Secondary rhabdoid tumors (RTs) with atypical teratoid/rhabdoid tumor-like features rarely arise from, or coexist with, pleomorphic xanthoastrocytomas (PXAs), and their clinicopathological and molecular characteristics remain poorly understood. We report a 17-year-old girl with a temporal lobe mass that, upon gross total resection, pathologically contained both RT and PXA components. Immunohistochemistry revealed loss of INI1 expression restricted to the RT component, while the PXA area retained INI1. Next-generation sequencing identified a shared BRAF::TRIM24 fusion and homozygous deletion of CDKN2A/2B in both components, indicating a shared clonal origin. Additionally, a germline ATM frameshift mutation (c.5288_5289insGA) was identified in both tumor components, making the first such report in central nervous system tumors. SMARCB1 loss was confined to the RT component, further supporting the hypotheses of clonal evolution and secondary transformation. Despite gross total resection, craniospinal irradiation, and chemotherapy, the patient developed rapid leptomeningeal dissemination and died 5 months after surgery. This case provides clinicopathological and molecular evidence for clonal evolution and secondary transformation of PXA into an RT. The presence of germline ATM mutation may have therapeutic and biological relevance. Further studies are required to clarify the pathogenesis and optimal management of these rare and aggressive tumors.

Background: While the clinical course of radiation-induced meningioma (RIM) is considered to be more aggressive than that of sporadic meningioma (SM), the genetic predisposition for RIM is not established well. The present study aimed to analyze the clinical and genetic characteristics of RIMs to increase understanding of the tumorigenesis and prognosis of RIMs. Methods: We investigated a database of 24 patients who met the RIM criteria between January 2000 and April 2023. Genetic analysis through next-generation sequencing with a targeted gene panel was performed on 10 RIM samples. Clinical, radiological, and pathological parameters were evaluated with genetic analyses. Results: The median ages for receiving radiotherapy (RT) and RIM diagnosis were 8.0 and 27.5 years, respectively, with an interval of 17.5 years between RT and RIM diagnosis. RIMs tended to develop in non-skull bases and multifocal locations. Most primary pathologies included germ cell tumors and medulloblastoma. The tumor growth rate was 3.83 cm 3 per year, and the median doubling time was 0.8 years. All patients underwent surgical resection of RIMs. The histological grade of RIMs was World Health Organization grade 1 (64%) or 2 (36%). RIMs showed higher incidences in young-age (63%), high-dose (75%), and extendedfield (79%) RT groups. The recurrence rate was 21%. Genetic analysis revealed NF2 one copy loss in 90% of the patients, with truncating NF2 mutations and additional copy number aberrations in grade 2 RIMs. TERT promoter mutation and CDKN2A/B deletion were not identified. Notably, loss of H3K27me3 was identified in 26% of RIMs. H3K27me3 loss was associated with a higher prevalence of grade 2 RIMs (67%) and high recurrence rates (33%). Conclusion The study reveals a higher prevalence of high-grade tumors among RIMs with more rapid growth and higher recurrences than SMs. Genetically, RIMs are primarily associated with NF-2 alterations with chromosomal abnormalities in grade 2 tumors, along with a higher proportion of H3K27me3 loss.

Rhabdoid tumor predisposition syndrome (RTPS) is a rare autosomal dominant disorder characterized by an increased risk of developing malignant rhabdoid tumors in early childhood. This syndrome is primarily caused by germline heterozygous loss-of-function pathogenic variants in the SMARCB1 gene (RTPS1) and rarely in the SMARCA4 gene (RTPS2). RTPS is characterized by the development of atypical teratoid rhabdoid tumors of the central nervous system, malignant rhabdoid tumors of the kidney, and/or extrarenal extracranial rhabdoid tumors. The syndrome demonstrates high penetrance, with most tumors developing before age 3 years, and carries a poor prognosis despite intensive multimodal therapy. Early diagnosis through genetic testing, implementation of surveillance protocols, and aggressive treatment approaches are crucial for improving outcomes. This review comprehensively examines the genetic basis, clinical manifestations, surveillance strategies, and current management approaches for RTPS, with particular emphasis on emerging therapeutic options and the importance of multidisciplinary care.

Schwannomatosis (SWN) is now recognized as a broad classification that includes neurofibromatosis (NF) type 2, reflecting their shared genetic and phenotypic characteristics. Previously, SWN and NF type 2 were considered distinct clinical entities; however, the 2022 classification revision has unified them under the umbrella of SWN, with NF type 2 now referred to as NF2-related SWN. SWN arises from mutations in NF2, SMARCB1 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily b, member 1) or LZTR1 (leucine zipper like transcription regulator 1). Recent diagnostic criteria for SWN incorporate molecular classification, including “NF2-related SWN”, “SMARCB1-related SWN”, “LZTR1-related SWN”, “22q-related SWN”, “SWN-not otherwise specified”, or “SWN-not elsewhere classified”. NF2-related SWN is a genetic condition where all individuals with a germline or constitutional NF2 mutation are destined to develop the disease. The pathogenesis of SMARCB1- or LZTR1-related SWN follows a three-step, four-hit model. This involves retention of the mutated germline SMARCB1 or LZTR1 allele in the tumor, loss of the wild-type chromosome 22, and somatic mutation in the NF2 gene. Clinically, NF2-related SWN involves bilateral vestibular schwannomas, with treatment options including microsurgery, radiotherapy, and bevacizumab, each with specific benefits and limitations. Patients with SWN frequently present with chronic pain caused by schwannomas, which often does not correlate with tumor size, location, or burden. Management of SWN is primarily symptom-based. Surgical intervention is reserved for symptomatic lesions, particularly in cases of spinal cord compression or significant functional impairments. Multidisciplinary approaches to pain management are critical for enhancing quality of life. Although malignant transformation of schwannomas is a potential risk, the life expectancy of individuals with SWN is nearly normal. Despite advancements in understanding SWN, further research is necessary to elucidate the underlying genetic mechanisms and to develop targeted therapeutic strategies for this complex disorder.

Background: While the clinical course of radiation-induced meningioma (RIM) is considered to be more aggressive than that of sporadic meningioma (SM), the genetic predisposition for RIM is not established well. The present study aimed to analyze the clinical and genetic characteristics of RIMs to increase understanding of the tumorigenesis and prognosis of RIMs. Methods: We investigated a database of 24 patients who met the RIM criteria between January 2000 and April 2023. Genetic analysis through next-generation sequencing with a targeted gene panel was performed on 10 RIM samples. Clinical, radiological, and pathological parameters were evaluated with genetic analyses. Results: The median ages for receiving radiotherapy (RT) and RIM diagnosis were 8.0 and 27.5 years, respectively, with an interval of 17.5 years between RT and RIM diagnosis. RIMs tended to develop in non-skull bases and multifocal locations. Most primary pathologies included germ cell tumors and medulloblastoma. The tumor growth rate was 3.83 cm 3 per year, and the median doubling time was 0.8 years. All patients underwent surgical resection of RIMs. The histological grade of RIMs was World Health Organization grade 1 (64%) or 2 (36%). RIMs showed higher incidences in young-age (63%), high-dose (75%), and extendedfield (79%) RT groups. The recurrence rate was 21%. Genetic analysis revealed NF2 one copy loss in 90% of the patients, with truncating NF2 mutations and additional copy number aberrations in grade 2 RIMs. TERT promoter mutation and CDKN2A/B deletion were not identified. Notably, loss of H3K27me3 was identified in 26% of RIMs. H3K27me3 loss was associated with a higher prevalence of grade 2 RIMs (67%) and high recurrence rates (33%). Conclusion The study reveals a higher prevalence of high-grade tumors among RIMs with more rapid growth and higher recurrences than SMs. Genetically, RIMs are primarily associated with NF-2 alterations with chromosomal abnormalities in grade 2 tumors, along with a higher proportion of H3K27me3 loss.

Rhabdoid tumor predisposition syndrome (RTPS) is a rare autosomal dominant disorder characterized by an increased risk of developing malignant rhabdoid tumors in early childhood. This syndrome is primarily caused by germline heterozygous loss-of-function pathogenic variants in the SMARCB1 gene (RTPS1) and rarely in the SMARCA4 gene (RTPS2). RTPS is characterized by the development of atypical teratoid rhabdoid tumors of the central nervous system, malignant rhabdoid tumors of the kidney, and/or extrarenal extracranial rhabdoid tumors. The syndrome demonstrates high penetrance, with most tumors developing before age 3 years, and carries a poor prognosis despite intensive multimodal therapy. Early diagnosis through genetic testing, implementation of surveillance protocols, and aggressive treatment approaches are crucial for improving outcomes. This review comprehensively examines the genetic basis, clinical manifestations, surveillance strategies, and current management approaches for RTPS, with particular emphasis on emerging therapeutic options and the importance of multidisciplinary care.

Schwannomatosis (SWN) is now recognized as a broad classification that includes neurofibromatosis (NF) type 2, reflecting their shared genetic and phenotypic characteristics. Previously, SWN and NF type 2 were considered distinct clinical entities; however, the 2022 classification revision has unified them under the umbrella of SWN, with NF type 2 now referred to as NF2-related SWN. SWN arises from mutations in NF2, SMARCB1 (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily b, member 1) or LZTR1 (leucine zipper like transcription regulator 1). Recent diagnostic criteria for SWN incorporate molecular classification, including “NF2-related SWN”, “SMARCB1-related SWN”, “LZTR1-related SWN”, “22q-related SWN”, “SWN-not otherwise specified”, or “SWN-not elsewhere classified”. NF2-related SWN is a genetic condition where all individuals with a germline or constitutional NF2 mutation are destined to develop the disease. The pathogenesis of SMARCB1- or LZTR1-related SWN follows a three-step, four-hit model. This involves retention of the mutated germline SMARCB1 or LZTR1 allele in the tumor, loss of the wild-type chromosome 22, and somatic mutation in the NF2 gene. Clinically, NF2-related SWN involves bilateral vestibular schwannomas, with treatment options including microsurgery, radiotherapy, and bevacizumab, each with specific benefits and limitations. Patients with SWN frequently present with chronic pain caused by schwannomas, which often does not correlate with tumor size, location, or burden. Management of SWN is primarily symptom-based. Surgical intervention is reserved for symptomatic lesions, particularly in cases of spinal cord compression or significant functional impairments. Multidisciplinary approaches to pain management are critical for enhancing quality of life. Although malignant transformation of schwannomas is a potential risk, the life expectancy of individuals with SWN is nearly normal. Despite advancements in understanding SWN, further research is necessary to elucidate the underlying genetic mechanisms and to develop targeted therapeutic strategies for this complex disorder.

Background: While the clinical course of radiation-induced meningioma (RIM) is considered to be more aggressive than that of sporadic meningioma (SM), the genetic predisposition for RIM is not established well. The present study aimed to analyze the clinical and genetic characteristics of RIMs to increase understanding of the tumorigenesis and prognosis of RIMs. Methods: We investigated a database of 24 patients who met the RIM criteria between January 2000 and April 2023. Genetic analysis through next-generation sequencing with a targeted gene panel was performed on 10 RIM samples. Clinical, radiological, and pathological parameters were evaluated with genetic analyses. Results: The median ages for receiving radiotherapy (RT) and RIM diagnosis were 8.0 and 27.5 years, respectively, with an interval of 17.5 years between RT and RIM diagnosis. RIMs tended to develop in non-skull bases and multifocal locations. Most primary pathologies included germ cell tumors and medulloblastoma. The tumor growth rate was 3.83 cm 3 per year, and the median doubling time was 0.8 years. All patients underwent surgical resection of RIMs. The histological grade of RIMs was World Health Organization grade 1 (64%) or 2 (36%). RIMs showed higher incidences in young-age (63%), high-dose (75%), and extendedfield (79%) RT groups. The recurrence rate was 21%. Genetic analysis revealed NF2 one copy loss in 90% of the patients, with truncating NF2 mutations and additional copy number aberrations in grade 2 RIMs. TERT promoter mutation and CDKN2A/B deletion were not identified. Notably, loss of H3K27me3 was identified in 26% of RIMs. H3K27me3 loss was associated with a higher prevalence of grade 2 RIMs (67%) and high recurrence rates (33%). Conclusion The study reveals a higher prevalence of high-grade tumors among RIMs with more rapid growth and higher recurrences than SMs. Genetically, RIMs are primarily associated with NF-2 alterations with chromosomal abnormalities in grade 2 tumors, along with a higher proportion of H3K27me3 loss.