MD
Editor's Email:	Stephan A Grupp, MD, PhD

eMedicine Journal, January 8 2007, VOLUME 8, Number 1

INTRODUCTION

Section 2 of 12

Background:

Introduction

Malignant rhabdoid tumor (MRT) is one of the most aggressive and lethal malignancies in pediatric oncology. MRT 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 MRT 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, an MRT 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 MRTs is only 20-25%.

Since 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 MRTs frequently contain deletions at chromosome locus 22q11.1. Positional cloning efforts revealed that this locus contains the INI1 gene (also known as hSNF5, SMARCB1, or BAF47), which encodes a member of the human SWI-SNF complex. The SWI-SNF complex acts in an adenosine triphosphate (ATP)–dependent manner to remodel chromatin, which regulates gene transcription. Because most MRTs have biallelic, inactivating mutations of INI1 consistent with the 2-hit model of tumor formation, this gene is presumed to function as a classic tumor suppressor. An observation that supports this premise is that 15-30% of INI1 heterozygotic mice develop rhabdoid tumors that have lost the functional INI1 allele.

The biologic mechanism by which the INI1 deletion promotes tumorigenesis is beginning to be elucidated. Recent studies involving cell lines and INI1 knockout mouse have demonstrated that INI1 deletion leads to upregulation of targets of the p16INK4a-Rb-E2F pathway. Tumor development in INI1-deficient mice is greatly accelerated in the absence of functional p53 protein. This finding suggests a cooperative effect of these 2 pathways in tumorigenesis. Other studies have shown that INI1 expression suppresses cyclin D1 and that INI1 heterozygotic mice lacking cyclin D1 do not develop rhabdoid tumors.

Pathophysiology: The histogenetic origin of 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 MRTs are the same as rhabdoid tumors of the kidney. The recent 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. Moreover, 10-15% of patients with MRTs have synchronous or metachronous brain tumors, many of which are second primary malignant rhabdoid tumors. Germline INI1 mutations were detected in some of these patients.

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 INI1 mutations.

The Children's Oncology Group (COG) has initiated an effort to prospectively screen all types of MRT for INI1 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 MRTs, see Histologic Findings below.

Frequency:

• In the US: MRT is a rare tumor. According to registration data from NWTS 1-5, MRT 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 MRT. About 15 cases of extrarenal or non-CNS MRTs are diagnosed each year in the North America.

Mortality/Morbidity: The overall survival rate for patients with MRT enrolled in NWTS 1-5 was 23.2%.

• MRT 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, and brain.

• 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 0-5 months, 17.2% for patients 6-11 months, 28.6% for patients 12-23 months, and 41.1% for patients >24 months.

• High-stage disease is correlated with an adverse outcome, and most patients present with stage III or IV disease (see Table 1 below).
  
  Table 1. Survival of Patients with MRT in NWTS 1-5
  
  

  Stage	No. (%) of Patients
  I	15 (33.3)
  II	25 (46.9)
  III	58 (21.8)
  IV	41 (8.4)
  V	3 (0)

Race: MRT has no apparent racial predilection.

Sex: MRT 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. MRT 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

Section 3 of 12

History: Children with rhabdoid tumor of the kidney 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.

Physical: The physical findings of patients with 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 MRT 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 INI1 gene play a role in the development of MRT, the events that incite these genetic alterations are unknown. Several cases of familial MRT are reported. No environmental or infectious associations with MRT have been established.

DIFFERENTIALS

Section 4 of 12

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

Other Problems to be Considered:

For 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 MRT
Rhabdomyosarcoma
Nonrhabdomyosarcoma soft tissue sarcomas

WORKUP

Section 5 of 12

Lab Studies:

• Although 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 determination: Approximately 55% of patients with MRT present with a hemoglobin level <9 g/dL. Only 25% of patients with Wilms tumor are anemic at presentation.
  
  
  
  • Urinalysis: Microscopic hematuria is seen in 75% of patients with MRT. Approximately 25% of patients with MRTs have proteinuria; this prevalence is similar to that of patients with Wilms tumors.
  
  
  
  • Serum calcium measurement: As many as 25% of patients with MRT 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 it is associated with congenital mesoblastic nephroma.
  
  
  

Imaging Studies:

• No pathognomonic imaging feature aids in distinguishing MRT from the other renal tumors of childhood. However, several features may raise the suspicion for MRT.



• The following imaging studies are suggested for the diagnosis and staging of MRT:


• • Abdominal CT: MRT 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 MRT. MRT-associated calcifications are often linear or curvilinear, and they may outline tumor lobules (see Image 2).

    • A peripheral, subcapsular, crescent-shaped fluid collection is often seen in association with MRT (see Image 3). In a recent study, this finding was present in 15 (71%) of 21 patients with MRT, but it was present in only 8 (9%) of 93 with Wilms tumors, 6 (14%) of 44 with congenital mesoblastic nephromas, and 3 (25%) of 12 with clear cell sarcomas. These subcapsular fluid collections may be due either to hemorrhage or tumor necrosis.
  
  
  
  • Abdominal ultrasonography: Tumoral invasion of the renal vein and/or the inferior vena cava is sometimes seen with MRT 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.
  
  
  

Procedures:

• Bone marrow aspiration and biopsy are not necessary in the workup of MRT because MRT rarely metastasizes to the bone marrow.



• Lumbar puncture is not necessary unless a CNS tumor is diagnosed.

On microscopic examination, MRTs are characterized by sheets of large tumor cells with vesicular nuclei, prominent red nucleoli; moderate amounts of eosinophilic cytoplasm; and pale intracytoplasmic, rhabdoid inclusions (see Image 1).

Other patterns described as sclerosing (including chondroid), epithelioid, spindled, lymphomatoid or histiocytoid, and vascular may coexist with the classic pattern. Unlike a Wilms tumor, an MRT 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; this correlated with the rhabdoid inclusion seen with light microscopy. Dilated rough endoplasmic reticulum, rudimentary cell junctions, and cytoplasmic tonofilament-like 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 MRT. Recent studies have demonstrated that MRT lacks INI1 immunohistochemical staining, whereas most other tumors have detectable INI1 protein. Therefore, INI1 immunohistochemical studies can be used in conjunction with other studies to confirm the histologic diagnosis of MRT.

Staging: In North America, MRTs are staged according to the staging system of the NWTS Group, which the COG recently modified.

Table 2. COG Staging System

Stage	Findings
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.
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.
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.
IV	Hematogenous metastases or lymph node metastases are present outside the abdominal and/or pelvic cavity.
V	Tumors are bilateral.

TREATMENT

Section 6 of 12

Medical Care: After the primary tumor is surgically removed, chemotherapy is indicated as adjuvant treatment for MRT. Chemotherapy for MRT 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 MRT 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 MRT 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 MRT may be derived from the experience with 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- to 96-month follow-up. 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 general, the experience with AT/RT indicated that these tumors initially respond to chemotherapy but then quickly become refractory to treatment.

The lack of treatment uniformity among reported patients makes it difficult to determine if radiotherapy is effective for MRT. 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 MRT 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 MRT is intensive and requires a multidisciplinary effort.



• Practitioners who should be consulted include the following:


• • Pediatric oncologist
  
  
  
  • Pediatric surgeon or urologist
  
  
  
  • Radiation oncologist
  
  
  
  • Social worker

  • Nutritionist
  
  
  

Diet:

• No dietary restrictions are necessary.



• The patient’s nutritional status should be monitored closely to ensure adequate caloric intake during the intensive chemotherapy. It is not uncommon for parenteral nutrition to be required at some point during treatment.

Activity: No restrictions on activity are necessary except during periods of thrombocytopenia.

MEDICATION

Section 7 of 12

The treatment for 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 ICE alternating with VDC has been used to treat patients with MRT at St. Jude Children’s Research Hospital.

Table 3. St. Jude Children’s Research Hospital ICE regimen for MRT

Drug	Dosage	Route	Schedule
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, 6, and 9 h after ifosfamide
Filgrastim G-CSF	5 mcg/kg/dose	SC	Start 24 h after chemotherapy and continue until ANC recovers

Note.—AUC = area under the concentration-time curve; IV = intravenous; G-CSF = granulocyte colony-stimulating factor; SC = subcutaneous; ANC = absolute neutrophil count.
^*See the drug table for Carboplatin in the Medication section.

Table 4. St. Jude Children’s Research Hospital VDC regimen for MRT

Drug	Dosage	Route	Schedule
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

Drug Category: Antineoplastic agents -- For children older than 12 months and more than 10 kg, dose chemotherapy drugs according to their body surface area. At St. Jude Children's Research Hospital, ICE has been given for 5 courses (courses 1, 2, 4, 6, and 8), and VDC for 3 courses (courses 3, 5, and 7), to treat MRT.

Drug Name	Ifosfamide (Ifex) -- Inhibits DNA and protein synthesis and, therefore, cellular proliferation by causing DNA cross-linking and denaturation of double helix.
Pediatric Dose	Dosages and schedules vary; St. Jude Children’s Research Hospital protocol is 65 mg/kg/dose or 2 g/m2/dose
Contraindications	Documented hypersensitivity; severely depressed bone marrow function
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
Pregnancy	D - Unsafe in pregnancy
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

Drug Name	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 according to Calvert equation: total dose (mg) = (target AUC in mg/mL/min) X (GFR + 25), where GFR is glomerular filtration rate in mL/min.
Pediatric Dose	Dosages and schedules vary; St. Jude Children’s Research Hospital uses dose to achieve AUC of 6 mg/mL/min using Calvert equation
Contraindications	Documented hypersensitivity to carboplatin or other platinum-containing compounds; severely depressed bone marrow function
Interactions	Nephrotoxicity increases with aminoglycosides and other nephrotoxic drugs
Pregnancy	D - Unsafe in pregnancy
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

Drug Name	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.
Pediatric Dose	Dosages and schedules vary; St. Jude Children’s Research Hospital protocol is 3.3 mg/kg/dose or 100 mg/m2/dose
Contraindications	Documented hypersensitivity
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
Pregnancy	D - Unsafe in pregnancy
Precautions	Severe allergic reactions with anaphylaxis may occur; myelosuppression and hepatotoxicity may occur; risk for secondary acute myeloid leukemia (AML)

Drug Name	Vincristine (Oncovin, Vincasar PFS) -- Inhibits cellular mitosis by inhibiting intracellular tubulin function, binding to microtubule and spindle proteins in S phase.
Pediatric Dose	1.5 mg/m2/dose or 0.05 mg/kg/dose; not to exceed 2 mg/dose
Contraindications	Documented hypersensitivity; demyelinating form of Charcot-Marie-Tooth syndrome; intrathecal use
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
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

Drug Name	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.
Pediatric Dose	Dosages and schedules vary; St. Jude Children’s Research Hospital protocol is 1.2 mg/kg/dose IV or 37.5 mg/m2/dose
Contraindications	Documented hypersensitivity to the drug; severe congestive heart failure, cardiomyopathy, arrhythmias; severe myelosuppression
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
Pregnancy	D - Unsafe in pregnancy
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

Drug Name	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.
Pediatric Dose	Doses and schedules vary; St. Jude Children’s Research Hospital protocol is 60 mg/kg/dose or 1.8 g/m2/dose
Contraindications	Documented hypersensitivity; severely depressed bone marrow function
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
Pregnancy	D - Unsafe in pregnancy
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

Drug Category: 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.

Drug Name	Mesna (Mesnex) -- Inactivates acrolein and prevents urothelial toxicity without affecting cytostatic activity.
Pediatric Dose	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
Contraindications	Documented hypersensitivity
Interactions	May increase warfarin effects; adjust dose according to INR target
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

Section 8 of 12

Further Inpatient Care:

• Treatment for 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 MRT 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 the nephrotoxic agents ifosfamide and carboplatin. Electrolyte supplementation is not uncommonly required.

In/Out Patient Meds:

• Chemotherapy regimens for MRT are immunosuppressive.



• As such, prophylaxis for Pneumocystis carinii pneumonia (PCP) is recommended. Trimethoprim-sulfamethoxazole or aerosolized 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:

• Because the cause of MRT is unknown, no preventive measures can be prescribed.

Complications:

• Complications related to tumoral progression: MRT in the abdomen can rapidly progress, as can those at metastatic sites, including the lungs, liver, and brain. MRT can be associated with tumoral hemorrhage and organ failure.



• Complications related to treatment


• • Hematologic complications: The major acute complication of chemotherapy for MRT 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 MRT is rare and the survival rate is low. Renal failure is uncommon in patients with unilateral Wilms tumor; however, patients with MRT are treated intensively and with additional nephrotoxic drugs.
  
  
  
  • Cardiac complications: Some treatment regimens for MRT 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.
  
  
  

Prognosis:

• The prognosis for children with MRT remains fair to poor, depending on the stage of the tumor at presentation and on the patient’s age at diagnosis.



• 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 MRT 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 MRT. Families must also understand the risks of intensive chemotherapy and the signs and symptoms that require immediate medical attention.

MISCELLANEOUS

Section 9 of 12

Medical/Legal Pitfalls:

• The diagnosis of 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 MRT 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.

TEST QUESTIONS

Section 10 of 12

CME Question 1: Which battery of studies is most appropriate for evaluating a patient with malignant rhabdoid tumor (MRT)?

A: Chest and abdominal CT, bone scanning, and bone marrow biopsy
B: Chest and abdominal CT, intravenous pyelography
C: Chest and abdominal CT, brain MRI
D: Chest and abdominal CT, lumbar puncture, renal scanning
E: None of the above

The correct answer is C: No pathognomonic imaging feature aids in distinguishing MRT from the other renal tumors of childhood. However, several features may raise the suspicion for MRT. The following imaging studies are suggested for the diagnosis and staging of MRT: chest and abdominal CT, abdominal ultrasonography, and MRI or CT of the brain.

CME Question 2: Which clinical features are clearly associated with adverse prognosis in patients with a malignant rhabdoid tumor (MRT)?

A: Extrarenal location
B: Vimentin staining on immunohistochemical evaluation
C: Male sex
D: Young age at diagnosis
E: None of the above

The correct answer is C: 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 0-5 months, 17.2% for patients 6-11 months, 28.6% for patients 12-23 months, and 41.1% for patients ¡Ý24 months.

Pearl Question 1 (T/F): Malignant rhabdoid tumor (MRT) is one of the most common renal tumors of childhood.

The correct answer is False: MRT is a rare tumor. According to registration data from National Wilms Tumor Studies (NWTS) 1-5, MRT 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 MRT. About 15 cases of extrarenal or non-CNS MRTs are diagnosed each year in the North America.

Pearl Question 2 (T/F): The combination of ifosfamide, carboplatin, and etoposide (ICE) is effective against malignant rhabdoid tumors (MRTs).

The correct answer is True: Recent case reports have documented successful outcomes in patients with metastatic MRT treated with ICE or ifosfamide-etoposide (IE) alternating with vincristine-doxorubicin-cyclophosphamide (VDC).

Pearl Question 3 (T/F): A tumor-suppressor gene has been implicated in the pathogenesis of malignant rhabdoid tumors (MRTs).

The correct answer is True: Cytogenetic, fluorescence in situ hybridization (FISH), and loss-of-heterozygosity (LOH) studies have revealed that MRTs frequently contain deletions at chromosome locus 22q11.1. This locus contains the INI1 gene (also known as hSNF5, SMARCB1, or andBAF47), which encodes a member of the human SWI-SNF complex. The SWI-SNF complex acts in an adenosine triphosphate (ATP)–dependent manner to remodel chromatin, which regulates gene transcription. Because most MRTs have biallelic, inactivating mutations of INI1 consistent with the 2-hit model of tumor formation, this gene is presumed to function as a classic tumor suppressor.

PICTURES

Section 11 of 12

Caption: Picture 1. Histology of malignant rhabdoid tumors (MRTs). Photomicrograph shows the typical large malignant cells with large, vesicular nuclei, prominent red nucleoli, and abundant eosinophilic cytoplasm. Tumor cells in the center of the field have a distinct, pale, rhabdoid inclusion in the cytoplasm (hematoxylin and eosin stain, original magnification x400)
	View Full Size Image
	eMedicine Zoom View (Interactive!)
Picture Type: CT
Caption: Picture 2. 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.
	View Full Size Image
	eMedicine Zoom View (Interactive!)
Picture Type: CT
Caption: Picture 3. 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.
	View Full Size Image
	eMedicine Zoom View (Interactive!)
Picture Type: Photo

BIBLIOGRAPHY

Section 12 of 12

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

eMedicine Journals > Pediatrics > Oncology > Malignant Rhabdoid Tumor

Please email us with any comments you have on our new chapter format.

Author Information | Introduction | Clinical | Differentials | Workup | Treatment | Medication | Follow-up | Miscellaneous | Test Questions | Pictures | Bibliography