Atrt-21. Rhabdoid Predisposition Syndrome: Report of Molecular Profiles and Treatment Approach in Three Children With Synchronous Atypical Teratoid/Rhabdoid Tumor and Malignant Rhabdoid Tumor

Abstract

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.

Rhabdoid tumor predisposition syndrome: A historical review of treatments and outcomes for associated pediatric malignancies

“…Four long‐term survivors (mean EFS of 7 years) had tumors all located in extracranial sites, with RTK in three; all four received high‐dose chemotherapy (HDC) with autologous stem cell rescue (ASCR) and gross total resection (GTR) of at least one tumor (two had GTR of both), and three patients received irradiation. Molecular profiling of three patients with synchronous ATRT and RTK revealed two had a SMARCB1 deletion and the third had a frameshift variant; the RTK were all identified as the MYC subtype, and one ATRT was classified as ATRT‐SHH and one as ATRT‐TYR 10,27 . Following use of GTR, adjuvant Intergroup Rhabdomyosarcoma Study III (IRS‐III) sarcoma‐styled chemotherapy, triple intrathecal chemotherapy (IT), and consolidation with triple HDC/ASCR, one patient was reported to be 3 years off therapy with no evidence of disease (NED), one passed away approximately 2 years after diagnosis with progression in the lungs and brain, and the third died over a year after diagnosis with retroperitoneal progression.…”

“…Molecular profiling of three patients with synchronous ATRT and RTK revealed two had a SMARCB1 deletion and the third had a frameshift variant; the RTK were all identified as the MYC subtype, and one ATRT was classified as ATRT-SHH and one as ATRT-TYR. 10,27 16 Several ATRT registries published their findings between 1995 and 2015 (Table 1). These reports sought to determine the prognostic roles of GTR, timing and extent of radiation therapy, and role and type of chemotherapy.…”

“…Genetic diagnosis of RTPS involves clinical assessment and a immunohistochemical result indicating SMARCB1/SMARCA4 deficiency, in addition to screening for somatic mutations 9 . Gonadal mosaicism is thought to often account for inherited rhabdoid tumors, 8,10–12 but unusual reports of gain‐in‐function of SMARCB1 resulting in a similar phenotype have also been reported 13 . Case reports have found that not only do patients with synchronous rhabdoid tumors have varied methylation profiles, but also patients with metachronous rhabdoid tumors arising from RTPS, in which different DNA methylation patterns and copy number aberrations have been observed; these findings indicate that RTPS leads to non‐clonal formation of rhabdoid tumors 14,15 …”