Accelarated immune ageing is associated with COVID-19 disease severity.

BACKGROUND: The striking increase in COVID-19 severity in older adults provides a clear example of immunesenescence, the age-related remodelling of the immune system. To better characterise the association between convalescent immunesenescence and acute disease severity, we determined the immune phenotype of COVID-19 survivors and non-infected controls. RESULTS: We performed detailed immune phenotyping of peripheral blood mononuclear cells isolated from 103 COVID-19 survivors 3-5 months post recovery who were classified as having had severe (n = 56; age 53.12 ± 11.30 years), moderate (n = 32; age 52.28 ± 11.43 years) or mild (n = 15; age 49.67 ± 7.30 years) disease and compared with age and sex-matched healthy adults (n = 59; age 50.49 ± 10.68 years). We assessed a broad range of immune cell phenotypes to generate a composite score, IMM-AGE, to determine the degree of immune senescence. We found increased immunesenescence features in severe COVID-19 survivors compared to controls including: a reduced frequency and number of naïve CD4 and CD8 T cells (p < 0.0001); increased frequency of EMRA CD4 (p < 0.003) and CD8 T cells (p < 0.001); a higher frequency (p < 0.0001) and absolute numbers (p < 0.001) of CD28-ve CD57+ve senescent CD4 and CD8 T cells; higher frequency (p < 0.003) and absolute numbers (p < 0.02) of PD-1 expressing exhausted CD8 T cells; a two-fold increase in Th17 polarisation (p < 0.0001); higher frequency of memory B cells (p < 0.001) and increased frequency (p < 0.0001) and numbers (p < 0.001) of CD57+ve senescent NK cells. As a result, the IMM-AGE score was significantly higher in severe COVID-19 survivors than in controls (p < 0.001). Few differences were seen for those with moderate disease and none for mild disease. Regression analysis revealed the only pre-existing variable influencing the IMM-AGE score was South Asian ethnicity ([Formula: see text] = 0.174, p = 0.043), with a major influence being disease severity ([Formula: see text] = 0.188, p = 0.01). CONCLUSIONS: Our analyses reveal a state of enhanced immune ageing in survivors of severe COVID-19 and suggest this could be related to SARS-Cov-2 infection. Our data support the rationale for trials of anti-immune ageing interventions for improving clinical outcomes in these patients with severe disease.

Histological and neuroimaging comparison of SMART syndrome versus focal neuronal gigantism.

Two of the rarest radiation-induced adverse effects are focal neuronal gigantism (FNG) and SMART syndrome (stroke-like migraine attacks after radiation therapy). Both conditions develop years, and sometimes decades, after receipt of therapeutic radiation to the brain. To date, there are only 3 previously reported cases of FNG, all of which describe cortical thickening, enlarged "hypertrophic" neurons, and neuronal cytological changes. No detailed studies exist of histological features of SMART or the comparison between FNG and SMART. In this study, we contrast histological and neuroimaging features of 3 FNG vs. 4 SMART cases, the latter diagnosed by a neuroradiologist, neurooncologist, and/or neurosurgeon. We confirm the cortical thickening, dyslamination, neuronal cytomegaly, and gliosis in FNG vs. cortical architectural preservation and normal neuronal cytology in SMART, although both showed gliosis, scattered neurons with cytoplasmic accumulation of tau and neurofibrillary protein and variable co-existence of other radiation-induced lesions. Both conditions lacked significant inflammation or consistent small vessel hyalinization throughout the entire resection specimen. The absence of pathognomonic histologic alterations in SMART cases suggests underlying vascular dysregulation. Despite differing histology, some overlap may exist in neuroimaging features. Molecular assessment conducted in 2 cases of FNG was negative for significant alterations including in the MAPK pathway.

Immunohistochemical and Histopathological Characterization of Spina Bifida Defect Tissues Removed After Prenatal and Postnatal Surgical Repair.

Background: Myelomeningocele or spina bifida is an open neural tube defect that is characterized by protrusion of the meninges and the spinal cord through a deformity in the vertebral arch and spinous process. Myelomeningocele of post-natal tissue is well described; however, pre-natal tissue of this defect has no known previous histologic characterization. We compared the histology of different forms of pre-natal myelomeningocele and post-natal myelomeningocele tissue obtained via prenatal intrauterine and postnatal surgical repairs. Methods: Pre-and post-natal tissues from spina bifida repair surgeries were obtained from lipomyelomeningocele, myeloschisis, and myelomeningocele spina bifida defects. Tissue samples were processed for H&E and immunohistochemical staining (KRT14 and p63) to assess epidermal and dermal development. Results: Prenatal skin near the defect site develops with normal epidermal, dermal, and adnexal structures. Within the grossly cystic specimens, histology shows highly dense fibrous connective tissue with complete absence of a normal epidermal development with a lack of p63 and KRT14 expression. Conclusion: Tissues harvested from prenatal and postnatal spina bifida repair surgeries appear as normal skin near the defect site. However, cystic tissues consist of highly dense fibrous connective tissue with complete absence of normal epidermal development.

Protocol: revolutionizing central nervous system tumour diagnosis in low- and middle-income countries: an innovative observational study on intraoperative smear and deep learning.

OBJECTIVE: The aim of this study is to assess the feasibility and implementation of a novel approach for intraoperative brain smears within the operating room, which is augmented with deep learning technology. Materials and methods: This study is designed as an observational to evaluate the feasibility and implementation of using an innovative approach to intraoperative brain smears within the operating room, augmented with deep learning technology. The study will be conducted at Aga Khan University Hospital in Karachi, Pakistan, from May 2024 to July 2026, with an estimated sample size of 258. A neurosurgical trainee, trained by the study neuropathologist, will prepare and examine the smears under a microscope in the operating room. The findings of the trainee will be documented and compared to routine intraoperative consultations (smear and/or frozen section) and final histopathology results obtained from the pathology department. Additionally, the study will incorporate artificial intelligence tools to assist with the interpretation of smear and a telepathology interface to enable consultation from an off-site neuropathologist. CONCLUSIONS: The results of this study will hold significant potential to revolutionise neurosurgery practices in lowand middle-income countries by introducing a cost-effective, efficient, and high-quality intraoperative consultation method to settings that currently lack the necessary infrastructure and expertise. The implementation of this innovative approach has the potential to improve patient outcomes and increase access to intraoperative diagnosis, thereby addressing a significant unmet need in LMICs.

Consensus guidelines for the management of vestibular schwannoma for lowand middle-income countries.

Vestibular Schwannoma (VS), previously known as acoustic neuroma, constitutes the majority of tumours found in the cerebellopontine angle (CPA). Most guidelines for managing CPA tumours have been developed by high-income countries (HICs). However, these guidelines often fall short in addressing the unique challenges encountered in low- and middle-income countries (LMICs), such as Pakistan. In LMICs, issues related to a limited healthcare workforce, inadequate infrastructure, and constrained financial resources hinder the effective implementation of these HIC-derived guidelines. Additionally, it has been observed that VS tends to present at a larger size in LMICs compared to HICs. Given that VS is the predominant type of CPA tumour and other types are covered under separate guidelines, this article aims to provide practical, contextspecific recommendations for the screening, diagnosis, and management of Vestibular Schwannoma in LMIC settings. Our focus is to bridge the gap in care strategies and adapt them to the resource constraints and clinical realities of LMICs.

Consensus guidelines for the management of adult high-grade gliomas for low and middle-income countries.

High-grade glioma (HGG), a formidable and often incurable disease, presents an even greater challenge in low- and middle-income countries (LMICs) where resources and medical expertise are scarce. This scarcity not only exacerbates the suffering of patients but also contributes to poorer clinical outcomes. Particularly in LMICs, the underrepresentation of the population in clinical trials and the additional hurdles posed by financial constraints underscore an urgent need for contextspecific management strategies. In response, we have rigorously evaluated recent guidelines from leading medical societies, adapting them to suit the specific needs and limitations of the local context in Pakistan. This effort, undertaken in collaboration with local physicians, aims to provide a comprehensive, standardised approach to diagnose, treat, and follow-up with HGG patients. By focussing on the best available clinical evidence and judicious use of limited resources, we strive to improve patient care and outcomes in these challenging settings.

Consensus guidelines for the management of primary central nervous system lymphoma for low and middle-income countries.

Primary lymphoma of the central nervous system (PCNSL) is a rare and aggressive form of extranodal non-Hodgkin lymphoma primarily involving the brain, spinal cord, cerebrospinal fluid, and eyes. The role of surgical intervention in PCNSL is currently limited to biopsy and decompression of critical structures if needed - extended resection is debated. Chemotherapy is the mainstay of treatment. In lower and middle-income countries (LMICs), issues like delayed diagnosis and resource constraints are widespread. These guidelines provide a framework for addressing PCNSL in LMICs, emphasizing the importance of early diagnosis, tailored treatment approaches, and ongoing patient monitoring to improve outcomes for this rare and aggressive disease.

Consensus guidelines for the management of adult low-grade gliomas for low and middle-income countries.

Low-grade gliomas (LGG) are brain tumors of glial cells origin. They are grade 1 and grade 2 tumors according to the WHO classification. Diagnosis of LGG is made through imaging, histopathological analysis, and use of molecular markers. Imaging alone does not establish the grade of the tumor and thus a histopathological examination of tissue is crucial in establishing the definite histopathological diagnosis. Clinical presentation varies according to the location and size of the tumor. Surgical resection is strongly recommended in LGG over observation to improve overall survival as surgery leads to greater benefit due to progression-free survival. Radiation has shown benefits in LGG patients in randomized controlled trials and chemotherapy with temozolomide has also shown good results. This paper covers the principles of low-grade gliomas management and summarizes the recommendations for the LMICs.

Consensus guidelines for the management of intracranial ependymoma for low- and middle-income countries.

This paper presents comprehensive consensus guidelines for the management of intracranial ependymoma, neoplasms arising from ependymal cells in the central nervous system's ventricular system, in low- and middleincome countries (LMICs). Acknowledging the distinct epidemiological patterns of ependymomas, notably their higher incidence in paediatric patients, and variable survival rates, these guidelines emphasize tailored management approaches for different age groups. An expert panel, comprising specialists in neuro-oncology, convened to address gaps in diagnosis and management within LMICs, considering the varying clinical presentation based on tumour size and location. Emphasizing surgical intervention as the cornerstone of treatment, the guidelines also address challenges such as intraoperative bleeding and tumour location impacting complete resection. The role of molecular subgrouping in stratifying treatment and predicting prognosis is highlighted, alongside a careful consideration of radiotherapy timing, dose, and volume based on risk factors. Chemotherapy's role, especially in paediatric cases, is explored. The paper synthesizes current research and expert opinions, including the need for standardisation, genetic testing, and exploration of less invasive treatment modalities, to address the unique healthcare infrastructure challenges in LMICs. The guidelines also emphasize multidisciplinary teams, aiming to bridge the care gap between high-income countries and LMICs, and improve survival rates and quality of life for patients with intracranial ependymoma. This article serves as a valuable resource for clinicians, researchers, and policymakers in Pakistan and beyond, facilitating the development of evidence-based strategies in diverse healthcare settings.

Consensus guidelines for the management of craniopharyngioma in low- and middle-income countries.

Craniopharyngiomas are benign, extra-axial epithelial tumours originating from the pituitary stalk, impacting areas such as the hypothalamus, optic chiasm, and various cranial nerves. These tumours present unique surgical challenges due to their proximity to critical neurovascular structures. Management typically involves maximal safe resection as the primary approach. However, in low- and middle-income countries (LMICs), factors like late presentation, higher risks of endocrine and visual complications, frequent recurrence, and potential for incomplete resection complicate treatment. These challenges are exacerbated by limited access to specialised expertise and surgical equipment, increasing the risk of damage during surgery compared to High- Income Countries. This manuscript outlines management guidelines tailored for LMICs, emphasizing that a combination of surgical resection and chemoradiation therapy, as advised by a neuro-oncology tumour board, often yields the best outcomes.

Consensus guidelines for the management of pineal region tumours for low- and middle-income countries.

Pineal region tumours are rare and mainly arise at a younger age. They can be categorized into various types: germ cell tumours (GCT), pineal parenchymal tumours (PPT), meningiomas, gliomas, pineoblastoma, pineal parenchymal tumours of intermediate differentiation, papillary tumours of the pineal region, and SMARCB1- mutant desmoplastic myxoid tumour. Within GCT, germinomas are the most prevalent, comprising the majority of tumours in this region, while nongerminomatous GCTs are also present. In rare instances, metastases from other sites may manifest. These tumours often lead to obstructive hydrocephalus and commonly exhibit symptoms related to mass effect, including headache, nausea, vomiting, and impaired gait stability. Different subtypes of pineal region tumours exhibit distinct radiological characteristics, thus imaging remains the primary diagnostic tool. Histologic diagnosis necessitates biopsy, unless in cases of germ cell tumours, particularly germinomas, which can be identified through elevated levels of tumour markers like alpha-fetoprotein (AFP) and human chorionic gonadotropin (HCG) in both cerebrospinal fluid (CSF) and serum. While benign tumours might be effectively treated with radical resection alone, malignant tumours demand additional chemotherapy and radiotherapy following surgical removal.

Consensus guidelines for the management of brain stem and diffuse midline glioma for low- and middle-income countries.

The understanding of brainstem gliomas and diffuse midline gliomas has significantly increased in the last decade. However, the management paradigm remains a dilemma. The critical location is the foremost factor dictating the outcome. Recent advancements in the field of neuro-oncology are pushing the boundaries of optimal care in the developed world nevertheless, the strategies in low- and middle-income countries (LMICs) need to be tailored according to the resources to improve outcome. The objective of these guidelines is to provide an algorithm-based management plan to cater challenges for healthcare providers in LMICs.

Consensus guidelines for the management of pediatric medulloblastoma in low and middle-income countries.

The management of medulloblastoma, a pediatric brain tumor, has evolved significantly with the advent of genomic subgrouping, yet morbidity and mortality remain high in LMICs like Pakistan due to inadequate multidisciplinary care infrastructure. This paper aims to establish evidence-based guidelines tailored to the constraints of such countries. An expert panel comprising neuro-oncologists, neurosurgeons, radiologists, radiation oncologists, neuropathologists, and pediatricians collaborated to develop these guidelines, considering the specific challenges of pediatric brain tumor care in Pakistan. The recommendations cover various aspects of medulloblastoma treatment, including pre-surgical workup, neurosurgery, neuropathology, chemotherapy, radiation therapy, and supportive care. They offer both minimum required and additional optional protocols for more advanced centers, ensuring comprehensive patient management with attention to complications and complexities encountered in Pakistan. The paper's consensus guidelines strive for uniformity in healthcare delivery and address significant gaps in diagnosis, treatment, and follow-up of pediatric medulloblastoma patients.

Childhood Small-Vessel Primary Angiitis of the Central Nervous System: Overlap With MOG-Associated Disease.

BACKGROUND: Childhood (c) primary angiitis of the central nervous system (PACNS) is a rare condition that most often affects small vessels (SV), is nearly exclusively lymphocytic, and devoid of vessel necrosis. Diagnosis of cSV-PACNS is challenging. We noted possible histological overlap of cSV-PACNS with myelin oligodendrocyte glycoprotein disease (MOGAD) on biopsy, prompting a 10-year retrospective review of our experience. MATERIALS AND METHODS: Database-search for brain biopsy cases, age <18 years, performed for an acquired neurological deficit with suspicion of vasculitis, with histological evidence of lymphocytic small-vessel inflammation. RESULTS: We identified 7 patients; 2/7 were serum-positive for anti-MOG antibodies and 1/7 for anti-NMDA antibodies. The remaining 4/7 proved to be idiopathic lymphocytic vasculitis/cSV-PACNS. All 7 showed overlapping features of lymphocytes permeating parenchymal SV walls, vessel wall distortion without fibrinoid necrosis, and absence of microglial clusters or intravascular thrombi. Tissue infarction was confined to a single case of idiopathic lymphocytic vasculitis. Although demyelination was diligently sought, only subtle demyelination was identified in the 2 MOGAD cases and absent in the remainder. CONCLUSION: There is considerable histological overlap between cSV-PACNS and at least some cases of MOGAD or anti-NMDA-encephalitis; at diagnosis, the differential should include cSV-PACNS but correct classification requires post-biopsy serological testing.

Some CNS sarcomas seen: A 22-year series.

AIMS: Central nervous system (CNS) and spine are seldom impacted by primary or metastatic sarcomas. We reviewed our 22-year experience with metastatic versus primary mesenchymal sarcomas in adults versus pediatric patients, additionally asking how many might today undergo nomenclature changes using CNS World Health Organization, 5th edition criteria. MATERIALS AND METHODS: Case identification via text word search of pathology databases from our adult and pediatric referral hospitals, 2000 to August 2022, with exclusion of peripheral nervous system and primary chondro-osseous and notochordal tumors. Demographic, immunohistochemical, fluorescence in situ hybridization (FISH), and fusion results performed at the time of original diagnosis were acquired from reports. RESULTS: 57 cases were identified, with a 16 : 15 primary and 19 : 7 metastatic ratio in adult versus pediatric patients. Ewing sarcoma was the most frequent type (n = 18, 7 adult, 11 pediatric), with a rare primary PEComa, 2 alveolar soft part sarcomas, and metastatic angiosarcoma in the cohort. Only 3 cases, an intracranial sarcoma, DICER-1 mutant formerly diagnosed as rhabdomyosarcoma, an intracranial mesenchymal tumor, FET::CREB fusion-positive formerly diagnosed as angiomatoid fibrous histiocytoma, and a CIC-rearranged sarcoma required nomenclature updating by CNS WHO5 criteria. CONCLUSIONS: Few primary or metastatic, adult or pediatric, CNS/spinal sarcomas required nomenclature updates; almost all had been satisfactorily classified at the time of diagnosis, using immunohistochemistry, FISH, or fusion results.

Genomic and epigenomic re-categorization of congenital glioblastoma and desmoplastic infantile ganglioglioma.

INTRODUCTION: The recently updated World Health Organization classification of central nervous system (CNS) tumors, 5th edition, (CNS5) reclassifies pediatric tumors according to their distinct molecular drivers, recognizing a new entity-infant-type hemispheric glioma (IHG). Defined by its unique epigenetic signature, and/or genomic fusions in ALK, ROS1, NTRK, or MET gene, IHG subsumes many cases previously classified as congenital glioblastoma (cGBM). Histologic features of IHG are still poorly defined with known overlap with a clinic radiologically similar entity-desmoplastic infantile ganglioglioma/astrocytoma (DIG). METHODS: We revisited our cohort of cGBMs and DIGs, now reclassifying them according to CNS5 and compared the clinical, radiologic, molecular and histologic features between the two. RESULTS: 3/6 cases of cGBM that underwent targeted NGS fusion mutation panel were positive for ALK fusions (involving MAP4, MZT2Bex2, and EML4 genes as fusion partners), and 1/6 showed GOPC:ROS1 fusion. Interestingly, GOPC:ROS1 fusion was also shared by 1/5 cases of histologically defined DIG. DNA methylation profiling using the Heidelberg classifier (v12.3) recategorized 2/5 DIG cases as IHG (including the case with ROS1 alteration). CONCLUSION: In conclusion, histology alone is insufficient to distinguish IHG from DIG, necessitating epigenomic and genomic testing for the diagnosis of early-life gliomas.

Population-based analysis of CNS tumor diagnoses, treatment, and survival in congenital and infant age groups.

BACKGROUND: Congenital (< 3 months) and infant (3 to 11 months) brain tumors are biologically different from tumors in older children, but their epidemiology has not been studied comprehensively. Insight into epidemiological differences could help tailor treatment recommendations by age and increase overall survival (OS). METHODS: Population-based data from SEER were obtained for 14,493 0-19-year-olds diagnosed with CNS tumors 1990-2015. Congenital and infant age groups were compared to patients aged 1-19 years based on incidence, treatment, and survival using Chi-square and Kaplan-Meier analyses. Hazard ratios were estimated from univariate and multivariable Cox proportional hazards survival analyses. RESULTS: Between the < 3-month, 3-5-month, 6-11 month, and 1-19-year age groups, tumor type distribution differed significantly (p < 0.001). 5-year OS for all tumors was 36.7% (< 3 months), 56.0% (< 3-5 months), 63.8% (6-11 months), and 74.7% (1-19 years) (p < 0.001). Comparing between age groups by tumor type, OS was worst for < 3-month-olds with low-grade glioma, medulloblastoma, and other embryonal tumors; OS was worst for 3-5-month-olds with ependymoma, < 1-year-olds collectively with atypical teratoid-rhabdoid tumor, and 1-19-year-olds with high-grade glioma (HGG) (log rank p < 0.02 for all tumor types). Under 3-month-olds were least likely to receive any treatment for each tumor type and least likely to undergo surgery for all except HGG. Under 1-year-olds were far less likely than 1-19-year-olds to undergo both radiation and chemotherapy for embryonal tumors. CONCLUSIONS: Subtype distribution, treatment patterns, and prognosis of congenital/infant CNS tumors differ from those in older children. Better, more standardized treatment guidelines may improve poorer outcomes seen in these youngest patients.

Preliminary Results of a Reverse Thermal Gel Patch for Fetal Ovine Myelomeningocele Repair.

BACKGROUND: Prenatal surgical closure of Myelomeningocele (MMC) is considered part of the current age armamentarium. Clinical data has demonstrated the need for innovative patches to maximize the benefits and decrease the risks of this approach. Our team has developed a minimally invasive reverse thermal gel (RTG) patch with cellular scaffolding properties. Here, we demonstrate the initial gross and microscopic histological effects of this RTG patch in the fetal ovine model of MMC. MATERIALS AND METHODS: A fetal ovine MMC defect was created at 68-75 days gestation, RTG patch application or untreated at 100-103 days, and harvest at 135-140 days. The RTG was applied to the defect and secured in place with an overlay sealant. Defect areas underwent gross and microscopic analysis for inflammation and skin development. Brains were analyzed for hindbrain herniation and hydrocephalus. RESULTS: The untreated fetus (n = 1) demonstrated an open defect lacking tissue coverage, evidence of spinal cord injury, increased caspase-3, Iba1 and GFAP in spinal cord tissues, and hindbrain herniation and ventricular dilation. RTG treated fetuses (n = 3) demonstrated defect healing with well-organized dermal and epidermal layers throughout the entire healed tissue area overlaying the defect with minimal inflammation, reduced caspase-3, Iba1 and GFAP in spinal cord tissues, and no hindbrain herniation or ventricular dilation. CONCLUSION: An RTG patch applied to MMC defects in fetal sheep promoted skin coverage over the defect, was associated with minimal inflammation of the spinal cord tissues and prevented brain abnormalities. The present findings provide exciting results for future comprehensive radiological, functional, and mechanistic evaluation of the RTG.

Innumerable Meningiomas Arising in a Patient With Tuberous Sclerosis Complex Decades After Radiation Therapy.

Meningioma is the most common radiation-induced brain neoplasm, usually occurring after a latency of 20 - 35 years, with multiplicity in 10% of cases. Radiation-induced meningiomas (RIMs) have not previously been reported in patients with tuberous sclerosis complex (TSC), unlike their well-known occurrence in other familial tumor predisposition syndrome patients. We report a TSC patient who developed numerous intracranial meningiomas twenty five year after radiation therapy for subependymal giant cell astrocytoma (SEGA). Autopsy examination showed innumerable, coalescent, benign, meningothelial meningiomas, WHO grade 1, ranging in size from 0.2 cm to 3.3 cm. Autopsy also showed small residual SEGA, radiation-induced cerebral vasculopathy, and classic TSC features including several small subependymal nodules ("candle gutterings"), white matter radial heterotopia, facial angiofibromas, dental enamel pitting, one ash leaf spot, and multiple hepatic and renal angiomyolipomas. Next-generation sequencing analysis utilizing a 500+ gene cancer panel demonstrated chromosomal loss involving the majority of chromosome 22, including the NF2 gene locus, as well as a truncating nonsense mutation in TSC1 p. R509*. While TSC patients rarely require radiation therapy, this striking case suggests that patients with TSC should be monitored closely if cranial therapeutic radiation is administered.

Morphological diversity in H3G34-mutant high-grade gliomas: Ganglionic and epithelioid features.

Although increasing numbers of central nervous system (CNS) tumors with stereotypic morphological, molecular, and/or site-specific features have been recently reported, morphological diversity is often recognized within a tumor category as more cases are encountered. Such was the case with diffuse midline gliomas, H3K27M-mutant. Therefore, it is not surprising that two cases of H3G34-mutant. CNS tumors with advanced ganglionic differentiation were recently published, especially given the posited role of this mutation in neuronal differentiation. We have encountered, in a 17-year-old female, a third example with advanced neoplastic ganglion cell differentiation that mimicked anaplastic ganglioglioma, with the ganglionic elements further confirmed as neoplastic by H3G34 immunohistochemistry (IHC). We therefore sought to review our experience with H3G34-mutant tumors, assessing for morphological diversity, supplemented by IHC. Six cases (ages 17 - 33 years), all confirmed on mutational analyses, were identified that were further negative for BRAFV600E or other major oncogenic mutations/fusions. The index anaplastic ganglioglioma-like case manifested multifocal large dysmorphic ganglion cells IHC+ for synaptophysin, chromogranin, and neurofilament, but no CD34 immunopositivity. A tumor from a 33-year-old male contained rare neuronal-like cells, with subtler enlargement, that were synaptophysin and neurofilament protein IHC+ and exceeded the size expected in "primitive neuroectodermal like (PNET)" tumors. A third example with morphological diversity was a glioblastoma with prominent epithelioid cells. We conclude that a spectrum of morphological differentiation does occur beyond the well-known glioblastoma or PNET-like morphology in H3G34-mutant tumors, adding to the literature one more example with advanced ganglionic differentiation and one with epithelioid features.