The 2021 WHO Classification of Tumors of the Central Nervous System incorporates integrated molecular diagnostics into the classification of diffuse gliomas; however, access to comprehensive molecular testing remains limited in some settings. This study retrospectively evaluated grade-associated patterns of PCR-based loss of heterozygosity (LOH) and microsatellite instability (MSI) in a historical, morphology-defined cohort of diffuse astrocytic gliomas from the pre-IDH era. LOH and MSI analyses were performed using 14 LOH and 5 MSI microsatellite markers in 40 archival diffuse astrocytic gliomas, including 12 diffuse astrocytomas, NOS (WHO grade 2), 15 anaplastic astrocytomas, NOS (WHO grade 3), and 13 glioblastomas, NOS (WHO grade 4), collected between 1997 and 2002 prior to the availability of IDH immunohistochemistry. LOH-high (LOH-H) was defined as LOH involving three or more of the seven microsatellite markers examined at each locus, and MSI-high (MSI-H) as instability at two or more of the five markers. LOH was detected in 77.5% of tumors. LOH-H at 10q23 (PTEN) correlated significantly with WHO grade (8.3%, 40.0%, and 61.5% in grades 2, 3, and 4, respectively; p = 0.022) and distinguished high-grade from low-grade tumors (p = 0.015). LOH-H at either 10q23 or 17p13 (TP53) was observed in 67.9% of high-grade tumors compared with 25.0% of grade 2 tumors (p = 0.013). MSI and MSI-H rates were 17.5% and 10.0%, respectively. Three of the four MSI-H tumors lacked concurrent LOH-H; given the small number of MSI-H tumors, this observation is preliminary and should not be interpreted as evidence of distinct genomic instability pathways. LOH-H at 10q23, alone or in combination with 17p13, was associated with higher morphology-based WHO grade, whereas 17p13 LOH alone showed no significant grade association. Because IDH mutation status could not be determined, these findings should not be extrapolated to contemporary WHO-defined astrocytic gliomas; whether these findings apply to molecularly defined gliomas would require validation.

Large cell/anaplastic medulloblastoma is a high-risk variant whose histopathological diagnosis can be challenging. We analyzed 12 pediatric cases enriched for LC/A morphology, with centralized review available for 11. In this deliberately selected, diagnostically challenging series, institutional and central LC/A versus non-LC/A assessments were discordant in 36% (4 of 11), illustrating the difficulty of applying the LC/A designation rather than a general estimate of inter-observer reproducibility. DNA methylation profiling was performed using four classifiers: Heidelberg CNS Tumor Methylation Classifier, Methylscape Analysis, EpiDiP, and the MAGIBU classifier, which applies a UMAP-based distance approach. Tumor classification was largely concordant across platforms, identifying two WNT-activated medulloblastomas, eight non-WNT/non-SHH medulloblastomas, and one tumor reclassified as an embryonal tumor with multilayered rosettes. One misclassification occurred with EpiDiP, where an SHH-activated medulloblastoma aligned with the normal cerebellar cortex reference profile. Copy number analysis revealed MYC amplification in two non-WNT/non-SHH tumors, chromosome 6 loss in both WNT-activated cases, and isochromosome 17q in one MYC-amplified non-WNT/non-SHH tumor. Adjunctive molecular data for a subset of cases were obtained from PedcBioPortal. The reclassified tumor lacked canonical molecular alterations but harbored additional CTNNB1 and TP53 variants whose contribution to its pathogenesis remains uncertain. One WNT-activated medulloblastoma also carried a CTNNB1 variant. The MAGIBU classifier correctly identified the ETMR case, classified all remaining tumors as medulloblastomas, and showed concordant subgroup assignment with the Heidelberg CNS Tumor Methylation Classifier and Methylscape Analysis, including the SHH-activated case misclassified by EpiDiP. On external validation across four independent medulloblastoma cohorts (n = 1063), MAGIBU achieved 98.5% family-level recall and 96.4% subclass-level recall. In conclusion, our findings indicate that, in these diagnostically challenging, LC/A-enriched cases, morphology-based diagnostic assessment can be inconsistent. DNA methylation profiling serves to refine tumor reclassification and ensure accurate risk stratification. Interpreting each tumor across complementary classifiers provides a triangulation that enhances diagnostic robustness.

We report a pediatric spinal cord tumor with prominent granular cell-like features that posed a significant diagnostic challenge. Intraoperative findings and the initial histopathological evaluation revealed marked granular cell proliferation, leading to a provisional diagnosis of granular cell astrocytoma. Notably, the classical histological features of pilocytic astrocytoma (PA) were not evident. However, molecular profiling identified a KIAA1549::BRAF fusion, prompting diagnostic reconsideration. Re-evaluation of the histopathological findings in conjunction with the molecular results supported an integrated diagnosis consistent with PA. This case highlights the marked morphological variability of PA and demonstrates that pediatric spinal circumscribed astrocytic gliomas with granular cell-like morphology may closely mimic granular cell tumors or granular cell astrocytomas. Our findings underscore the important complementary role of molecular genetic analyses, particularly the assessment of BRAF alterations, in supporting diagnosis and guiding appropriate therapeutic decision-making in diagnostically challenging pediatric spinal cord tumors.

Non-meningothelial mesenchymal tumors (NMMTs) of the central nervous system (CNS) are rare and diagnostically challenging neoplasms. Although World Health Organization (WHO) updates have incorporated molecularly defined entities, a subset of tumors remains difficult to classify because of overlapping morphology, nonspecific immunophenotype, and absence of canonical gene fusions. We report a supratentorial NMMT tumor in a 40-year-old man presenting with progressive left-sided paresthesia. Neuroimaging demonstrated a parasagittal mass. Following gross total resection, histological examination revealed a predominantly myxoid proliferation with focal cortical and dural infiltration. Immunohistochemistry was noncontributory, showing focal CD99 expression. Fluorescence in situ hybridization excluded EWSR1, FUS, and CIC rearrangements. Extended RNA-based next-generation sequencing identified a putative low-confidence SHISA5::BRAF fusion. This case illustrates the persistent diagnostic complexity of NMMTs despite integrated histological and molecular evaluation. The absence of canonical alterations not only complicates classification but also contributes to uncertainty regarding prognosis and optimal therapeutic strategies. Emerging evidence suggests that a subset of these tumors may be driven by alternative oncogenic mechanisms, including MAPK pathway activation beyond currently recognized fusion-defined entities. In this context, the identification of a putative SHISA5::BRAF fusion expands the molecular spectrum of these neoplasms, although its functional relevance remains uncertain. These challenges underscore the need for cautious long-term follow-up and individualized multidisciplinary management.

A case of primary sarcoma that arose in the right temporal lobe of a 59-year-old man is reported. The patient had a history of resection of a "pituitary tumor" and postoperative radiotherapy about 40 years earlier. The cerebral tumor consisted of loose and diffuse proliferation of large pleomorphic cells in a matrix showing a markedly myxoid change and containing a variable amount of delicate collagen fibers. Some tumor cells had a large intracytoplasmic vacuole containing acid mucopolysaccharide, thus featuring "pseudolipoblasts." Differentiation along other specific mesenchymal lineages was not found. Many tumor cells contained densely eosinophilic hyaline globules in the cytoplasm. Tumor cells showed a loss of the nuclear expression of H3K27me3. Although cerebral sarcomas showing similar histopathological features have not been previously reported, a markedly myxoid change of the stroma admixed with delicate collagen fibers and "pseudolipoblasts" suggests a close pathological kinship to myxofibrosarcoma. Another notable finding was the appearance of many hyaline globules, which has been considered a characteristic finding of primary intracranial sarcoma, DICER1-mutant. In the cytogenetic study of the present case, however, no DICER1 gene mutations were demonstrated.

Caveolin-1 (Cav-1) is a component of the vesicle-like structure of the plasma membrane called caveolae. Cav-1 is involved in the transport of substances from the plasma membrane to the intracellular space of various cells. It has been reported that it is involved in the growth mechanisms, angiogenesis, and immune evasion of various malignant tumors. In the present study, the relationships between Cav-1 expression in primary central nervous system lymphomas (PCNSLs) and clinicopathological characteristics were investigated to clarify the role of Cav-1 in the progression of PCNSLs and patient prognosis. The expression of Cav-1 was assessed in 39 PCNSLs (CNS diffuse large B-cell lymphomas) using immunostaining, and its prognostic significance was evaluated. Cav-1 expression by PCNSLs was evaluated using the histoscore (H-score). The H-score for Cav-1 in PCNSLs ranged from 0 to 90 (median 20); there were 12 cases showing no score (H-score 0), 11 cases with a low score (0 < H-score < 20), and 16 cases with a high score (H-score ≥ 20). Survival was significantly lower in patients with high H-scores than in those with no score and low H-scores (p < 0.01), and in patients with high numbers of Cav-1-positive vessels than in those with low numbers of Cav-1-positive vessels (p < 0.05). Cav-1 positivity in tumor cells was correlated with the Ki-67 labeling index and the number of Cav-1-positive vessels. These results suggest that Cav-1 may be involved in the proliferation and angiogenesis of PCNSL cells. The present study also demonstrated that overexpression of Cav-1 in PCNSLs is associated with tumor progression and a poor patient prognosis.

Variants in the valosin-containing protein (VCP) gene cause multisystem proteinopathy, typically characterized by TDP-43 pathology. However, there are few reports describing tau pathology in VCP variant carriers. Here, we report a Japanese woman carrying a heterozygous VCP R191Q variant, who developed progressive muscle weakness, frontotemporal dementia, and parkinsonism beginning in her mid-forties and died at the age of 61. Neuropathological examination demonstrated FTLD-TDP type D pathology involving the frontal and temporal cortices, limbic structures, brainstem, spinal cord, and skeletal muscle. In addition, a distinct pattern of tau pathology was identified, predominantly in astrocytes and extending from the lower brainstem throughout the spinal cord. Tau aggregates were distributed in perivascular, subpial, and central gray matter, with a rostrocaudal distribution. Immunohistochemistry and confocal microscopy demonstrated colocalization of 3-repeat (3R) and 4-repeat (4R) tau within astrocytes, with predominance of 3R tau. Western blot analysis confirmed these findings and showed a tau banding pattern similar to that in Alzheimer's disease. These features differ from those observed in disorders with astrocytic tau pathology, such as cervical spondylotic myelopathy, chronic traumatic encephalopathy, and aging-related tau astrogliopathy, which are typically characterized by predominance of 4R tau and minimal or absent 3R tau involvement. They also differ from the neuronal tau pathology observed in the frontotemporal cortex in patients with the VCP D395G variant. This case expands the neuropathological spectrum of VCP-related diseases and suggests a possible association between VCP variants and pathological tau aggregation.

Psammoma bodies, which are characterized by concentric lamellated calcifications, are among the most recognizable histological features in field of neuropathology. However, reason why they form abundantly in some WHO grade I meningiomas (psammomatous subtype), not in others remains unanswered question that persisted for three decades. The predominant perspective attributes psammoma bodies to passive dystrophic calcification. However, ultrastructural evidence and a seminal hypothesis by Das (2009) suggest that they may instead represent an active biological process linked to tumor cell death and growth limitation. The molecular environment that sustains this process remains to be elucidated. The question of whether psammoma body-rich (PB-rich) and psammoma body-poor (PB-poor) WHO grade I meningiomas inhabit different molecular worlds remains a potential inquiry. Utilizing sole public expression dataset with explicit psammomatous annotation (GSE43290; 8 PB-rich vs. 24 PB-poor WHO grade I tumors), we conducted differential expression analysis via the GEO2R platform and a functional enrichment analysis via g:Profiler. Two remarkably divergent transcriptional programs were identified: PB-rich tumors were found to be predominantly influenced by immune and inflammatory pathways, chemokine signaling, leukocyte activation, NF-κB, and Toll-like receptor cascades. In contrast, PB-poor tumors were found to be characterized by extracellular matrix remodeling, elastic fiber assembly, and collagen organization. These findings are consistent with recent literature on inflammation-driven ectopic mineralization, immune-enriched meningioma subtypes, and DAMP-TLR-NF-κB positive-feedback loops. In complementary enrichment analyses, the PB-rich core genes were found to be associated with NK-cell and cytotoxic T-cell signatures, while PB-poor core genes exhibited a preferential enrichment in extracellular matrix, elastic fiber, and fibroblast-like stromal pathways. These findings suggest psammoma body formation may be morphological footprint of chronically inflamed tumor microenvironment. This exploratory study proposes mechanistic framework linking immune activation to calcification in meningiomas and identifies candidate pathways and genes for future immunohistochemical and functional validation.

Central nervous system germ cell tumors are uncommon and include germinomas, teratomas, and other nongerminomatous germ cell tumors. Mature teratomas are usually cured by complete resection, but rare patients later develop a histologically distinct malignant germ cell tumor. We report a man who presented at age 20 years with a cystic pineal lesion. Gross-total resection at age 21 years showed a mature teratoma with bronchogenic differentiation and no overt immature or malignant component on H&E. Serial postoperative MRI for 3 years showed no recurrence. Eleven years after surgery, he developed headache, gait disturbance, and confusion due to a 4.6-cm pineal mass with obstructive hydrocephalus. Serum alpha-fetoprotein was normal, whereas beta-human chorionic gonadotropin (β-hCG) was elevated. The resected tumor showed sheets of large round cells with clear cytoplasm and dense lymphocytes. Immunohistochemistry demonstrated strong nuclear OCT4 and SALL4 and membranous c-KIT, with focal β-hCG-positive syncytiotrophoblastic giant cells. No nongerminomatous germ cell tumor component was identified, supporting a diagnosis of germinoma with focal syncytiotrophoblastic giant cells. After this diagnosis, retrospective evaluation of the initial tumor showed multifocal, patchy OCT4 immunoreactivity in scattered cells along the ciliated respiratory-type epithelial lining. SALL4, c-KIT, and PLAP were focally positive in corresponding regions. These findings raised the possibility of an occult germ cell marker-positive population, although no discrete expansile germinoma component was identified. This case illustrates that metachronous germinoma can develop after a long disease-free interval following resection of a mature teratoma and highlights the value of retrospective pathologic evaluation and long-term surveillance.

Non-diffuse large B-cell lymphomas (non-DLBCL) of the central nervous system (CNS) are rare and diagnostically challenging. This study aims to characterize the clinical, radiological, and pathological features of non-DLBCL CNS lymphomas diagnosed at a tertiary care center over 13 years, highlighting diagnostic pitfalls. A retrospective review was conducted of non-DLBCL CNS lymphoma cases diagnosed at Sunnybrook Health Sciences Centre, Toronto, from 2010 to 2022. Clinical, demographic, and radiological data were extracted from medical records. Imaging was reviewed by a neuroradiologist, and histopathological slides and molecular data were re-evaluated by a pathology team. Additional tests were performed to update classifications per the 5th edition of the WHO Classification of Haematolymphoid Tumors. Seventeen cases were identified (11 males, 6 females; age 38-76), compared to 72 DLBCL cases during the same period. Nine cases were extra-axial and eight intra-axial. Eight were primary and nine secondary CNS lymphomas. B-cell lymphomas (n = 13) included extra-nodal marginal zone lymphoma (n = 6), follicular lymphoma, mantle cell lymphoma, CLL, intravascular large B-cell lymphoma (n = 2), EBV+ LBCL, and polymorphic PTLD. T-cell lymphomas (n = 4) included PTCL, NOS (n = 2), ALK-negative ALCL, and secondary mycosis fungoides. Imaging revealed four major patterns, and symptoms were largely due to mass effect. This case series emphasizes the considerable heterogeneity of non-DLBCL CNS lymphomas and the diagnostic challenges they present. It highlights key features that can aid recognition and improve diagnostic accuracy for these rare CNS entities. Trial Registration: SUN-5771.

Glioblastoma is the most common primary malignant central nervous system (CNS) tumor; however, its microenvironment, including tumor-associated microglia/macrophages (TAMs), is not fully understood. Although ionized calcium-binding adaptor molecule 1 (IBA-1) is expressed in various microglial phenotypes in the healthy human brain, CD163 is a marker of activated/phagocytic microglia. Tissues from 34 patients with glioblastoma were analyzed, and 17.6% of cases were CD163-dominant. CD163-dominant patients showed better overall survival than IBA-1-dominant patients (p = 0.019). CD163 dominance was identified as an independent prognostic factor for overall survival (hazard ratio [HR], 0.17; p = 0.011). Compared with the IBA-1-dominant group, CD163-dominant tumors showed more CD4-positive cell infiltration (p = 0.005), fewer ameboid TAMs (p = 0.021), and fewer non-microvascular proliferation (non-MVP) vessels (p = 0.012). No significant differences were found in patient characteristics, such as age, sex, tumor location, or extent of resection. The CD163-to-IBA-1 ratio of TAMs is a significant independent prognostic factor in glioblastoma, suggesting that the activation status of these cells and their interactions with the vascular endothelium and T cells influence tumor progression. These findings highlight TAMs as potential therapeutic targets for glioblastoma.

CIC-rearranged sarcoma is a rare, aggressive tumor entity with a dismal outcome. We describe a patient with a history of B-cell acute lymphoblastic leukemia (B-ALL), presenting to our hospital with seizures and left-sided upper limb weakness. Brain imaging revealed a localized right frontal mass, which was surgically resected. Initial pathological analyses suggested a secondary malignant neoplasm, not otherwise specified. However, the tumor's methylome was profiled and analyzed using the DKFZ brain tumor classifier to reach a diagnosis of CIC-rearranged sarcoma, confirmed by FISH study. The patient received the ICE protocol, alongside focal radiotherapy. The patient experienced a local recurrence 14 months post-diagnosis. The brain tumor classifier significantly improved the efficiency of diagnosing this rare tumor in a pediatric patient. However, effective therapeutic regimens for CIC-rearranged sarcomas remain unavailable.

We report a rare case of oligosarcoma, IDH-mutant, arising from a recurrent astrocytoma in a male in his 50s. The patient was originally diagnosed with IDH-mutant astrocytoma, CNS WHO grade 2, lacking 1p/19q co-deletion. At recurrence, the tumor exhibited a pure spindle cell sarcoma morphology, with retained IDH1 R132H, ATRX, and TP53 mutations, homozygous CDKN2A/B deletion, and a methylation profile classifying it as oligosarcoma, IDH-mutant. Although next-generation sequencing (NGS) suggested non-specific partial 1p/19q deletion signals, a true whole-arm 1p/19q co-deletion was not confirmed by fluorescence in situ hybridization (FISH) or methylation-based copy-number analysis, as shown in Figure 4E. Only two prior reports describe oligosarcoma arising from astrocytoma. Based on the sarcomatous morphology, astrocytic molecular background, and methylation clustering, we interpret this case as post-treatment sarcomatous transformation of an IDH-mutant astrocytoma, CNS WHO grade 2, rather than a canonical oligosarcoma. This case highlights the limitations of methylation profiling in heavily treated gliomas and underscores the importance of multimodal molecular confirmation in diagnostically challenging tumors.

Japanese encephalitis (JE) is a mosquito-borne viral infection of the central nervous system for which no specific antiviral treatment is available. We report the case of a 79-year-old man residing in Kumamoto Prefecture, southwestern Japan, with JE who presented with fever, impaired consciousness, and respiratory failure, and subsequently died of multiple organ failure despite early supportive care. Magnetic resonance imaging (MRI) revealed characteristic bilateral thalamic lesions, leading to an early clinical suspicion of JE before serological confirmation. Neuropathological findings, particularly, the involvement of the thalamus, substantia nigra, hippocampus, and anterior horn of the spinal cord, were consistent with previously reported cases of JE, while also demonstrating a broader distribution of lesions than suggested by antemortem MRI. As most cases of JE occur in unvaccinated individuals, vaccination should be considered in middle-aged and older adults, particularly, those with low antibody titers against the JE virus.