Publications by authors named "David A Solomon"

164 Publications

Genetic and epigenetic characterization of posterior pituitary tumors.

Acta Neuropathol 2021 Oct 18. Epub 2021 Oct 18.

Department of Pathology, Neuropathology, University of Virginia Health System, Charlottesville, Virginia, USA.

Pituicytoma (PITUI), granular cell tumor (GCT), and spindle cell oncocytoma (SCO) are rare tumors of the posterior pituitary. Histologically, they may be challenging to distinguish and have been proposed to represent a histological spectrum of a single entity. We performed targeted next-generation sequencing, DNA methylation profiling, and copy number analysis on 47 tumors (14 PITUI; 12 GCT; 21 SCO) to investigate molecular features and explore possibilities of clinically meaningful tumor subclassification. We detected two main epigenomic subgroups by unsupervised clustering of DNA methylation data, though the overall methylation differences were subtle. The largest group (n = 23) contained most PITUIs and a subset of SCOs and was enriched for pathogenic mutations within genes in the MAPK/PI3K pathways (12/17 [71%] of sequenced tumors: FGFR1 (3), HRAS (3), BRAF (2), NF1 (2), CBL (1), MAP2K2 (1), PTEN (1)) and two with accompanying TERT promoter mutation. The second group (n = 16) contained most GCTs and a subset of SCOs, all of which mostly lacked identifiable genetic drivers. Outcome analysis demonstrated that the presence of chromosomal imbalances was significantly associated with reduced progression-free survival especially within the combined PITUI and SCO group (p = 0.031). In summary, we observed only subtle DNA methylation differences between posterior pituitary tumors, indicating that these tumors may be best classified as subtypes of a single entity. Nevertheless, our data indicate differences in mutation patterns and clinical outcome. For a clinically meaningful subclassification, we propose a combined histo-molecular approach into three subtypes: one subtype is defined by granular cell histology, scarcity of identifiable oncogenic mutations, and favorable outcome. The other two subtypes have either SCO or PITUI histology but are segregated by chromosomal copy number profile into a favorable group (no copy number changes) and a less favorable group (copy number imbalances present). Both of the latter groups have recurrent MAPK/PI3K genetic alterations that represent potential therapeutic targets.
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http://dx.doi.org/10.1007/s00401-021-02377-1DOI Listing
October 2021

Deconvoluting Mechanisms of Acquired Resistance to RAF Inhibitors in BRAF-Mutant Human Glioma.

Clin Cancer Res 2021 Aug 25. Epub 2021 Aug 25.

Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado.

Purpose: Selective RAF-targeted therapy is effective in some patients with BRAF-mutated glioma, though emergent and adaptive resistance occurs through ill-defined mechanisms.

Experimental Design: Paired pre-/post- RAF inhibitor (RAFi)-treated glioma samples ( = 15) were obtained and queried for treatment-emergent genomic alterations using DNA and RNA sequencing (RNA-seq). Functional validation of putative resistance mechanisms was performed using established and patient-derived BRAF-mutant glioma cell lines.

Results: Analysis of 15 tissue sample pairs identified 13 alterations conferring putative resistance were identified among nine paired samples (including mutations involving , and ). We performed functional validation of mechanisms of resistance, including loss of , or , in BRAF-mutant glioma lines, and demonstrate they are capable of conferring resistance . Knockdown of CBL resulted in increased expression and phosphorylation, a possible mechanism for maintaining ERK signaling within the cell. Combination therapy with a MEKi or EGFR inhibitor was able to overcome resistance to BRAFi, in NF1 knockdown and CBL knockdown, respectively. Restoration of wild-type PTEN in B76 cells (PTEN) restored sensitivity to BRAFi. We identified and validated CRAF upregulation as a mechanism of resistance in one resistant sample. RNA-seq analysis identified two emergent expression patterns in resistant samples, consistent with expression patterns of known glioma subtypes.

Conclusions: Resistance mechanisms to BRAFi in glioma are varied and may predict effective precision combinations of targeted therapy, highlighting the importance of a personalized approach.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-2660DOI Listing
August 2021

A multicenter analysis of the prognostic value of histone H3 K27M mutation in adult high-grade spinal glioma.

J Neurosurg Spine 2021 Aug 20:1-10. Epub 2021 Aug 20.

1Department of Neurosurgery, Mayo Clinic, Jacksonville, Florida.

Objective: High-grade spinal glioma (HGSG) is a rare but aggressive tumor that occurs in both adults and children. Histone H3 K27M mutation correlates with poor prognosis in children with diffuse midline glioma. However, the role of H3 K27M mutation in the prognosis of adults with HGSG remains unclear owing to the rarity of this mutation, conflicting reports, and the absence of multicenter studies on this topic.

Methods: The authors studied a cohort of 30 adult patients with diffuse HGSG who underwent histological confirmation of diagnosis, surgical intervention, and treatment between January 2000 and July 2020 at six tertiary academic centers. The primary outcome was the effect of H3 K27M mutation status on progression-free survival (PFS) and overall survival (OS).

Results: Thirty patients (18 males and 12 females) with a median (range) age of 50.5 (19-76) years were included in the analysis. Eighteen patients had H3 K27M mutation-positive tumors, and 12 had H3 K27M mutation-negative tumors. The median (interquartile range) PFS was 3 (10) months, and the median (interquartile range) OS was 9 (23) months. The factors associated with increased survival were treatment with concurrent chemotherapy/radiation (p = 0.006 for PFS, and p ≤ 0.001 for OS) and American Spinal Injury Association grade C or better at presentation (p = 0.043 for PFS, and p < 0.001 for OS). There were no significant differences in outcomes based on tumor location, extent of resection, sex, or H3 K27M mutation status. Analysis restricted to HGSG containing necrosis and/or microvascular proliferation (WHO grade IV histological features) revealed increased OS for patients with H3 K27M mutation-positive tumors (p = 0.017).

Conclusions: Although H3 K27M mutant-positive HGSG was associated with poor outcomes in adult patients, the outcomes of patients with H3 K27M mutant-positive HGSG were somewhat more favorable compared with those of their H3 K27M mutant-negative HGSG counterparts. Further preclinical animal studies and larger clinical studies are needed to further understand the age-dependent effects of H3 K27M mutation.
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http://dx.doi.org/10.3171/2021.2.SPINE201675DOI Listing
August 2021

Sarcomatous Meningioma: Diagnostic Pitfalls and the Utility of Molecular Testing.

J Neuropathol Exp Neurol 2021 Sep;80(8):764-768

Department of Pathology, San Francisco, California, USA.

Anaplastic meningiomas can have a sarcomatous appearance on histology but true sarcomatous (metaplastic) differentiation is rare. These tumors follow an aggressive clinical course with recurrence and poor clinical outcomes. Due to significant overlap in morphology and immunohistochemical profiles, distinguishing between sarcomatous transformation of a meningioma and a true sarcoma can be challenging. Here, we outline potential diagnostic pitfalls and the utility of ancillary molecular testing in 3 patients diagnosed with sarcomatous meningiomas. We report loss of typical meningothelial markers in sarcomatous meningiomas. Ancillary molecular testing can support the diagnosis of sarcomatous meningioma when a molecular signature consistent with meningioma is seen, such as inactivation of the NF2 gene. Recognition of this rare transformation in meningioma can prevent a misdiagnosis of a primary sarcoma, whether sporadic or radiation-induced from prior treatment of a more classic meningioma.
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http://dx.doi.org/10.1093/jnen/nlab053DOI Listing
September 2021

Molecular characterisation of sporadic endolymphatic sac tumours and comparison to von Hippel-Lindau disease-related tumours.

Neuropathol Appl Neurobiol 2021 10 24;47(6):756-767. Epub 2021 Jun 24.

Department of Neuropathology, Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.

Aims: Although inactivation of the von Hippel-Lindau gene (VHL) on chromosome 3p25 is considered to be the major cause of hereditary endolymphatic sac tumours (ELSTs), the genetic background of sporadic ELST is largely unknown. The aim of this study was to determine the prevalence of VHL mutations in sporadic ELSTs and compare their characteristics to VHL-disease-related tumours.

Methods: Genetic and epigenetic alterations were compared between 11 sporadic and 11 VHL-disease-related ELSTs by targeted sequencing and DNA methylation analysis.

Results: VHL mutations and small deletions detected by targeted deep sequencing were identified in 9/11 sporadic ELSTs (82%). No other cancer-related genetic pathway was altered except for TERT promoter mutations in two sporadic ELST and one VHL-disease-related ELST (15%). Loss of heterozygosity of chromosome 3 was found in 6/10 (60%) VHL-disease-related and 10/11 (91%) sporadic ELSTs resulting in biallelic VHL inactivation in 8/10 (73%) sporadic ELSTs. DNA methylation profiling did not reveal differences between sporadic and VHL-disease-related ELSTs but reliably distinguished ELST from morphological mimics of the cerebellopontine angle. VHL patients were significantly younger at disease onset compared to sporadic ELSTs (29 vs. 52 years, p < 0.0001, Fisher's exact test). VHL-disease status was not associated with an increased risk of recurrence, but the presence of clear cells was found to be associated with shorter progression-free survival (p = 0.0002, log-rank test).

Conclusion: Biallelic inactivation of VHL is the main mechanism underlying ELSTs, but unknown mechanisms beyond VHL may rarely be involved in the pathogenesis of sporadic ELSTs.
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http://dx.doi.org/10.1111/nan.12741DOI Listing
October 2021

Temozolomide-induced hypermutation is associated with distant recurrence and reduced survival after high-grade transformation of low-grade IDH-mutant gliomas.

Neuro Oncol 2021 Apr 5. Epub 2021 Apr 5.

Department of Neurological Surgery, University of California, San Francisco, CA, USA.

Background: Chemotherapy improves overall survival after surgery and radiotherapy for newly diagnosed high-risk IDH-mutant low-grade gliomas, but a proportion of patients treated with temozolomide (TMZ) will develop recurrent tumors with TMZ-induced hypermutation. We aimed to determine the prevalence of TMZ-induced hypermutation at recurrence and prognostic implications.

Methods: We sequenced recurrent tumors from 82 patients with initially low-grade IDH-mutant gliomas who underwent re-operation and correlated hypermutation status with grade at recurrence and subsequent clinical outcomes.

Results: Hypermutation was associated with high-grade disease at the time of re-operation (OR 12.0 95% CI 2.5-115.5, p=0.002) and was identified at transformation in 57% of recurrent LGGs previously exposed to TMZ. After anaplastic (grade III) transformation, hypermutation was associated with shorter survival on univariate and multivariate analysis (HR 3.4, 95% CI 1.2-9.9, p=0.024), controlling for tumor grade, subtype, age, and prior radiotherapy. The effect of hypermutation on survival after transformation was validated in an independent, published dataset. Hypermutated (HM) tumors were more likely to develop discontiguous foci of disease in the brain and spine (p=0.003). To estimate the overall incidence of high-grade transformation among low-grade IDH-mutant tumors, data from a phase II trial of TMZ for LGG were analyzed. 8-year transformation-free survival was 53.8% (95% CI 42.8-69.2) and 61% of analyzed transformed cases were HM.

Conclusions: TMZ-induced hypermutation is a common event in transformed LGG previously treated with TMZ, and is associated with worse prognosis and development of discontiguous disease after recurrence. These findings impact tumor classification at recurrence, prognostication, and clinical trial design.
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http://dx.doi.org/10.1093/neuonc/noab081DOI Listing
April 2021

Clinical, radiologic, and genetic characteristics of histone H3 K27M-mutant diffuse midline gliomas in adults.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa142. Epub 2020 Oct 22.

Department of Neurological Surgery, University of California, San Francisco, San Francisco, California, USA.

Background: "Diffuse midline glioma (DMG), H3 K27M-mutant" is a new tumor entity established in the 2016 WHO classification of Tumors of the Central Nervous System that comprises a set of diffuse gliomas arising in midline structures and is molecularly defined by a K27M mutation in genes encoding the histone 3 variants H3.3 or H3.1. While this tumor entity is associated with poor prognosis in children, clinical experience in adults remains limited.

Methods: Patient demographics, radiologic and pathologic characteristics, treatment course, progression, and patient survival were collected for 60 adult patients with DMG, H3 K27M-mutant. A subset of tumors also underwent next-generation sequencing. Analysis of progression-free survival and overall survival was conducted using Kaplan-Meier modeling, and univariate and multivariate analysis.

Results: Median patient age was 32 years (range 18-71 years). Tumors were centered in the thalamus ( = 34), spinal cord (10), brainstem (5), cerebellum (4), or other midline sites (4), or were multifocal (3). Genomic profiling revealed p.K27M mutations exclusively in the gene and an absence of mutations in , which are present in approximately one-third of pediatric DMGs. Accompanying mutations in , , , , and were frequently found. The overall survival of this adult cohort was 27.6 months, longer than historical averages for both H3 K27M-mutant DMG in children and IDH-wildtype glioblastoma in adults.

Conclusions: Together, these findings indicate that H3 K27M-mutant DMG represents a heterogeneous disease with regard to outcomes, sites of origin, and molecular pathogenesis in adults versus children.
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http://dx.doi.org/10.1093/noajnl/vdaa142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739048PMC
October 2020

Intracranial mesenchymal tumor with FET-CREB fusion-A unifying diagnosis for the spectrum of intracranial myxoid mesenchymal tumors and angiomatoid fibrous histiocytoma-like neoplasms.

Brain Pathol 2021 07 28;31(4):e12918. Epub 2021 Jan 28.

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Intracranial mesenchymal tumors with FET-CREB fusions are a recently described group of neoplasms in children and young adults characterized by fusion of a FET family gene (usually EWSR1, but rarely FUS) to a CREB family transcription factor (ATF1, CREB1, or CREM), and have been variously termed intracranial angiomatoid fibrous histiocytoma or intracranial myxoid mesenchymal tumor. The clinical outcomes, histologic features, and genomic landscape are not well defined. Here, we studied 20 patients with intracranial mesenchymal tumors proven to harbor FET-CREB fusion by next-generation sequencing (NGS). The 16 female and four male patients had a median age of 14 years (range 4-70). Tumors were uniformly extra-axial or intraventricular and located at the cerebral convexities (n = 7), falx (2), lateral ventricles (4), tentorium (2), cerebellopontine angle (4), and spinal cord (1). NGS demonstrated that eight tumors harbored EWSR1-ATF1 fusion, seven had EWSR1-CREB1, four had EWSR1-CREM, and one had FUS-CREM. Tumors were uniformly well circumscribed and typically contrast enhancing with solid and cystic growth. Tumors with EWSR1-CREB1 fusions more often featured stellate/spindle cell morphology, mucin-rich stroma, and hemangioma-like vasculature compared to tumors with EWSR1-ATF1 fusions that most often featured sheets of epithelioid cells with mucin-poor collagenous stroma. These tumors demonstrated polyphenotypic immunoprofiles with frequent positivity for desmin, EMA, CD99, MUC4, and synaptophysin, but absence of SSTR2A, myogenin, and HMB45 expression. There was a propensity for local recurrence with a median progression-free survival of 12 months and a median overall survival of greater than 60 months, with three patients succumbing to disease (all with EWSR1-ATF1 fusions). In combination with prior case series, this study provides further insight into intracranial mesenchymal tumors with FET-CREB fusion, which represent a distinct group of CNS tumors encompassing both intracranial myxoid mesenchymal tumor and angiomatoid fibrous histiocytoma-like neoplasms.
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http://dx.doi.org/10.1111/bpa.12918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8089120PMC
July 2021

A subset of pediatric-type thalamic gliomas share a distinct DNA methylation profile, H3K27me3 loss and frequent alteration of EGFR.

Neuro Oncol 2021 01;23(1):34-43

Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.

Background: Malignant astrocytic gliomas in children show a remarkable biological and clinical diversity. Small in-frame insertions or missense mutations in the epidermal growth factor receptor gene (EGFR) have recently been identified in a distinct subset of pediatric-type bithalamic gliomas with a unique DNA methylation pattern.

Methods: Here, we investigated an epigenetically homogeneous cohort of malignant gliomas (n = 58) distinct from other subtypes and enriched for pediatric cases and thalamic location, in comparison with this recently identified subtype of pediatric bithalamic gliomas.

Results: EGFR gene amplification was detected in 16/58 (27%) tumors, and missense mutations or small in-frame insertions in EGFR were found in 20/30 tumors with available sequencing data (67%; 5 of them co-occurring with EGFR amplification). Additionally, 8 of the 30 tumors (27%) harbored an H3.1 or H3.3 K27M mutation (6 of them with a concomitant EGFR alteration). All tumors tested showed loss of H3K27me3 staining, with evidence of overexpression of the EZH inhibitory protein (EZHIP) in the H3 wildtype cases. Although some tumors indeed showed a bithalamic growth pattern, a significant proportion of tumors occurred in the unilateral thalamus or in other (predominantly midline) locations.

Conclusions: Our findings present a distinct molecular class of pediatric-type malignant gliomas largely overlapping with the recently reported bithalamic gliomas characterized by EGFR alteration, but additionally showing a broader spectrum of EGFR alterations and tumor localization. Global H3K27me3 loss in this group appears to be mediated by either H3 K27 mutation or EZHIP overexpression. EGFR inhibition may represent a potential therapeutic strategy in these highly aggressive gliomas.
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http://dx.doi.org/10.1093/neuonc/noaa251DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850075PMC
January 2021

The immunohistochemical, DNA methylation, and chromosomal copy number profile of cauda equina paraganglioma is distinct from extra-spinal paraganglioma.

Acta Neuropathol 2020 12 6;140(6):907-917. Epub 2020 Sep 6.

Division of Neuropathology, Department of Pathology, University of California, San Francisco, 505 Parnassus Avenue, San Francisco, CA, 94143, USA.

Paragangliomas are neuroendocrine tumors of the autonomic nervous system that are variably clinically functional and have a potential for metastasis. Up to 40% occur in the setting of a hereditary syndrome, most commonly due to germline mutations in succinate dehydrogenase (SDHx) genes. Immunohistochemically, paragangliomas are characteristically GATA3-positive and cytokeratin-negative, with loss of SDHB expression in most hereditary cases. In contrast, the rare paragangliomas arising in the cauda equina (CEP) or filum terminale region have been shown to be hormonally silent, clinically indolent, and have variable keratin expression, suggesting these tumors may represent a separate pathologic entity. We retrospectively evaluated 17 CEPs from 11 male and 6 female patients with a median age of 38 years (range 21-82), none with a family history of neuroendocrine neoplasia. Six of the 17 tumors demonstrated prominent gangliocytic or ganglioneuromatous differentiation. By immunohistochemistry, none of the CEPs showed GATA3 positivity or loss of SDHB staining; all 17 CEPs were cytokeratin positive. Genome-wide DNA methylation profiling was performed on 12 of the tumors and compared with publicly available genome-wide DNA methylation data. Clustering analysis showed that CEPs form a distinct epigenetic group, separate from paragangliomas of extraspinal sites, pheochromocytomas, and other neuroendocrine neoplasms. Copy number analysis revealed diploid genomes in the vast majority of CEPs, whereas extraspinal paragangliomas were mostly aneuploid with recurrent trisomy 1q and monosomies of 1p, 3, and 11, none of which were present in the cohort of CEP. Together, these findings indicate that CEPs likely represent a distinct entity. Future genomic studies are needed to further elucidate the molecular pathogenesis of these tumors.
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http://dx.doi.org/10.1007/s00401-020-02221-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682537PMC
December 2020

A Prognostic Gene-Expression Signature and Risk Score for Meningioma Recurrence After Resection.

Neurosurgery 2020 12;88(1):202-210

Department of Radiation Oncology, University of California San Francisco, San Francisco, California.

Background: Prognostic markers for meningioma are needed to risk-stratify patients and guide postoperative surveillance and adjuvant therapy.

Objective: To identify a prognostic gene signature for meningioma recurrence and mortality after resection using targeted gene-expression analysis.

Methods: Targeted gene-expression analysis was used to interrogate a discovery cohort of 96 meningiomas and an independent validation cohort of 56 meningiomas with comprehensive clinical follow-up data from separate institutions. Bioinformatic analysis was used to identify prognostic genes and generate a gene-signature risk score between 0 and 1 for local recurrence.

Results: We identified a 36-gene signature of meningioma recurrence after resection that achieved an area under the curve of 0.86 in identifying tumors at risk for adverse clinical outcomes. The gene-signature risk score compared favorably to World Health Organization (WHO) grade in stratifying cases by local freedom from recurrence (LFFR, P < .001 vs .09, log-rank test), shorter time to failure (TTF, F-test, P < .0001), and overall survival (OS, P < .0001 vs .07) and was independently associated with worse LFFR (relative risk [RR] 1.56, 95% CI 1.30-1.90) and OS (RR 1.32, 95% CI 1.07-1.64), after adjusting for clinical covariates. When tested on an independent validation cohort, the gene-signature risk score remained associated with shorter TTF (F-test, P = .002), compared favorably to WHO grade in stratifying cases by OS (P = .003 vs P = .10), and was significantly associated with worse OS (RR 1.86, 95% CI 1.19-2.88) on multivariate analysis.

Conclusion: The prognostic meningioma gene-expression signature and risk score presented may be useful for identifying patients at risk for recurrence.
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http://dx.doi.org/10.1093/neuros/nyaa355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7735867PMC
December 2020

Comprehensive analysis of diverse low-grade neuroepithelial tumors with FGFR1 alterations reveals a distinct molecular signature of rosette-forming glioneuronal tumor.

Acta Neuropathol Commun 2020 08 28;8(1):151. Epub 2020 Aug 28.

Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.

The FGFR1 gene encoding fibroblast growth factor receptor 1 has emerged as a frequently altered oncogene in the pathogenesis of multiple low-grade neuroepithelial tumor (LGNET) subtypes including pilocytic astrocytoma, dysembryoplastic neuroepithelial tumor (DNT), rosette-forming glioneuronal tumor (RGNT), and extraventricular neurocytoma (EVN). These activating FGFR1 alterations in LGNET can include tandem duplication of the exons encoding the intracellular tyrosine kinase domain, in-frame gene fusions most often with TACC1 as the partner, or hotspot missense mutations within the tyrosine kinase domain (either at p.N546 or p.K656). However, the specificity of these different FGFR1 events for the various LGNET subtypes and accompanying genetic alterations are not well defined. Here we performed comprehensive genomic and epigenomic characterization on a diverse cohort of 30 LGNET with FGFR1 alterations. We identified that RGNT harbors a distinct epigenetic signature compared to other LGNET with FGFR1 alterations, and is uniquely characterized by FGFR1 kinase domain hotspot missense mutations in combination with either PIK3CA or PIK3R1 mutation, often with accompanying NF1 or PTPN11 mutation. In contrast, EVN harbors its own distinct epigenetic signature and is characterized by FGFR1-TACC1 fusion as the solitary pathogenic alteration. Additionally, DNT and pilocytic astrocytoma are characterized by either kinase domain tandem duplication or hotspot missense mutations, occasionally with accompanying NF1 or PTPN11 mutation, but lacking the accompanying PIK3CA or PIK3R1 mutation that characterizes RGNT. The glial component of LGNET with FGFR1 alterations typically has a predominantly oligodendroglial morphology, and many of the pilocytic astrocytomas with FGFR1 alterations lack the biphasic pattern, piloid processes, and Rosenthal fibers that characterize pilocytic astrocytomas with BRAF mutation or fusion. Together, this analysis improves the classification and histopathologic stratification of LGNET with FGFR1 alterations.
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http://dx.doi.org/10.1186/s40478-020-01027-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456392PMC
August 2020

Pathology of meningiomas.

Handb Clin Neurol 2020 ;169:87-99

Division of Neuropathology, Department of Pathology, University of California San Francisco, San Francisco, CA, United States.

Meningiomas are a diverse group of neoplasms that exhibit a wide range of morphologies and clinical behavior. They are generally accepted to originate from arachnoid cap cells within the leptomeninges. Classic histologic features include whorl formations, psammoma bodies, nuclear holes, and nuclear pseudoinclusions. Meningiomas are classified as benign, atypical, or anaplastic (grades I, II, or III) based on histologic features including mitotic activity, brain invasion, and presence of other minor criteria. There are numerous histologic variants of meningiomas, and some are associated with worse clinical outcomes and therefore are assigned a higher grade. The majority of meningiomas show diffuse positivity for vimentin and epithelial membrane antigen, supporting the dual mesenchymal and epithelial nature of meningothelial cells. The presence of an elevated proliferation index (as measured by Ki-67 immunohistochemical stain) and loss of progesterone receptor expression are associated with the higher grade. Pathologic features including histologic variants, grading criteria, and ancillary tests such as special and immunohistochemical stains are discussed.
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http://dx.doi.org/10.1016/B978-0-12-804280-9.00005-6DOI Listing
April 2021

DNA methylation profiling demonstrates superior diagnostic classification to RNA-sequencing in a case of metastatic meningioma.

Acta Neuropathol Commun 2020 06 9;8(1):82. Epub 2020 Jun 9.

Department of Radiation Oncology, University of California San Francisco, California, 94143, USA.

Meningiomas are the most common primary intracranial tumors, but meningioma metastases are rare. Accordingly, the clinical workup, diagnostic testing, and molecular classification of metastatic meningioma is incompletely understood. Here, we present a case report of multiply recurrent meningioma complicated by liver metastasis. We discuss the patient presentation, imaging findings, and conventional histopathologic characterization of both the intracranial lesion and the metastatic focus. Further, we perform multiplatform molecular profiling, comprised of DNA methylation arrays and RNA-sequencing, of six stereotactically-guided samples from the intracranial meningioma and a single ultrasound-guided liver metastasis biopsy. Our results show that DNA methylation clusters distinguish the liver metastasis from the intracranial meningioma samples, and identify a small focus of hepatocyte contamination with the liver biopsy. Nonetheless, DNA methylation-based classification accurately identifies the liver metastasis as a meningioma with high confidence. We also find that clustering of RNA-sequencing results distinguishes the liver metastasis from the intracranial meningiomas samples, but that differential gene expression classification is confounded by hepatocyte-specific gene expression programs in the liver metastasis. In sum, this case report sheds light on the comparative biology of intracranial and metastatic meningioma. Furthermore, our results support methylation-based classification as a robust method of diagnosing metastatic lesions, underscore the broad utility of DNA methylation array profiling in diagnostic pathology, and caution against the routine use of bulk RNA-sequencing for identifying tumor signatures in heterogeneous metastatic lesions.
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http://dx.doi.org/10.1186/s40478-020-00952-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285578PMC
June 2020

Eye-sparing Treatment of Localized Orbital Medulloepithelioma With Neoadjuvant Chemoradiation.

Ophthalmic Plast Reconstr Surg 2021 Jan-Feb 01;37(1):e13-e16

Department of Oculoplastic Surgery, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, Florida.

A 9-year-old girl presented with a 3-day history of progressive proptosis accompanied by transient discomfort and blurry vision in the OD. MRI revealed a heterogeneously enhancing intraconal lesion that partially encased and displaced the optic nerve. There was no intraocular or intracranial involvement, nor were there signs of distant metastasis. Histopathologic evaluation and immunohistochemistry were consistent with orbital medulloepithelioma. The patient received 4 cycles of chemoradiation per a retinoblastoma protocol. Repeat MRI scans showed significant tumor regression, and further surgical debulking was performed. There has been no evidence of recurrence for over 14 months. Herein, the authors describe an eye-sparing, multimodal treatment of a rare case of localized orbital medulloepithelioma.
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http://dx.doi.org/10.1097/IOP.0000000000001703DOI Listing
April 2021

cIMPACT-NOW update 6: new entity and diagnostic principle recommendations of the cIMPACT-Utrecht meeting on future CNS tumor classification and grading.

Brain Pathol 2020 07 19;30(4):844-856. Epub 2020 Apr 19.

Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-University, Heidelberg, Germany.

cIMPACT-NOW (the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy) was established to evaluate and make practical recommendations on recent advances in the field of CNS tumor classification, particularly in light of the rapid progress in molecular insights into these neoplasms. For Round 2 of its deliberations, cIMPACT-NOW Working Committee 3 was reconstituted and convened in Utrecht, The Netherlands, for a meeting designed to review putative new CNS tumor types in advance of any future World Health Organization meeting on CNS tumor classification. In preparatory activities for the meeting and at the actual meeting, a list of possible entities was assembled and each type and subtype debated. Working Committee 3 recommended that a substantial number of newly recognized types and subtypes should be considered for inclusion in future CNS tumor classifications. In addition, the group endorsed a number of principles-relating to classification categories, approaches to classification, nomenclature, and grading-that the group hopes will also inform the future classification of CNS neoplasms.
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http://dx.doi.org/10.1111/bpa.12832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018152PMC
July 2020

Pediatric bithalamic gliomas have a distinct epigenetic signature and frequent EGFR exon 20 insertions resulting in potential sensitivity to targeted kinase inhibition.

Acta Neuropathol 2020 06 17;139(6):1071-1088. Epub 2020 Apr 17.

Division of Hematology/Oncology, Department of Pediatrics, Nicklaus Children's Hospital, Miami, FL, USA.

Brain tumors are the most common solid tumors of childhood, and the genetic drivers and optimal therapeutic strategies for many of the different subtypes remain unknown. Here, we identify that bithalamic gliomas harbor frequent mutations in the EGFR oncogene, only rare histone H3 mutation (in contrast to their unilateral counterparts), and a distinct genome-wide DNA methylation profile compared to all other glioma subtypes studied to date. These EGFR mutations are either small in-frame insertions within exon 20 (intracellular tyrosine kinase domain) or missense mutations within exon 7 (extracellular ligand-binding domain) that occur in the absence of accompanying gene amplification. We find these EGFR mutations are oncogenic in primary astrocyte models and confer sensitivity to specific tyrosine kinase inhibitors dependent on location within the kinase domain or extracellular domain. We initiated treatment with targeted kinase inhibitors in four children whose tumors harbor EGFR mutations with encouraging results. This study identifies a promising genomically-tailored therapeutic strategy for bithalamic gliomas, a lethal and genetically distinct brain tumor of childhood.
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http://dx.doi.org/10.1007/s00401-020-02155-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792550PMC
June 2020

Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes.

Cancer Discov 2020 07 1;10(7):942-963. Epub 2020 Apr 1.

Department of Neuropathology, University Hospital Hamburg-Eppendorf, and Research Institute Children's Cancer Center, Hamburg, Germany.

Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an "intrinsic" spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ( = 31), ( = 21), ( = 9), and ( = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management. SIGNIFICANCE: Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of , or gene fusions. Kinase fusion-positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype...
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http://dx.doi.org/10.1158/2159-8290.CD-19-1030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8313225PMC
July 2020

Catastrophic stroke burden in a patient with uncontrolled psoriasis and psoriatic arthritis: a case report.

BMC Neurol 2020 Mar 21;20(1):106. Epub 2020 Mar 21.

Department of Neurology, University of California, San Francisco, California, USA.

Background: Psoriasis is the most common chronic inflammatory condition involving the T helper cell system. Population studies have demonstrated that patients with psoriasis and/or psoriatic arthritis have an increased risk of developing vascular risk factors, including diabetes, hypertension, and obesity, and increased risk of adverse vascular events, including myocardial infarction and stroke. Population studies have generally investigated the individual contributions of psoriasis and psoriatic arthritis to development of vascular risk factors; fewer studies have investigated the additive contribution of comorbid inflammatory disorders. We present a case of a woman with psoriasis, psoriatic arthritis, and comorbid vascular risk factors.

Case Presentation: A 49 year-old Caucasian woman with a history of severe psoriasis and psoriatic arthritis since adolescence presented with bilateral lower extremity weakness. She was found to have acute bilateral watershed infarcts and multifocal subacute infarcts. Her evaluation revealed vascular risk factors and elevated non-specific systemic inflammatory markers; serum and cerebral spinal fluid did not reveal underlying infection, hypercoagulable state, or vasculitis. Over the course of days, she exhibited precipitous clinical deterioration related to multiple large vessel occlusions, including the bilateral anterior cerebral arteries and the left middle cerebral artery. Autopsy revealed acute thrombi and diffuse, severe atherosclerosis.

Conclusion: Patients with early onset inflammatory disease activity or comorbid inflammatory disorders may have an even higher risk of developing metabolic syndrome and adverse vascular events compared to patients with late-onset disease activity or with a single inflammatory condition. The described case illustrates the complex relationship between inflammatory disorders and vascular risk factors. The degree of systemic inflammation, as measured by severity of disease activity, has been shown to have a dose-response relationship with comorbid vascular risk factors and vascular events. Dysregulation of the Th1 and Th17 system has been implicated in the development of atherosclerosis and may explain the severe atherosclerosis seen in such chronic inflammatory conditions. Further research will help refine screening and management guidelines to account for comorbid inflammatory disorders and related disease severity.
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http://dx.doi.org/10.1186/s12883-020-01681-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7085172PMC
March 2020

Next-Generation Sequencing of Retinoblastoma Identifies Pathogenic Alterations beyond RB1 Inactivation That Correlate with Aggressive Histopathologic Features.

Ophthalmology 2020 06 12;127(6):804-813. Epub 2019 Dec 12.

Department of Ophthalmology, University of California, San Francisco, San Francisco, California; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, United Kingdom.

Purpose: To determine the usefulness of a comprehensive, targeted-capture next-generation sequencing (NGS) assay for the clinical management of children undergoing enucleation for retinoblastoma.

Design: Cohort study.

Participants: Thirty-two children with retinoblastoma.

Methods: We performed targeted NGS using the UCSF500 Cancer Panel (University of California, San Francisco, San Francisco, CA) on formalin-fixed, paraffin-embedded tumor tissue along with constitutional DNA isolated from peripheral blood, buccal swab, or uninvolved optic nerve. Peripheral blood samples were also sent to a commercial laboratory for germline RB1 mutation testing.

Main Outcome Measures: Presence or absence of germline RB1 mutation or deletion, tumor genetic profile, and association of genetic alterations with clinicopathologic features.

Results: Germline mutation or deletion of the RB1 gene was identified in all children with bilateral retinoblastoma (n = 12), and these NGS results were 100% concordant with commercial germline RB1 mutation analysis. In tumor tissue tested with NGS, biallelic inactivation of RB1 was identified in 28 tumors and focal MYCN amplification was identified in 4 tumors (2 with wild-type RB1 and 2 with biallelic RB1 inactivation). Additional likely pathogenic alterations beyond RB1 were identified in 13 tumors (41%), several of which have not been reported previously in retinoblastoma. These included focal amplifications of MDM4 and RAF1, as well as damaging mutations involving BCOR, ARID1A, MGA, FAT1, and ATRX. The presence of additional likely pathogenetic mutations beyond RB1 inactivation was associated with aggressive histopathologic features, including higher histologic grade and anaplasia, and also with both unilateral and sporadic disease.

Conclusions: Comprehensive NGS analysis reliably detects relevant mutations, amplifications, and chromosomal copy number changes in retinoblastoma. The presence of genetic alterations beyond RB1 inactivation correlates with aggressive histopathologic features.
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http://dx.doi.org/10.1016/j.ophtha.2019.12.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7246167PMC
June 2020

An update on the central nervous system manifestations of familial tumor predisposition syndromes.

Authors:
David A Solomon

Acta Neuropathol 2020 04 3;139(4):609-612. Epub 2020 Feb 3.

Division of Neuropathology, Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, 513 Parnassus Ave, Health Sciences West 451, San Francisco, CA, 94143, USA.

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http://dx.doi.org/10.1007/s00401-020-02130-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7102922PMC
April 2020

Multiregion exome sequencing of ovarian immature teratomas reveals 2N near-diploid genomes, paucity of somatic mutations, and extensive allelic imbalances shared across mature, immature, and disseminated components.

Mod Pathol 2020 06 7;33(6):1193-1206. Epub 2020 Jan 7.

Department of Dermatology, University of California, San Francisco, CA, USA.

Immature teratoma is a subtype of malignant germ cell tumor of the ovary that occurs most commonly in the first three decades of life, frequently with bilateral ovarian disease. Despite being the second most common malignant germ cell tumor of the ovary, little is known about its genetic underpinnings. Here we performed multiregion whole-exome sequencing to interrogate the genetic zygosity, clonal relationship, DNA copy number, and mutational status of 52 pathologically distinct tumor components from ten females with ovarian immature teratomas, with bilateral tumors present in five cases and peritoneal dissemination in seven cases. We found that ovarian immature teratomas are genetically characterized by 2N near-diploid genomes with extensive loss of heterozygosity and an absence of genes harboring recurrent somatic mutations or known oncogenic variants. All components within a single ovarian tumor (immature teratoma, mature teratoma with different histologic patterns of differentiation, and yolk sac tumor) were found to harbor an identical pattern of loss of heterozygosity across the genome, indicating a shared clonal origin. In contrast, the four analyzed bilateral teratomas showed distinct patterns of zygosity changes in the right versus left sided tumors, indicating independent clonal origins. All disseminated teratoma components within the peritoneum (including gliomatosis peritonei) shared a clonal pattern of loss of heterozygosity with either the right or left primary ovarian tumor. The observed genomic loss of heterozygosity patterns indicate that diverse meiotic errors contribute to the formation of ovarian immature teratomas, with 11 out of the 15 genetically distinct clones determined to result from nondisjunction errors during meiosis I or II. Overall, these findings suggest that copy-neutral loss of heterozygosity resulting from meiotic abnormalities may be sufficient to generate ovarian immature teratomas from germ cells.
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http://dx.doi.org/10.1038/s41379-019-0446-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286805PMC
June 2020

Clinicopathologic and molecular features of intracranial desmoplastic small round cell tumors.

Brain Pathol 2020 03 29;30(2):213-225. Epub 2019 Dec 29.

Department of Pathology, University of California, San Francisco, CA.

Desmoplastic small round cell tumors (DSRCTs) are highly aggressive sarcomas that most commonly occur intra-abdominally, and are defined by EWSR1-WT1 gene fusion. Intracranial DSRCTs are exceptionally rare with only seven previously reported fusion-positive cases. Herein, we evaluate the clinical, morphologic, immunohistochemical and molecular features of five additional examples. All patients were male (age range 6-25 years; median 11 years), with four tumors located supratentorially and one within the posterior fossa. The histologic features were highly variable including small cell, embryonal, clear cell, rhabdoid, anaplastic and glioma-like appearances. A prominent desmoplastic stroma was seen in only two cases. The mitotic index ranged from <1 to 12/10 HPF (median 5). While all tumors showed strong desmin positivity, epithelial markers such as EMA, CAM 5.2 and other keratins were strongly positive in only one, focally positive in two and negative in two cases. EWSR1-WT1 gene fusion was present in all cases, with accompanying mutations in the TERT promoter or STAG2 gene in individual cases. Given the significant histologic diversity, in the absence of genetic evaluation these cases could easily be misinterpreted as other entities. Desmin immunostaining is a useful initial screening method for consideration of a DSRCT diagnosis, prompting confirmatory molecular testing. Demonstrating the presence of an EWSR1-WT1 fusion provides a definitive diagnosis of DSRCT. Genome-wide methylation profiles of intracranial DSRCTs matched those of extracranial DSRCTs. Thus, despite the occasionally unusual histologic features and immunoprofile, intracranial DSRCTs likely represent a similar, if not the same, entity as their soft tissue counterpart based on the shared fusion and methylation profiles.
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http://dx.doi.org/10.1111/bpa.12809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780368PMC
March 2020

A review of recently described genetic alterations in central nervous system tumors.

Hum Pathol 2020 02 31;96:56-66. Epub 2019 Oct 31.

Department of Pathology, University of California, San Francisco, CA, 94143 USA; Department of Neurological Surgery, University of California, San Francisco, CA, 94143 USA. Electronic address:

Advances in molecular profiling of central nervous system tumors have enabled the development of classification schemes with improved diagnostic and prognostic accuracy. As such, the 2016 World Health Organization Classification of Tumors of the Central Nervous System (WHO 2016) introduced a paradigm shift in the diagnosis of brain tumors. For instance, integrated assessment incorporating both histologic features and genetic alterations was introduced into the diagnostic framework of gliomas. IDH1/2 mutation status now represents the most important initial stratifier of diffuse gliomas in adults, although rarer subtypes within the IDH-wildtype category continue to be elucidated. Medulloblastomas and other embryonal neoplasms were also genetically defined and segregated based on molecular subtypes, and 1 molecular subtype of ependymoma was added. In this review, we summarize the rapidly evolving spectrum of recurrent genetic alterations described in central nervous system tumor entities since the publication of the WHO 2016.
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http://dx.doi.org/10.1016/j.humpath.2019.10.009DOI Listing
February 2020
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