Publications by authors named "Tarik Tihan"

230 Publications

Concurrent presentation of brain arteriovenous malformation, peripheral arteriovenous malformation, and cerebellar astrocytoma: Case report.

Interdiscip Neurosurg 2020 Jun 14;20. Epub 2020 Feb 14.

Department of Radiology and Biomedical Imaging, Division of Neurointerventional Radiology, University of California, San Francisco School of Medicine, San Francisco, CA, United States.

Background: We report a rare case of a 19-year-old female progressively affected by a peripheral arteriovenous malformation (pAVM), a midline cerebellar astrocytoma, and a brain arteriovenous malformation (bAVM).

Case Description: She presented with a pulsatile mass on her left cheek, which was classified as a pAVM through angiography. Following treatment with embolization and surgical resection, she returned with enlargement of the mass and imaging incidentally identified a cerebellar astrocytoma. Suboccipital craniotomy, C1 laminectomy, and endoscopic third ventriculostomy were subsequently performed. She was later treated again for growth of her pAVM, and angiography revealed the presence of a left temporal bAVM, which was resected via a pterional craniotomy.

Conclusions: Pathological staining identified activation of mTOR and RAS/MAPK pathway in the patient's pAVM and bAVM tissue samples. Furthermore, genetic sequencing demonstrated an activating MAPK21 (K57N) mutation in the pAVM and a gain of distal chromosome 7q in the pilocytic astrocytoma. No germline mutation was identified to explain all pathologies. This case demonstrates the need for continued development and further integration of multi-disciplinary genetic, radiological, and neurological treatment teams to effectively care for such complex presentations.
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http://dx.doi.org/10.1016/j.inat.2020.100689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8302203PMC
June 2020

Immune cell analysis of pilocytic astrocytomas reveals sexually dimorphic brain region-specific differences in T-cell content.

Neurooncol Adv 2021 Jan-Dec;3(1):vdab068. Epub 2021 May 20.

Division of Neuropathology, Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

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http://dx.doi.org/10.1093/noajnl/vdab068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8284620PMC
May 2021

Somatic mosaicism in the MAPK pathway in sporadic brain arteriovenous malformation and association with phenotype.

J Neurosurg 2021 Jul 2:1-8. Epub 2021 Jul 2.

Departments of1Anesthesia and Perioperative Care.

Objective: Sporadic brain arteriovenous malformation (BAVM) is a tangled vascular lesion characterized by direct artery-to-vein connections that can cause life-threatening intracerebral hemorrhage (ICH). Recently, somatic mutations in KRAS have been reported in sporadic BAVM, and mutations in other mitogen-activated protein kinase (MAPK) signaling pathway genes have been identified in other vascular malformations. The objectives of this study were to systematically evaluate somatic mutations in MAPK pathway genes in patients with sporadic BAVM lesions and to evaluate the association of somatic mutations with phenotypes of sporadic BAVM severity.

Methods: The authors performed whole-exome sequencing on paired lesion and blood DNA samples from 14 patients with sporadic BAVM, and 295 genes in the MAPK signaling pathway were evaluated to identify genes with somatic mutations in multiple patients with BAVM. Digital droplet polymerase chain reaction was used to validate KRAS G12V and G12D mutations and to assay an additional 56 BAVM samples.

Results: The authors identified a total of 24 candidate BAVM-associated somatic variants in 11 MAPK pathway genes. The previously identified KRAS G12V and G12D mutations were the only recurrent mutations. Overall, somatic KRAS G12V was present in 14.5% of BAVM lesions and G12D was present in 31.9%. The authors did not detect a significant association between the presence or allelic burden of KRAS mutation and three BAVM phenotypes: lesion size (maximum diameter), age at diagnosis, and age at ICH.

Conclusions: The authors confirmed the high prevalence of somatic KRAS mutations in sporadic BAVM lesions and identified several candidate somatic variants in other MAPK pathway genes. These somatic variants may contribute to understanding of the etiology of sporadic BAVM and the clinical characteristics of patients with this condition.
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http://dx.doi.org/10.3171/2020.11.JNS202031DOI Listing
July 2021

Detection of glioma infiltration at the tumor margin using quantitative stimulated Raman scattering histology.

Sci Rep 2021 Jun 9;11(1):12162. Epub 2021 Jun 9.

Department of Neurological Surgery, University of California, 505 Parnassus Ave., Rm. M-779, San Francisco, CA, 94143-0112, USA.

In the management of diffuse gliomas, the identification and removal of tumor at the infiltrative margin remains a central challenge. Prior work has demonstrated that fluorescence labeling tools and radiographic imaging are useful surgical adjuvants with macroscopic resolution. However, they lose sensitivity at the tumor margin and have limited clinical utility for lower grade histologies. Fiber-laser based stimulated Raman histology (SRH) is an optical imaging technique that provides microscopic tissue characterization of unprocessed tissues. It remains unknown whether SRH of tissues taken from the infiltrative glioma margin will identify microscopic residual disease. Here we acquired glioma margin specimens for SRH, histology, and tumor specific tissue characterization. Generalized linear mixed models were used to evaluate agreement. We find that SRH identified residual tumor in 82 of 167 margin specimens (49%), compared to IHC confirming residual tumor in 72 of 128 samples (56%), and H&E confirming residual tumor in 82 of 169 samples (49%). Intraobserver agreements between all 3 modalities were confirmed. These data demonstrate that SRH detects residual microscopic tumor at the infiltrative glioma margin and may be a promising tool to enhance extent of resection.
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http://dx.doi.org/10.1038/s41598-021-91648-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190264PMC
June 2021

Neurological manifestations of polyarteritis nodosa: a tour of the neuroaxis by case series.

BMC Neurol 2021 May 21;21(1):205. Epub 2021 May 21.

Weill Institute for Neurosciences, University of California, San Francisco, California, USA.

Background: Heterogenous central nervous system (CNS) neurologic manifestations of polyarteritis nodosa (PAN) are underrecognized. We review three cases of patients with PAN that illustrate a range of nervous system pathology, including the classical mononeuritis multiplex as well as uncommon brain and spinal cord vascular manifestations.

Case Presentation: Case 1 presented with mononeuritis multiplex and characteristic skin findings. Case 2 presented with thunderclap headache and myelopathy due to spinal artery aneurysm rupture. Both patients experienced disease remission upon treatment. Case 3 presented with headache and bulbar symptoms due to partially thrombosed intracranial aneurysms, followed by systemic manifestations related to visceral aneurysms. She demonstrated clinical improvement with treatment, was lost to follow-up, then clinically deteriorated and entered hospice care.

Conclusions: Although the peripheral manifestations of PAN are well-known, PAN association with CNS neurovascular disease is relatively underappreciated. Clinician awareness of the spectrum of neurologic disease is required to reduce diagnostic delay and promote prompt diagnosis and treatment with immunosuppressants.
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http://dx.doi.org/10.1186/s12883-021-02228-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138997PMC
May 2021

Plurihormonal PIT-1-Positive Pituitary Adenomas: A Systematic Review and Single-Center Series.

World Neurosurg 2021 Jul 20;151:e185-e191. Epub 2021 Apr 20.

Department of Neurological Surgery, University of California, San Francisco, School of Medicine, San Francisco, California, USA. Electronic address:

Objective: The 2017 World Health Organization classification of pituitary adenomas identified the plurihormonal PIT-1-positive (PP1) adenoma as a distinct subtype. The reported data suggest that PP1 adenomas encompass the former class of silent subtype 3 (SS3) adenomas and might have an aggressive phenotype. In the present study, we summarized the current clinical data on PP1 and SS3 adenomas and compared the reported data with the data from a single institutional cohort.

Methods: Medline and Google Scholar were searched from 1990 to 2020 for clinical series of PP1 and SS3 adenomas in accordance with the PRISMA (preferred reporting items for systematic reviews and meta-analyses) guidelines. Studies were included if they had reported pituitary pathology as PP1 or SS3 adenomas and had reported the clinical outcomes after surgical intervention. To better define the PP1 phenotype compared with non-PP1 adenomas, we also reviewed the adenomas treated surgically at our institution from 2012 to 2019.

Results: Of all the tumors reported in the studies as PP1 or SS3, 99% were macroadenomas and 18% were giant adenomas (>4 cm). Of the reported patients, 31.8% had received radiotherapy, and 22.9% had undergone multiple surgeries for their pituitary tumor. In our single-center experience, 20 patients had an adenoma that met the criteria for a PP1 adenoma. Compared with the 1146 non-PP1 tumors, the PP1 tumors did not show statistically significant differences in the extent of resection, size, number of previous surgeries, future reoperations, rate of radiotherapy, p53 staining, or MIB-1 labeling index.

Conclusions: The findings from the present large, single-center study comparing PP1 and non-PP1 adenomas do not suggest that PP1 tumors are more aggressive. Further work is warranted to identify the pathologic subtypes of pituitary adenomas that are consistently more clinically aggressive.
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http://dx.doi.org/10.1016/j.wneu.2021.04.003DOI Listing
July 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

Mutations and Copy Number Alterations in Wild-Type Glioblastomas Are Shaped by Different Oncogenic Mechanisms.

Biomedicines 2020 Dec 7;8(12). Epub 2020 Dec 7.

Department of Neurosurgery, School of Medicine, Acibadem Mehmet Ali Aydinlar University, Istanbul 34752, Turkey.

Little is known about the mutational processes that shape the genetic landscape of gliomas. Numerous mutational processes leave marks on the genome in the form of mutations, copy number alterations, rearrangements or their combinations. To explore gliomagenesis, we hypothesized that gliomas with different underlying oncogenic mechanisms would have differences in the burden of various forms of these genomic alterations. This was an analysis on adult diffuse gliomas, but -mutant gliomas as well as diffuse midline gliomas -K27M were excluded to search for the possible presence of new entities among the very heterogenous group of -WT glioblastomas. The cohort was divided into two molecular subsets: (1) Molecularly-defined GBM (mGBM) as those that carried molecular features of glioblastomas (including promoter mutations, 7/10 pattern, or -amplification), and (2) those who did not (others). Whole exome sequencing was performed for 37 primary tumors and matched blood samples as well as 8 recurrences. Single nucleotide variations (SNV), short insertion or deletions (indels) and copy number alterations (CNA) were quantified using 5 quantitative metrics (SNV burden, indel burden, copy number alteration frequency-wGII, chromosomal arm event ratio-CAER, copy number amplitude) as well as 4 parameters that explored underlying oncogenic mechanisms (chromothripsis, double minutes, microsatellite instability and mutational signatures). Findings were validated in the TCGA pan-glioma cohort. mGBM and "Others" differed significantly in their SNV (only in the TCGA cohort) and CNA metrics but not indel burden. SNV burden increased with increasing age at diagnosis and at recurrences and was driven by mismatch repair deficiency. On the contrary, indel and CNA metrics remained stable over increasing age at diagnosis and with recurrences. Copy number alteration frequency (wGII) correlated significantly with chromothripsis while CAER and CN amplitude correlated significantly with the presence of double minutes, suggesting separate underlying mechanisms for different forms of CNA.
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http://dx.doi.org/10.3390/biomedicines8120574DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762325PMC
December 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 Jul 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

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

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

Extradural thoracic meningeal cyst without spinal dysraphism causing adulthood myelopathy: Case illustration and review of the literature.

J Clin Neurosci 2020 Aug 26;78:433-438. Epub 2020 Jun 26.

Department of Neurological Surgery, University of California San Francisco, United States.

Extradural spinal meningeal cysts are rare lesions in the adult spine and are an uncommon cause of neurologic deficits. We present the case of an adult who presented with myelopathic symptoms related to a dorsally based extradural thoracic meningeal cyst in the absence of any defect in the posterior spinal elements and no history of spinal dysraphism or trauma. We also performed a review of the literature to evaluate the surgical techniques for extradural meningeal cysts. Most thoracic cysts are intradural arachnoid cysts, yet this lesion is an extradural meningeal cyst, not an intradural arachnoid cyst. Because of the rarity of this lesion, its anatomic characterization can be difficult to conceptualize. An artist's illustration helps illustrate the anatomic characteristics of this cyst and our surgical management.
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http://dx.doi.org/10.1016/j.jocn.2020.05.039DOI Listing
August 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

Machine Learning Decision Tree Models for Differentiation of Posterior Fossa Tumors Using Diffusion Histogram Analysis and Structural MRI Findings.

Front Oncol 2020 7;10:71. Epub 2020 Feb 7.

Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA, United States.

We applied machine learning algorithms for differentiation of posterior fossa tumors using apparent diffusion coefficient (ADC) histogram analysis and structural MRI findings. A total of 256 patients with intra-axial posterior fossa tumors were identified, of whom 248 were included in machine learning analysis, with at least 6 representative subjects per each tumor pathology. The ADC histograms of solid components of tumors, structural MRI findings, and patients' age were applied to construct decision models using Classification and Regression Tree analysis. We also compared different machine learning classification algorithms (i.e., naïve Bayes, random forest, neural networks, support vector machine with linear and polynomial kernel) for dichotomized differentiation of the 5 most common tumors in our cohort: metastasis ( = 65), hemangioblastoma ( = 44), pilocytic astrocytoma ( = 43), ependymoma ( = 27), and medulloblastoma ( = 26). The decision tree model could differentiate seven tumor histopathologies with terminal nodes yielding up to 90% accurate classification rates. In receiver operating characteristics (ROC) analysis, the decision tree model achieved greater area under the curve (AUC) for differentiation of pilocytic astrocytoma ( = 0.020); and atypical teratoid/rhabdoid tumor ATRT ( = 0.001) from other types of neoplasms compared to the official clinical report. However, neuroradiologists' interpretations had greater accuracy in differentiating metastases ( = 0.001). Among different machine learning algorithms, random forest models yielded the highest accuracy in dichotomized classification of the 5 most common tumor types; and in multiclass differentiation of all tumor types random forest yielded an averaged AUC of 0.961 in training datasets, and 0.873 in validation samples. Our study demonstrates the potential application of machine learning algorithms and decision trees for accurate differentiation of brain tumors based on pretreatment MRI. Using easy to apply and understandable imaging metrics, the proposed decision tree model can help radiologists with differentiation of posterior fossa tumors, especially in tumors with similar qualitative imaging characteristics. In particular, our decision tree model provided more accurate differentiation of pilocytic astrocytomas from ATRT than by neuroradiologists in clinical reads.
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http://dx.doi.org/10.3389/fonc.2020.00071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7018938PMC
February 2020

Loss of H3K27 trimethylation by immunohistochemistry is frequent in oligodendroglioma, IDH-mutant and 1p/19q-codeleted, but is neither a sensitive nor a specific marker.

Acta Neuropathol 2020 03 7;139(3):597-600. Epub 2020 Jan 7.

Department of Pathology, University of California, San Francisco (UCSF), 505 Parnassus Ave, Room M551, San Francisco, CA, 94143, USA.

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http://dx.doi.org/10.1007/s00401-019-02123-8DOI Listing
March 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

Myxoid glioneuronal tumor, PDGFRA p.K385-mutant: clinical, radiologic, and histopathologic features.

Brain Pathol 2020 05 6;30(3):479-494. Epub 2019 Nov 6.

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

"Myxoid glioneuronal tumor, PDGFRA p.K385-mutant" is a recently described tumor entity of the central nervous system with a predilection for origin in the septum pellucidum and a defining dinucleotide mutation at codon 385 of the PDGFRA oncogene replacing lysine with either leucine or isoleucine (p.K385L/I). Clinical outcomes and optimal treatment for this new tumor entity have yet to be defined. Here, we report a comprehensive clinical, radiologic, and histopathologic assessment of eight cases. In addition to its stereotypic location in the septum pellucidum, we identify that this tumor can also occur in the corpus callosum and periventricular white matter of the lateral ventricle. Tumors centered in the septum pellucidum uniformly were associated with obstructive hydrocephalus, whereas tumors centered in the corpus callosum and periventricular white matter did not demonstrate hydrocephalus. While multiple patients were found to have ventricular dissemination or local recurrence/progression, all patients in this series remain alive at last clinical follow-up despite only biopsy or subtotal resection without adjuvant therapy in most cases. Our study further supports "myxoid glioneuronal tumor, PDGFRA p.K385-mutant" as a distinct CNS tumor entity and expands the spectrum of clinicopathologic and radiologic features of this neoplasm.
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http://dx.doi.org/10.1111/bpa.12797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780370PMC
May 2020

Exploratory proteomic analysis implicates the alternative complement cascade in primary CNS vasculitis.

Neurology 2019 07 3;93(5):e433-e444. Epub 2019 Jul 3.

From the Departments of Biochemistry and Biophysics (C.M.-B., H.R., H.A.S., K.C.Z., J.L.D.), Pharmaceutical Chemistry (G.M.K., A.Y.), Pathology and Laboratory Medicine (T.T.), and Neurology (S.A.J., V.C.D., J.M.G., M.R.W.), University of California, San Francisco; Department of Rheumatology/Immunology (R.A.H.-A., L.H.C.), Cleveland Clinic, OH; Department of Neurology (M.P.G.), Boston Children's Hospital, MA; Division of Neurology (J.M.C.), Connecticut Children's Medical Center, Hartford; Division of Rheumatology (A.G.S.), University of Pennsylvania, Philadelphia; Kaiser Permanente (J.F.M.), San Francisco Medical Center; UCSF Weill Institute for Neurosciences (S.A.J., V.C.D., J.M.G., M.R.W.); and Chan Zuckerberg Biohub (J.L.D.), San Francisco, CA.

Objective: To identify molecular correlates of primary angiitis of the CNS (PACNS) through proteomic analysis of CSF from a biopsy-proven patient cohort.

Methods: Using mass spectrometry, we quantitatively compared the CSF proteome of patients with biopsy-proven PACNS (n = 8) to CSF from individuals with noninflammatory conditions (n = 11). Significantly enriched molecular pathways were identified with a gene ontology workflow, and high confidence hits within enriched pathways (fold change >1.5 and concordant Benjamini-Hochberg-adjusted < 0.05 on DeSeq and test) were identified as differentially regulated proteins.

Results: Compared to noninflammatory controls, 283 proteins were differentially expressed in the CSF of patients with PACNS, with significant enrichment of the complement cascade pathway (C4-binding protein, CD55, CD59, properdin, complement C5, complement C8, and complement C9) and neural cell adhesion molecules. A subset of clinically relevant findings were validated by Western blot and commercial ELISA.

Conclusions: In this exploratory study, we found evidence of deregulation of the alternative complement cascade in CSF from biopsy-proven PACNS compared to noninflammatory controls. More specifically, several regulators of the C3 and C5 convertases and components of the terminal cascade were significantly altered. These preliminary findings shed light on a previously unappreciated similarity between PACNS and systemic vasculitides, especially anti-neutrophil cytoplasmic antibody-associated vasculitis. The therapeutic implications of this common biology and the diagnostic and therapeutic utility of individual proteomic findings warrant validation in larger cohorts.
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http://dx.doi.org/10.1212/WNL.0000000000007850DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693432PMC
July 2019

Intraoperative Consultations of Central Nervous System Tumors: A Review for Practicing Pathologists and Testing of an Algorithmic Approach.

Turk Patoloji Derg 2019 ;35(3):173-184

Department of Pathology, Karadeniz Technical University Faculty of Medicine, TRABZON, TURKEY.

Intraoperative consultations or frozen sections for central nervous system (CNS) tumors present a significant challenge for surgical pathologists because of their relative rarity and diversity. Yet, such lesions are encountered by every surgical pathologist, and a basic understanding of clinical, radiological and genetic information is critical to successfully evaluate CNS frozen sections. It is often beneficial to have a systematic approach or an algorithm, and to be aware of the common pitfalls and mimickers when dealing with these lesions. We propose such an algorithm in an effort to construct a sensible approach to CNS frozen sections that considers recent developments in the WHO CNS tumor classification. The algorithm was developed for surgical pathologists who are occasionally faced with making diagnosis of CNS tumors on frozen sections. To test the algorithm and its practicability, we selected a group of tumors among a total of 3288 consecutive intraoperative consultations performed at UCSF between 2013 and 2017. The selected cases represented lesions that may be encountered in everyday surgical pathology and constituted a fair reflection of the main group. The algorithm was used by three of the authors who did not have formal neuropathology training and had been in surgical pathology practice for at least 3 years. There was a very high level of concordance among the authors' diagnosis (interobserver concordance: 0.83-0.97-kappa value) using the algorithm with high intraobserver reliability (concordance 93%, p < 0.001). We suggest that an algorithmic approach is an effective means for the surgical pathologists, and may help reach diagnosis during frozen sections.
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http://dx.doi.org/10.5146/tjpath.2018.01460DOI Listing
February 2020

High-grade neuroepithelial tumor with BCOR exon 15 internal tandem duplication-a comprehensive clinical, radiographic, pathologic, and genomic analysis.

Brain Pathol 2020 01 10;30(1):46-62. Epub 2019 Jun 10.

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

High-grade neuroepithelial tumor with BCOR exon 15 internal tandem duplication (HGNET BCOR ex15 ITD) is a recently proposed tumor entity of the central nervous system (CNS) with a distinct methylation profile and characteristic genetic alteration. The complete spectrum of histologic features, accompanying genetic alterations, clinical outcomes, and optimal treatment for this new tumor entity are largely unknown. Here, we performed a comprehensive assessment of 10 new cases of HGNET BCOR ex15 ITD. The tumors mostly occurred in young children and were located in the cerebral or cerebellar hemispheres. On imaging all tumors were large, well-circumscribed, heterogeneous masses with variable enhancement and reduced diffusion. They were histologically characterized by predominantly solid growth, glioma-like fibrillarity, perivascular pseudorosettes, and palisading necrosis, but absence of microvascular proliferation. They demonstrated sparse to absent GFAP expression, no synaptophysin expression, variable OLIG2 and NeuN positivity, and diffuse strong BCOR nuclear positivity. While BCOR exon 15 internal tandem duplication was the solitary pathogenic alteration identified in six cases, four cases contained additional alterations including CDKN2A/B homozygous deletion, TERT amplification or promoter hotspot mutation, and damaging mutations in TP53, BCORL1, EP300, SMARCA2 and STAG2. While the limited clinical follow-up in prior reports had indicated a uniformly dismal prognosis for this tumor entity, this cohort includes multiple long-term survivors. Our study further supports inclusion of HGNET BCOR ex15 ITD as a distinct CNS tumor entity and expands the known clinicopathologic, radiographic, and genetic features.
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http://dx.doi.org/10.1111/bpa.12747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859193PMC
January 2020

Sporadic and Von-Hippel Lindau disease-associated spinal hemangioblastomas: institutional experience on their similarities and differences.

J Neurooncol 2019 Jul 14;143(3):547-552. Epub 2019 May 14.

Division of Neuropathology, UCSF School of Medicine, 505 Parnassus Avenue, Room M551, San Francisco, CA, 94143, USA.

Introduction: Hemangioblastomas are uncommon tumors of the central nervous system that can be seen in Von Hippel-Lindau (VHL) disease. Despite their benign histology, hemangioblastomas can cause substantial morbidity due to involvement of critical structures. In order to better understand the clinical behavior of spinal cord hemangioblastomas, we have analyzed the clinical, pathologic, radiologic characteristics and management of sporadic and VHL-associated cases at our institution.

Methods: We performed a database search to identify all spinal hemangioblastomas at our institution between 1997 and 2016. Tumor characteristics were analyzed for sporadic and VHL-associated tumors separately in order to understand the differences in groups.

Results: We included 20 patients with VHL-associated spinal hemangioblastomas, and 22 patients with sporadic spinal hemangioblastomas. VHL-associated patients were significantly younger at time of presentation compared to sporadic patients (p < 0.0025). Thirty-two patients (76.2%) presented with focal weakness, 34 (81.0%) with sensory loss, and 22 (52.4%) with pain. VHL patients were more likely to present with multiple symptoms (p < 0.001). Median follow-up time was 20.9 months, during which 17 tumors recurred. The median recurrence free interval was 44 months. There were no differences in gross total resection rates between sporadic and VHL-associated cases (p = 0.197). VHL-associated cases had a higher rate of repeat surgery for recurrence (14 patients-73.6%) compared to sporadic cases (3 patients-13.6%; p < 0.001).

Conclusion: VHL-associated spinal hemangioblastomas differ from sporadic tumors in terms of age, presenting symptoms, multifocality, and rate of recurrence. Recurrences seem to be unrelated to the extent of resection, indicating the need for life-long follow up for VHL patients.
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http://dx.doi.org/10.1007/s11060-019-03189-wDOI Listing
July 2019

Pilomyxoid astrocytomas: a short review.

Brain Tumor Pathol 2019 Apr 3;36(2):52-55. Epub 2019 Apr 3.

Neuropathology Division, Department of Pathology, UCSF School of Medicine, Moffitt, M551C, University of California, 505 Parnassus Avenue, Box 0102, San Francisco, CA, 94143, USA.

Pilomyxoid astrocytoma is a variant of pilocytic astrocytoma and the clinical, histological and molecular data point to a very close relationship as well as a more aggressive biological behavior for the former. WHO 2016 classification does not provide a specific grade for these neoplasms, but there is sufficient evidence in the literature that pilomyxoid astrocytoma has slightly worse prognosis than typical pilocytic astrocytoma. There is increasing evidence that in addition to the MAPK pathway alterations, pilomyxoid astrocytomas harbor genetic alterations that distinguish them from typical pilocytic astrocytoma.
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http://dx.doi.org/10.1007/s10014-019-00343-0DOI Listing
April 2019

Clinicopathologic features of anaplastic myxopapillary ependymomas.

Brain Pathol 2019 01;29(1):75-84

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

Myxopapillary ependymomas (MPE) are considered benign (World Health Organization (WHO) grade I) neoplasms with favorable prognosis. However, malignant behavior occurs in a small subset. To our knowledge, only five anaplastic MPEs have been reported without consensus on diagnostic criteria. We retrieved 14 anaplastic MPEs from the pathology archives of six institutions. Each tumor included at least two of the following features: ≥5 mitoses per 10 high power fields, Ki-67 labeling index (LI) ≥10%, microvascular proliferation (MVP) and spontaneous necrosis. These features were typically encountered in the foci of hypercellularity and reduced mucin. There were eight male and six female patients (age range 6-57 years, median = 16.5). Ten tumors displayed anaplasia at initial resection, and 4 were anaplastic at a second surgery for recurrence (ranging from 9 months to 14 years following initial resection). The Ki-67 LI ranged between 8% and 40% in the anaplastic foci and <3% in the foci of classic MPE. There was documented cerebrospinal fluid (CSF) dissemination in seven cases, recurrence following an anaplastic diagnosis in three cases and bone or soft tissue invasion in two cases. One patient suffered lung metastases. Two cases evaluated by targeted next-generation sequencing and one evaluated by fluorescence in situ hybridization (FISH) showed nonspecific chromosomal gains. We conclude that although rare, anaplastic MPE occurs in both pediatric and adult patients, similar to other ependymomas. At a minimum, closer follow-up is recommended, given the concern for aggressive biologic potential. Further study is needed to determine WHO grading criteria and genetic indicators of tumor progression.
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http://dx.doi.org/10.1111/bpa.12673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444646PMC
January 2019

Video-Teleconferencing in Pediatric Neuro-Oncology: Ten Years of Experience.

J Glob Oncol 2018 09 18;4:1-7. Epub 2017 Apr 18.

Nisreen Amayiri, Maisa Swaidan, Najiyah Abuirmeileh, Maysa Al-Hussaini, Awni Musharbash, and Hadeel Halalsheh, King Hussein Cancer Center, Amman, Jordan; Tarik Tihan, University of California San Francisco, San Francisco, CA; James Drake, Uri Tabori, Ute Bartels, and Eric Bouffet, The Hospital for Sick Children, University of Toronto, Ontario, Canada; Ibrahim Qaddoumi, St Jude Children's Research Hospital, Memphis, TN.

Purpose: The management of central nervous system tumors is challenging in low- and middle-income countries. Little is known about applicability of twinning initiatives with high-income countries in neuro-oncology. In 2004, a monthly neuro-oncology video-teleconference program was started between King Hussein Cancer Center (Amman, Jordan) and the Hospital for Sick Children (Toronto, Ontario, Canada). More than 100 conferences were held and > 400 cases were discussed. The aim of this work was to assess the sustainability of such an initiative and the evolution of the impact over time.

Methods: We divided the duration in to three eras according to the initial 2 to 3 years of work of three consecutive oncologists in charge of the neuro-oncology program at King Hussein Cancer Center. We retrospectively reviewed the written minutes and compared the preconference suggested plans with the postconference recommendations. Impact of changes on the patient care was recorded.

Results: Thirty-three sets of written minutes (covering 161 cases) in the middle era and 32 sets of written minutes (covering 122 cases) in the last era were compared with the initial experience (20 meetings, 72 cases). Running costs of these conferences has dropped from $360/h to < $40/h. Important concepts were introduced, such as multidisciplinary teamwork, second-look surgery, and early referral. Suggestions for plan changes have decreased from 44% to 30% and 24% in the respective consecutive eras. Most recommendations involved alternative intervention modalities or pathology review. Most of these recommendations were followed.

Conclusion: Video-teleconferencing in neuro-oncology is feasible and sustainable. With time, team experience is built while the percentage and the type of treatment modifications change. Commitment and motivation helped maintain this initiative rather than availability of financial resources. Improvement in patients' care was achieved, in particular, with the implementation of a multidisciplinary team and the continuous effort to implement recommendations.
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http://dx.doi.org/10.1200/JGO.2016.008276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6180801PMC
September 2018

Volumetric voxelwise apparent diffusion coefficient histogram analysis for differentiation of the fourth ventricular tumors.

Neuroradiol J 2018 Dec 19;31(6):554-564. Epub 2018 Sep 19.

1 Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, USA.

Purpose: We applied voxelwise apparent diffusion coefficient (ADC) histogram analysis in addition to structural magnetic resonance imaging (MRI) findings and patients' age for differentiation of intraaxial posterior fossa tumors involving the fourth ventricle.

Participants And Methods: Pretreatment MRIs of 74 patients with intraaxial brain neoplasm involving the fourth ventricle, from January 1, 2004 to December 31, 2015, were reviewed. The tumor solid components were segmented and voxelwise ADC histogram variables were determined. Histogram-driven variables, structural MRI findings, and patient age were combined to devise a differential diagnosis algorithm.

Results: The most common neoplasms were ependymomas ( n = 21), medulloblastoma ( n = 17), and pilocytic astrocytomas ( n = 13). Medulloblastomas followed by atypical teratoid/rhabdoid tumors had the lowest ADC histogram percentile values; whereas pilocytic astrocytomas and choroid plexus papillomas had the highest ADC histogram percentile values. In a multivariable multinominal regression analysis, the ADC 10th percentile value from voxelwise histogram was the only independent predictor of tumor type ( p < 0.001). In separate binary logistic regression analyses, the 10th percentile ADC value, tumor morphology, enhancement pattern, extension into Luschka/Magendie foramina, and patient age were predictors of different tumor types. Combining these variables, we devised a stepwise diagnostic model yielding 71% to 82% sensitivity, 91% to 95% specificity, 75% to 78% positive predictive value, and 89% to 95% negative predictive value for differentiation of ependymoma, medulloblastoma, and pilocytic astrocytoma.

Conclusion: We have shown how the addition of quantitative voxelwise ADC histogram analysis of the tumor solid component to structural findings and patient age can help with accurate differentiation of intraaxial posterior fossa neoplasms involving the fourth ventricle based on pretreatment MRI.
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http://dx.doi.org/10.1177/1971400918800803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6243467PMC
December 2018

The genetic landscape of gliomas arising after therapeutic radiation.

Acta Neuropathol 2019 01 8;137(1):139-150. Epub 2018 Sep 8.

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

Radiotherapy improves survival for common childhood cancers such as medulloblastoma, leukemia, and germ cell tumors. Unfortunately, long-term survivors suffer sequelae that can include secondary neoplasia. Gliomas are common secondary neoplasms after cranial or craniospinal radiation, most often manifesting as high-grade astrocytomas with poor clinical outcomes. Here, we performed genetic profiling on a cohort of 12 gliomas arising after therapeutic radiation to determine their molecular pathogenesis and assess for differences in genomic signature compared to their spontaneous counterparts. We identified a high frequency of TP53 mutations, CDK4 amplification or CDKN2A homozygous deletion, and amplifications or rearrangements involving receptor tyrosine kinase and Ras-Raf-MAP kinase pathway genes including PDGFRA, MET, BRAF, and RRAS2. Notably, all tumors lacked alterations in IDH1, IDH2, H3F3A, HIST1H3B, HIST1H3C, TERT (including promoter region), and PTEN, which genetically define the major subtypes of diffuse gliomas in children and adults. All gliomas in this cohort had very low somatic mutation burden (less than three somatic single nucleotide variants or small indels per Mb). The ten high-grade gliomas demonstrated markedly aneuploid genomes, with significantly increased quantity of intrachromosomal copy number breakpoints and focal amplifications/homozygous deletions compared to spontaneous high-grade gliomas, likely as a result of DNA double-strand breaks induced by gamma radiation. Together, these findings demonstrate a distinct molecular pathogenesis of secondary gliomas arising after radiation therapy and identify a genomic signature that may aid in differentiating these tumors from their spontaneous counterparts.
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http://dx.doi.org/10.1007/s00401-018-1906-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589431PMC
January 2019

Perilesional edema associated with an intracranial calcifying pseudoneoplasm of the neuraxis in a child: case report and review of imaging features.

J Neurosurg Pediatr 2018 Nov;22(5):528-531

1Department of Neurological Surgery, University of California, San Francisco.

Calcifying pseudoneoplasms of the neuraxis (CAPNONs) are rare, nonneoplastic lesions of the CNS. Their radiographic features have been well described, with prominent calcifications seen on CT imaging and generally uniform hypointensity on T1- and T2-weighted MRI sequences, with variable patterns of contrast enhancement. They are not associated with significant perilesional edema. The authors present an unusual case of an 8-year-old boy who was found to have a 2.5-cm right frontal mass that demonstrated reduced signal on T2-weighted sequences, heterogeneous contrast enhancement, and extensive perilesional edema on MRI sequences. The differential diagnoses included a chronic infection or neoplasm. He underwent gross-total resection of a firm, calcified mass that had clear boundaries between it and the surrounding gliotic brain. Pathological analysis demonstrated a well-circumscribed lesion with islands of lamellar calcifications and intervening spindle cells, consistent with a CAPNON. At 8 months after surgery the patient remained seizure free, and MRI revealed no evidence of residual lesion and significant improvement in perilesional edema. This particular case highlights the potential for unusual presentation of CAPNON and the rare presence of perilesional edema.
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http://dx.doi.org/10.3171/2018.5.PEDS18104DOI Listing
November 2018
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