Wilms Tumor and Other Childhood Kidney Tumors Treatment (PDQ®)–Health Professional Version - National Cancer Institute

Wilms Tumor and Other Childhood Kidney Tumors Treatment (PDQ®)–Health Professional Version

Rhabdoid Tumors of the Kidney

General Information About Rhabdoid Tumors of the Kidney

Rhabdoid tumors are extremely aggressive malignancies that generally occur in infants and young children. The most common locations are the kidney (termed malignant rhabdoid tumors) and the central nervous system (CNS) (atypical teratoid/rhabdoid tumor), although rhabdoid tumors can also arise in most soft tissue sites. (Refer to the PDQ summary on Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor Treatment for information about the treatment of CNS disease.) Relapses occur early (median time from diagnosis, 8 months).[1,2]

A distinct clinical presentation that suggests a diagnosis of rhabdoid tumor of the kidney includes the following:[3]

Fever.
Hematuria.
Young age (mean age, 11 months).
Advanced tumor stage at presentation.

(Refer to the Clinical Features of Wilms Tumor and Diagnostic and Staging Evaluation for Wilms Tumor sections of this summary for more information about the clinical features and diagnostic evaluation of childhood kidney tumors.)

Approximately two-thirds of patients will present with advanced-stage disease. Bilateral cases have been reported.[1] Rhabdoid tumors of the kidney tend to metastasize to the lungs and the brain. As many as 10% to 15% of patients with rhabdoid tumors of the kidney also have CNS lesions.[4] The staging system used for rhabdoid tumor of the kidney is the same system used for Wilms tumor. (Refer to the Stage Information for Wilms Tumor section of this summary for more information.)

Histologically, the most distinctive features of rhabdoid tumors of the kidney are rather large cells with large vesicular nuclei, a prominent single nucleolus, and in some cells, the presence of globular eosinophilic cytoplasmic inclusions.

Genomics of Rhabdoid Tumors of the Kidney

Rhabdoid tumors in all anatomical locations have a common genetic abnormality—loss of function of the SMARCB1 (INI1/SNF5/BAF47) gene located at chromosome 22q11.2. The following text refers to rhabdoid tumors without regard to their primary site. SMARCB1 encodes a component of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex that has an important role in controlling gene transcription.[5,6] Loss of function occurs by deletions that lead to loss of part or all of the SMARCB1 gene and by mutations that are commonly frameshift or nonsense mutations that lead to premature truncation of the SMARCB1 protein.[6,7] A small percentage of rhabdoid tumors are caused by alterations in SMARCA4, which is the primary ATPase in the SWI/SNF complex.[8,9] Exome sequencing of 35 cases of rhabdoid tumor identified a very low mutation rate, with no genes having recurring mutations other than SMARCB1, which appeared to contribute to tumorigenesis.[10]

Germline mutations of SMARCB1 have been documented in patients with one or more primary tumors of the brain and/or kidney, consistent with a genetic predisposition to the development of rhabdoid tumors.[11,12] Approximately one-third of patients with rhabdoid tumors have germline SMARCB1 alterations.[6,13] In most cases, the mutations are de novo and not inherited. The median age at diagnosis of children with rhabdoid tumors and a germline mutation or deletion is younger (6 months) than that of children with apparently sporadic disease (18 months).[14] Germline mosaicism has been suggested for several families with multiple affected siblings. It appears that patients with germline mutations may have the worst prognosis.[15,16] Germline mutations in SMARCA4 have also been reported in patients with rhabdoid tumors.[8,17]

Rhabdoid Tumor Predisposition Syndrome

Early-onset, multifocal disease and familial cases strongly support the possibility of a rhabdoid tumor predisposition syndrome. This has been confirmed by the presence of germline mutations of SMARCB1 in rare familial cases and in a subset of patients with apparently sporadic rhabdoid tumors. These cases have been labeled as rhabdoid tumor predisposition syndrome, type 1. Thirty-five patients (N = 100) with rhabdoid tumors of the brain, kidney, or soft tissues were found to have a germline SMARCB1 abnormality. These abnormalities included point and frameshift mutations, intragenic deletions and duplications, and larger deletions. Nine cases demonstrated parent-to-child transmission of a mutated copy of SMARCB1. In eight of the nine cases, one or more family members were also diagnosed with rhabdoid tumor or schwannoma; two of the eight families presented with multiple affected children, consistent with gonadal mosaicism.[6]

Two cases of inactivating mutations in the SMARCA4 gene have been found in three children from two unrelated families, establishing the phenotypically similar syndrome now known as rhabdoid tumor predisposition syndrome, type 2.[8,9] In these cases, SMARCA4 behaves as a classical tumor suppressor, with one deleterious mutation inherited in the germline and the other acquired in the tumor. Another report describes an autosomal dominant pattern of inheritance discovered through an exome sequencing project.[18]

Genetic Testing and Surveillance of Rhabdoid Tumors of the Kidney

Germline analysis is suggested for individuals of all ages with rhabdoid tumors. Genetic counseling is also part of the treatment plan, given the low-but-actual risk of familial recurrence. In cases of mutations, parental screening should be considered, although such screening carries a low probability of positivity. Prenatal diagnosis can be performed in situations in which a specific SMARCB1 mutation or deletion has been documented in the family.[6]

To date, there is little evidence regarding the effectiveness of surveillance for patients with rhabdoid tumor predisposition syndrome, type 1 caused by loss-of-function germline SMARCB1 mutations. However, because of the aggressive nature of the tumors with significant lethality and young age of onset in SMARCB1 carriers with truncating mutations, consensus recommendations have been developed. These recommendations were developed by a group of pediatric cancer genetic experts (including oncologists, radiologists, and geneticists). They have not been formally studied to confirm the benefit of monitoring patients with germline SMARCB1 mutations. Given the potential survival benefit of surgically resectable disease, it is postulated that early detection might improve overall survival (OS).[19-21]

Surveillance for patients with germline SMARCB1 mutations includes the following:

Brain magnetic resonance imaging (MRI) every 3 months from birth (or diagnosis) until age 5 years.
Abdominal ultrasonography with a focus on the kidneys are suggested every 3 months.

Prognosis and Prognostic Factors for Rhabdoid Tumors of the Kidney

Patients with rhabdoid tumors of the kidney continue to have a poor prognosis. In a review of 142 patients from the National Wilms Tumor Studies (NWTS) (NWTS-1, NWTS-2, NWTS-3, NWTS-4, and NWTS-5 [COG-Q9401/NCT00002611]), age and stage were identified as important prognostic factors:[4]

Age at diagnosis. Infants younger than 6 months at diagnosis demonstrated a 4-year OS rate of 9%, whereas the OS rate in patients aged 2 years and older was 41% (highly significant).
Stage of disease. Patients with stage I and stage II disease had an OS rate of 42%; higher stage was associated with a 16% OS rate.
Presence of a CNS lesion. All but one patient with a CNS lesion (n = 32) died.

Treatment of Rhabdoid Tumor of the Kidney

Because of the relative rarity of this tumor, all patients with rhabdoid tumor of the kidney should be considered for entry into a clinical trial. Treatment planning by a multidisciplinary team of cancer specialists (pediatric surgeon or pediatric urologist, pediatric radiation oncologist, and pediatric oncologist) with experience treating renal tumors is required to determine and implement optimal treatment.

There is no standard treatment option for rhabdoid tumor of the kidney.[22]

The following results have been observed in studies of rhabdoid tumor of the kidney:

On the basis of a retrospective comparison of tumor response to preoperative treatment with vincristine/dactinomycin versus vincristine/dactinomycin/doxorubicin, doxorubicin is considered an active drug in malignant rhabdoid tumor of the kidney.[23][Level of evidence: 3iiiDiv]
The NWTS-5 trial closed the arm for rhabdoid tumor treatment with cyclophosphamide, etoposide, and carboplatin because poor outcome was observed. Combinations of etoposide and cisplatin; etoposide and ifosfamide; and ifosfamide, carboplatin, and etoposide (ICE chemotherapy) have been used.[24,25]
Treatment with high-dose alkylator therapy followed by consolidation with high-dose chemotherapy and, in some cases, autologous stem cell transplant after achieving a radiographic remission has resulted in some long-term survival (5 of 13 patients). None of the patients with unresectable primary tumors survived in this small series (N = 21).[26]
A retrospective analysis of 58 patients with malignant rhabdoid tumor of the kidney from the International Society of Pediatric Oncology (SIOP), Gesellschaft für Pädiatrische Onkologie und Hämatologie (GPOH), and European Rhabdoid Tumor Registry was performed.[27]
- For the entire group, the 2-year event-free survival (EFS) rate was 37%, and the OS rate was 38%.
- Patients with multifocal involvement (n = 12) had significantly inferior survival than did patients with pulmonary or mediastinal metastases or local disease.
- Patients who underwent upfront chemotherapy had a lower, but not statistically significant, 2-year EFS than did patients who underwent immediate surgical resection.
- Younger age (<12 months) and local stage III disease were associated with significantly inferior survival than were stage I and stage II disease.
- No difference was seen in 2-year EFS for patients without progression within 90 days consolidated by high-dose stem cell transplantation (SCT) (n = 10) compared with patients without consolidation by SCT (n = 21).

Treatment Options Under Clinical Evaluation for Rhabdoid Tumors of the Kidney

Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following are examples of national and/or institutional clinical trials that are currently being conducted:

APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI–Children's Oncology Group Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.
NCT02601937 (A Phase 1 Study of the EZH2 Inhibitor Tazemetostat in Pediatric Subjects With Relapsed or Refractory INI1-Negative Tumors or Synovial Sarcoma): Patients with INI1-negative tumors are eligible for targeted treatment with an EZH2 inhibitor. This is a phase I, open-label, dose-escalation, and dose-expansion study with a twice-daily oral dose of tazemetostat.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

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