Pituitary Adenoma Coexistent with Sellar Clear Cell Meningioma Unattached to the Dura: Case Report and Treatment Considerations.

Collision tumors involving the sella are rare. Intrasellar collision tumors are most commonly composed of a combination of pituitary adenomas and pituitary neuroendocrine tumors; however, collision tumors consisting of a pituitary adenoma and intrasellar meningioma are exceedingly rare. The authors present the case of a 47-year-old man who presented with progressive right eye vision loss. Magnetic resonance imaging showed a large, heterogeneously enhancing sellar mass with suprasellar extension. Using a transcranial approach with a right subfrontal craniotomy, near-total resection of the mass was achieved. Histologic analysis confirmed a diagnosis of a gonadotroph adenoma with concomitant clear cell meningioma (CCM). This patient was discharged with improvement in visual acuity and no signs of diabetes insipidus. Given the indistinguishable radiographic characteristics of pituitary adenoma and CCM, a preoperative diagnosis of a collision tumor was difficult. This case was uniquely challenging since the CCM component lacked the classic dural attachment that is associated with meningiomas on neuroimaging. CCMs are classified as central nervous system (CNS) World Health Organization (WHO) grade 2 tumors and tend to behave more aggressively, therefore warranting close surveillance for signs of tumor recurrence. This is the first case to report a collision tumor consisting of pituitary adenoma and CCM.

Unusual features of neurosarcoidosis: A 18-year retrospective.

BACKGROUND: Neurosarcoidosis (NS) is a challenging diagnosis for clinicians and pathologists. NS most often presents with leptomeningeal involvement where it mimics infectious or neoplastic meningitis, and in up to half of cases, systemic signs of sarcoidosis are lacking. Rare presentations include dural-based mass(es) (mimicking meningioma), hypothalamic/sellar-based lesions (mimicking pituitary adenoma), or as myelopathy (mimicking tumor or neurodegenerative condition). For pathologists, the morphological effects of prior therapy are not well documented. NS as an unsuspected cause of demise today is even less well known. METHODS: Search of departmental databases and personal files, 2004-2022, for NS cases, with focus on the subset with features of interest to pathologists. RESULTS: 22 cases were identified (8 M: 14F, 13-66 years), in 11 of which the CNS specimen represented first diagnosis of sarcoidosis. 20 were surgical and 2 were autopsy cases. Focus of the study revolved around 2 surgical cases with NS granulomas intimately admixed with tumor (1 meningoma, 1 gonadotroph pituitary adenoma/pituitary neuroendocrine tumor (PitNET). One surgical and one autopsy case each had decrease in lymphocytes and well-formed granulomas, with increased fibrosis and hemosiderin in post-treatment tissues. We speculate, but cannot prove, that this may be due to prior steroid therapy. Both autopsy cases were women (38, 43-years), both with cauda equina syndrome/ progressive weakness as first presentation, and extensive spinal cord/nerve root sarcoidosis at demise. First diagnosis of NS/sarcoidosis was at autopsy in the 38-year-old. CONCLUSIONS: Unusual features for pathologists are that NS can co-exist within benign tumors, prior therapy alters histological features, and even in the modern era, may be first diagnosed at autopsy.

Double-stranded RNA immunohistochemistry as a screening tool for viral encephalitis.

OBJECTIVES: Viral infections of the central nervous system can be challenging to diagnose because of the wide range of causative agents and nonspecific histologic features. We sought to determine whether detection of double-stranded RNA (dsRNA), produced during active RNA and DNA viral infections, could be used to select cases for metagenomic next-generation sequencing (mNGS) from formalin-fixed, paraffin-embedded brain tissue. METHODS: Eight commercially available anti-dsRNA antibodies were optimized for immunohistochemistry (IHC) and the top antibody tested in a series of cases with confirmed viral infections (n = 34) and cases with inflammatory brain lesions of unclear etiology (n = 62). RESULTS: Among known positives, anti-dsRNA IHC produced a strong cytoplasmic or nuclear staining pattern for Powassan virus, West Nile virus, rabies virus, JC polyoma virus, and adenovirus while failing to detect Eastern equine encephalitis virus, Jamestown Canyon virus, or any herpesvirus. All the unknown cases were negative by anti-dsRNA IHC, while mNGS detected rare viral reads (0.3-1.3 reads per million total reads) in 2 cases (3%), with only 1 having potential clinical significance. CONCLUSIONS: Anti-dsRNA IHC can effectively identify a subset of clinically relevant viral infections but not all. The absence of staining should not exclude cases from mNGS if sufficient clinical and histologic suspicion exists.

Urothelial carcinoma metastases impacting the CNS: A 20-year retrospective series.

INTRODUCTION: Our group has a longstanding interest in metastases impacting the central nervous system (CNS), including spread from prostatic adenocarcinomas, thyroid carcinomas, and breast carcinomas, most of which metastasize to CNS sites at a later time after the primary tumor is well-known. However, one of the least frequent types of systemic malignancies to metastasize to brain or spine is urothelial carcinoma. Thus, few large studies from a single institution exist. Fewer still detail the interval between first diagnosis of primary tumor and CNS lesion, or whether a patient might have their first presentation of cancer in the brain or spine, thus prompting review of our 20-year experience. MATERIALS: Case identification via text word search of pathology databases from our adult and referral hospitals, 2002 to present. Demographic and clinical data were extracted from reports and the medical record. RESULTS: 15 cases, 11 male: 4 female, age range 37-82 years were identified. Nine had metastases to brain parenchyma, 5 to vertebral column impacting spinal cord, and 2 to skull, one of which had tumor extension into right parietal lobe. Strikingly, 5 of 15 patients had had their CNS-impacting metastasis as their first presentation of neoplastic disease. CONCLUSIONS: CNS metastasis of urothelial carcinoma is a rare occurrence; nevertheless, pathologists should include urothelial carcinoma in their differential diagnosis as a type of cancer that can first present with a CNS-impacting metastasis.

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.

Expanded analysis of high-grade astrocytoma with piloid features identifies an epigenetically and clinically distinct subtype associated with neurofibromatosis type 1.

High-grade astrocytoma with piloid features (HGAP) is a recently recognized glioma type whose classification is dependent on its global epigenetic signature. HGAP is characterized by alterations in the mitogen-activated protein kinase (MAPK) pathway, often co-occurring with CDKN2A/B homozygous deletion and/or ATRX mutation. Experience with HGAP is limited and to better understand this tumor type, we evaluated an expanded cohort of patients (n = 144) with these tumors, as defined by DNA methylation array testing, with a subset additionally evaluated by next-generation sequencing (NGS). Among evaluable cases, we confirmed the high prevalence CDKN2A/B homozygous deletion, and/or ATRX mutations/loss in this tumor type, along with a subset showing NF1 alterations. Five of 93 (5.4%) cases sequenced harbored TP53 mutations and RNA fusion analysis identified a single tumor containing an NTRK2 gene fusion, neither of which have been previously reported in HGAP. Clustering analysis revealed the presence of three distinct HGAP subtypes (or groups = g) based on whole-genome DNA methylation patterns, which we provisionally designated as gNF1 (n = 18), g1 (n = 72), and g2 (n = 54) (median ages 43.5 years, 47 years, and 32 years, respectively). Subtype gNF1 is notable for enrichment with patients with Neurofibromatosis Type 1 (33.3%, p = 0.0008), confinement to the posterior fossa, hypermethylation in the NF1 enhancer region, a trend towards decreased progression-free survival (p = 0.0579), RNA processing pathway dysregulation, and elevated non-neoplastic glia and neuron cell content (p < 0.0001 and p < 0.0001, respectively). Overall, our expanded cohort broadens the genetic, epigenetic, and clinical phenotype of HGAP and provides evidence for distinct epigenetic subtypes in this tumor type.

Diagnostic challenges of neurosarcoidosis in non-endemic areas.

Background: Neurosarcoidosis (NS) is a challenging diagnosis, particularly when cases occur in low-prevalence, non-endemic geographic regions. In the United States, the highest incidence is in the Midwest and Northeast, compared to our Southwest location. While it is well known that NS may clinically and neuroradiographically mimic meningeal carcinomatosis, autoimmune or infectious pachymeningitis, neurosyphilis, or tuberculosis, diagnosis may be particularly challenging if systemic signs of sarcoidosis are lacking or unconfirmed or if dural-based masses are present. We reviewed our Colorado experience with NS cases, focusing our study on cases where NS represented the first histological confirmation of disease. Methods: A search of departmental databases was conducted with the search term "neurosarcoidosis" to identify cases 1-2008 to 12-2019, inclusive of the given case numbers. Patients were only included if their clinical and neuroimaging features were unusual and only when a biopsy of the central nervous system (CNS) represented the first confirmed diagnosis of sarcoidosis. Results: A total of 17 cases were identified, of which the biopsy of the CNS was used for the initial confirmation of the disease in 9 of them. The most unusual findings were two patients with dural-based masses, one of which had pure NS as the cause of meningioma-like lesions and the second of which had coexistent meningioma and intimately admixed non-necrotizing granulomas of NS. Conclusion: NS with unusual features, especially in non-endemic areas, continues to yield diagnostic challenges for neurologists, neuroradiologists, and pathologists.

Extra-CNS and dural metastases in FGFR3::TACC3 fusion+ adult glioblastoma, IDH-wildtype.

Background: Adult glioblastomas (GBMs), IDH-wildtype, WHO grade 4 with FGFR3::TACC3 fusion have a better prognosis than standard GBMs. Whether this extended survival leads to late biological consequences is unknown. Although constituting only 4% of all GBMs, FGFR3::TACC3 fusion-positive GBMs manifest recurrent morphological features that allow prediction of this subtype, possibly affecting trial eligibility and/or targeted therapies. However, we have previously shown that an identical histological pattern can be present in wildtype examples, and conversely, occasional FGFR3::TACC3 fusion-positive tumors lack this stereotypic morphology; thus, ultimately molecular characterization is required. We now report for the first time an adult with FGFR3::TACC3 fusion-positive GBM showing archetypal histological features who developed extracranial metastases to provide further insight into potential behavior of the GBM type. Methods: Report of a 70-year-old man with left parietal GBM who developed 2 subsequent metastases, all 3 of which were assessed by next-generation sequencing (NGS) and DNA methylation. Results: Biopsy-proven dural metastases occurred at 8 months and cervical lymph node metastasis at 12-month post-diagnosis before the patient succumbed at 23 months. By NGS, all 3 tumors showed FGFR3::TACC3 fusion as well as an additional PDZD2::TERT fusion of uncertain significance. DNA methylation profiling demonstrated mesenchymal subtype in the initial biopsy and RTKII subtype in subsequent dural and lymph node metastases, indicating intratumor spatial heterogeneity or temporal evolution. Conclusion: Rarely, FGFR3::TACC3 fusion-positive GBM patients may develop dural and extracranial metastatic spread, the latter with subclass switching on epigenomic analysis.

Alpha-synuclein supports type 1 interferon signalling in neurons and brain tissue.

The protein alpha-synuclein is predominantly expressed in neurons and is associated with neurodegenerative diseases like Parkinson's disease and dementia with Lewy bodies. However, the normal function of alpha-synuclein in neurons is not clearly defined. We have previously shown that mice lacking alpha-synuclein expression exhibit markedly increased viral growth in the brain, increased mortality and increased neuronal cell death, implicating alpha-synuclein in the neuronal innate immune response. To investigate the mechanism of alpha-synuclein-induced immune responses to viral infections in the brain, we challenged alpha-synuclein knockout mice and human alpha-synuclein knockout dopaminergic neurons with RNA virus infection and discovered that alpha-synuclein is required for neuronal expression of interferon-stimulated genes. Furthermore, human alpha-synuclein knockout neurons treated with type 1 interferon failed to induce a broad range of interferon stimulated genes, implying that alpha-synuclein interacts with type 1 interferon signalling. We next found that alpha-synuclein accumulates in the nucleus of interferon-treated human neurons after interferon treatment and we demonstrated that interferon-mediated phosphorylation of STAT2 is dependent on alpha-synuclein expression in human neurons. Next, we found that activated STAT2 co-localizes with alpha-synuclein following type 1 interferon stimulation in neurons. Finally, we found that brain tissue from patients with viral encephalitis expresses increased levels of phospho-serine129 alpha-synuclein in neurons. Taken together, our results show that alpha-synuclein expression supports neuron-specific interferon responses by localizing to the nucleus, supporting STAT2 activation, co-localizing with phosphorylated STAT2 in neurons and supporting expression of interferon-stimulated genes. These data provide a novel mechanism that links interferon activation and alpha-synuclein function in neurons.

Myxoid glioneuronal tumor, PDGFRA p.K385L-mutant, arising in midbrain tectum with multifocal CSF dissemination.

This myxoid glioneuronal tumor, PDGFRA p.K385L-mutant, arose in the midbrain tectum rather than in the septum pellucidum, as in the previously-reported cases.

Histopathologic features of nasal glial heterotopia (nasal glioma).

PURPOSE: Nasal glioneuronal heterotopia (NGH) is an uncommon developmental abnormality of the nasal cavity or paranasal soft tissue. Few detailed histologic studies of NGH exist, and molecular analyses have not been performed to date. METHODS: We describe six cases of pediatric NGH and two representative encephaloceles encountered in our practice over the past 20 years. RESULTS: Two clinically distinct patient groups were noted, those with 1) intranasal nasal cavity mass (n = 3), or 2) extranasal cutaneous mass on the nose (n = 3, 1 on nasal apex, 2 on nasal bridge). Intranasal cases presented within the first week of life, whereas the extranasal NGH presented at ages of 4, 7, and 8 months. Resection was curative in 5/6 cases, with a single case showing local recurrence. Histologic examination showed a predominantly glial cell composition, with nests of GFAP-immunoreactive neuropil containing large, often multinucleated astrocytes. Neurons, although difficult to identify on H&E-stains, were readily observed in all cases by NeuN-immunostain. At least focal leptomeninges were noted in 2/3 intranasal and 1/3 extranasal NGHs on routine histology, SSTR2A immunohistochemistry further confirmed leptomeninges/ arachnoid cells in 4/6 cases. 1 of 4 NGH (extranasal) cases showed copy number variations in chromosome 16, 17 and 19, which were also present in 1/2 encephalocele cases. The full significance of these alterations remains unknown. CONCLUSION: We find evidence of histologic overlap between NGH and encephalocele, and, for the first time, report molecular alterations shared between the two entities, suggesting that these conditions may represent spectrum of the same histopathologic entity.

Metastases to the Pituitary Gland: Histological Patterns of Spread and Review of the Literature.

Few studies have focused on histological patterns of metastatic spread to the pituitary gland. We review our experience and that in the literature, 1970-present. Departmental cases, 1998-2021, were assessed for anterior versus posterior gland and/or capsular involvement and cohesive tumor obliterating underlying pituitary architecture versus metastatic cells filling pituitary acini with relative acinar preservation. Eleven autopsy/15 surgical cases, including 2 metastases to pituitary adenomas, were identified. Cohesive/obliterative patterns predominated histologically in both surgical and autopsy cases, but acinar filling by metastatic cells was extensive in 3/26 cases, focal in 5/26, and had resulted in initial erroneous impressions of atypical pituitary adenoma/pituitary carcinoma in 1 case and pituitary adenoma with apoplexy in another, likely due to focusing on necrotic areas in the specimen where the acinar pattern had been broken down and not appreciating nearby areas with acinar filling by metastatic cells. Although most pituitary metastases produce readily identifiable cohesive/obliterative patterns, diagnostic challenges remain with the less frequently seen "acinar filling" pattern. A dichotomy exists between patients with symptomatic pituitary metastases occurring early in the disease course and requiring surgical excision versus patients in whom asymptomatic small pituitary metastases are found incidentally at autopsy, the latter almost invariably in late disease stages, with widely disseminated metastatic disease.

Clinical Features of Pineal Parenchymal Tumors of Intermediate Differentiation (PPTID): A Single-Institution Series.

OBJECTIVE: Pineal parenchymal tumors of intermediate differentiation (PPTID) are rare tumors of the pineal gland. Their treatment is often heterogeneous due to the lack of literature to compile standardized treatments. Although no single institution has large numbers of cases, our experience has been that the clinical course is more varied and complicated than reported. METHODS: We reviewed the clinical data for all patients with pathology found to be consistent with PPTID at our institution between the years 2006 and 2019. RESULTS: Nine patients were identified. At initial diagnosis, all were treated with surgery and 4 of 9 patients underwent gross total resection. Adjuvant radiation therapy to the resection bed was administered in 6 of 9 patients. Mean follow-up time was 95.3 months. Mean progression-free survival was 50.5 months, with a tendency to be longer for male sex and after gross total resection. Seven patients developed a recurrence. Five of 6 known locations of first recurrences had either distant metastases or dissemination of disease. First recurrences were treated with radiation alone in 5 patients, craniospinal radiation with multiagent chemotherapy in 1 patient, and surgery with radiation therapy in 1. At last follow-up, 2 patients had died. CONCLUSIONS: Herein, we report clinical patterns of disease progression and treatment patterns of PPTID. Many patients progressed during the follow-up period. Disseminated disease was the most common presentation at recurrence. Ultimately, given the risk of recurrence and dissemination at recurrence, more aggressive treatment strategies should be considered. Specifically, our series suggests a benefit of adjuvant radiation at initial diagnosis for grade II patients.

Secondary parenchymal CNS involvement by lymphoma including rare types: Follicular and EBV-positive NK/T cell lymphoma, nasal type.

BACKGROUND: Secondary CNS involvement by systemic lymphomas (SCNSL) is uncommon, but when it occurs, is usually due to diffuse large B cell lymphoma (DLBCL). Three recent unusual cases serve to highlight diagnostic challenges. OBJECTIVE: To report SCNSL from DLBCL and two unusual lymphoma types: follicular lymphoma with high-grade transformation to DLBCL and NK/T cell lymphoma, nasal type (ENKL), nasal type. RESULTS: SCNSL in the DLBCL case occurred at 7-year interval from primary in a 54-year-old woman who presented with stroke-like symptoms and a right postcentral gyrus 2.6 × 2.9 × 2.6 cm. mass. The follicular lymphoma occurred at 6-month interval in a 69-year-old woman with 1 month of diplopia and 2 weeks of cognitive decline; multifocal lesions involved temporal lobe, subependymal periventricular areas, brainstem, cerebellum, hypothalamus, corpus callosum and gyrus rectus. The ENKL occurred at 25-month interval from nasal biopsy in a 45-year-old man with 1 week of altered mental status; multifocal cerebral and brainstem lesions were identified. Histological features in cases 1 and 3 were identical to the primary lymphoma, with high-grade transformation to DLBCL in the follicular lymphoma. CONCLUSION: Unusual features in our series include longer interval from primary to relapse in case 1 with DLBCL (usually <2 years of diagnosis), and SCNSL occurring from either follicular lymphoma or EKNL, nasal type (<6% of cases). Pathologists play an important role in excluding infectious, especially in cases with parenchymal lesions and characterizing the lymphoma type in SCNSL.

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.

Clinical and molecular characterization of a multi-institutional cohort of pediatric spinal cord low-grade gliomas.

BACKGROUND: The mitogen-activated protein kinases/extracelluar signal-regulated kinases pathway is involved in cell growth and proliferation, and mutations in BRAF have made it an oncogene of interest in pediatric cancer. Previous studies found that BRAF mutations as well as KIAA1549-BRAF fusions are common in intracranial low-grade gliomas (LGGs). Fewer studies have tested for the presence of these genetic changes in spinal LGGs. The aim of this study was to better understand the prevalence of BRAF and other genetic aberrations in spinal LGG. METHODS: We retrospectively analyzed 46 spinal gliomas from patients aged 1-25 years from Children's Hospital Colorado (CHCO) and The Hospital for Sick Children (SickKids). CHCO utilized a 67-gene panel that assessed BRAF and additionally screened for other possible genetic abnormalities of interest. At SickKids, BRAF V600E was assessed by droplet digital polymerase chain reaction and immunohistochemistry. BRAF fusions were detected by fluorescence in situ hybridization, reverse transcription polymerase chain reaction, or NanoString platform. Data were correlated with clinical information. RESULTS: Of 31 samples with complete fusion analysis, 13 (42%) harbored KIAA1549-BRAF. All 13 (100%) patients with confirmed KIAA1549-BRAF survived the entirety of the study period (median [interquartile range] follow-up time: 47 months [27-85 months]) and 15 (83.3%) fusion-negative patients survived (follow-up time: 37.5 months [19.8-69.5 months]). Other mutations of interest were also identified in this patient cohort including BRAF V600E , PTPN11, H3F3A, TP53, FGFR1, and CDKN2A deletion. CONCLUSION: KIAA1549-BRAF was seen in higher frequency than BRAF V600E or other genetic aberrations in pediatric spinal LGGs and experienced lower death rates compared to KIAA1549-BRAF negative patients, although this was not statistically significant.

Glioblastoma as an autoimmune limbic encephalitis mimic: A case and review of the literature.

A 43-year-old woman presented with cognitive decline, focal seizures, brain MRI showing non-enhancing, bilateral hippocampal lesions, but normal cerebrospinal fluid findings, which fulfilled the Graus et al., 2016 criteria for autoimmune limbic encephalitis (ALE). Subjective improvements were observed after immunotherapy. A repeat brain MRI showed new contrast enhancement and positron emission tomography revealed left hippocampal uptake. Biopsy of the right parahippocampus yielded high-grade glioma. Five similar cases, among the 14 with unilateral hippocampal lesions on MRI, were identified in the literature whereby suspected ALE preceded the high-grade glioma diagnosis. Gliomas confined to hippocampi can have clinical features overlapping with ALE.

Targetable molecular alterations in congenital glioblastoma.

INTRODUCTION: Congenital glioblastomas (cGBMs) are uncommon tumors presenting in early infancy, variably defined as diagnosed at birth or at age less than 3 months by strict criteria, or more loosely, as occurring in very young children less than 12 months of age. Previous studies have shown that cGBMs are histologically indistinguishable from GBMs in older children or adults, but may have a more favorable clinical outcome, suggesting biological differences between congenital versus other GBMs. Due to the infrequency of cGBMs, especially when employing strict inclusion criteria, molecular features have not been sufficiently explored. METHODS: Archer FusionPlex Solid Tumor Kit, Archer VariantPlex Solid Tumor Kit, Illumina RNAseq were utilized to study cGBMs seen at our institution since 2002. A strict definition for cGBM was utilized, with only infants less than age 3 months at clinical presentation sought for this study. RESULTS: Of the 8 cGBM cases identified in our files, 7 had sufficient materials for molecular analyses, and 3 of 7 cases analyzed showed fusions of the ALK gene (involving MAP4, MZT2Bex2 and EML4 genes as fusion partners). One case showed ROS1 fusion. Somatic mutations in TSC22D1, BMG1 and DGCR6 were identified in 1 case. None of the cases showed alterations in IDH1/2, histone genes, or the TERT gene, alterations which can be associated with GBMs in older children or adults. CONCLUSIONS: Our results show that cGBMs are genetically heterogeneous and biologically different from pediatric and adult GBMs. Identification of ALK and ROS1 raise the possibility of targeted therapy with FDA-approved targeted inhibitors.

Neuropathological Findings in a Case of IFIH1-Related Aicardi-Goutières Syndrome.

Aicardi-Goutières syndrome (AGS) is a rare syndrome characterized by calcification, diffuse demyelination, and variable degree of brain atrophy. The syndrome is genetically heterogeneous with mutations in 7 genes, including TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, and IFIH1 (interferon-induced helicase c domain-containing protein 1) associated with the syndrome, so far. These mutations lead to the overproduction of α-interferon within the central nervous system. Mutations in IFIH1 have been recently described in a subset of AGS, with only 1 previous report of neuropathological findings. We report neuropathological findings in a second case of AGS with a known mutation in IFIH1 gene. The patient is a 16-year-old adolescent boy with early-onset symptoms that progressed to profound loss of cognitive and motor functions. The patient experienced sudden cardiopulmonary arrest at the age of 16 years. At autopsy, the cause of death was determined to be pulmonary thromboembolism. Neuropathological examination revealed microcephaly (brain weight: 916 g) with relatively mild brain atrophy on gross examination. Microscopic examination revealed multifocal calcifications limited to small to medium central nervous system arteries (no evidence of calcification in other organs), involving bilateral cerebral cortex, basal ganglia, thalamus, and cerebellum. Ultrastructural examination showed Calcospherules limited to the vessel walls and the perivasulcar area without evidence of neuronal ferrugination or tubuloreticular bodies. The extent of calcifications was variable across different brain regions, resembling findings in previously reported cases and correlated with the extent of IFIH1 protein expression (data derived from Allen Brain Institute). AGS is a rare cause of brain calcifications that can closely mimic congenital and neonatal infections such as Rubella and similar infections.