Malignant Rhabdoid Tumor
Based on the morphologic and immunohistochemical findings, the tumor was diagnosed as a Malignant Rhabdoid tumor. Loss of heterozygosity at Chromosome 22 was identified by SNP microarray, which is a common secondary event in the development of malignant rhabdoid tumors resulting in biallelic inactivation of the SMARCB1 gene at 22q11.23.
Malignant rhabdoid tumors are highly aggressive tumors which typically arise during infancy (1-5). Although they were first described in the kidney by Beckwith in 1978 (at which time they were categorized as sarcomatoid Wilms) they have since been reported in a variety of extrarenal sites, including the central nervous system (CNS), soft parts, liver, and peripheral nerves. Morphologically, they are characterized by "rhabdoid" cells - large polygonal cells with prominent nucleoli, vesicular chromatin and eosinophilic inclusions. A solid growth pattern (seen in this case) is most common. Trabecular, pseudo-alveolar and myxoid patterns have also been described. The histopathologic differential diagnosis includes epithelioid sarcoma and rhabdomyosarcoma with rhabdoid inclusions (4). The immunophenotypic profile demonstrates variable positivity for EMA, cytokeratin, NSE, S-100, CD99, and desmin. Exome analysis of rhabdoid tumors consistently demonstrate biallelic inactivation of SMARCB1 (INI1) - which is reflected by consistent immunohistochemical negativity for INI-1 - and few other genomic alterations (1).
SMARCB1 (also known as INI1 and hSNF5), encodes for the protein BAF47, a subunit of SWI/SNF complexes. SWI/SNF complexes are highly conserved, ATP dependent global regulators of transcription through chromatin modification (1-2). The particular composition of SWI/SNF complexes varies widely depending on the cellular or developmental context (1-2). In fact, lineage differentiation appears to be mediated by variations in SWI/SNF subunit composition (1-2). In this respect, BAF47 is considered one of the core subunits, being found in all varieties of the SWI/SNF complexes (1-2). Biallelic inactivation of SMARCB1 can occur through a variety of mechanisms, including whole-gene deletions, intragenic deletions, splice-site mutations, missense mutations, as well as LOH at chromosome 22 (1-3). Of interest, approximately 25-30% of patients with a malignant rhabdoid tumor have a germline alteration in the SMARCB1 gene and are at risk of developing multiple tumors (5). In patients with germline mutations, the majority appear to occur de nuovo, although rare instances of inherited mutations have been reported (OMIM 609322) (5). Molecular genetic testing of SMARCB1 at 22q11.23 was therefore recommended to rule out the rhabdoid tumor predisposition syndrome -1 (RTPS-1).
Contributed by Binara Assylbekova, MD and Octavia M. Peck-Palmer, PhD