Malignant Rhabdoid Tumor 

Updated: Oct 09, 2018
Author: James I Geller, MD; Chief Editor: Max J Coppes, MD, PhD, MBA 

Overview

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 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 MRT of the kidney was originally described, MRTs 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 MRTs 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 SWI/SNF related, matrix-associated, actin-dependent regulator of chromatin, subfamily B, member 1 (SMARCB1) gene, also known as human sucrose non-fermenting 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 MRTs, 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 MRT 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 MRTs, 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, MRTs are generally diploid and genomically stable, without recurrent gene amplifications or deletions. Therefore, the mechanism by which SMARCB1 perturbation leads to aggressive neoplasia 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. Whole-exome sequencing studies of primary MRTs have shown that biallelic mutations or copy number alterations of SMARCB1 seem to be both necessary and sufficient to cause cancer.[4]

The distribution of SMARCB1 and chromosome 22-inactiving mutations, deletions, and copy number loss of heterozygosity (CN-LOH) in 200 sporadic AT/RTs, renal MRTs, and extrarenal MRTs is shown in Table 1 below. In the majority of tumors (43%), there is a mutation in one allele, and the second copy of the gene is lost as a result of a structural deletion in 22q11.2, monosomy 22, or an acquired CN LOH event. Compound heterozygous mutations are infrequent in these patients (4%). Partial deletions and duplications are detected in approximately 15% of tumors. Homozygous deletions of exons 1-9 of SMARCB1 are present in approximately 40% of rhabdoid tumors overall, although there is an unequal distribution with respect to anatomic location. Approximately 25% of AT/RTs, 40% of renal MRTs, and 70% of extrarenal MRTs have homozygous deletions of the entire locus.[4]

Table 1. Acquired SMARCB1 Alterations in 200 Sporadic Rhabdoid Tumors (Adapted from Geller JI, Roth JJ, Biegel JA. Biology and Treatment of Rhabdoid Tumor. Crit Rev Oncog. 2015. 20 [3-4]:199-216) (Open Table in a new window)

Allele 1 Alteration

Allele 2 Alteration

Total

Mutation

Partial Gene Deletion/Duplication

Whole Gene Deletion

CN-LOH

Mutation

8 (4%)

1 (0.50%)

58 (29%)

27 (13.5%)

94 (47%)

Partial Gene Deletion/Duplication

-

5 (2.5%)

14 (7%)

11 (5.3%)

30 (15%)

Whole Gene Deletion

-

 

76 (38%)

-

76 (38%)

Total

8 (4%)

6 (3%)

148 (74%)

38 (19%)

200 (100%)

Although SMARCB1 is the predominant gene altered in MRTs, approximately 2-3% retain expression of the SMARCB1 protein on immunohistochemistry and do not display inactivating mutations in the gene.[4] A small number of families and patients with MRT have been shown to have germline or somatic mutations in SMARCA4, which is the primary ATPase in the SWI/SNF complex.[5, 6]

 

Pathophysiology

The histogenetic origin of malignant rhabdoid tumor (MRT) remains obscure. Rhabdoid tumor cells are polyphenotypic, with an immunostaining pattern that shows evidence of mesenchymal, epithelial, and neural differentiation. Polyantigenic expression suggests that MRTs arises from a pluripotent cell capable of differentiating along several lines.

Considerable debate has been focused on whether extrarenal MRTs are the same as renal MRTs. The recognition that CNS AT/RTs have deletions of the SMARCB1 gene indicates that MRTs of the kidney and brain are 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 non-CNS MRTs have synchronous or metachronous brain tumors, many of which are second primary AT/RTs.

More convincingly, the same germline mutations (outside of frameshift mutations) predispose carriers to atypical teratoid/rhabdoid tumor (AT/RT), renal MRTs, and to a lesser extent extrarenal MRTs. The majority of extrarenal MRTs are sporadic and arise as a consequence of homozygous loss of SMARCB1. The most frequent second hit in patients with a germline mutation is a large 22q deletion or monosomy 22, or a copy number loss of heterozygosity (CN-LOH) generating event.[4]

Reports to date have demonstrated that SMARCB1 loss can promote cell cycle progression resulting from upregulation of targets of the p16INK4a-Rb-E2F pathway, primarily including CyclinD1 as well as several cyclin-dependent kinases (CDK). Rb family loss has been shown to increase MRT tumorigenesis and progression, whereas ablation of CyclinD1 abrogates MRT 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 Tp53 pathways. The loss of SMARCB1 is postulated to result in a global failure of the repressive H3K27 trimethylation mark present on bivalently modified histones, mediated by the polycomb complex 2, resulting in widespread epigenetic modifications and leading to arrested development and abnormal proliferation. Two members of the polycomb complex 2, CBX6 and EZH2, are upregulated in MRT.[7] Aurora-A-kinase is also expressed in high levels in MRT and is repressible with SMARCB1 reintroduction into rhabdoid tumor cells via transcriptional down-regulation. SMARCB1 loss also leads to increased expression of GLI1, supporting a role in the biology of the sonic hedgehog pathway.[8] Bromodomain containing protein 9 (BRD9) is also a subunit of the SWI/SNF complex that is involved in epigenetic mechanisms such as regulation of transcription, chromatin remodeling and histone modification.[9] These findings suggest possible therapeutic targets for MRT. For CNS MRT (atypical teratoid/rhabdoid tumor (AT/RT)), biologic heterogeneity has been discovered. There are three distinct molecular subgroups of AT/RT tumors, termed ATRT-TYR, ARTR-SHH, and ATRT-MYC, that are associated with differences in demographics, tumor location, and type of SMARCB1 mutations.[10] The ATRT-TRY group is composed of mostly infratentorial tumors with broad SMARCB1 deletions and overexpression of melanosomal genes. The ATRT-SHH group is associated with both supra- and infratentorial lesions, has focal SMARCB1 aberrations, and shows overexpression of SHH pathways. The ATRT-MYC group is comprised of mostly supratentorial tumors with focal SMARCB1 deletions and over-expression of the MYC and HOX cluster.[10] The development of these molecular subgroups with associated regulatory networks and pathways will help to develop more effective, subgroup specific treatment options.

Similarly, comprehensive genomic analysis was performed on non-CNS MRTs through the Therapeutically Applicable Research to Generate Effective Targets (TARGET) initiative.[11] This analysis showed evidence for epigenetic reprogramming of HOX genes with loss of H3K27me3 marks, as well as dysregulated expression of genes involved in neural crest development and of oncogenes and tumor suppressor genes. Although SMARCB1 alterations were shown to be the dominant genetic driver in MRTs, the effects of that loss on transcriptional regulation were not uniform across all cases. 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,[12] proximal-type epithelioid sarcoma, epithelioid malignant peripheral nerve sheath tumor, renal medullary carcinoma,[13] chordoma, and pediatric undifferentiated sarcoma lacking rhabdoid features.[14] Inactivation of SMARCB1 has also been identified in the small cell undifferentiated variant of hepatoblastoma, which may suggest that such tumors are better characterized as hepatic rhabdoid tumors.[15, 16] Whether extrarenal MRTs have the same histogenetic origin as that of their renal counterparts is unclear. Although some extrarenal MRTs are considered to be undifferentiated sarcomas or carcinomas with rhabdoid features, others represent true rhabdoid tumors because they have documented SMARCB1 mutations.[17] To date, the only tumor outside of MRT to demonstrate biallelic inactivation of SMARCA4, consistent with a cancer-predisposing germline mutation and second somatic alteration, is small cell carcinoma of the ovary, hypercalcemic type (SCCOHT).[18] Based on the early age at presentation and presence of rhabdoid-appearing cells on histology, it has been proposed that SCCOHT represents another type of extrarenal MRT.[19]

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

Epidemiology

Frequency

United States

Malignant rhabdoid tumor (MRT) is a rare tumor. According to registration data from NWTS 1-5, MRT of the kidney 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. Of the first 4,000 patients enrolled on the COG study AREN03B2, renal and extrarenal MRTs accounted for 3.71% combined.[20] About 15 cases of extrarenal, non-CNS MRTs are diagnosed each year in the North America. MRTs in infants (age 0-12 months) account for 18% of renal tumors, 14% of soft tissue tumors, and 9% of liver tumors.[21]

International

The incidence of MRT in most countries has not been reported. Between 1984 and 1999, approximately 6 patients per year diagnosed with MRT were enrolled onto various national registries or protocols in Germany.[22] Between 1993 and 2005, a total of 207 renal MRT K patients were enrolled on SIOP renal tumor treatment study group protocols.[23]

Mortality/Morbidity

The overall survival rate for patients with MRT enrolled in NWTS 1-5 was 23.2%.[24]

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, brain, and less commonly bone (1.4%).

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).[24]

High-stage (stage III/IV) disease is also correlated with an adverse outcome (p=0.014); most patients present with stage III or IV disease.

The survival of patients with MRT 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 MRT and AT/RT from Germany, metastatic disease at diagnosis maintained prognostic value, although age did not.[22] 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.

Survival outcomes remained poor for those patients with higher stage disease treated on the most recent COG study AREN0321 (regimen UH1), a more intensive chemotherapy regimen than previously used in NWTSG trials. The 4-year EFS and OS for the entire cohort were both 35.9%.[25]  

The survival of patients with MRT in AREN0321 was as follows:

  • Stage I - 2 patients (100%)
  • Stage II - 5 patients (100%)
  • Stage III - 23 patients (26.1%)
  • Stage IV - 9 patients (11.1%)
  • Stage V - 0 patients

Such data suggest that intensive therapy may benefit rare low stage MRT patients (stage 1 and 2), but novel therapy is necessary for stage 3 and 4 patients.

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 1.37:1.[24]

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 older patients have a biologically distinct subtype of MRT is unclear.

 

Presentation

History

Children with malignant rhabdoid tumor (MRT) 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 MRT of the kidney, compared with 25% of patients with a Wilms tumor.
  • As many as 20% of patients with a MRT of the kidney have synchronous or metachronous CNS lesions, including both metastases and second primary AT/RTs.

A detailed family cancer history should be obtained.

Physical

The physical findings of patients with MRT depend on the site of origin of the tumor.[26, 27]

  • For MRT 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, a 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 consists of 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 AT/RTs.

Causes

See the list below:

  • Although mutations or deletions of the SMARCB1 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.
 

DDx

Diagnostic Considerations

See the list below:

  • 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 MRT:

    • Rhabdomyosarcoma

    • Nonrhabdomyosarcoma soft tissue sarcomas

    • Hepatoblastoma/small cell undifferentiated tumor

Differential Diagnoses

 

Workup

Laboratory Studies

See the list below:

  • Although malignant rhabdoid tumor (MRT) is definitively diagnosed by means of histologic analysis (see Histologic Findings below), laboratory studies can help in distinguishing a MRT of the kidney from a Wilms tumor.
  • The following tests may be helpful:
    • CBC count: Approximately 55% of patients with MRT 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 MRT. Approximately 25% of patients with MRT 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 is associated with congenital mesoblastic nephroma.
  • Liver function test results may be abnormal in infants and children with primary hepatic MRT or in the case of hepatic metastases from a renal or soft tissue primary MRT.

Imaging Studies

See the list below:

  • 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 or MRI: 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 hypo-attenuating 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 MRTs. MRT-associated calcifications are often linear or curvilinear, and they may outline tumor lobules, as is shown in the image below.

See the list below:

Nonenhanced CT scan demonstrates linear and curvil 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.

See the list below:

  • A peripheral, subcapsular, crescent-shaped fluid collection is often seen in association with MRT, as is shown in the image below. In one study, this finding was present in 15 of 21 patients (71%) with MRT, 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.

See the list below:

  • Contrast-enhanced CT scan demonstrates a subcapsul 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.
  • Chest CT: Lungs remain the most common site of metastatic disease from non-CNS MRT; the lungs are involved in 83% of infants and children with metastatic MRT 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 MRT and is best diagnosed with Doppler ultrasonography or magnetic resonance angiography.
  • MR, CT, FDG, and/or PET imaging of the brain: Imaging of the head is indicated to exclude the possibility of a synchronous primary or metastatic brain tumor. [27]
  • Bone Scan: Historically, bone metastases were present in 5% of infants and children with metastatic MRT at diagnosis, which approximates 1% of MRT overall. As such, the most recent COG MRT research protocol required a bone scan at diagnosis. Whether all children with MRT require a bone scan at diagnosis is unclear.

Other Tests

See the list below:

  • 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 25-30% of patients with MRT. Testing of all MRT patients for germline SMARCB1 perturbations is advised.

Procedures

See the list below:

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

Histologic Findings

See the list below:

  • On gross examination, MRTs are heterogeneous, bulky, lobulated, friable, solid, gray-tan masses with areas of necrosis and hemorrhage.

  • On microscopic examination, MRTs 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). Thi 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, MRT 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 MRT. 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 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 MRT.

Staging

See the list below:

  • In North America, MRTs 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. 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. 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 or pelvic 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. (7) Tumor is removed in greater than one piece.
    • 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 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. Subsequent case reports 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, the most recent COG study AREN0321, regimen UH-1, used cyclophosphamide-carboplatin-etoposide (CCE) alternating with VDC. The 4-year EFS and OS estimates for the entire cohort of patients were both 35.9%, with a median time to progression of 2.7 months.[25] There was a trend towards improved outcomes for low stage patients (100% 4-year EFS for 2 patients with stage 1 disease and 5 with stage 2 disease), but continued dismal outcomes for those with higher stage disease.  

Insights into the treatment of MRT 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. Current treatment involves a multimodal approach with a combination of surgery, radiation therapy, and various chemotherapy regimens (systemic and intrathecal) that typically included cisplatin, etoposide, vincristine, ifosfamide, doxorubicin, actinomycin, cyclophosphamide, methotrexate, and intrathecal agents with or without autologous stem-cell rescue. These treatments have improved the survival rates of patients with AT/RT from historical controls.  

In a review by Tekautz et al of children treated at St. Jude Children’s Research Hospital from 1984-2003 showed that AT/RT presenting in patients older than 3 demonstrated a 2-year event-free survival of 78% when treated with a combination of radiation and high-dose alkylating therapy.[28] Subsequently, the Dana Farber Consortium AT/RT study which was a multisite study of multimodal therapy incorporating surgery, age- and stage-directed radiation, and a systemic and intrathecal conventional chemotherapeutic regimen based on a modified IRS-III regimen, demonstrated a 2-year progression-free survival of 53%. This later study included infants younger than 3 years of age.[29] Additionally, There are reports that describe the successful use of high dose chemotherapy with stem cell rescue to treat non-CNS malignant rhabdoid tumor.[30] Considering all data, the recently closed COG AT/RT protocol ACNS0333 used a regimen incorporating surgery, conventional chemotherapy, age- and stage-directed radiation, and three cycles of high dose chemotherapy with stem cell rescue. This study showed an overall 2-year progression-free survival of 42% in the entire cohort and of 39% for those < 3 years of age.[31] In Europe, the registry study (Eu-Rhab) for all rhabdoid tumors (AT/RT, RTK, and MRT) recommends using combination therapy including surgery, radiotherapy, and chemotherapy with permissive use of high-dose chemotherapy with stem cell rescue.[32]

Venkatramani et al. discussed a potential role for higher dose alkylator therapy and/or high dose chemotherapy with stem cell rescue for MRT patients, analogous to approaches for AT/RT, but no formal trial has demonstrated a therapeutic advantage in treatment of non-CNS MRT.[33] 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 MRT is unclear.

Similarly, anecdotal reports suggest a benefit from the use of radiotherapy as part of multimodal therapy for MRT. However, the lack of treatment uniformity among reported patients makes it difficult to determine if radiotherapy is effective for MRT outside the CNS. In NWTS 1-5, radiation therapy was given to the flank or abdomen at total doses of 1080-3500 cGy and to total doses of 1080-2100 cGy on AREN0321. However, the optimal dose remains to be determined. Radiation therapy is a cornerstone of treatment for CNS AT/RT, with use of radiation therapy being an independent predictor of overall survival (hazard ratio 0.1, p= 0.02), with the benefit being more pronounced in patients < 3 years of age.[34]

Furtwängler et al. conducted a review of 3 prospective studies comparing the change of tumor volume as a result of treatment with either actinomycin D and vincristine combination therapy (AV) or doxorubicin-intensified actinomycin D and vincristine combination therapy (AVD) in all patients with MRT of the kidney who had been treated from 1991 to 2013 in Austria, Switzerland, and Germany. The investigators concluded that a significantly better treatment response is achieved with neoadjuvant AVD than with AV alone.[35]

In sum, while the prognosis for select patients, particularly those with localized MRT associated with an older age and lower stage disease, has improved, the overall outcomes of MRT remain poor despite maximized therapy intensity, leading to an emphasis on the integration of novel therapies that target the underlying biology as the next steps needed for advancements in cure for stage 3 and 4 MRT patients.

Novel Therapeutics

EZH2 is a histone methyltransferase that is upregulated in rhabdoid tumors. EZH2 can now be targeted with EZH2 inhibitors that have been shown to have anti-rhabdoid tumor effects both in vitro and in vivo. Tazemetostat (EPZ-6438), a selective, orally bioavailable, small molecule inhibitor of the EZH2 gene, has been shown to have pre-clinical and clinical activity in MRT. Knutson et al have shown that Tazemetostat induces apoptosis and differentiation specifically in SMARBC1-depleted MRT cells and treatment of mice with the drug leads to dose-depended regression of MRTs and prevention of regrowth after dosing cessation.[36] Additional pre-clinical investigations have demonstrated tazemetostat to have enhanced antitumor activity when administered in combination with chemotherapy regimens including vincristine, doxorubicin, and cyclophosphamide (Epizyme, Investigator Brochure, March 2016). In addition, the Pediatric Pre-clinical Testing Program published results showing significant antitumor activity of tazemetostat in MRT xenograft models (3/5 xenograft models), without demonstrable effect in the other histologies tested (0/22).[37] Clinical activity of tazemetostat has been shown in subjects with genetically-defined SMARCB1 altered tumors, including those with epitheliod sarcoma and MRT of the ovary. The current on-going Phase 1 pediatric study EZH-102 is evaluating the administration of tazemetostat to patients with relapsed/refractory MRT and other SMARCB1/SMARCB4 mutated tumors or synovial sarcoma; a recommended phase 2 dose has been determined and the protocol is currently enrolling expansion cohorts. This promising agent may be combined with a chemotherapy backbone for future clinical trials in MRT.  Cyclin dependent kinases (CDK) 4/6 activity is upregulated by the loss of SMARCB1 in MRTs. Ribociclib (LEE011) is an orally bioavailable, specific inhibitor of CDK4/6 which has been shown to have in vitro activity in MRT cell lines. A Phase 1 study of ribociclib in pediatric patients with neuroblastoma, MRT, or other cyclin D-CDK4/6-INK4-retinoblastoma pathway-altered tumors showed prolonged stable disease that support further testing of ribociclib in combination with other agents.[38]

BRD9, which forms a subunit of the SWI/SNF complex, inhibition has been investigated by Krӓmer et al.[9] Two specific chemical probes (I-BRD9 and BI-9564) that selectively target BRD9 were evaluated in 5 MRT cell lines alone and in combination with cytotoxic drugs. Single compound treatment with I-BRD9 and BI-9864 resulted in decreased cell proliferation and apoptosis. Combined treatment of doxorubicin or carboplatin with I-BRD9 resulted in additive to synergistic inhibitor effects on cell proliferation. Therefore, BRD9 is an attractive target for novel therapeutic agents.[9]

MRT xenografts are being tested against new drugs through the Pediatric Pre-clinical Testing Program, which will lead to continued development of novel therapeutic agents in the future.  

 

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 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

  • 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 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

Medication Summary

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 MRT.

Due to excessive toxicity in affected infants and young children, chemotherapeutic doses in the most recent COG protocol AREN0321, which uses CyCE (rather than ICE) alternating with VDC, have been decreased. In general, infants and children undergoing intensive chemotherapy for MRT, with either VDC/CyCE (possibly adequate for patients with stage 1 and 2 non-CNS MRT) 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 MRT (Open Table in a new window)

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 h, 6 h, and 9 h after ifosfamide

Filgrastim G-CSF

5 mcg/kg/dose

SC

Start 24 h after chemotherapy and continue until ANC recovers

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 MRT (Open Table in a new window)

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

Antineoplastic agents

Class Summary

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 MRT is unknown. Some investigators have advocated for between 8-10 cycles of chemotherapy total. The most recent COG MRT protocol used 5 cycles each of VDC and CyCE (10 cycles total).

Ifosfamide (Ifex)

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

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.

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.

Vincristine (Oncovin, Vincasar PFS)

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

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.

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.

Uroprotective antidote

Class Summary

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.

 

Follow-up

Further Outpatient Care

See the list below:

  • 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.

Further Inpatient Care

See the list below:

  • 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.

Inpatient & Outpatient Medications

See the list below:

  • 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

See the list below:

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

Deterrence/Prevention

See the list below:

  • In most cases, the cause of MRT 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 MRT 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, the current screening plan includes the use of serial abdominal and transcranial ultrasonography (monthly for 1 year) 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

See the list below:

  • Complications related to tumoral progression: MRTs in the abdomen can rapidly progress, as can those at metastatic sites, including the lungs, liver, and brain. MRTs can be associated with tumoral hemorrhage and organ failure.
  • Complications related to treatment:
    • Hematologic complications: The major acute complication of chemotherapy for MRTs 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 MRTs are rare and the survival rate is low. Renal failure is uncommon in patients with unilateral Wilms tumor; however, patients with MRTs are treated intensively and with additional nephrotoxic drugs.
    • Cardiac complications: Some treatment regimens for MRTs 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

See the list below:

  • The prognosis for children with MRTs 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

See the list below:

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

Genetic counseling

See the list below:

  • Genetic counseling is highly recommended for all MRT affected families.

  • The incidence of germline deletions or missense mutations of SMARCB1 in infants and children with MRT 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 MRT 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 MRT may be advisable (see Deterrence/Prevention).