SMARCB1/INI1-deficient peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), is a rare entity with limited reported cases. We present two additional cases in young women presenting with aggressive, treatment-refractory PTCL-NOS, and further characterizing their clinicopathologic and molecular features. Both cases demonstrated a monotonous proliferation of medium-sized atypical αβ T cells with clear cytoplasm, dual CD4/CD8 negativity, aberrant CD117 expression, cytotoxic and PTCL-TBX21 phenotype, and loss of SMARCB1/INI1 expression. Molecular analyses revealed copy-neutral loss of heterozygosity and two-copy/homozygous deletion involving the SMARCB1 gene, supporting a heterogeneous genetic basis for SMARCB1 inactivation. Clinically, both patients exhibited rapidly progressive disease with poor response to multi-modality treatment, highlighting the aggressive nature of this tumor. Our findings are consistent with prior reports, suggesting that SMARCB1/INI1-deficient PTCL-NOS preferentially affects children and young adults and demonstrates distinctive morphologic and molecular features that may facilitate recognition. Emerging evidence also indicates that SMARCB1/INI1 loss may confer sensitivity to histone deacetylase inhibitors (HDACi), supporting their potential therapeutic role in this tumor. Given the dismal outcomes associated with this entity, assessment of SMARCB1/INI1 expression should be considered in younger patients with PTCL-NOS displaying these characteristic features. Continued accumulation of cases with integrated molecular profiling, along with prospective evaluation of HDACi-based therapies, will be essential to better define disease biology and establish evidence-based treatment strategies for this aggressive lymphoma.

Comprehensive genomic profiling of paediatric tumours has shown promise in guiding precision oncology approaches. However, the clinical utility of targeted sequencing panels in routine practice remains unclear. The results of such testing have not been reported in Southeast Asia. We implemented the AmpliSeq Childhood Cancer Panel for prospective molecular profiling of 130 paediatric patients with various solid tumours. The panel detects single nucleotide variants, gene fusions and amplifications. Clinical impact was assessed through a molecular tumour board. Clinically significant variants were identified in 52.8% of patients, with diagnostic, therapeutic and prognostic relevance in 52%, 30% and 18% of cases, respectively. Central nervous system (CNS) tumours showed the highest yield (70%). Seven patients (5.7%) received targeted therapy based on the sequencing results. The panel was particularly useful for CNS tumours, fusion-driven sarcomas, neuroblastomas and DICER1-associated tumours. Limitations included the need for additional testing in some cases and the inability to distinguish germline from somatic variants. In conclusion, targeted panel sequencing is feasible and clinically useful for paediatric tumour profiling, with the highest yield in CNS tumours. While the proportion of patients receiving targeted therapy was relatively low, the genetic information obtained is valuable for biomarker-directed trials and advancing precision oncology in paediatric cancers.

Pleuropulmonary blastoma and hepatoblastoma are 2 well-recognized embryonal tumors of the thorax and liver respectively occurring in children. The simultaneous presentation of 2 or more pediatric embryonal tumors in the same patient is extremely rare. Specifically, cases of concomitant pleuropulmonary blastoma and hepatoblastoma in the same patient are extremely rare with only a single clinical case report published thus far. We report a case of a 25-month-old boy presenting with concomitant pleuropulmonary blastoma and hepatoblastoma, and describe the clinical, imaging, and histopathological findings. We additionally describe the underlying DICER1 alterations in both tumors. This is the first case described in Vietnam and only the second such case reported globally.

Abstract Introduction Diffuse Midline Glioma (DMG) of the pons, formerly known as Diffuse Intrinsic Pontine Glioma (DIPG), has a dismal prognosis and limited treatment options. Traditionally, these tumours have been irradiated based on radiological diagnosis alone. However, newer surgical techniques have enabled biopsies to be performed safely, allowing for pathological confirmation and molecular profiling, which may yield potentially targetable mutations for treatment. This study describes our institution’s experience with this newer strategy. Methods We retrospectively reviewed the records of 18 consecutive patients with DMG of pons from 2020 to 2025 in our tertiary institution, who underwent stereotactic biopsies and molecular profiling. Outcomes and toxicity of patients with targetable mutations who were treated with targeted therapies were compared to those who did not receive targeted therapies. Results Age of diagnosis ranged from 4.5 to 13 years, with 9 out of 18 patients female. 8 patients (44%) had targetable mutations (MET / PIK3CA / PIK3R1 / PDGFRA / KIT / RET alterations). Mean age of diagnosis was significantly lower in patients without targetable alterations (5.8 years versus 9.3, p = 0.01). Targeted therapy was administered in 4 out of 18 patients (22.2%). Out of these 4 patients, mean survival duration was 11.2 months, compared to 9.4 months for patients who did not receive targeted therapy (p = 0.30). In terms of targeted therapy toxicity, 1 patient experienced CTCAE grade 3 transaminitis and abdominal pain. Conclusion Stereotactic biopsies and molecular profiling detected targetable mutations in a substantial proportion of patients. Although promising, future studies on a larger scale are needed to investigate the survival benefit of routine biopsy in DMG. If surgical expertise is available, we recommend this approach after a nuanced discussion with the caregivers.

Glycogen storage disease (GSD) type IV is an autosomal recessive disorder due to a deficiency of glycogen branching enzyme (GBE), leading to accumulation of polyglucosan inclusion in tissues. The congenital neuromuscular variant is a severe subtype presenting as hypotonia, respiratory distress and dilated cardiomyopathy, resulting in early death. Cardiac manifestations as a primary presentation are uncommon in this subtype.We report the case of a male preterm infant who presented with heart failure attributed initially solely to hypertrophic cardiomyopathy. Genetic testing identified compound heterozygous GBE1 variants. Enzymatic testing demonstrated reduced GBE activity, and histopathological findings showed myocardial Periodic acid-Schiff-positive and diastase-resistant inclusions, confirming the diagnosis. Neurological symptoms developed later, increasing the suspicion of a metabolic disorder.This case represents a unique presentation of this variant of GSD IV, primarily manifesting with hypertrophic cardiomyopathy. It underscores the importance of considering metabolic disorders in infants with cardiomyopathy, even when neurological symptoms are initially absent.

Metastasizing leiomyoma is a rare condition characterized by the development of benign-appearing smooth muscle neoplasms at extrauterine sites in patients with a history of uterine leiomyoma. These lesions occur most commonly in the lung, with the abdominopelvic and mediastinal lymph nodes being other reported sites. Malignant transformation of metastasizing leiomyoma is extremely rare, with only a few cases described in the literature. We describe a case of metastasizing leiomyoma with malignant transformation in a middle-aged Asian lady, who developed pulmonary metastatic foci 12 years after surgical excision of the original uterine leiomyomata. Molecular analysis showed a common RAB2A-PLAG1 fusion gene and identical single nucleotide variants in both tumor foci, with significantly more pronounced segmental chromosomal copy number variations in one focus showing high-grade features. A comprehensive review of the literature lends support to the hypothesis that the original leiomyomata and the metastatic foci are clonally related, with high-grade features being associated with more complex genomic signatures.

BACKGROUND:Identifying the genetic signatures in bone and soft tissue tumors enhances our understanding of tumor biology and aids in the subclassification of tumors for personalized treatment. Histone H3.3 alterations play a pivotal role in H3F3A/B K36M-mutant chondroblastomas and H3F3A G34W/L-mutant giant cell tumors of the bone. METHODS AND RESULTS:In this report, we describe 2 cases of a distinct epithelioid neoplasm with H3F3A K36M mutation but lacking features of chondroblastoma, which extends the spectrum of H3.3-mutant mesenchymal tumors. The 2 cases occurred in pediatric patients, had an aggressive clinical presentation, distinct epithelioid histomorphology with diffuse cytokeratin and TFE3 expression, and identical H3F3A K36M mutations. No gene fusions were identified. Methylation analysis using the DKFZ sarcoma classifier v12.3 pipeline did not classify these tumors with known entities, suggesting the existence of non-chondrogenic mesenchymal tumors within the H3.3-mutant tumor spectrum. CONCLUSIONS:The distinctive histological and molecular features of these 2 cases expand the spectrum of H3.3-mutant tumors and call for further investigation of the biological underpinnings of this group of tumors.

Introduction: Risk stratification for neuroblastoma includes parameters such as segmental chromosome aberrations (SCA) like 1p loss, 11q loss, MYCN amplification, and DNA content. Fluorescence in situ hybridisation (FISH) and flow cytometry are the traditional methods used to iterate the above. The current study aims to evaluate the ThermoFisher OncoScan chromosomal microarray platform as a one-stop platform to iterate the above parameters in formalin-fixed paraffin-embedded (FFPE) neuroblastoma samples.

Abstract BACKGROUND: In the current World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS) (5th edition), the introduction of a molecular layer to the integrated diagnosis not only helps to characterize and prognosticate paediatric CNS tumors but the molecular alteration may predict a potential therapeutic option with a targeted agent. Furthermore, certain gene alterations may be a presage of germline alterations or cancer predisposition syndromes, portending significant implications to the index patients and their families. We report a 5-year-old boy diagnosed with non-metastatic left hemispheric H3-wildtype and IDH-wildtype diffuse paediatric-type high-grade glioma with MYCN-amplification, who was subsequently found to have Li-Fraumeni syndrome. He presented with a 3-day history of facial asymmetry, unsteady gait and right sided weakness. There was no family history of malignancy. Initial MRI revealed a restricting and enhancing solid cystic lesion (5.9 x 4.3 x 5.8cm) in the left frontal-temporal-parietal region. Tumor debulking was performed. Histopathological examination by the local pathologist revealed features of high-grade glioma. Second pathology review with next generation sequencing confirmed H3-wildtype and IDH-wildtype diffuse paediatric-type high-grade glioma with MYCN-amplification and TP53 p.Y103* mutation. He was started on focal radiotherapy and oral temozolomide but succumbed to local and metastatic progressive disease. After genetic counselling, his DNA extracted from blood was sent for targeted exome sequencing and germline mutation of TP53 was demonstrated. Cascade screening of the family members were negative of TP53 mutation. Guerrini-Rousseau et al reported that 57% (n=7) of H3-wildtype and IDH-wildtype diffuse paediatric-type high-grade glioma with MYCN-amplification harboured germline TP53 pathogenic variants. This case further highlights the importance of screening of Li-Fraumeni syndrome in patient with H3-wildtype and IDH-wildtype diffuse paediatric-type high-grade glioma with MYCN-amplification even in the absence of a family history.

Introduction: Pilomatrixoma and superficial angiomyxoma are distinct histological and molecular entities originating from their respective hair follicle matrical and myo-/fibroblastic cells. Despite only five documented cases in the literature describing their coexistence, this report introduces the sixth case, emphasising the unusual combination.1–3

The differential diagnosis for neonatal primary lung masses includes developmental anomalies and congenital lung tumors. Fetal lung interstitial tumor (FLIT) is a rare benign mesenchymal lesion which presents either antenatally or within the first 3 months of age. FLIT is a circumscribed solid-cystic mass which histologically resembles the fetal lung during the canalicular stage at 20-24 weeks of gestation. It is composed of immature mesenchymal cells expanding the interstitium and irregular airspace-like structures. Of all published cases, only 1 identified an α2-macroglobulin (A2M)::anaplastic lymphoma kinase (ALK) fusion and all cases underwent surgical resection in the neonatal or infancy period. We present the second case of FLIT with an A2M::ALK fusion diagnosed postnatally in a neonate which partially regressed spontaneously during conservative management with interim resection at 39 months of age, and provide a review of the literature.

Introduction:. Genetic mutations have been identified in the pathogenesis of vascular anomalies. Due to overlaps in genetic variants causing vascular anomalies and cancer, we used a next-generation sequencing panel for genomic profiling of childhood cancers to detect somatic mutations in children with vascular anomalies. We aim to review the utility of an oncology panel for the molecular diagnosis of vascular anomalies. Methods:. Nine patients with histologically confirmed vascular anomalies were included. DNA was extracted from formalin-fixed paraffin-embedded tissue specimens obtained from affected tissue following diagnostic punch biopsies of the skin and core biopsies of the vascular malformation or tumor during sclerotherapy or surgical excision. Molecular analysis of the tissue samples was performed using AmpliSeq for Childhood Cancer DNA Assay Panel. Results:. Two patients had antenatally detected vascular anomalies. The median age at diagnosis for the remaining patients was 7.0 years (IQR, 0.6–10.0 years). Seven were diagnosed with vascular malformations, while 2 had vascular tumors. Pathological somatic mutations were identified in 4 patients, leading to a diagnostic yield of 44.4%. Two different PIK3CA mutations were identified in 3 cases: 1 in a case of macrocystic lymphatic malformation, the other in a case of Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevus, Spinal/Skeletal anomalies syndrome and Klippel–Trenaunay syndrome. BRAF mutation was identified in a patient with a veno-lymphatic malformation. Conclusion:. An oncology next-generation sequencing panel can be used for genetic profiling of vascular anomalies. However, a more customized and sensitive panel may be of better diagnostic yield, as detection of somatic mutations in vascular anomalies is challenging due to tissue mosaicism, low-abundant genetic variants, and specimen limitations.

Molecular characteristics of pediatric high-grade gliomas are largely based on cohorts derived from North America and Europe. In this study, we compare the molecular findings of a Southeast Asian cohort of pediatric high-grade gliomas with published data. We collated clinical, histopathological, and molecular data from pediatric high-grade gliomas diagnosed in our laboratory over the past 5 years. Molecular testing methods used included Illumina’s Childhood Cancer Panel (26 cases), FoundationOne’s CDx panel (2 cases), and Archer FUSIONPlex Pan Solid Tumour v2 panel (2 cases). 7 cases had no molecular data. 11 cases underwent additional DNA methylation analysis using Illumina’s Infinium MethylationEPIC v1.0 kit. 37 cases of pediatric high-grade gliomas from 34 patients were identified. Patient age ranged from 2 to 26 years (median 14 years). The male-female ratio was 1.1:1. Diffuse midline gliomas, H3K27-altered (DMG, H3K27-altered) constituted 51% of the cases (19/37), followed by diffuse pediatric-type high-grade gliomas, H3-wildtype and IDH-wildtype (32%; 12/37) and diffuse hemispheric gliomas H3G34-mutant (16%; 6/37). The commonest genes with pathogenic single nucleotide variants were TP53 (79%;22/28), followed by H3F3A (54%;15/28). The commonest amplified genes were MYCN and EGFR (both 4/28; 14%). Three gene fusions were detected, none of which arose from infants – 2 were found in diffuse pediatric-type high-grade gliomas, H3-wildtype and IDH-wildtype (CSTF3::ALK and PRCC::NTRK1 fusions), and one occurred in a DMG, H3K27-altered (ERC1::RET fusion). The most common methylation groups identified were DMG, H3K27-altered and diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype, MYCN subtype (both 3/11; 27%). Although small, our Southeast Asian cohort comprised a higher percentage of TP53-mutant high-grade gliomas amongst all pediatric high-grade gliomas as a group. The commonest amplified genes were MYCN and EGFR. We detected gene fusions in non-infant gliomas. These findings suggest geographical differences in the biology of pediatric high-grade gliomas.

BackgroundPleomorphic xanthoastrocytoma (PXA) is a rare brain tumor that accounts for <1% of all gliomas. An in-depth understanding of PXA's molecular makeup remains a work in progress due to its limited numbers globally. Separately, spontaneous intracranial hemorrhage (pICH) is an uncommon but potentially devastating emergency in young children, often caused by vascular malformations or underlying hematological conditions. We describe an interesting case of a toddler who presented with pICH, later found to have a PXA as the underlying cause of hemorrhage. Further molecular interrogation of the tumor revealed a neurotrophic tyrosine receptor kinase (NTRK) gene fusion and CDKN2A deletion more commonly seen in infantile high-grade gliomas. The unusual clinicopathological features of this case are discussed in corroboration with published literature.Case presentationA previously well 2-year-old male presented with acute drowsiness and symptoms of increased intracranial pressure secondary to a large right frontoparietal intracerebral hematoma. He underwent an emergency craniotomy and partial evacuation of the hematoma for lifesaving measures. Follow-up neuroimaging reported a likely right intra-axial tumor with hemorrhagic components. Histology confirmed the tumor to be a PXA (WHO 2). Additional molecular investigations showed it was negative for BRAFV600E mutation but was positive for CDKN2A homozygous deletion and a unique neurotrophic tyrosine receptor kinase (NTRK) gene fusion. The patient subsequently underwent second-stage surgery to proceed with maximal safe resection of the remnant tumor, followed by the commencement of adjuvant chemotherapy.ConclusionTo date, there are very few pediatric cases of PXA that present with spontaneous pICH and whose tumors have undergone thorough molecular testing. Our patient's journey highlights the role of a dedicated multidisciplinary neuro-oncology team to guide optimal treatment.

Introduction: Spinal ependymoma is a CNS WHO grade 2/3 circumscribed glioma characterised by pseudo- or ependymal rosettes and round cells within a fibrillary matrix. We present an extramedullary tanycytic variant, composed of spindle cells and bipolar processes, necessitating differentiation from schwannoma.1

Tumor budding (TB) has been associated with poor survival in a variety of cancers including intrahepatic cholangiocarcinoma (iCCA). As tumor histomorphological features are significantly altered after neoadjuvant therapy (NAT), our study aims to assess the prognostic significance of TB in iCCA patients before and after NAT, by the modified International Tumor Budding Consensus Conference (ITBCC) criteria. 147 NAT-treated iCCA cases were included in this study. In biopsy specimens obtained before NAT, the TB-positive subgroup had lower overall survival (OS) in univariate analysis (P = 0.010). In resection specimens obtained after NAT, the TB-positive subgroup had reduced OS (P = 0.002) and recurrence-free survival (RFS) (P = 0.013) in univariate analysis. In multivariate analysis including TNM stage, lymphovascular invasion and perineural invasion, TB-positive in post-NAT resection was also found as an independent prognostic factor for both OS and RFS (OS, HR, 3.005; 95

EWSR1::CREM gene fusions are increasingly being recognized in a diverse number of soft tissue tumors, including well-defined entities such as angiomatoid fibrous histiocytoma or clear cell sarcoma, and other unclassifiable tumors. As a group, EWSR1::CREM fused tumors often demonstrate primitive spindle or epithelioid cells, myxoid stroma, and a broad immunophenotype. Herein we present an unusual case of a child diagnosed with an intranasal malignant myxoid tumor harboring an EWSR1::CREM gene fusion. To the best of our knowledge, this is the first case of intranasal myxoid tumor with this particular fusion. Diagnosis and management of the case is discussed.

Osteosarcoma is the commonest malignant bone tumor of children and adolescents and is characterized by a high risk of recurrence despite multimodal therapy, especially in metastatic disease. This suggests the presence of clinically undetected cancer cells that persist, leading to cancer recurrence. We sought to evaluate the utility of peripheral blood exosomes as a more sensitive yet minimally invasive blood test that could aid in evaluating treatment response and surveillance for potential disease recurrence. We extracted exosomes from the blood of pediatric osteosarcoma patients at diagnosis (n=7) and after neoadjuvant chemotherapy (n=5 subset), as well as from age-matched cancer-free controls (n=3). We also obtained matched tumor biopsy samples (n=7) from the cases. Exosome isolation was verified by CD9 immunoblot and characterized on electron microscopy. Profiles of 780 cancer-related transcripts were analysed in mRNA from exosomes of osteosarcoma patients at diagnosis and control patients, matched post-chemotherapy samples, and matched primary tumor samples. Peripheral blood exosomes of osteosarcoma patients at diagnosis were significantly smaller than those of controls and overexpressed extracellular matrix protein gene THBS1 and B cell markers MS4A1 and TCL1A. Immunohistochemical staining of corresponding tumor samples verified the expression of THBS1 on tumor cells and osteoid matrix, and its persistence in a treatment-refractory patient, as well as the B cell origin of the latter. These hold potential as liquid biopsy biomarkers of disease burden and host immune response in osteosarcoma. Our findings suggest that exosomes may provide novel and clinically-important insights into the pathophysiology of cancers such as osteosarcoma.