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. The polyantigenic expression suggests that RTK arises from a pluripotent cell capable of differentiating along several lines.

Cytogenetic studies, fluorescent in situ hybridization (FISH), and loss of heterozygosity (LOH) studies have revealed that RTK frequently contains deletions at band 22q11.1. Through positional cloning efforts, this locus recently was found to contain the hSNF5/INI1 gene, 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 RTKs demonstrate biallelic inactivating mutations of hSNF5/INI1 consistent with the 2-hit model of tumor formation, this gene is presumed to function as a classic tumor suppressor. The observation that mice haplo-insufficient for hSNF5/INI1 are predisposed to rhabdoid tumor supports this premise. The hSNF5/INI1 gene likely regulates the transcription of numerous human genes; however, the precise molecular pathways involved in rhabdoid tumorigenesis remain unknown.

Since the original description of RTK, malignant rhabdoid tumors have been described at multiple anatomic sites, including the brain, liver, soft tissues, lung, skin, and heart. Considerable debate has focused on whether extrarenal rhabdoid tumors represent the same entity as RTK. The recent recognition that CNS atypical teratoid/rhabdoid tumors (AT/RTs) have mutations or deletions of the hSNF5/INI1 gene indicates that rhabdoid tumors of the kidney and of the brain are identical or closely related entities. This is not surprising, because rhabdoid tumors at both locations possess similar histologic, clinical, and demographic features. Moreover, 10-15% of patients with RTK have synchronous or metachronous brain tumors; germline hSNF5/INI1 mutations were demonstrated in several such patients. Renal tumors and brain tumors had distinct hSNF5/INI1 mutations; this indicates that the patients had multifocal, rather than metastatic, disease.

Whether extrarenal/extracranial rhabdoid tumors have the same histogenetic origin as their renal counterparts is less clear. Whereas some extrarenal/extracranial rhabdoid tumors are considered undifferentiated sarcomas or carcinomas with rhabdoid features, others likely represent true rhabdoid tumors because they have documented hSNF5/INI1 mutations. As screening for hSNF5/INI1 mutations becomes more widespread, the classification and prognostication of tumors with rhabdoid features should become better defined. Furthermore, as molecular-based targeted therapies emerge, the distinction between true and pseudorhabdoid tumors may prove to have important therapeutic implications.

Frequency:

• In the US: RTK is a rare tumor. According to registration data from the NWTSG, RTK comprises only 1.6% of childhood renal tumors. Approximately 5-10 newly diagnosed patients are registered with the NWTSG per year.

• Internationally: The International Society of Paediatric Oncology (SIOP) has reported that RTK comprises 0.9% of childhood renal tumors.

Race: No apparent racial predilection exists.

Sex: RTK occurs slightly more frequently in males than in females, with a male-to-female ratio of 1.4:1.

History:

• Children with RTK present with signs and symptoms related to a renal mass.

• Pain is difficult to assess because the median presenting age is 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 RTK, compared to 25% of patients with Wilms tumor.

• Approximately 10% of patients with RTK have synchronous CNS lesions. Symptoms of increased intracranial pressure or neurologic changes should prompt further evaluation.

Physical:

• The physical examination of patients with RTK is most remarkable for the presence of a large intraabdominal mass.

• Hypertension (ie, blood pressure >95th percentile) is observed in as many as 70% of patients.

• In contrast to Wilms tumor, RTK is not associated with the WAGR syndrome (ie, Wilms [tumor], aniridia, genitourinary [anomalies], and [mental] retardation) or with Beckwith-Wiedemann syndrome (ie, 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.

Lab Studies:
 

• The definitive diagnosis of RTK is indicated by histologic analysis. However, laboratory studies can be used to differentiate patients with RTK and patients with Wilms tumor.

• CBC: Approximately 55% of patients with RTK present with a hemoglobin level less than 9 g/dL. Only 25% of patients with Wilms tumor are anemic at presentation.

• Urinalysis: Hematuria is observed in 75% of patients with RTK. Approximately 25% of patients have proteinuria.

• Serum calcium determination: As many as 25% of patients with RTK present with paraneoplastic hypercalcemia. This 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.

Imaging Studies:
 

• No pathognomonic imaging feature can distinguish RTK from the other renal tumors occurring in childhood; however, several features may raise suspicion of RTK. The following imaging studies are suggested for the diagnosis and staging of RTK:

Medical Care: Following surgical removal of the primary tumor, chemotherapy is indicated as adjuvant treatment of RTK. Historically, chemotherapy for RTK was based on therapy for Wilms tumor, which included vincristine, actinomycin, and doxorubicin, with or without cyclophosphamide. With these agents, the projected rate of survival for patients with RTK was only 23%.

To improve upon these results, the NWTS-5 used a strategy consisting of carboplatin/etoposide alternating with cyclophosphamide. This treatment arm recently was closed because preliminary analysis indicated that this regimen was unlikely to improve patient outcome. Recent case reports have documented successful outcomes in patients with metastatic RTK treated with ifosfamide/carboplatin/etoposide (ICE) or ifosfamide/etoposide (IE) and alternating with vincristine/doxorubicin/cyclophosphamide (VDC). Based on these reports, an ICE/VDC regimen likely will constitute the backbone of the next national clinical trial.

Insights into the treatment of RTK may be derived from the experience with CNS AT/RT. Like RTK, AT/RT is associated with a very unfavorable prognosis and is characterized by resistance to chemotherapy. A literature review by Hilden and colleagues revealed that only 17% of patients (6 of 35) with AT/RT survived disease free, with a follow-up range of 5-89 months. Survivors were treated with surgery, radiation therapy (XRT), and various chemotherapy regimens, typically including cisplatin, etoposide, vincristine, ifosfamide, doxorubicin, actinomycin, cyclophosphamide, and intrathecal chemotherapy. One survivor was treated with high-dose therapy and autologous stem cell rescue. Experience with AT/RT has demonstrated that these tumors generally are initially responsive to chemotherapy, but then they quickly become refractory to treatment.

The lack of treatment uniformity among reported patients makes determination of radiotherapy efficacy for RTK difficult. In NWTS-1 to NWTS-5, XRT has been administered to the flank or abdomen at total doses of 1080-3500 cGy, but the optimal dose is yet to be determined. XRT is a cornerstone of therapy for CNS AT/RT, and the high doses delivered to the posterior fossa may improve patient outcome.

Surgical Care: Refer children with a suspected renal malignancy to a pediatric surgeon or urologist with experience in oncologic surgery.

A large transabdominal, transperitoneal incision is recommended for adequate exposure. Once the peritoneal cavity is entered, the extent of the tumor should be assessed, including inspection of the contralateral kidney to exclude bilateral disease. If the mass is unilateral, a radical nephrectomy with subtotal ureterectomy should be performed. Because tumor spillage upstages the tumor, removing the tumor en bloc, avoiding tumor spillage into the peritoneal cavity, is important. If the mass involves the upper pole of the kidney, the adrenal gland should be removed. Lymph nodes from the iliac, paraaortic, and celiac areas should be sampled, even if they do not appear abnormal. A lymph node dissection is not indicated. If the tumor is bilateral or unresectable, biopsies should be performed. If Wilms tumor is diagnosed, then preoperative chemotherapy is recommended to shrink the tumor, facilitating subsequent resection. If RTK is diagnosed, then complete removal of the tumor is advised.

Consultations: Therapy for RTK is intensive and requires a multidisciplinary effort. Consider consulting a pediatric oncologist, a pediatric surgeon or urologist, a radiation oncologist, a social worker, and a nutritionist.

Diet: No dietary restrictions are necessary. Closely monitor patients' nutritional status to ensure adequate caloric intake during the intensive chemotherapy. Requirement of parenteral nutrition at some point during treatment is not uncommon.

Treatment of RTK remains investigational, and no accepted standard therapy exists for this disease. Enrolling patients on clinical trials is encouraged strongly. At St. Jude Children's Research Hospital, a regimen of ICE alternating with VDC has been used to treat patients with RTK.
 

Drug Category: Antineoplastics agents -- Antineoplastic agents interfere with cell reproduction. Some agents are cell cycle specific, while others (eg, alkylating agents, anthracyclines, cisplatin) are not phase specific. Cellular apoptosis (ie, programmed cell death) is also a potential mechanism of many antineoplastic agents.

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.

Further Inpatient Care:

• Treatment for RTK requires frequent inpatient admissions for chemotherapy administration and for complications of treatment (eg, febrile neutropenia). The duration of therapy is approximately 6-12 months.

Further Outpatient Care:

• Outpatient care during chemotherapy: The myelosuppressive effects of chemotherapy used to treat RTK necessitate frequent monitoring of blood counts on an outpatient basis. Additionally, serum electrolyte levels and renal function must be observed closely because these patients have a single kidney and often receive the nephrotoxic agents ifosfamide and carboplatin. A requirement for electrolyte supplementation is not uncommon.

• Outpatient care after the completion of therapy: The current NWTSG recommendations for follow-up monitoring of patients with RTK are as follows:

• Chest radiograph - Every 3 months (6X), every 6 months (3X), yearly (2X), and then as indicated

• Abdominal ultrasound - Every 3 months (6X), every 6 months (3X), yearly (2X), and then as indicated

• MRI scan of the head (alternatively, CT scan) - At the end of therapy and as indicated

In/Out Patient Meds:

• Chemotherapy regimens for RTK are myelosuppressive. The use of hematopoietic growth factors, such as granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF), is recommended. In addition, because the therapy is immunosuppressive, prophylaxis against Pneumocystis carinii pneumonia (PCP) with trimethoprim/sulfamethoxazole or aerosolized pentamidine is recommended.

Transfer:

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

Deterrence/Prevention:

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

Complications:

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

• Complications related to treatment: RTK can be associated with both acute and chronic toxicities.

• Hematologic: The major acute complication of chemotherapy for RTK is myelosuppression, which places patients at risk of serious infections. Patients require frequent red blood cell and platelet transfusions.

• Renal: Patients may have renal tubular dysfunction, with wasting of protein, phosphorous, bicarbonate, and other electrolytes, if platinum drugs or ifosfamide is used. Vincristine and cyclophosphamide rarely can cause the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). The long-term prevalence of renal failure is unknown because RTK is rare and the survival rate is low. Renal failure is uncommon in patients with unilateral Wilms tumor; however, patients with RTK are treated more intensively and with more nephrotoxic drugs.

• Cardiac: Some treatment regimens for RTK include anthracyclines, which can cause arrhythmias and congestive heart failure. Monitor cardiac function periodically.

• Gastrointestinal: Chemotherapy agents used for the treatment of RTK can cause mucositis, nausea, and vomiting. Vincristine can cause severe constipation with abdominal cramping and ileus.

• Neurologic: Vincristine can cause neurologic problems including ptosis, vocal cord paralysis, intestinal ileus, foot drop, and seizures. Ifosfamide can induce altered mental status and coma.

• Urologic: Cyclophosphamide and ifosfamide can cause hemorrhagic cystitis, which can be prevented by vigorous hydration and the use of mesna.

• Reproductive: Abdominal irradiation and alkylating agents can cause infertility. Girls who have Wilms tumor and receive abdominal irradiation are predisposed to premature labor.

• Second malignancies: Irradiation, alkylating agents, and etoposide have been implicated as risk factors for second malignancies.

Prognosis:

• The prognosis for children with RTK remains fair to poor, depending upon the stage at presentation and the age at diagnosis. The authors hope that new multi-institutional clinical trials are able to identify novel therapies that can improve the outcomes of patients affected with this disease.

Patient Education:

• Educate patients and families about RTK and its aggressive biological behavior. While families must be provided with hope for a cure, they also must be aware of the unfavorable prognosis associated with RTK. Furthermore, families must understand the risks of intensive chemotherapy and the signs and symptoms that require immediate medical attention.