A Novel Variant of SMARCB1 in Rare Familial Schwannomatosis Identified by Whole-Exome Sequencing and Genotype-Phenotype Correlation Analysis.

Background: Variants in the tumor suppressor gene SMARCB1 could cause different conditions. In some cases, germline and somatic variants in SMARCB1 are implemented in schwannomatosis. But the genotype and phenotype correlation for variants in SMARCB1 has not been determined.Methods: A Chinese schwannomatosis family with an autosomal dominant inheritance pattern was recruited. Whole-exome sequencing (WES) was performed to discover the causative variant, followed by Sanger sequencing. We evaluated the Human Gene Mutation Database (HGMD) regarding SMARCB1 variants and validated associated phenotype records to assess phenotype-genotype relationships. Results: A novel deletion variant c.885_896delGAAGCTGTGCTC p.(295_299del） in SMARCB1 was identified in the affected family members and cosegregated with phenotypes in the pedigree. About 51.1% of variants in SMARCB1 located in Snf5 subunit, 80.7% of variants were loss-of-function (LOF) variants, and more variants located in the Snf5 subunit of SMARCB1 in Rhabdoid tumour (67.8%) than that in schwannomatosis (25.7%).Conclusions: Our study expands the variant spectrum of SMARCB1 and the genetic background of schwannomatosis, confirms the clinical indications for genetic screening of the SMARCB1 gene, and has implications for genetic counseling in this disease.

Atypical Teratoid Rhabdoid Tumours Are Susceptible to Panobinostat-Mediated Differentiation Therapy

Atypical teratoid rhabdoid tumour (ATRT) is a rare but highly aggressive undifferentiated solid tumour arising in the central nervous system and predominantly affecting infants and young children. ATRT is exclusively characterized by the inactivation of SMARCB1, a member of the SWI/SNF chromatin remodelling complex that is essential for the regulation of large sets of genes required for normal development and differentiation. Histone deacetylase inhibitors (HDACi) are a promising anticancer therapy and are able to mimic the normal acetylation functions of SMARCB1 in SMARCB1-deficient cells and drive multilineage differentiation in extracranial rhabdoid tumours. However, the potential efficacy of HDACi in ATRT is unknown. Here, we show that human ATRT cells are highly responsive to the HDACi panobinostat and that sustained treatment leads to growth arrest, increased cell senescence, decreased clonogenicity and induction of a neurogenesis gene-expression profile. Furthermore, in an orthotopic ATRT xenograft model, continuous panobinostat treatment inhibits tumour growth, increases survival and drives neuronal differentiation as shown by the expression of the neuronal marker, TUJ1. Collectively, this preclinical study supports the therapeutic potential of panobinostat-mediated differentiation therapy for ATRT.

Extrarenal rhabdoid tumour of the vulva: diagnostic and management challenges

Extrarenal rhabdoid tumour (ERT) of vulva is a rare gynaecological neoplasm with an aggressive course and no clear management guidelines. We present the case of a 25-year-old woman with a rapidly increasing mass in right vulva suggestive of sarcoma. Wide local excision was done. Histopathology examination revealed ERT of vulva. Six weeks later she manifested lung metastases. Despite adjuvant chemotherapy, the disease progressed and she died 8 months later. We review the literature and briefly discuss the epidemiology, treatment approaches, prognostic factors and expected outcomes of this rare disease.

Multimodal management of locally advanced rhabdoid tumour of the kidney in an adult

Malignant rhabdoid tumours of the kidney (MRTK) are rare paediatric tumours known for their aggressive nature and early metastasis. However, MRTK in adults are even more rare with only a few cases reported in the literature. Herein, we report a case of 65-year-old woman with rapidly progressive left renal mass requiring en-bloc radical nephrectomy, splenectomy and distal pancreatectomy. Histopathology revealed a malignant rhabdoid tumour with characteristic histological and immunohistochemical findings with negative margins. To the best of our knowledge, this is the first reported case of aggressive surgical management of locally advanced MRTK. Despite surgery with curative intent, the patient developed early recurrence and started on tyrosine kinase inhibitor. Unfortunately, the patient expired after 8 months of surgery due to disease progression.

Successful Multimodality Management of Atypical Teratoid/Rhabdoid Tumour of the Lower Dorsal Spine with Spinal Drop Metastasis: Illustrated Review

<b><i>Introduction:</i></b> Spinal atypical teratoid/rhabdoid tumour (AT/RT) is exquisitely rare and constitutes 2% of all AT/RTs. <b><i>Case Presentation:</i></b> A 6-year-old boy presented with low backache for the last 5 months. MRI of the spine showed a 1.5 × 1.5 × 4.7 cm intradural extramedullary mass extending from D10 to D12, causing compression of the conus medullaris. With a preoperative diagnosis of ependymoma, a gross total resection (GTR) of tumour was performed. Post-operative histopathology showed AT/RT. The tumour cells were immunopositive for cytokeratin, epithelial membrane antigen, smooth muscle actin, and p53 and immunonegative for MIC2, desmin, glial fibrillary acidic protein, and INI1. Post-operative neuraxis MRI revealed post-operative changes (D10–D12) with a 9 mm enhancing lesion at L5-S1 junction suggesting drop metastasis. There was no lesion in brain. Cerebrospinal fluid cytology did not show any malignant cell. The metastatic work-up was normal. He received 3 cycles of chemotherapy with ICE regimen (ifosfamide, carboplatin, and etoposide). Subsequently, he received craniospinal irradiation (CSI)-36 Gy/20 fractions/4 weeks followed by focal boost to primary tumour bed and spinal drop metastasis-14.4 Gy/8 fractions/1.5 weeks. Thereafter, he received 3 more cycles of ICE regimen. End-of-treatment MRI spine showed post-op changes (D10–D12) and 38.9% reduction of the L5-S1 lesion suggesting partial response. Six monthly spinal MRI showed serial reduction of the metastatic lesion leading to complete response (CR) 1 year after completion of treatment. On last follow-up (30 months from the initial diagnosis), he was neurologically intact and in CR. <b><i>Conclusion:</i></b> Multimodality management comprising GTR of tumour, CSI followed by focal boost, and multiagent chemotherapy (ICE) can lead to successful outcome in patients with this rare and aggressive spinal tumour.

Somatic mutations and single-cell transcriptomes reveal the root of malignant rhabdoid tumours

Malignant rhabdoid tumour (MRT) is an often lethal childhood cancer that, like many paediatric tumours, is thought to arise from aberrant fetal development. The embryonic root and differentiation pathways underpinning MRT are not firmly established. Here, we study the origin of MRT by combining phylogenetic analyses and single-cell mRNA studies in patient-derived organoids. Comparison of somatic mutations shared between cancer and surrounding normal tissues places MRT in a lineage with neural crest-derived Schwann cells. Single-cell mRNA readouts of MRT differentiation, which we examine by reverting the genetic driver mutation underpinning MRT, SMARCB1 loss, suggest that cells are blocked en route to differentiating into mesenchyme. Quantitative transcriptional predictions indicate that combined HDAC and mTOR inhibition mimic MRT differentiation, which we confirm experimentally. Our study defines the developmental block of MRT and reveals potential differentiation therapies.

ATRT-31. SUCCESSFUL MULTIMODALITY MANAGEMENT OF ATRT OF THE LOWER DORSAL SPINE WITH SPINAL DROP METASTASIS

A 6 year old boy presented with low backache for the last 5 months. MRI of the spine showed a 1.5x1.5x4.7cm intradural mass extending from D10-D12, causing compression of the conus medullaris. With a preoperative diagnosis of intradural ependymoma, a gross total resection (GTR) of tumour was performed. Post-operative histopathology showed a markedly cellular, malignant tumour with frequent mitotic figures. Cells were round to polygonal with vesicular nuclei, prominent nucleoli and were immunopositive for CK,EMA,p53 and immunonegative for MIC2,desmin,SMA,GFAP,INI-1(MIB1 labeling index-35–40%). The overall impression was spinal atypical teratoid rhabdoid tumour(ATRT). Post-operative neuraxis MRI revealed post-operative changes(D10-D12) with a 9 mm enhancing lesion at L5-S1 junction suggesting drop metastasis. There was no brain lesion. CSF cytology did not show any malignant cell. The metastatic work-up was normal. He was started on chemotherapy with ICE regimen (Ifosfamide-2g/m2IVD1–D3,Carboplatin-500mg/m2IVD3,Etoposide-100mg/m2IVD1–D3q3weeks). Subsequently he received craniospinal irradiation (CSI)-36Gray/20fractions/4weeks→ focal boost to primary tumour bed and spinal drop metastasis-14.4Gray/8fractions/1.5 weeks. Thereafter he received 3 more cycles of ICE regimen. End-of-treatment MRI spine showed post-op changes(D10-D12) and 38.9%reduction of the L5-S1 lesion suggesting partial response. Six monthly spinal MRI showed serial reduction of the metastatic lesion leading to complete response (CR) 1 year after completion of treatment. On last follow-up (30 months from initial diagnosis), he was neurologically intact and in CR. Multimodality management comprising GTR,CSI followed by focal boost and multiagent chemotherapy(ICE) can lead to successful outcome in patients with this rare and aggressive spinal tumour.