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BACKGROUND Rhabdoid predisposition syndrome is characterized by germline alterations in SMARCB1 or SMARCA4, leading to synchronous or metachronous central nervous system (CNS) and extra-CNS rhabdoid tumors. Rare survivors have been reported to date. METHODS We describe the molecular profiling and treatment regimen of three patients with synchronous atypical teratoid/rhabdoid tumor (ATRT) and malignant rhabdoid tumor of the kidney (MRT-K). All patients underwent radical nephrectomy of the kidney, and gross total resection of the primary CNS tumor was achieved for two patients. An intensive chemotherapy regimen was administered; an induction phase based on the modified Third Intergroup Rhabdomyosarcoma Study (IRS-III) for ATRT followed by a consolidation phase with three cycles of high-dose chemotherapy and autologous hematopoietic progenitor cell rescue, without irradiation. All three patients were enrolled on an institutional comprehensive genomic profiling protocol. RESULTS A germline focal 22q deletion, including SMARCB1, was detected in two patients, while the third patient had a maternally-inherited heterozygous frameshift variant in SMARCB1. Somatic loss of heterozygosity of 22q was identified in all patients, resulting in biallelic inactivation of SMARCB1. Divergent tumor subgroups were described using DNA methylation. The three MRT-K samples were classified as MYC subtype. One ATRT was classified as SHH while the other as TYR. One patient is currently three years off-therapy without evidence of disease, while the other two patients have completed the consolidation phase without recurrent disease. CONCLUSION Molecular profiling of CNS and extra-CNS rhabdoid tumors revealed different epigenetic subgroups. An intensive multimodal therapeutic approach without irradiation may achieve prolonged survival.

BACKGROUND: CNS AT/RTs with synchronous/ metachronous extra-CNS primary tumors are a rare entity with a dismal prognosis. METHODS: A literature review was conducted on patients diagnosed with CNS AT/RT and synchronous/ metachronous extra-CNS primary tumors. RESULTS: Our review yielded information on 32 children diagnosed with CNS AT/RT with additional extra-CNS primary tumors. The median age at diagnosis was four months. Male: female ratio was 2:1. Twenty-three patients presented within the age of six months. The most common extra-CNS site was the kidney (69%). Germline SMARCB1 mutation was found in all of the tested patients. The median overall survival was 5.8 months post-diagnosis. Only four patients were found to be alive with no evidence of relapse. All of the survivors receive high-dose chemotherapy (HDCT) followed by autologous peripheral blood stem cell transplant (PBSCT). Three of them had gross-total resection of the intracranial tumor and one did not receive any intracranial surgical resection. Two of the survivors did not receive any radiotherapy. One child received upfront focal radiotherapy, while the remaining patient received focal radiotherapy only after the progression of the intracranial tumor. Three of the surviving patients received intrathecal chemotherapy; two of them included methotrexate. CONCLUSION: The rarity of patients with CNS AT/RT with additional extra-CNS manifestations and the lack of a standard treatment protocol have contributed to the reported dismal prognosis. A multimodal treatment approach including maximal surgical resection, intrathecal chemotherapy, and HDCT with peripheral PBSCT may improve the outcomes for this patient population, without the need for upfront radiotherapy.