Embryonal and pineal tumours.

Embryonal and pineal tumours represent a diverse group of central nervous system (CNS) neoplasms. While many of the small round blue cell tumours that make up the embryonal neoplasms share similar histologic qualities, there are several morphologic and cytologic characteristics that are useful in distinguishing different tumour types. Similarly, pineal parenchymal tumours represent clinically diverse tumours, ranging from benign to overtly malignant. The most recent iteration of the World Health Organization Classification of CNS Tumours expanded greatly on the significance of molecular alterations in brain tumour diagnostics. In this article, we summarize the salient cytologic and histologic features of CNS embryonal and pineal tumours, and highlight diagnostically relevant molecular alterations within each tumour type.

Variant allelic frequencies of driver mutations can identify gliomas with potentially false-negative MGMT promoter methylation results.

MGMT promoter methylation testing is required for prognosis and predicting temozolomide response in gliomas. Accurate results depend on sufficient tumor cellularity, but histologic estimates of cellularity are subjective. We sought to determine whether driver mutation variant allelic frequency (VAF) could serve as a more objective metric for cellularity and identify possible false-negative MGMT samples. Among 691 adult-type diffuse gliomas, MGMT promoter methylation was assessed by pyrosequencing (N = 445) or DNA methylation array (N = 246); VAFs of TERT and IDH driver mutations were assessed by next generation sequencing. MGMT results were analyzed in relation to VAF. By pyrosequencing, 56% of all gliomas with driver mutation VAF ≥ 0.325 had MGMT promoter methylation, versus only 37% with VAF < 0.325 (p < 0.0001). The mean MGMT promoter pyrosequencing score was 19.3% for samples with VAF VAF ≥ 0.325, versus 12.7% for samples with VAF < 0.325 (p < 0.0001). Optimal VAF cutoffs differed among glioma subtypes (IDH wildtype glioblastoma: 0.12-0.18, IDH mutant astrocytoma: ~0.33, IDH mutant and 1p/19q co-deleted oligodendroglioma: 0.3-0.4). Methylation array was more sensitive for MGMT promoter methylation at lower VAFs than pyrosequencing. Microscopic examination tended to overestimate tumor cellularity when VAF was low. Re-testing low-VAF cases with methylation array and droplet digital PCR (ddPCR) confirmed that a subset of them had originally been false-negative. We conclude that driver mutation VAF is a useful quality assurance metric when evaluating MGMT promoter methylation tests, as it can help identify possible false-negative cases.

Differential Diagnosis of Tumor-like Brain Lesions.

Purpose of Review: Tumor-like brain lesions are rare and commonly suggest a neoplastic etiology. Failure to rapidly identify non-neoplastic causes can lead to increased morbidity and mortality. In this review, we describe 10 patients who presented with atypical, non-neoplastic tumor-like brain lesions in which brain biopsy was essential for a correct diagnosis and treatment. Recent Findings: There has been increasing recognition of autoimmune conditions affecting the nervous system, and many of those diseases can cause tumor-like brain lesions. Currently available reports of non-neoplastic tumor-like brain lesions are scarce. Most case series focus on tumefactive demyelinating lesions, and a comprehensive review including other neuroimmunological conditions such as CNS vasculitis, neurosarcoidosis, histiocytic and infectious etiologies is lacking. Summary: We review the literature on tumor-like brain lesions intending to increase the awareness and differential diagnosis of non-neoplastic brain tumor mimics. We advocate for earlier brain biopsies, which, in our case series, significantly changed diagnosis, management, and outcomes.

Post-Surgical Prognosis of Patients with Pineoblastoma: A Systematic Review and Individual Patient Data Analysis with Trends over Time.

Most of the literature on pineoblastoma consists of case reports and single-institution series. The goal of this systematic review and individual patient data (IPD) analysis was to summarize the existing literature, identify factors associated with overall survival (OS), and provide a contemporary update on prognosis for patients with pineoblastoma. Forty-four studies were identified with 298 patients having IPD. Kaplan-Meier analyses were used to report survival outcomes based on age, tumor metastases, extent of resection (EOR), adjuvant therapy, and publication year. Cox regression was performed to identify independent predictors of time to mortality. Multivariable recursive partitioning analysis was used to identify the most important subgroups associated with mortality. Patients were classified based on publication year before and after the last systematic review on this topic (pre-2012 and 2012 onwards) and compared using univariate and multivariable analyses. This study demonstrates that EOR less-than-gross total resection, metastatic presentation, adjuvant chemotherapy without radiation, and tumor presentation in children less than three years old are associated with poorer prognosis. Since 2012, the 5-year actuarial OS has improved from 32.8% to 56.1%, which remained significant even after accounting for EOR, age, and adjuvant therapy. Pineoblastoma remains a severe rare disease, but survival outcomes are improving.

Chronic traumatic encephalopathy neuropathologic change is uncommon in men who played amateur American football.

Introduction: We examined postmortem brain tissue from men, over the age of 50, for chronic traumatic encephalopathy neuropathologic change (CTE-NC). We hypothesized that (i) a small percentage would have CTE-NC, (ii) those who played American football during their youth would be more likely to have CTE-NC than those who did not play contact or collision sports, and (iii) there would be no association between CTE-NC and suicide as a manner of death. Methods: Brain tissue from 186 men and accompanying clinical information were obtained from the Lieber Institute for Brain Development. Manner of death was determined by a board-certified forensic pathologist. Information was obtained from next of kin telephone interviews, including medical, social, demographic, family, and psychiatric history. The 2016 and 2021 consensus definitions were used for CTE-NC. Two authors screened all cases, using liberal criteria for identifying "possible" CTE-NC, and five authors examined the 15 selected cases. Results: The median age at the time of death was 65 years (interquartile range = 57-75; range = 50-96). There were 25.8% with a history of playing American football and 36.0% who had suicide as their manner of death. No case was rated as definitively having "features" of CTE-NC by all five authors. Ten cases were rated as having features of CTE-NC by three or more authors (5.4% of the sample), including 8.3% of those with a personal history of playing American football and 3.9% of those who did not play contact or collision sports. Of those with mood disorders during life, 5.5% had features of CTE-NC compared to 6.0% of those who did not have a reported mood disorder. Of those with suicide as a manner of death, 6.0% had features of CTE-NC compared to 5.0% of those who did not have suicide as a manner of death. Discussion: We did not identify a single definitive case of CTE-NC, from the perspective of all raters, and only 5.4% of cases were identified as having possible features of CTE-NC by some raters. CTE-NC was very uncommon in men who played amateur American football, those with mood disorders during life, and those with suicide as a manner of death.

Neuropathology of Anti-Amyloid-ß Immunotherapy: A Case Report.

Host responses to anti-amyloid-ß (Aß) antibody therapy are evident in neuroimaging changes and clinical symptoms in a subset of clinical trial subjects receiving such therapy. The pathological basis for the imaging changes and clinical symptoms is not known, nor is the precise mechanism of Aß clearing. We report the autopsy findings in a 65-year-old woman who received three open label infusions of the experimental anti-Aß drug lecanemab over about one month. Four days after the last infusion, she was treated with tissue plasminogen activator for acute stroke symptoms and died several days later with multifocal hemorrhage. Neuropathological examination demonstrated histiocytic vasculitis involving blood vessels with cerebral amyloid angiopathy. Fragmentation and phagocytosis of vascular Aß were present throughout the cerebral cortex. Phagocytosis of parenchymal Aß plaques was noted. Changes suggestive of Aß and phosphorylated tau "clearing" were also noted. The findings overall suggest that anti-Aß treatment stimulated a host response to Aß, i.e., target engagement. The findings also provide evidence that amyloid-related imaging abnormalities might be indicative of an Aß phagocytic syndrome within cerebral vasculature and parenchymal brain tissue in some cases.

Frontotemporal Degeneration with Transactive Response DNA-Binding Protein Type C at the Anterior Temporal Lobe.

The anatomical distribution of most neurodegenerative diseases shows considerable interindividual variations. In contrast, frontotemporal lobar degeneration with transactive response DNA-binding protein type C (TDP-C) shows a consistent predilection for the anterior temporal lobe (ATL). The relatively selective atrophy of ATL in TDP-C patients has highlighted the importance of this region for complex cognitive and behavioral functions. This review includes observations on 28 TDP-C patients, 18 with semantic primary progressive aphasia and 10 with other syndromes. Longitudinal imaging allowed the delineation of progression trajectories. At post-mortem examination, the pathognomonic feature of TDP-C consisted of long, thick neurites found predominantly in superficial cortical layers. These neurites may represent dystrophic apical dendrites of layer III and V pyramidal neurons that are known to play pivotal roles in complex cortical computations. Other types of frontotemporal lobar degeneration TDP, such as TDP-A and TDP-B, are not associated with long dystrophic neurites in the cerebral cortex, and do not show similar predilection patterns for ATL. Research is beginning to identify molecular, structural, and immunological differences between pathological TDP-43 in TDP-C versus TDP-A and B. Parallel investigations based on proteomics, somatic mutations, and genome-wide association studies are detecting molecular features that could conceivably mediate the selective vulnerability of ATL to TDP-C. Future work will focus on characterizing the distinctive features of the abnormal TDP-C neurites, the mechanisms of neurotoxicity, initial cellular targets within the ATL, trajectory of spread, and the nature of ATL-specific markers that modulate vulnerability to TDP-C. ANN NEUROL 2023;94:1-12.

Programmed Death Ligand-1 Combined Positive Score Concordance and Interrater Reliability in Primary Tumors and Synchronous Lymph Node Metastases in Resected Cases of p16+ Oropharyngeal Squamous Cell Carcinoma.

CONTEXT.­: Pembrolizumab is used in patients with metastatic head and neck squamous cell carcinoma contingent upon the programmed death ligand-1 (PD-L1) combined positive score (CPS). OBJECTIVE.­: To compare PD-L1 CPS scores derived from paired resected primary tumors (PTs) and lymph node metastases (LMs) in patients with p16+ oropharyngeal squamous cell carcinoma (OPSCC). DESIGN.­: We identified 38 resected p16+ OPSCCs for which paired PTs and LMs were available. PD-L1 immunohistochemistry using the SP263 antibody clone was done on both the PT and the LM. CPS scoring was performed by 4 observers, and data were analyzed at the CPS cut points of greater than or equal to 1 and 20 in regard to interobserver and interspecimen agreement. RESULTS.­: Overall agreement between consensus CPS scoring of PT and LM was seen in 76% of paired specimens (κ = 0.53). No specimen received a negative consensus score. Interobserver agreement for both PT and LM was fair to substantial (κ = 0.54 and 0.51, respectively) and was inferior to that seen in a prospective series of unselected head and neck squamous carcinoma cases evaluated at our institution (κ = 0.84). CONCLUSIONS.­: Given the high rates of interobserver and interspecimen variability, evaluation of additional material or by additional observers may be of value in performing CPS scoring in cases of p16+ OPSCC. This is particularly the case when a negative or low-positive result is being evaluated in a patient who is otherwise a good candidate for immunotherapy.

The 2021 WHO classification of central nervous system tumors: what neurologists need to know.

PURPOSE OF REVIEW: The recently published WHO Classification of Tumours, Central Nervous System Tumours, Fifth Edition (WHO CNS-5) introduces substantial clinically relevant changes based on improved understanding of the molecular underpinnings of brain tumor types as biological entities. This review highlights pertinent changes for practicing neurologists. RECENT FINDINGS: Diffuse gliomas are now divided into adult and pediatric types. Adult types are greatly simplified, being classified into three groups based on IDH and 1p/19q status, with molecular grading criteria now included. Pediatric types are divided into low-grade or high-grade and further classified based on molecular features corresponding to clinical behavior. While still recognizing previous morphological subtypes, meningioma is now a single tumor type, with greatly advanced correlations between molecular alterations, locations, morphologic subtypes, and grades. For the first time, ependymomas are classified based on integration of anatomical location, histopathology, and molecular alterations. Importantly, WHO CNS-5 includes a number of new tumor types that have similar clinicopathologic features and are grouped together by their distinctive molecular characteristics. SUMMARY: The classification of CNS tumors according to objective, reproducible molecular genetic alterations, provides greater opportunity for neurologists to offer individualized treatment options, enroll homogenous patient populations into clinical trials, and ultimately discover novel therapeutics.

Validation of Whole Genome Methylation Profiling Classifier for Central Nervous System Tumors.

The 2021 WHO Classification of Tumors of the Central Nervous System includes several tumor types and subtypes for which the diagnosis is at least partially reliant on utilization of whole genome methylation profiling. The current approach to array DNA methylation profiling utilizes a reference library of tumor DNA methylation data, and a machine learning-based tumor classifier. This approach was pioneered and popularized by the German Cancer Research Network (DKFZ) and University Hospital Heidelberg. This research group has kindly made their classifier for central nervous system tumors freely available as a research tool via a web-based portal. However, their classifier is not maintained in a clinical testing environment. Therefore, the Northwestern Medicine (NM) classifier was developed and validated. The NM classifier was validated using the same training and validation data sets as the DKFZ group. Using the DKFZ validation data set, the NM classifier's performance showed high concordance (92%) and comparable accuracy (specificity 94.0% versus 84.9% for DKFZ, sensitivity 88.6% versus 94.7% for DKFZ). Receiver-operator characteristic curves showed areas under the curve of 0.964 versus 0.966 for NM and DKFZ classifiers, respectively. In addition, in-house validation was performed and performance was compared using both classifiers. The NM classifier performed comparably well and is currently offered for clinical testing.

Clinicopathologic and Proteomic Analysis of Amyloidomas Involving the Ocular Surface and Adnexa.

OBJECTIVES: Ocular amyloidoma is a rare disorder characterized by deposition of insoluble proteinaceous fibrils in the extracellular space of the ocular adnexa. This study details the clinicopathologic features and proteomic characteristics of periocular amyloid deposition. METHODS: Specimens (1991-2020) were retrieved and reviewed. All available H&E slides and special stains were reviewed. Proteomic analysis was performed using immunohistochemistry (IHC) for IgG, IgG4, IgA, IgD, IgM, CD20, CD3, CD138, and κ/λ, as well as chromatography-electrospray tandem mass spectrometry on formalin-fixed, paraffin-embedded tissue. RESULTS: There were 14 patients (7 men, 7 women). The depositions involved eyelid (n = 3), conjunctiva (n = 8), and orbit (n = 3). All patients were adults with a median age at diagnosis of 56 (range, 39-88) years. The deposits were predominantly λ light chain restricted (n = 6) and mixed light chains (n = 2), and one case was κ predominant. Two of the cases with a mixture of κ and λ light chains had an excess of transthyretin by mass spectrometry. Four of the cases did not have adequate material for proteomic subtyping. CONCLUSIONS: Amyloidomas involving ocular adnexa contain a variety of amyloid-related and immunoglobulin-associated peptides. The λ light chain predominates as in other body sites, but mixed patterns and rarely κ light chain restriction may be encountered.

Prediction of persistent ventricular dilation by initial ventriculomegaly and clot volume in a porcine model.

OBJECTIVE: While intraventricular hemorrhage (IVH) is associated with posthemorrhagic ventricular dilation (PHVD), not all infants affected by high-grade IVH develop PHVD. The authors aimed to determine clot-associated predictors of PHVD in a porcine model by varying the amount and rate of direct intraventricular injection of whole autologous blood. METHODS: Seven 1-week-old piglets underwent craniectomy and injection of autologous blood into the right lateral ventricle. They survived for a maximum of 28 days. MRI was performed prior to injection, immediately postoperatively, and every 7 days thereafter. T1-weighted, T2-weighted, and susceptibility-weighted imaging (SWI) sequences were used to segment ventricular and clot volumes. Spearman correlations were used to determine the relationship between blood and clot volumes and ventricular volumes over time. RESULTS: The maximum ventricular volume was up to 12 times that of baseline. One animal developed acute hydrocephalus on day 4. All other animals survived until planned endpoints. The interaction between volume of blood injected and duration of injection was significantly associated with clot volume on the postoperative scan (p = 0.003) but not the amount of blood injected alone (p = 0.38). Initial postoperative and day 7 clot volumes, but not volume of blood injected, were correlated with maximum (p = 0.007 and 0.014) and terminal (p = 0.014 and 0.036) ventricular volumes. Initial postoperative ventricular volume was correlated with maximum and terminal ventricular volume (p = 0.007 and p = 0.014). CONCLUSIONS: Initial postoperative, maximum, and terminal ventricular dilations were associated with the amount of clot formed, rather than the amount of blood injected. This supports the hypothesis that PHVD is determined by clot burden rather than the presence of blood products and allows further testing of early clot lysis to minimize PHVD risk.

Distribution of TDP-43 Pathology in Hippocampal Synaptic Relays Suggests Transsynaptic Propagation in Frontotemporal Lobar Degeneration.

Hyperphosphorylation, nuclear depletion, and aggregation of TDP-43 in ubiquitinated inclusions is a hallmark of frontotemporal lobar degeneration (FTLD-TDP). Evidence of potential spread of TDP-43 along synaptic connections in the human is largely limited to qualitative and semiquantitative observations. We quantitatively investigated potential transsynaptic propagation of TDP-43 across the well-established chain of single synaptic connections of the hippocampus. Hippocampi from 5 participants with clinical diagnoses of primary progressive aphasia and 2 participants with behavioral variant frontotemporal dementia, all with postmortem diagnoses of FTLD-TDP, were examined. TDP-43-positive mature (darkly stained) and pre-inclusions (diffuse puncta or fibrillar staining) in the granule cell layer of dentate gyrus (DG) and pyramidal cell layers of Cornu Ammonis (CA)3, CA2, and CA1 were quantified using unbiased stereology. The density of mature TDP-43 inclusions was higher in the DG than in the CA fields (p < 0.05). There were no differences in inclusion densities across the CA fields. TDP-43 pre-inclusions densities were not different across the 4 subregions. There was significantly higher preinclusion density than mature inclusions in CA3, but not in other subregions. Analysis of normalized total counts in place of densities revealed virtually identical results. Our finding of greatest mature inclusion deposition in the DG, coupled with more preinclusions than mature inclusions at the next relay station (CA3), and reduced densities of both in CA2-CA1, provide evidence in support of a sequential transsynaptic propagation mechanism of TDP-43 aggregates.