Rhabdoid Tumor of the Kidney

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.

Mortality/Morbidity: The overall survival rate for patients with RTK enrolled in NWTS-1 to NWTS-4 was 23.6%. Higher-stage disease correlates with more adverse outcome; most patients present with stage III or IV disease (see Table 1). In addition, diagnosis when patients are younger than 1 year is associated with an unfavorable prognosis. RTK 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.

Table 1. Survival Rates for Patients with Rhabdoid Tumor of the Kidney in National Wilms Tumor Study, 1969-1994