Central nervous system embryonal tumors with EWSR1-PLAGL1 rearrangements reclassified as INI-1 deficient tumors at relapse.

PURPOSE: Central nervous system (CNS) embryonal tumors are a diverse group of malignant tumors typically affecting pediatric patients that recently have been better defined, and this paper describes evolution of a unique type of embryonal tumor at relapse. METHODS: Two pediatric patients with CNS embryonal tumors with EWSR1-PLAGL1 rearrangements treated at Arkansas Children's Hospital with histopathologic and molecular data are described. RESULTS: These two patients at diagnosis were classified as CNS embryonal tumors with EWSR1-PLAGL1 rearrangements based on histologic appearance and molecular data. At relapse both patient's disease was reclassified as atypical teratoid rhabdoid tumor (ATRT) based on loss of INI-1, presence of SMARCB1 alterations, and methylation profiling results. CONCLUSION: CNS embryonal tumors with EWSR1-PLAGL1 rearrangements acquire or include a population of cells with SMARCB1 alterations that are the component that predominate at relapse, suggesting treatment aimed at this disease component at diagnosis should be considered.

A rare case of atypical intradural extramedullary glioblastoma diagnosed utilizing next-generation sequencing and methylation profiling: illustrative case.

BACKGROUND: Primary spinal cord tumors, especially primary spinal cord glioblastoma multiforme (PSC-GBM), are exceptionally rare, accounting for less than 1.5% of all spinal tumors. Their infrequency and aggressive yet atypical presentation make diagnosis challenging. In uncertain cases, a surgical approach for tissue diagnosis is often optimal. OBSERVATIONS: A 76-year-old male presented with a rapidly progressing clinical history marked by worsening extremity weakness, urinary retention, and periodic fecal incontinence alongside diffuse changes on neuraxis imaging. The patient, in whom subacute polyneuropathy was initially diagnosed, received multiple rounds of steroids and intravenous immunoglobulin without clinical improvement. Histopathological review of the biopsy tissue yielded an initial diagnosis of spindle cell neoplasm. Next-generation sequencing (NGS) is done routinely on all neuropathology specimens at the authors' institution, and methylation profiling is pursued in difficult cases. Ultimately, NGS and methylation profiling results were essential to an integrated final diagnosis of GBM. LESSONS: PSC-GBM is a rare but highly aggressive occurrence of this tumor. Prolonged back pain, rapid neurological decline, and imaging changes warrant the consideration of lesional biopsy for precise disease characterization. In inconclusive cases, NGS has proved invaluable for clinical clarification and diagnosis, underscoring its importance for integrated diagnoses in guiding appropriate treatment strategies.

SMARCA4-deficient central nervous system metastases: A case series and systematic review.

SMARCA4 alterations can be encountered in a variety of human neoplasms, and metastases to the central nervous system (CNS) are rare, offering a challenge to neuropathologists despite not representing a distinct diagnostic entity. To better understand the clinical and histologic presentation of such neoplasms, we report an observational case series and systematic review of 178 unique articles that yielded 15 published cases and 7 cases from institutional files. In the systematic review, the median age was 58 years, the male-to-female ratio was 2:1, and the most common diagnosis was lung adenocarcinoma; all CNS metastases were discovered within 1 year of presentation. In the case series, the median age was 58 years, the male-to-female ratio was 6:1, and all known metastases originated from the lung. Most patients had a smoking history and died of disease. GATA-3 positivity was seen in most case series examples. Concurrent TP53 mutations (83.3%) and a high tumor mutation rate (60%) were common. To our knowledge, this is the only case series and systematic review in the English literature aimed at assessing SMARCA4-altered metastases in the CNS and vertebral column. We highlight the challenges of neuropathologic evaluation of such tumors and provide observational evidence of early metastases, histologic appearances, and immunohistochemical findings, including previously unreported GATA-3 positivity.

Brain Banking in Dementia Studies.

It is now well-established practice in dementia that one clinical entity may be caused by various neurodegenerative disorders, each with different histopathological findings, whereas neuropathologically confirmed patients may have different, unusual, and atypical clinical manifestations.This inconsistency in dementia patients leads to neuropathological examination of cases, and neuropathological examination seems to be an inevitable part of dementia practice, at least until all clinical entities are properly identified for humans.Additionally, the development of disease-modifying therapies and confirmation of the actual accurate diagnosis of the neurodegenerative disease that the drug is thought to modify or act upon are of great importance for neuropathological evaluation in brain banks.Neuropathological processes coexisting among patients diagnosed with established clinical criteria or international guidelines have provided a new perspective in the context of drug development.Here, we review our routinely used methodology in the context of the brain banking process.

Brain Autopsy Findings in a Patient Who Received Lipid Emulsion Therapy for Suspected Drug Intoxication.

ABSTRACT: Lipid emulsion therapy (LET) is the intravenous administration of lipid solution for parenteral alimentation, especially in preterm infants and adults with debilitating illnesses. It has also been used in attempts of detoxification in suspected cases of drug overdose. Whether this interferes with circulation and/or perfusion is debatable, and it is suggested that it may interfere with coagulation process. The emulsifying agent has been identified microscopically mainly in the lungs of these patients, with rare reports in adults and even more rare ones in the brain; however, although it is rarely reported in other organs, to our knowledge, no reports of gross autopsy findings in the brain are available in the English literature, nor are there reports of pathologic findings after lipid emulsion therapy administration for drug toxicity. Although it is also debated in the literature whether this material forms as an artifact or represents the actual agent, here we report the gross and microscopic autopsy findings in the brain of a patient who received LET for suspected beta-blocker intoxication. It will be beneficial for pathologists who perform autopsies in the forensic or medical settings to be aware of these findings, along with the uses and potential complications of LET.

Operative planning for a functional precision medicine assay of recurrent high-grade glioma: illustrative case.

BACKGROUND: Functional precision medicine (FPM) represents a personalized and efficacious modality for treating malignant neoplasms. However, acquiring sufficient live tissue to perform FPM analyses is complicated by both difficult identification on imaging and radiation necrosis, particularly in cases of recurrence. The authors describe a case of planning biopsy trajectories for an FPM assay in a patient with recurrent high-grade glioma. OBSERVATIONS: A 25-year-old male with a history of recurrent high-grade glioma was scheduled for laser ablation and biopsy with ChemoID assaying after regions of potential recurrence were identified on follow-up imaging. Preoperative magnetic resonance (MR) spectroscopy of the regions showed areas of high choline/creatine ratios within lesions of radiation necrosis, which helped in planning the biopsy trajectories to selectively target malignancies for FPM analysis. ChemoID results showed high tumor susceptibility to lomustine, which was implemented as adjuvant therapy. LESSONS: FPM therapy in the setting of recurrence is complicated by radiation necrosis, which can present as malignancy on imaging and interfere with tissue acquisition during biopsy or resection. Thus, operative approaches should be carefully planned with the assistance of imaging modalities such as MR spectroscopy to better ensure effective tissue acquisition for accurate FPM analysis and to promote more definitive treatment of recurrence.

Potential prognostic determinants for FET::CREB fusion-positive intracranial mesenchymal tumor.

Intracranial mesenchymal tumor (IMT), FET::CREB fusion-positive is a provisional tumor type in the 2021 WHO classification of central nervous system tumors with limited information available. Herein, we describe five new IMT cases from four females and one male with three harboring an EWSR1::CREM fusion and two featuring an EWSR1::ATF1 fusion. Uniform manifold approximation and projection of DNA methylation array data placed two cases to the methylation class "IMT, subclass B", one to "meningioma-benign" and one to "meningioma-intermediate". A literature review identified 74 cases of IMTs (current five cases included) with a median age of 23 years (range 4-79 years) and a slight female predominance (female/male ratio = 1.55). Among the confirmed fusions, 25 (33.8%) featured an EWSR1::ATF1 fusion, 24 (32.4%) EWSR1::CREB1, 23 (31.1%) EWSR1::CREM, one (1.4%) FUS::CREM, and one (1.4%) EWSR1::CREB3L3. Among 66 patients with follow-up information available (median: 17 months; range: 1-158 months), 26 (39.4%) experienced progression/recurrences (median 10.5 months; range 0-120 months). Ultimately, three patients died of disease, all of whom underwent a subtotal resection for an EWSR1::ATF1 fusion-positive tumor. Outcome analysis revealed subtotal resection as an independent factor associated with a significantly shorter progression free survival (PFS; median: 12 months) compared with gross total resection (median: 60 months; p < 0.001). A younger age (< 14 years) was associated with a shorter PFS (median: 9 months) compared with an older age (median: 49 months; p < 0.05). Infratentorial location was associated with a shorter overall survival compared with supratentorial (p < 0.05). In addition, the EWSR1::ATF1 fusion appeared to be associated with a shorter overall survival compared with the other fusions (p < 0.05). In conclusion, IMT is a locally aggressive tumor with a high recurrence rate. Potential risk factors include subtotal resection, younger age, infratentorial location, and possibly EWSR1::ATF1 fusion. Larger case series are needed to better define prognostic determinants in these tumors.

Diffuse Leptomeningeal Glioneuronal Tumor: First Description of Metastasis to the Lung and Bone Marrow.

Diffuse leptomeningeal glioneuronal tumor (DLGNT) is a rare neoplasm of the central nervous system (CNS) that primarily affects the leptomeninges. However, it can also involve the brain parenchyma and spinal cord. We report the first case of metastasis of this primary CNS tumor to the lung and bone marrow. An 18-year-old male was diagnosed with DLGNT through meningeal biopsy after multiple events of transient neurologic signs and symptoms that included recurrent episodes of encephalopathy, seizures, cerebral vasospasms, cranial nerve palsy, and urinary dysfunction. Five months after diagnosis, the patient presented with pancytopenia and pulmonary effusion. At that time, he was being treated with temozolomide, after radiation treatment to the brain and spinal cord. Bone marrow biopsy and pleural cytology revealed systemic metastases from the primary CNS tumor. He was then treated with chemotherapy with carboplatin and vincristine which improved his condition for two and a half months. Unfortunately, the patient died of a high systemic metastatic burden. Primary CNS tumors rarely produce systemic metastases, and this is the first report of DLGNT with bone marrow and pulmonary metastases. Chemotherapy with carboplatin and vincristine should be considered as a treatment for patients with DLGNT, as the patient presented a systemic response with clinical and radiological improvement.

Intracranial hematolymphoid malignancies: A case series with molecular characterization.

OBJECTIVE: Central nervous system (CNS) manifestations of hematologic malignancies are uncommon and often have a poor prognosis. As hematologic neoplasms are typically chemotherapy- and radiotherapy-sensitive, surgical resection is usually not indicated; thus, opportunities for in-depth characterization of CNS hematologic tumors are limited. Here, we report four cases of rare intracranial hematologic tumors requiring surgical intervention, allowing for histopathologic and genomic characterization. METHODS: The clinical course, genetic perturbations, and histopathological features are described for a case of 1) primary marginal zone B-cell lymphoma of the dura as well as cases of brain metastases of 2) cutaneous T-cell lymphoma, 3) acute myeloid leukemia/myeloid sarcoma, and 4) multiple myeloma. Targeted DNA sequencing, fluorescence in situ hybridization, cytogenetic analysis, flow cytometry and immunohistochemical staining were used to assess the lesions. RESULT: Molecular and histopathological characterizations of four unusual presentations of hematolymphoid diseases involving the CNS are presented. Genetic abnormalities were identified in each lesion, including chromosomal aberrations and single nucleotide variants resulting in missense or nonsense mutations in oncogenes. CONCLUSIONS: Our case series provides insight into unique pathological phenotypes of hematologic neoplasms with atypical CNS involvement. We offer targets for future studies by identifying potentially pathogenic genetic variants in these lesions, as the full implications of the novel molecular abnormalities described remain unclear.

Clinical utility of whole-genome DNA methylation profiling as a primary molecular diagnostic assay for central nervous system tumors-A prospective study and guidelines for clinical testing.

Background: Central nervous system (CNS) cancer is the 10th leading cause of cancer-associated deaths for adults, but the leading cause in pediatric patients and young adults. The variety and complexity of histologic subtypes can lead to diagnostic errors. DNA methylation is an epigenetic modification that provides a tumor type-specific signature that can be used for diagnosis. Methods: We performed a prospective study using DNA methylation analysis as a primary diagnostic method for 1921 brain tumors. All tumors received a pathology diagnosis and profiling by whole genome DNA methylation, followed by next-generation DNA and RNA sequencing. Results were stratified by concordance between DNA methylation and histopathology, establishing diagnostic utility. Results: Of the 1602 cases with a World Health Organization histologic diagnosis, DNA methylation identified a diagnostic mismatch in 225 cases (14%), 78 cases (5%) did not classify with any class, and in an additional 110 (7%) cases DNA methylation confirmed the diagnosis and provided prognostic information. Of 319 cases carrying 195 different descriptive histologic diagnoses, DNA methylation provided a definitive diagnosis in 273 (86%) cases, separated them into 55 methylation classes, and changed the grading in 58 (18%) cases. Conclusions: DNA methylation analysis is a robust method to diagnose primary CNS tumors, improving diagnostic accuracy, decreasing diagnostic errors and inconclusive diagnoses, and providing prognostic subclassification. This study provides a framework for inclusion of DNA methylation profiling as a primary molecular diagnostic test into professional guidelines for CNS tumors. The benefits include increased diagnostic accuracy, improved patient management, and refinements in clinical trial design.

Miyoshi Muscular Dystrophy Due to Novel Splice Site Variants in DYSF Gene.

Dysferlinopathies are a group of phenotypically heterogeneous disorders caused by pathogenic variants in the DYSF (DYStrophy-associated Fer-1-like) gene encoding dysferlin. The phenotypic spectrum includes Miyoshi muscular dystrophy (MMD), limb-girdle muscular dystrophy type R2, distal myopathy with anterior tibial onset, and isolated hyperCKemia. MMD is characterized by muscle weakness and atrophy predominantly affecting the calf muscles with symptoms onset between 14 and 40 years of age. There is no clear phenotype - genotype correlation for dysferlinopathy. We describe a 15-year-old girl who presented with a phenotype consistent with MMD. However, she was initially treated for presumed polymyositis without improvement. Subsequent genetic testing revealed two novel variants in DYSF: c.3225dup (p.Gly1076Trpfs*38) in exon 30 and c.3349-2A > G (Splice acceptor) in intron 30. No dysferlin was detected in a muscle biopsy using immunostains and western blots, a result consistent with dysferlinopathy that supports the pathogenicity of the DYSF variants.

CD8 Encephalitis: A Diagnostic Dilemma.

CD8+ encephalitis is a subacute encephalopathy associated with HIV infection. Pathophysiology is thought to be auto-reactive CD8+ cells attacking on HIV infected CD4+ cells and 'viral escape' phenomena (replication of CD8+ cells in CSF). We present a case of a 45-year-old man with well controlled HIV who developed CD8 encephalitis following Herpes simplex encephalitis. He had persistent encephalopathy for several weeks with status epilepticus and agitated delirium, and diagnosis remained elusive until a brain biopsy confirmed the diagnosis.

Limb-Girdle Muscular Dystrophy R9 due to a Novel Complex Insertion/Duplication Variant in FKRP Gene.

Limb-girdle muscular dystrophy R9 (LGMD2I, LGMDR9) is an autosomal recessive disorder caused by pathogenic variants in the fukutin-related protein (FKRP) gene. We describe a 17 year old boy with LGMDR9 whose symptoms began at age 5 years. Muscle histopathology, immunostaining, and western blotting were consistent with a dystroglycanopathy. Genetic testing identified maternal inheritance of the most common pathogenic FKRP variant c.826C>A (p.L276I). Also detected was a novel insertion and duplication on the paternally inherited FKRP allele: a single nucleotide insertion (c.948_949insC) and an eighteen nucleotide duplication (c.999_1017dup18) predicted to result in premature translation termination (p.E389*). Based on the clinical features and course of the patient, heterozygosity for the common pathogenic FKRP variant, and abnormal glycosylation of alpha-dystroglycan, we suggest that the novel FKRP insertion and duplication are pathogenic. This case expands the genetic heterogeneity of LGMDR9 and emphasize the importance of muscle biopsy for precise diagnosis.

Spectrum of Hemorrhagic Encephalitis in COVID-19 Patients: A Case Series and Review.

Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) is an ongoing pandemic that has affected over 400 million people worldwide and caused nearly 6 million deaths. Hemorrhagic encephalitis is an uncommon but serious complication of COVID-19. The etiology of this disease is multifactorial, including secondary to severe hypoxemia, systemic inflammation, direct viral invasion, hypercoagulability, etc. The clinical spectrum of COVID-19-related hemorrhagic encephalitis is also varied, ranging from leukoencephalopathy with microhemorrhage, acute necrotizing hemorrhagic encephalitis (ANHE) involving the cortex, basal ganglia, rarely brain stem and cervical spine, hemorrhagic posterior reversible encephalopathy syndrome (PRES) to superimposed co-infection with other organisms. We report a case series of three young patients with different presentations of hemorrhagic encephalitis after COVID-19 infection and a review of the literature. One patient had self-limiting ANHE in the setting of mild COVID-19 systemic illness. The second patient had self-limiting leukoencephalopathy with microhemorrhages in the setting of severe systemic diseases and ARDS, and clinically improved with the resolution of systemic illness. Both patients were healthy and did not have any premorbid conditions. The third patient with poorly controlled diabetes and hypertension had severe systemic illness with neurological involvement including multiple ischemic strokes, basal meningitis, hemorrhagic encephalitis with pathological evidence of cerebral mucormycosis, and Epstein-Barr virus coinfection, and improved after antifungal therapy.

Astroblastomas exhibit radial glia stem cell lineages and differential expression of imprinted and X-inactivation escape genes.

Astroblastomas (ABs) are rare brain tumors of unknown origin. We performed an integrative genetic and epigenetic analysis of AB-like tumors. Here, we show that tumors traceable to neural stem/progenitor cells (radial glia) that emerge during early to later brain development occur in children and young adults, respectively. Tumors with MN1-BEND2 fusion appear to present exclusively in females and exhibit overexpression of genes expressed prior to 25 post-conception weeks (pcw), including genes enriched in early ventricular zone radial glia and ependymal tumors. Other, histologically classic ABs overexpress or harbor mutations of mitogen-activated protein kinase pathway genes, outer and truncated radial glia genes, and genes expressed after 25 pcw, including neuronal and astrocyte markers. Findings support that AB-like tumors arise in the context of epigenetic and genetic changes in neural progenitors. Selective gene fusion, variable imprinting and/or chromosome X-inactivation escape resulting in biallelic overexpression may contribute to female predominance of AB molecular subtypes.

Subepidermal Calcified Nodule in a Child With Neurofibromatosis Type 1.

Calcinosis cutis (CC) is characterized by calcium deposition in the subcutaneous tissues. Subepidermal calcified nodule (SCN) is a variant of idiopathic calcinosis most commonly seen in the head and neck region of children and adolescents as a single, small, painless, yellow-white papule. A 13-year-old boy with a medical history of neurofibromatosis type 1 (NF1) presented with a firm 0.3 cm white papule in the lower eyelid. He also had neurofibromas of the left forearm and spinal cord, and a malignant peripheral nerve sheath tumor of the right forearm. The eyelid lesion showed hyperkeratotic epidermis, papillomatosis, and elongated rete ridges, with a radial arrangement at the periphery of the well-circumscribed lesion comprising many dystrophic calcifications, histiocytes, and foreign body giant cell reactions. To our knowledge, this is the first case of SCN reported in the context of NF1 or any other systemic disease in the English literature. Although a coincidence is likely, rare observations of the parathyroid gland and calcium metabolism disorders in association with NF1 may provide an explanation that requires further investigation.

IgG4-Related Disease Presenting as Hypertrophic Pachymeningitis.

IgG4-related disease (IgG4-RD) is a multi-organ, immune-mediated inflammatory condition of unknown etiology characterized by infiltration of tissues by IgG4 producing plasma cells. IgG4-related disease (IgG4-RD) can ideally affect any organs, but the involvement of the central nervous system (CNS) is a rare entity. We present a case of a 67-year-old male who presented with diplopia with imaging showing hypertrophic pachymeningitis (HPM) and was diagnosed with IgG4-RD of the CNS based on histopathology report.