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.

Campylobacter fetus seeding of a cavernous malformation resulting in brain abscess: case report and literature review.

Microbial seeding of a cerebral cavernous malformation is an extremely rare occurrence with only 3 cases reported in the literature thus far. Campylobacter fetus is an opportunistic pathogen that rarely causes neurological infection with only 3 cases of C. fetus cerebral abscesses and 38 cases of C. fetus meningitis reported in the literature. There have been no cases of cerebral cavernous malformation seeding by C. fetus reported to date. We report the first case of cerebral cavernous malformation seeding by C. fetus, a case occurring in a previously healthy 16-year-old female who presented with suspected left cerebellar cavernous malformation with subacute hemorrhage. She underwent a suboccipital craniectomy for the resection of the cavernous malformation with additional intraoperative findings suggestive of cerebral abscess. Following positive blood and CSF cultures and surgical pathology results, the patient was diagnosed with C. fetus meningoencephalitis with co-infected left cerebellar cavernous malformation. This is the fourth reported case of microbial seeding of a cerebral cavernous malformation, and to our knowledge, the first case of a C. fetus-infected cavernous malformation. Compared to previous reports, the clinical events of this case strongly support the presence of a preexisting lesion that was secondarily seeded versus de novo formation as a result of prior infection.

Neurosarcoidosis: Phenotypes, Approach to Diagnosis and Treatment.

PURPOSE OF REVIEW: The aim of this review is to provide an update of clinical presentation, diagnosis, differential diagnoses, and treatment according to recent evidence. RECENT FINDINGS: Neurosarcoidosis remains a diagnosis of exclusion, with infectious and malignant etiologies recognized as important mimickers. Corticosteroids remain as first-line therapy. In recent years, however, studies have demonstrated the effectiveness of anti-tumor necrosis factor (anti-TNF) therapy in the treatment of neurosarcoidosis, leading to improved outcomes. Neurosarcoidosis is a granulomatous disease with protean manifestations that may affect any part of the central and peripheral nervous system. It has many mimickers, and potentially devastating complications necessitating long-term follow-up. Early initiation of treatment, particularly with anti-TNF therapy, may lead to better outcomes and fewer relapses. There is an unmet need for randomized controlled trials that provide robust data to guide therapy and the long-term management of neurosarcoidosis patients.

Clinical Reasoning: A 67-Year-Old Woman With Abdominal Pain, Constipation, and Urinary Retention.

Meningeal melanocytomas are an extremely rare, pigmented tumors of the central nervous system (CNS). They generally carry a favorable prognosis, although recurrence and transformation into the more aggressive malignant melanoma has been reported. We present a case of a patient who reported constipation and abdominal pain around the umbilicus, which progressed into cord compression with lower extremity weakness and gait instability. Spinal magnetic resonance imaging (MRI) revealed a tumor at the level of T11, and she underwent gross total resection of the mass. Pathology demonstrated a meningeal melanocytoma with intermediate features. She received post-operative radiation therapy and had stable disease for three years, at which time she developed new weakness and drop metastases. This case represents a rare presentation of a rare disease, in which a spinal cord tumor presented with constipation and abdominal distress. Intradural-extramedullary tumors of the thoracic spine are most commonly nerve sheath tumors or meningiomas, but rare entities such as melanocytomas can present in this location; even more rarely, these tumors can have an aggressive course with delayed recurrence.

Multifocal metastases to choroid plexus from papillary thyroid carcinoma: illustrative case.

BACKGROUND: Choroid plexus metastases are extremely rare from all types of malignancy, with only 42 cases reported in the literature thus far. Most of these originate from renal cell carcinoma and present as a solitary choroid plexus lesion; only two cases of multifocal choroid plexus metastases have been reported to date. OBSERVATIONS: The authors report the third case of multifocal metastases to the choroid plexus, that of a 75-year-old man who developed three measurable choroid plexus lesions approximately 3.5 years after undergoing total thyroidectomy and chemotherapy for papillary thyroid carcinoma. He underwent intraventricular biopsy of the largest lesion and subsequently died of hydrocephalus after opting for comfort care only. LESSONS: This is the third case of multifocal choroid plexus metastasis in the literature and the second case of multifocal metastasis from thyroid carcinoma. As such, the natural disease course is not well characterized. This case is compared with the previous eight reports of choroid plexus metastases from thyroid carcinoma, seven of which involved solitary lesions. The eight prior cases are evaluated with attention to treatment modalities used and factors potentially influencing prognosis, specifically those that might contribute to hydrocephalus, a reported complication for this pathology.

A Simplified Brain Blocking Protocol Optimized for the Diagnosis of Neurodegenerative Disease Saves Time and Money While Preserving Anatomic Relationships.

CONTEXT.­: Postmortem evaluation for neurodegenerative disease is expensive in time and materials. These challenges can be met by implementing simpler sampling protocols while preserving anatomic relations. OBJECTIVE.­: To determine the diagnostic effectiveness and cost-effectiveness of a simplified brain blocking protocol compared with the standard blocking protocol used in our Alzheimer's Disease Research Center (ADRC). DESIGN.­: We prospectively compared the neuropathologic diagnoses established from our standard 19-cassette/19 brain sites ADRC protocol to a simplified 6-cassette/12 brain sites protocol in 52 consecutive cases. The simplified protocol generated 14 slides for comparison to 52 slides from our standard protocol. RESULTS.­: Compared with the ADRC protocol the simplified protocol produced Alzheimer Disease Neuropathologic Changes probability scores that were the same in 50 of 52 cases (r = 0.99). Staging for Lewy pathology was equivalent in 45 of 52 (r = 0.98), scoring for cerebral amyloid angiopathy was equivalent in 48 of 52 (r = 0.97), and grading for arteriolosclerosis was the same in 45 of 52 cases (r = 0.92). Progressive supranuclear palsy (n = 4), multiple system atrophy (n = 2), and corticobasal degeneration (n = 1) could be diagnosed by either protocol independently. The estimated savings per case was 72% or $1744.89 ($2436.37 [ADRC] versus $691.48 [simplified]). CONCLUSIONS.­: The diagnosis of neurodegenerative disease at autopsy can be done accurately with a less expensive, simplified protocol. Our protocol is similar to those of previously published approaches, but it has a simpler organization scheme. This method should be valuable to institutions where autopsy cost considerations may be important.

Primary age-related tauopathy (PART) in the general autopsy setting: Not just a disease of the elderly.

Primary age-related tauopathy (PART) is generally considered a diagnosis of the elderly. In this letter, the authors present data showing that the pathologic changes of PART can occur in the general autopsy population significantly earlier than largely reported in the recent literature, particularly in woman.

Metastatic Lung Cancer Presenting as Monocular Blindness and Panhypopituitarism Secondary to a Pituitary Metastasis.

BACKGROUND Sellar masses are most commonly pituitary adenomas, however, about 1% of surgical resected pituitary lesions are found to be metastatic disease. It is hard to distinguish pituitary adenomas from metastatic disease. The most common primary sources for pituitary metastases are breast and lung cancer. CASE REPORT In this paper, we report the case of a woman who presented with right-sided vision loss who was found to have a sellar mass and panhypopituitarism. Subsequent imaging showed a large mass in her left upper lung with additional lesions in the spleen and adrenal glands. Neurosurgery performed an urgent transsphenoidal resection, with pathology confirming lung adenocarcinoma. CONCLUSIONS This is an unusual presentation of metastatic lung cancer, with the patient's primary symptoms being related to her pituitary metastasis and panhypopituitarism. Pituitary metastases are most commonly asymptomatic, although they can present with visual disturbances, diabetes insipidus, or panhypopituitarism. Pituitary metastases should be on the differential for sellar masses, particularly with specific radiographic findings, visual disturbances, and/or the presence of diabetes insipidus.

Resolving medulloblastoma cellular architecture by single-cell genomics.

Medulloblastoma is a malignant childhood cerebellar tumour type that comprises distinct molecular subgroups. Whereas genomic characteristics of these subgroups are well defined, the extent to which cellular diversity underlies their divergent biology and clinical behaviour remains largely unexplored. Here we used single-cell transcriptomics to investigate intra- and intertumoral heterogeneity in 25 medulloblastomas spanning all molecular subgroups. WNT, SHH and Group 3 tumours comprised subgroup-specific undifferentiated and differentiated neuronal-like malignant populations, whereas Group 4 tumours consisted exclusively of differentiated neuronal-like neoplastic cells. SHH tumours closely resembled granule neurons of varying differentiation states that correlated with patient age. Group 3 and Group 4 tumours exhibited a developmental trajectory from primitive progenitor-like to more mature neuronal-like cells, the relative proportions of which distinguished these subgroups. Cross-species transcriptomics defined distinct glutamatergic populations as putative cells-of-origin for SHH and Group 4 subtypes. Collectively, these data provide insights into the cellular and developmental states underlying subtype-specific medulloblastoma biology.

Financially effective test algorithm to identify an aggressive, EGFR-amplified variant of IDH-wildtype, lower-grade diffuse glioma.

BACKGROUND: Update 3 of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) recognizes amplification of epidermal growth factor receptor (EGFR) as one important aberration in diffuse gliomas (World Health Organization [WHO] grade II/III). While these recommendations endorse testing, a cost-effective, clinically relevant testing paradigm is currently lacking. Here, we use real-world clinical data to propose a financially effective diagnostic test algorithm in the context of new guidelines. METHODS: To determine the prevalence, distribution, neuroradiographic features (Visually Accessible REMBRANDT Images [VASARI]), and prognostic relevance of EGFR amplification in lower-grade gliomas, we assembled a consecutive series of diffuse gliomas. For validation we included publicly available data from The Cancer Genome Atlas. For a cost-utility analysis we compared combined EGFR and isocitrate dehydrogenase (IDH) testing, EGFR testing based on IDH results, and no EGFR testing. RESULTS: In n = 71 WHO grade II/III gliomas, we identified EGFR amplification in 28.2%. With one exception, all EGFR amplifications occurred in IDH-wildtype gliomas. Comparison of overall survival showed that EGFR amplification denotes a significantly more aggressive subset of tumors (P < 0.0001, log-rank). The radiologic phenotype in the EGFR-amplified tumors includes diffusion restriction (15%, P = 0.02), >5% tumor contrast enhancement (75%, P = 0.016), and mild (not avid) enhancement (P = 0.016). The proposed testing algorithm reserves EGFR fluorescence in situ hybridization (FISH) testing for IDH-wildtype cases. Implementation would result in ~37.9% cost reduction at our institution, or about $1.3-4 million nationally. CONCLUSION: EGFR-amplified diffuse gliomas are "glioblastoma-like" in their behavior and may represent undersampled glioblastomas, or subsets of IDH-wildtype diffuse gliomas with inherently aggressive biology. EGFR FISH after IDH testing is a financially effective and clinically relevant test algorithm for routine clinical practice.

Cost-effectiveness of IDH testing in diffuse gliomas according to the 2016 WHO classification of tumors of the central nervous system recommendations.

BACKGROUND: Due to the decreasing prevalence of IDH1 mutations in older patients, the 2016 World Health Organization (WHO) classification of brain tumors proposed not to perform sequencing for isocitrate dehydrogenase (IDH) in glioblastoma patients ≥55 years old. We present a cost-effectiveness analysis to estimate the financial impact of these guidelines. METHODS: From 2010 to 2015 we performed 1023 IDH tests in gliomas, amounting to ~$1.09 million in direct laboratory test costs. Samples were tested using R132H-specific immunohistochemistry, DNA sequencing validated for detection of noncanonical IDH1/2 mutations, or both methods. RESULTS: In cases tested by DNA sequencing, the fraction of non-R132H mutations was 5.4%, which included only 2 high-grade gliomas in patients ≥55 years (0.9%). When remodeling the optimal age cutoff in our patient population using 5-year age-binning, we found a 10-times higher pretest probability for the presence of a noncanonical IDH1 mutation in the setting of a negative IDH1-R132H immunohistochemistry result in patients <55 years. Applying the independently confirmed age cutoff of 55 years to glioblastoma patients (64%) would result in $403200 saved (43%). By not performing sequencing in patients ≥55 years, the turn-around time to final integrated neuropathological diagnosis is reduced by 53%, allowing these patients to gain earlier benefits from personalized genomic medicine. CONCLUSION: The negligible prevalence of noncanonical IDH mutations in glioblastoma patients ≥55 years argues against universal IDH sequencing in this population. We predict that adoption of this age-based sequencing cutoff recommendation from the 2016 WHO guidelines will result in significant cost and time savings throughout the global health care system.

The 2016 WHO classification of central nervous system tumors: what neurologists need to know.

PURPOSE OF REVIEW: The 2016 WHO classification of tumors of the central nervous system (2016 CNS WHO) features many changes that are relevant to neurologists treating patients with brain tumors as well as neurologists involved in basic, clinical, and epidemiological research. This review summarizes what neurologists need to know and will need to know in the next years. RECENT FINDINGS: The 2016 CNS WHO introduces diagnostic terms that 'integrate' histological and molecular information and suggests presenting diagnoses in a four-layered reporting format. In addition, it utilizes a 'not otherwise specified' designation to identify diagnostic categories that are not precisely defined. A better understanding of the biology of entities further led to changes in the tumor nosology, for example, diffuse gliomas based on IDH gene status. Meaningful molecular subgroups could also be identified in embryonal tumors and other entities. Given the pace of change in the field of brain tumor classification, there will likely be additional practical advances that emerge over the next few years. A new initiative entitled Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy intends to formulate recommendations between WHO updates. SUMMARY: The 2016 CNS WHO includes major changes in the way brain tumors are classified, with molecular parameters being incorporated into diagnostic criteria for a substantial number of such entities.

Sporadic NF2 Mosaic: Multiple spinal schwannomas presenting with severe, intractable pain following pregnancy.

The aim of the present paper is to report undiagnosed sporadic neurofibromatosis type 2 presenting with symptomatic compressive spinal tumors following pregnancy. A 36-year-old woman experienced progressive, severe lumbar radicular pain in the second trimester of pregnancy which became intractable soon after delivery. Magnetic resonance imaging revealed a complex heterogeneous hypointense mass lesion around the conus. There were two small punctate lesions in the cauda equina suggestive of myxopapillary ependymoma with 'drop metastases.' The patient underwent surgical resection of two cystic compressive conus masses. Her low back pain improved after surgery. The masses were consistent with cystic/cellular schwannomas. An incidental finding was of a small, low-grade spinal ependymoma which lacked the characteristic histologic features of myxopapillary ependymoma. Multiple, large cystic schwannomas are not uncommon in schwannomatosis, however, the co-occurrence of low-grade ependymoma strongly suggests a clinical diagnosis of new, sporadic neurofibromatosis type 2. Although cranial nerve schwannomas (orbital, auditory) have been reported to enlarge during pregnancy, to our knowledge, this is the first report of multiple cystic/cellular schwannomas causing severe pain (due to conus compression) during and immediately after pregnancy.

Thoracic exophytic ependymoma masquerading as a benign extra-axial tumor.

Spinal tumors are conventionally differentiated based on location in relation to the spinal cord. Benign spinal tumors such as schwannomas and meningiomas are typically extra-axial (intradural extramedullary) lesions, whereas more aggressive primary spinal tumors such as ependymomas are typically intramedullary masses. Rarely, ependymomas can have both intramedullary and extramedullary components (typically referred to as exophytic ependymomas). We report a case of a spinal exophytic ependymoma that radiographically masqueraded as a benign intradural extramedullary lesion causing cord compression and neurologic deficit in a 47-year-old man. The diagnosis of exophytic ependymoma was made intra-operatively, with resultant gross total resection of the extramedullary portion and subtotal resection of the intramedullary portion. Histopathological examination confirmed ependymoma with World Health Organization grade II/IV. Pre-operative suspicion of an exophytic ependymoma influences operative planning and clinical management. We review the literature and discuss clinical management strategies for these interesting spinal tumors.

Rapid Neurological Recovery Following Partial Surgical Resection of Spinal Glioblastoma Multiforme in a Pediatric Patient Presenting With Complete Paraplegia.

Pediatric spinal cord glioblastoma multiforme is a rare entity with a poor prognosis often presenting with lower extremity weakness or paralysis. Previous literature suggests that aggressive surgical resection may provide overall survival benefit; however, there is limited concurrent analysis demonstrating neurological recovery following surgical resection. We report the case of a 9-year-old boy who presented with complete paraplegia and regained the ability to ambulate independently following subtotal surgical resection, radiation, and chemotherapy. The case demonstrates the balance between meaningful neurological recovery and overall survival when deciding on the extent of resection in cases of pediatric spinal glioblastoma multiforme.

Multiple signaling pathways converge to regulate bone-morphogenetic-protein-dependent glial gene expression.

A fundamental problem in developmental neuroscience is understanding how extracellular cues link to complex intracellular signaling pathways to drive stage-specific developmental decisions. During the formation of the mammalian peripheral nervous system, bone morphogenetic proteins (BMPs) promote neuronal differentiation. BMPs also maintain the expression of early glial genes such as GFAP, while blocking the acquisition of a mature, myelinating Schwann cell phenotype. We investigated the BMP-activated signaling pathways that contribute to early glial gene expression to address the question of how specific signaling interactions contribute to cell fate decisions in neural crest lineages. Using a neural-crest-derived cell line that exhibits the characteristics of immature Schwann cells, we found that BMP2 promotes GFAP expression using Smad signaling as well as the phosphoinositide-3 kinase (PI3K) and mitogen-activated protein kinase1/2extracellular signal-regulated kinase- (MEK1/2/ERK) pathways. The GFAP promoter does not contain known Smad consensus sites, suggesting that Smads may act indirectly to promote GFAP expression. We provide evidence that this indirect effect may be mediated via induction of immediate early genes and the transcription factor Sp1 by demonstrating that these transcriptional regulators are induced by BMP2 and contribute to GFAP promoter activity. These findings demonstrate new roles for intracellular kinase pathways in mediating the effects of BMPs during the early stages of glial differentiation and suggest that differential contributions by signaling and transcriptional networks may contribute to the range of effects of BMPs on neuronal and glial development during the formation of the peripheral nervous system.