Malignant Rhabdoid Tumor

Updated: Nov 07, 2017
  • Author: James I Geller, MD; Chief Editor: Max J Coppes, MD, PhD, MBA  more...
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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 malignant rhabdoid tumor of the kidney is characterized by the early onset of local and distant metastases and resistance to chemotherapy. Whereas the overall survival rate for Wilms tumors exceeds 85%, the survival rate for renal malignant rhabdoid tumors is only 20-25%.

Because rhabdoid tumor of the kidney was originally described, malignant rhabdoid tumors have been reported in practically every location in the body, including the brain, liver, soft tissues, lung, skin, and heart. This article focuses on renal and extrarenal rhabdoid tumors that arise outside the CNS.

Molecular genetics

Cytogenetic, fluorescence in situ hybridization (FISH), and loss-of-heterozygosity (LOH) studies have revealed that malignant rhabdoid tumors frequently contain deletions at chromosome locus 22q11.1. Positional cloning efforts revealed that this locus contains the SWI/SNF related, matrix-associated, actin-dependent regulator of chromatin, subfamily B, member 1 (SMARCB1) gene, also known as human sucrose nonfermenting gene number 5 (hSNF5), integrase interactor 1 (INI1) , or 47-Kd Brg1/Bam– associated factor (BAF47). [2] SMARCB1 encodes a member of the human SWI/SNF complex.

Combined analyses including FISH, coding sequence analysis, high-density single nucleotide polymorphism–based oligonucleotide arrays, and multiplex ligation-dependent probe amplification enable the identification of biallelic, inactivating perturbations of SMARCB1 in nearly all malignant rhabdoid tumors, consistent with the 2-hit model of tumor formation. [3] Thus, SMARCB1 is presumed to function as a classic tumor suppressor and the primary gene responsible for malignant rhabdoid tumor development.

Homozygous inactivation of SMARCB1 in mice demonstrates embryonic lethality, whereas heterozygous SMARCB1 mice demonstrate a normal phenotype at birth, with 20% developing sarcomas at a median age of 1 year. Similar to human malignant rhabdoid tumors, murine tumors in these mice acquire a second hit to the SMARCB1 locus. All mice harboring a conditional biallelic inactivation of SMARCB1 develop cancer with a median onset of 11 weeks, revealing one of the most aggressive cancer predisposition genotype-phenotype correlations known.

Unexpectedly, despite an aggressive clinical pattern of behavior, malignant rhabdoid tumors are generally diploid and genomically stable, without recurrent gene amplifications or deletions. The mechanism by which SMARCB1 perturbation leads to aggressive neoplasia therefore likely relates to its role in epigenetic modification. The SWI/SNF complex acts in an adenosine triphosphate (ATP)–dependent manner to remodel chromatin, which regulates gene transcription and DNA repair. Reports to date have demonstrated that SMARCB1 loss can promote cell cycle progression resulting from upregulation of targets of the p16INK4a-Rb-E2F pathway. Rb family loss has been shown to increase malignant rhabdoid tumor tumorigenesis and progression, whereas ablation of CyclinD1 abrogates malignant rhabdoid tumor evolution in mouse models.

Similarly, tumor development in SMARCB1 -deficient mice is greatly accelerated in the absence of functional p53 protein. These findings suggest a cooperative effect between SMARCB1 and the pRB, CyclinD1, and p53 pathways.

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Pathophysiology

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

Considerable debate has been focused on whether extrarenal malignant rhabdoid tumors are the same as RTK. The recent recognition that CNS atypical teratoid/rhabdoid tumors (AT/RT) have deletions of the SMARCB1 gene indicates that rhabdoid tumors of the kidney and brain are identical or closely related entities. This observation is not surprising because rhabdoid tumors at both locations possess similar histologic, clinical, and demographic features. Moreover, 10-15% of patients with malignant rhabdoid tumors have synchronous or metachronous brain tumors, many of which are second primary malignant rhabdoid tumors. Germline SMARCB1 mutations were detected in some of these patients.

Conversely, the spectrum of tumors characterized by mutations in the SMARCB1 gene has also been expanded beyond tumors with a rhabdoid histologic phenotype to include hereditary schwannomas, extraskeletal myxoid chondrosarcoma, [4] proximal-type epithelioid sarcoma, epithelioid malignant peripheral nerve sheath tumor, renal medullary carcinoma, [5] and pediatric undifferentiated sarcoma lacking rhabdoid features. [6] Inactivation of SMARCB1 has also been identified in small cell undifferentiated variant of hepatoblastoma. [7, 8] Whether extrarenal or extracranial rhabdoid tumors have the same histogenetic origin as that of their renal counterparts is unclear. Although some extrarenal or extracranial rhabdoid tumors are considered to be undifferentiated sarcomas or carcinomas with rhabdoid features, others represent true rhabdoid tumors because they have documented SMARCB1 mutations. [9]

The Children's Oncology Group (COG) has initiated an effort to prospectively screen all types of malignant rhabdoid tumor for SMARCB1 mutations and protein expression, which should improve the classification and prognostication of tumors with rhabdoid features. As molecular-based targeted therapies emerge, the distinction between true and pseudorhabdoid tumors may prove to have important therapeutic implications.

For details about the gross and histologic features of malignant rhabdoid tumors, see Histologic Findings below.

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Epidemiology

Frequency

United States

Malignant rhabdoid tumor is a rare tumor. According to registration data from NWTS 1-5, malignant rhabdoid tumor accounts for only 158 (1.6%) of 10,031 registrants with childhood renal tumors. Likewise, only 26 (0.9%) of 3000 participants in the Intergroup Rhabdomyosarcoma Studies I-III had tumors consistent with malignant rhabdoid tumor. About 15 cases of extrarenal or non-CNS malignant rhabdoid tumors are diagnosed each year in the North America.

International

The incidence of malignant rhabdoid tumor in most countries has not been reported. Between 1984 and 1999, approximately 6 patients per year diagnosed with malignant rhabdoid tumor were enrolled onto various national registries or protocols in Germany. [10]

Mortality/Morbidity

The overall survival rate for patients with malignant rhabdoid tumor enrolled in NWTS 1-5 was 23.2%.

Malignant rhabdoid tumor is a rapidly progressive tumor, with most deaths occurring within 12 months of presentation. The most common sites of metastasis at presentation are the lungs, abdominal lymph nodes, liver, brain and bone.

A young age at diagnosis is strongly associated with an adverse outcome. Four-year event-free survival rates according to age at diagnosis were 8.8% for patients aged 0-5 months, 17.2% for patients aged 6-11 months, 28.6% for patients aged 12-23 months, and 41.1% for patients aged 24 months or older (p < 0.0001).

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

The survival of patients with malignant rhabdoid tumor in NWTS was as follows:

  • Stage I - 15 patients (33.3%)
  • Stage II - 25 patients (46.9%)
  • Stage III - 58 patients (21.8%)
  • Stage IV - 41 patients (8.4%)
  • Stage V - 3 patients (0%)

In a smaller study of 70 patients with malignant rhabdoid tumor and AT/RT from Germany, metastatic disease at diagnosis maintains prognostic value, although age does not. [10] Additional preliminary data suggest that patients with germline mutations of SMARCB1 likely manifest disease at an earlier age, with a high risk of progression and inferior prognosis.

Race

Malignant rhabdoid tumor has no apparent racial predilection.

Sex

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

Age

The median age at presentation is 10.6 months, with a mean age of 15 months. Most patients are younger than 2 years. Malignant rhabdoid tumor has been reported in children older than this and in adults, but whether these patients have true rhabdoid tumors or other poorly differentiated tumors with rhabdoid features is unclear.

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