Sudden Death Associated With Possible Flare-Ups of Multiple Sclerosis After COVID-19 Vaccination and Infection: A Case Report and Literature Review.

We present an autopsy case of a 19-year-old man with a history of epilepsy whose unwitnessed sudden death occurred unexpectedly in the night. About 4 years before death, he was diagnosed with unilateral optic neuritis (ON). Demyelinating disease was suspected, but he was lost to follow up after the recovery. Six months before death, he received a second dose of mRNA coronavirus disease 2019 (COVID-19) vaccine. Three months before death, he experienced epileptic seizures for the first time. Seventeen days before death, he was infected with COVID-19, which showed self-limited course under home isolation. Several days before death, he complained of seizures again at night. Autopsy revealed multifocal gray-tan discoloration in the cerebrum. Histologically, the lesions consisted of active and inactive demyelinated plaques in the perivenous area of the white matter. Perivascular lymphocytic infiltration and microglial cell proliferation were observed in both white matter and cortex. The other major organs including heart and lung were unremarkable. Based on the antemortem history and postmortem findings, the cause of death was determined to be multiple sclerosis with suspected exacerbation. The direct or indirect involvement of cortex and deep gray matter by exacerbated multiple sclerosis may explain the occurrence of seizures. Considering the absence of other structural abnormalities except the inflammatory demyelination of the cerebrum, fatal arrhythmia or laryngospasm in the terminal epileptic seizure may explain his sudden unexpected death in the benign circumstances. In this case, the onset of seizure was preceded by COVID-19 vaccination, and the exacerbation of seizure was preceded by COVID-19 infection, respectively. Literature reporting first manifestation or relapse of multiple sclerosis temporally associated with COVID-19 vaccination or infection are reviewed.

Risk Stratification of Childhood Medulloblastoma Using Integrated Diagnosis: Discrepancies with Clinical Risk Stratification.

BACKGROUND: Recent genomic studies identified four discrete molecular subgroups of medulloblastoma (MB), and the risk stratification of childhood MB in the context of subgroups was refined in 2015. In this study, we investigated the effect of molecular subgroups on the risk stratification of childhood MB. METHODS: The nCounter® system and a customized cancer panel were used for molecular subgrouping and risk stratification in archived tissues. RESULTS: A total of 44 patients were included in this study. In clinical risk stratification, based on the presence of residual tumor/metastasis and histological findings, 24 and 20 patients were classified into the average-risk and high-risk groups, respectively. Molecular subgroups were successfully defined in 37 patients using limited gene expression analysis, and DNA panel sequencing additionally classified the molecular subgroups in three patients. Collectively, 40 patients were classified into molecular subgroups as follows: WNT (n = 7), SHH (n = 4), Group 3 (n = 8), and Group 4 (n = 21). Excluding the four patients whose molecular subgroups could not be determined, among the 17 average-risk group patients in clinical risk stratification, one patient in the SHH group with the TP53 variant was reclassified as very-high-risk using the new risk classification system. In addition, 5 out of 23 patients who were initially classified as high-risk group in clinical risk stratification were reclassified into the low- or standard-risk groups in the new risk classification system. CONCLUSION: The new risk stratification incorporating integrated diagnosis showed some discrepancies with clinical risk stratification. Risk stratification based on precise molecular subgrouping is needed for the tailored treatment of MB patients.

Incidence, clinicopathologic, and genetic characteristics of mismatch repair gene-mutated glioblastomas.

BACKGROUND: Glioblastoma (GBM) is the most common and malignant gliomas of adults and recur, resulting in death, despite surgery, radiotherapy, and temozolomide-based chemotherapy. There are a few reports on immunotherapy for the mismatch repair (MMR)-deficient GBMs with high tumor mutational burden (TMB). However, the clinicopathological and genetic features of the MMR genes altered in GBMs have not been elucidated yet. METHODS: The authors analyzed targeted next-generation sequencing (NGS) data from 282 (276 primary and 6 recurrent) glioblastomas to evaluate the mutational status of six DNA repair-related genes: MLH1, MSH2, MSH6, PMS2, POLE, and POLD1. Tumors harboring somatic or germline mutations in one or more of these six genes were classified as an MMR gene-altered GBM. The clinicopathologic and molecular characteristics of MMR gene-altered GBMs were compared to those of tumors without MMR gene alterations. RESULTS: Sixty germline or somatic mutations were identified in 37 cases (35 primary and two recurrent) of GBM. The most frequently mutated genes were MSH6 and POLE. Single nucleotide variants were the most common, followed by frameshift deletions or insertions and approximately 60% of the mutations were germline mutations. Two patients who showed MSH2 (c.2038C > T) and MSH6 (c.1082G > A) mutations had familial colon cancer. The clinical findings were not different between the two groups. However, the presence of MGMT promoter methylation and high tumor mutation burden (TMB) values (> 20) were correlated with MMR gene alterations. CONCLUSION: Since MMR-related genes can be found even in primary glioblastoma and are correlated with high TMB and MGMT promoter methylation, MMR genes should be carefully analyzed in NGS study on glioblastomas.

Tandem High-dose Chemotherapy without Craniospinal Irradiation in Treatment of Non-metastatic Malignant Brain Tumors in Very Young Children.

BACKGROUND: Infants and very young children with malignant brain tumors have a poorer survival and a higher risk for neurologic deficits. The present study evaluated the feasibility and effectiveness of multimodal treatment including tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT) in minimizing use of radiotherapy (RT) in very young children with non-metastatic malignant brain tumors. METHODS: Twenty consecutive patients younger than 3 years were enrolled between 2004 and 2017. Tandem HDCT/auto-SCT was performed after six cycles of induction chemotherapy. Local RT was administered only to patients with post-operative gross residual tumor at older than 3 years. Since September 2015, early post-operative local RT for patients with atypical teratoid/rhabdoid tumor or primitive neuroectodermal tumor was administered. RESULTS: All 20 enrolled patients underwent the first HDCT/auto-SCT, and 18 proceeded to the second. Two patients died from toxicity during the second HDCT/auto-SCT, and four patients experienced relapse/progression (one localized and three metastatic), three of whom remained alive after salvage treatment including RT. A total of 17 patients remained alive at a median 7.8 (range, 2.5-5.7) years from diagnosis. Nine survivors received no RT, six survivors received local RT alone, and two survivors who experienced metastatic relapse after tandem HDCT/auto-SCT received both local and craniospinal RT. The 5-year overall, event-free, and craniospinal RT-free survival rates were 85.0% ± 8.0%, 70.0% ± 10.2%, and 75.0% ± 9.7%, respectively. Neuroendocrine and neurocognitive functions evaluated 5 years after tandem HDCT/auto-SCT were acceptable. CONCLUSION: Our results suggest that non-metastatic malignant brain tumors in very young children could be treated with multimodal therapy including tandem HDCT/auto-SCT while minimizing RT, particularly craniospinal RT.

Pilosebaceous Malignant Transformation of Dermoid Cyst in the Orbit.

Dermoid cysts may occur in the orbit, most commonly in the superolateral area. Malignant transformation of such lesions has been previously reported; however, most turn out to be squamous cell carcinoma. The authors' patient initially presented with mild proptosis and limitation in extraocular movements. Preliminary biopsy showed whitish amorphous material and abundant hairs filling the thin-walled cyst, consistent with dermoid cyst. The patient underwent tumor resection via lateral orbitotomy with bone window and transorbital endoscopic approach for the dural involvement. Final biopsy showed dermoid cyst with pilosebaceous malignant transformation showing p53 expression and 30% of Ki-67 index. Adjuvant radiotherapy was performed. To the best of the authors' knowledge, this is the first reported case of this type. Despite its rarity, there should always be a high index of suspicion and complete work-up for an accurate diagnosis.

Chordomas: Histopathological Study in View of Anatomical Location.

BACKGROUND: Chordomas are aggressive bone tumors that have a predilection for the axial skeleton including the skull base and spinal/sacral bones. However, the histopathological and clinical differences between skull base chordoma (SBC) and sacral/spinal chordoma (SC) are unclear as previous studies have been focused on patient prognosis and treatment outcome. This study aimed to evaluate the clinicopathologic features and prognosis of chordoma according to its location. METHODS: Patients with chordomas were enrolled, and the histopathologic features were compared according to the tumor location. RESULTS: A total of 52 patients were enrolled. SBCs had more abundant chondroid matrix and diffuse growth pattern, while SCs had non-chondroid, myxoid matrix and a lobulating pattern, typical of chordoma. Old age and residual tumors were risk factors for shorter overall survival in SBCs. The chondroid matrix was an independent risk factor for shorter disease-free survival in the overall population. CONCLUSION: Chordomas have different histopathologic features depending on the anatomical location.

Fibromyxoma of the Orbit.

Fibromyxomas are rare tumors that are not commonly seen in the orbit. The authors present a case of orbital fibromyxoma. A 42-year-old male presented with proptosis of the right eye that began 1 month prior. Magnetic resonance imaging revealed the presence of an orbital mass in the right eye, with low signal intensity on T1-weighted images and heterogeneous high-signal intensity on T2-weighted images. The patient underwent excisional biopsy of the orbital tumor through a Krönlein approach. The tumor originated from the inferior rectus muscle. Histopathologic analysis demonstrated scattered spindle cells, with both fibrous and myxoid stroma. Immunohistochemical staining was positive for Vimentin and negative for S-100 protein and CD34. The tumor was diagnosed as orbital fibromyxoma. The patient showed no evidence of recurrence over 18 months of follow-up after operation.

Multimodal treatment including tandem high-dose chemotherapy and autologous stem cell transplantation in children with anaplastic ependymomas.

In this study, we evaluated the results of multimodal treatment that included tandem HDCT/auto-SCT in children with anaplastic ependymomas. Fourteen patients with anaplastic ependymomas were enrolled from 2006 to 2014. Six cycles of induction chemotherapy were administered to all patients before they underwent tandem HDCT/auto-SCT. Patients who were older than 3 years of age were administered RT after two cycles of induction chemotherapy. In patients under 3 years of age, RT was either omitted or delayed until they reached 3 years of age, if the patients experienced CR after tandem HDCT/auto-SCT. All patients, including two who experienced disease progression during induction treatment, underwent the first HDCT/auto-SCT, and 13 subsequently underwent the second HDCT/auto-SCT. One patient died from hepatic VOD during the second HDCT/auto-SCT; other toxicities occurring during tandem HDCT/auto-SCT were manageable. Relapses or progression occurred in seven patients, and five of seven of them remain alive till date after salvage treatment, including surgery and RT. The 5-year overall and event-free survival rates were 85.1% ± 9.7% and 50.0% ± 13.4%, respectively. These findings suggest that multimodal treatment including tandem HDCT/auto-SCT could be a feasible option for improving survival in children with anaplastic ependymomas.

Angiomatosis of the Orbit: Clinical, Imaging, and Histologic Findings.

Angiomatosis is a complex vascular malformation that denotes a clinically extensive hemangioma, which either involves multiple tissue planes or extensively infiltrates 1 type of tissue. It is a rare condition characterized by diffuse proliferation of blood vessels admixed with fat and fibrotic tissue. Typically, this process involves the limbs in multiple tissue planes, including dermis, subcutis, muscle, and bone. In this report, the authors present the first case of angiomatosis infiltrating the orbit, controlled effectively with a combination of systemic steroids, radiation, and beta-blocker therapy. The characteristic imaging and histologic features and management options are discussed.

SMARCE1 mutation screening in classification of clear cell meningiomas.

AIMS: Clear cell meningioma (CCM) is a rare subtype of meningioma and shows not only unusual histology, but also unique clinical features. Recently, SMARCE1 mutations have been shown to cause spinal and cranial CCMs. We present 12 cases which were diagnosed with CCM in a single institution between 1997 and 2014, and investigate their SMARCE1 mutation status. METHODS AND RESULTS: To investigate the SMARCE1 mutation status of these tumours, we used a combination of Sanger sequencing and multiplex ligation-dependent probe amplification analysis and also performed SMARCE1 immunohistochemical staining. We found both SMARCE1 mutational hits, including novel SMARCE1 mutations, in six of eight tested patients. Immunohistochemical analysis showed loss of SMARCE1 protein staining in all but two cases. Two individuals who were diagnosed originally with CCM were negative for SMARCE1 mutations, but tested positive for NF2 mutations. As a result, these two tumours were re-analysed and eventually reclassified, as a microcystic and a mixed pattern of meningothelial meningioma with focal clear cell areas, respectively. CONCLUSIONS: These results expand the spectrum of pathogenic variants in SMARCE1 and show that mutation screening can help to facilitate meningioma classification. This may have implications for prognosis and future clinical management of patients, as CCMs are classed as grade II tumours, while microcystic and meningothelial meningiomas are classed as grade I.

Negative prognostic effect of low nuclear GLI1 expression in glioblastomas.

The hedgehog signaling plays supportive roles in various aspects of tumorigenesis. Increased expression of the key component, GLI1, has been shown to correlate with poor prognosis in many types of cancers. We aimed to investigate the effect of GLI1 expression in glioblastoma focusing on the nuclear localization. Immunohistochemistry for GLI1, GLI2, PTCH1, SMO, and SHH were done in 140 glioblastoma tissues, and the staining was graded. For GLI1, nuclear and cytoplasmic expression was separately assessed. No significant correlation was found between clinicopathologic parameters and expression grades of the five proteins. Low nuclear GLI1 expression was associated with a worse progression-free survival while overall survival was not significantly affected. In contrast, cytoplasmic GLI1 expression did not have a prognostic effect. PTCH1 expression correlated with nuclear GLI1 expression without exerting a significant prognostic effect. Analysis of the TCGA-glioblastoma dataset revealed that low GLI1 mRNA level also correlated with a poor prognosis for both overall and progression-free survival. The adverse effect of low nuclear GLI1 expression in glioblastomas is in contrast with the negative prognostic effect of high GLI1 expression reported in non-cranial malignancies. The relative impact of hedgehog signaling among other oncogenic pathways in the brain may be responsible for the difference. The different implication of GLI1 expression in glioblastomas needs to be considered in studies of hedgehog signaling-targeted therapy.

Tandem High-Dose Chemotherapy and Autologous Stem Cell Transplantation for High-Grade Gliomas in Children and Adolescents.

With the aim to investigate the outcome of tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT) for high-grade gliomas (HGGs), we retrospectively reviewed the medical records of 30 patients with HGGs (16 glioblastomas, 7 anaplastic astrocytomas, and 7 other HGGs) between 2006 and 2015. Gross or near total resection was possible in 11 patients. Front-line treatment after surgery was radiotherapy (RT) in 14 patients and chemotherapy in the remaining 16 patients including 3 patients less than 3 years of age. Eight of 12 patients who remained progression free and 5 of the remaining 18 patients who experienced progression during induction treatment underwent the first HDCT/auto-SCT with carboplatin + thiotepa + etoposide (CTE) regimen and 11 of them proceeded to the second HDCT/auto-SCT with cyclophosphamide + melphalan (CyM) regimen. One patient died from hepatic veno-occlusive disease (VOD) during the second HDCT/auto-SCT; otherwise, toxicities were manageable. Four patients in complete response (CR) and 3 of 7 patients in partial response (PR) or second PR at the first HDCT/auto-SCT remained event free: however, 2 patients with progressive tumor experienced progression again. The probabilities of 3-year overall survival (OS) after the first HDCT/auto-SCT in 11 patients in CR, PR, or second PR was 58.2% ± 16.9%. Tumor status at the first HDCT/auto-SCT was the only significant factor for outcome after HDCT/auto-SCT. There was no difference in survival between glioblastoma and other HGGs. This study suggests that the outcome of HGGs in children and adolescents after HDCT/auto-SCT is encouraging if the patient could achieve CR or PR before HDCT/auto-SCT.

Hemangiopericytomas in the Central Nervous System: A Multicenter Study of Korean Cases with Validation of the Usage of STAT6 Immunohistochemistry for Diagnosis of Disease.

BACKGROUND: Hemangiopericytoma (HPC) in the central nervous system (CNS) is a rare disease with distinctive biological/clinical characteristics compared with meningioma. METHODS: Cases of HPCs of the CNS were collected, and clinicopathological records were retrospectively reviewed and analyzed. Immunohistochemistry (IHC) for proliferative markers (Ki-67, PHH3) and STAT6 were performed. RESULTS: A total of 140 cases were collected, with mean follow-up of 77 months (median 58.8 months; range 0.53-540.5 months). 1-, 5-, 10-, and 20-year survival rates were 99.1, 94.0, 74.4, and 61.9 %, respectively. Thirty-nine patients (27.9 %) had recurrent disease. Mean and median times to recurrence were 62.9 and 47.3 months with 1-, 5-, 10-, and 20-year recurrence-free survival rates of 98.3, 78.3, 50.1, and 11.0 %, respectively. Thirteen patients (9.3 %) developed extracranial metastases. No adjuvant radiation therapy, higher histologic grades, failure of gross-total resection, and cases with gamma-knife surgery (GKS) were factors associated with shorter disease-free survival (log-rank test, p = 0.02, 0.00, 0.02, 0.00), among which high histologic grade and cases with GKS were significant in multivariable analysis. Strong nuclear STAT6 expression was noted in HPCs in 62 cases of HPCs (60/62, 96.8 %), whereas diffuse weak positivity was demonstrated in all meningioma cases. CONCLUSIONS: The survival rate in patients with HPC of the CNS is comparable to that of previously reported series. Recurrence remains a critical clinical issue of the disease. Identification of NAB2-STAT6 fusion transcript with surrogate IHC marker is a valuable diagnostic tool in the differential diagnosis of the disease.

Coexistence of intracranial Langerhans cell histiocytosis and Erdheim-Chester disease in a pediatric patient: a case report.

INTRODUCTION: The co-occurrence of Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) is extremely rare and almost all cases were reported in adults. CASE REPORT: We describe a case of intracranial LCH and ECD that was confirmed by histopathological and molecular studies. A three-year-old boy presented with headache and right exophthalmos and brain magnetic resonance images (MRI) revealed multiple intracranial tumors. Whole body MRI showed osteolytic lesions typical of LCH in flat bones and osteosclerotic changes typical of ECD in long bones. DISCUSSION: Histologically, the biopsy samples from the posterior fossa and occipital skull mass revealed areas of both LCH and ECD. Immunohistochemically, the LCH contained CD1a-positive Langerhans cells and the ECD had CD1a-negative, CD68-positive foamy histiocytes. BRAF (V600E) mutations were detected in both the LCH and ECD areas. The coexistence of LCH and ECD in the same biopsy and the BRAF (V600E) mutation status in both histologic types support the recent re-classification of the histiocytic disorder into LCH, ECD, and "mixed histiocytosis", which reflects tumorigenesis for all three from a common progenitor cell.

BRAF V600E mutations are frequent in dysembryoplastic neuroepithelial tumors and subependymal giant cell astrocytomas.

BACKGROUND: BRAF mutation has received a great deal of attention in neuro-oncology field, recently. This study aimed to investigate the incidence and the clinical significance of BRAF(V600E) in low-grade glial tumors. METHODS: An institutional cohort of 105 brain tumors (51 dysembryoplastic neuroepithelial tumors (DNTs), 14 subependymal giant cell astrocytomas (SEGAs), 12 glioblastoma with neuronal marker expression (GBM-N), and 28 pleomorphic xanthoastrocytomas (PXAs)) from 100 patients were investigated for the presence of BRAF(V600E) by direct sequencing. RESULTS: We found frequent BRAF(V600E) in DNTs (26/51, 51%), SEGAs (6/14, 42.9%), and PXAs (14/28, 50%). In DNTs, BRAF(V600E) was more commonly detected in tumors with extra-temporal location (68.2% vs. 37.9%; P = 0.032). The diagnostic subgroups of tuberous sclerosis complex were not correlated with BRAF(V600E) in patients with SEGA (P = 0.533). One PXA case revealed a unique duplication mutation (p.Thr599dup) of codon 599. All GMB-N cases did not carry BRAF mutation. CONCLUSIONS: Our data indicate that BRAF(V600E) is a common genetic alteration in low-grade glial tumors with neuronal component or differentiation. High frequency of BRAF(V600E) in DNTs and SEGAs would be useful in the differential diagnosis, and also offers a potential specific treatment targeting BRAF(V600E) .

Intensive chemotherapy followed by reduced-dose radiotherapy for biopsy-proven CNS germinoma with elevated beta-human chorionic gonadotropin.

In this study, 10 patients with biopsy-proven germinoma with a beta-human chorionic gonadotropin (ß-HCG) level >50 mIU/ml received intensive chemotherapy followed by reduced-dose radiotherapy (RT) to reduce late effects from RT. CSF ß-HCG levels were >200 mIU/ml in five patients. After endoscopic or stereotactic biopsy, four cycles of induction chemotherapy were administered prior to RT. A CEB regimen (carboplatin + etoposide + bleomycin) and a CyEB regimen (cyclophosphamide + etoposide + bleomycin) were alternated. No residual tumor remained after induction chemotherapy in six patients, only cystic lesions were present at the primary tumor site in three, and a small solid residual tumor was observed in the remaining patient; however, all these patients had normal ß-HCG levels. If complete response was achieved before initiation of RT, 19.5 Gy craniospinal RT (CSRT) + 10.8 Gy local RT was administered to the tumor bed. If residual lesion was suspected, the dose of RT was selected according to the presence/absence of tumor dissemination at diagnosis (19.5 Gy CSRT + 19.8 Gy local RT for localized tumors and 24.0 Gy CSRT + 16.2 Gy local RT for disseminated tumors). Eight patients, including four patients with a ß-HCG level >200 mIU/ml, received 19.5 Gy CSRT. All patients remain disease free at a median follow-up of 58 (range 35-94) months from diagnosis. Our data suggest that pathologically pure germinoma with a significantly elevated ß-HCG level might be cured with reduced-dose RT if intensive chemotherapy is provided.

Supratentorial ependymoma with glial component of two different histologies and neuropil-like islands: a case report.

Glioneuronal tumors with neuropil-like islands (GTNIs) are a basically infiltrating astrocytoma or mixed oligoastrocytoma, containing large neuropil-like islands (NIs). Recently, we experienced a peculiar case of supratentorial ependymoma with NIs. A 29-month-old girl presented with seizure and a brain magnetic resonance image revealed a huge heterogeneous mass in the left lateral ventricle. Histologically, glial components of the tumor showed two different histologies: anaplastic ependymoma and myxopapillary ependymomatous features. The latter was admixed with numerous NIs. Immunohistochemically, the glial components expressed GFAP and a paranuclear dot pattern of EMA and CD99, whereas the NIs were positive for synaptophysin and MAP2. KI-67 was high in the anaplastic ependymoma, but very low in the fascicles of spindle cells and NIs. Quantitative PCR confirmed mRNA expression of five genes related to neuronal differentiation in both the glial and neuronal components of this tumor. Our case suggests that ependymoma with NIs may be in a spectrum of GTNIs.

Atypical teratoid/rhabdoid tumor arising in pleomorphic xanthoastrocytoma: a case report.

Atypical teratoid/rhabdoid tumor (AT/RT) is a rare, highly malignant, true rhabdoid tumor in the central nervous system predominantly presenting in young children.AT/RT typically shows rhabdoid cells which can also be seen in other tumors, but it is differentiated from other tumors by the specific genetic alteration involving the SMARCB1 gene. Only a few cases of AT/RT arising in low-grade glioma have been reported. A 13-year-old girl presented with headache, dizziness, nausea and vomiting.A 4.7 cm cerebellar mass was found on MRI.The mass was totally removed. Histologically, the tumor revealed two distinct morphologic appearances: central areas of AT/RT containing rhabdoid cells and sarcomatous component in the background of pleomorphic xanthoastrocytoma(PXA). Immunohistochemically, PXA areas retained nuclear expression of INI-1 and low Ki-67 proliferation index, whereas AT/RT component showed loss of INI-1 nuclear expression and markedly elevated Ki-67 proliferation index. Epithelial membrane antigen (EMA), smooth muscle actin (SMA), and p53 protein were positive only in AT/RT. BRAF V600E mutation was identified in PXA by real-time polymerase chain reaction.We report a rare case of AT/RT arising in PXA which is supposed to progress by inactivation of INI-1 in a pre-existing PXA.

Diagnostic utility of genetic alterations in distinguishing IDH-wildtype glioblastoma from lower-grade gliomas: Insight from next-generation sequencing analysis of 479 cases.

The accurate diagnosis and classification of gliomas are essential for appropriate treatment planning and prognosis prediction. This study aimed to investigate the molecular diagnostics of IDH-wildtype diffuse astrocytic gliomas and identify potential genetic variants that could differentiate glioblastoma (GBM) from lower-grade gliomas when DNA methylation analysis is not feasible. In total, 479 H3-and IDH-wildtype diffuse astrocytic gliomas were included in this study. All the cases were diagnosed according to the 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumors. Panel sequencing data were collected, and clinicopathological information was retrieved from medical records. Genetic alterations and histological findings were analyzed to determine their diagnostic utility and prognostic implications. Out of 479 cases, 439 (91.6%) were diagnosed with GBM, including 28 cases that were molecularly diagnosed as GBM. However, 40 (8.4%) cases could not be classified according to the 2021 WHO classification and were diagnosed as lower-grade diffuse astrocytic glioma, IDH-wildtype, not elsewhere classified (LGNEC). In addition to the three genetic alterations included in the diagnostic criteria of GBM, PTEN and EGFR mutations were found to be enriched in GBM. Patients harboring mTOR pathway mutations demonstrated a more favorable prognosis and often exhibited morphology resembling subependymal giant cell astrocytoma, along with a high tumor mutational burden. Among patients with mTOR pathway mutations, those lacking molecular diagnostic features of GBM exhibited outstanding survival outcomes, even in the presence of grade 4 histology. Integration of molecular features enhanced the diagnostic accuracy of IDH-wildtype gliomas. Some molecular alterations enriched in GBM offer valuable insights for molecular diagnosis and glioma classification. Furthermore, high-grade diffuse astrocytic gliomas featuring mTOR pathway mutations in the absence of molecular diagnostic features of GBM could represent more favorable tumor types distinct from GBM.

Clinicopathological and Molecular Characteristics of IDH-Wildtype Glioblastoma with FGFR3::TACC3 Fusion.

The World Health Organization Classification of Tumors of the Central Nervous System recently incorporated histological features, immunophenotypes, and molecular characteristics to improve the accuracy of glioblastoma (GBM) diagnosis. FGFR3::TACC3 (F3T3) fusion has been identified as an oncogenic driver in IDH-wildtype GBMs. Recent studies have demonstrated the potential of using FGFR inhibitors in clinical trials and TACC3-targeting agents in preclinical models for GBM treatment. However, there is limited information on the clinicopathological and genetic features of IDH-wildtype GBMs with F3T3 fusion. The aim of this study was to comprehensively investigate the clinical manifestations, histological features, and mutational profiles of F3T3-positive GBMs. Between September 2017 and February 2023, 25 consecutive cases (5.0%) of F3T3-positive GBM were extracted from 504 cases of IDH-wildtype GBM. Clinicopathological information and targeted sequencing results obtained from 25 primary and 4 recurrent F3T3-positive GBMs were evaluated and compared with those from F3T3-negative GBMs. The provisional grades determined by histology only were distributed as follows: 4 (26/29; 89.7%), 3 (2/29; 6.9%), and 2 (1/29; 3.4%). Grade 2-3 tumors were ultimately diagnosed as grade 4 GBMs based on the identification of the TERT promoter mutation and the combined gain of chromosome 7 and loss of chromosome 10 (7+/10-). F3T3-positive GBMs predominantly affected women (2.6 females per male). The mean age of patients with an F3T3-positive GBM at initial diagnosis was 62 years. F3T3-positive GBMs occurred more frequently in the cortical locations compared to F3T3-negative GBMs. Imaging studies revealed that more than one-third (12/29; 41.4%) of F3T3-positive GBMs displayed a circumscribed tumor border. Seven of the seventeen patients (41.2%) whose follow-up periods exceeded 20 months died of the disease. Histologically, F3T3-positive GBMs more frequently showed curvilinear capillary proliferation, palisading nuclei, and calcification compared to F3T3-negative GBMs. Molecularly, the most common alterations observed in F3T3-positive GBMs were TERT promoter mutations and 7+/10-, whereas amplifications of EGFR, PDGFRA, and KIT were not detected at all. Other genetic alterations included CDKN2A/B deletion, PTEN mutation, TP53 mutation, CDK4 amplification, and MDM2 amplification. Our observations suggest that F3T3-positive GBM is a distinct molecular subgroup of the IDH-wildtype GBM. Both clinicians and pathologists should consider this rare entity in the differential diagnosis of diffuse astrocytic glioma to make an accurate diagnosis and to ensure appropriate therapeutic management.