Publications by authors named "Fausto J Rodriguez"

191 Publications

RNA-sequencing highlights differential regulated pathways involved in cell cycle and inflammation in orbitofacial neurofibromas.

Brain Pathol 2021 Jul 23:e13007. Epub 2021 Jul 23.

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

Although most commonly benign, neurofibromas (NFs) can have devastating functional and cosmetic effects in addition to the possibility of malignant transformation. Orbitofacial NFs, in particular, may cause progressive, disfiguring tumors of the lid, brow, temple, face, and orbit, and clinical evidence suggests that they may have increased local aggressiveness compared to NFs developing at other sites. The purpose of this study was to identify biological differences between orbitofacial NFs and those occurring at other anatomic sites. We performed RNA-sequencing in orbitofacial (n = 10) and non-orbitofacial (n = 9) NFs. Differential gene expression analysis demonstrated that a variety of gene sets including genes involved in cell proliferation, interferon, and immune-related pathways were enriched in orbitofacial NF. Comparisons with publicly available databases of various Schwann cell tumors and malignant peripheral nerve sheath tumor (MPNST) revealed a significant overlap of differentially expressed genes between orbitofacial versus non-orbitofacial NF and plexiform NF versus MPNST. In summary, we identified gene expression differences between orbitofacial NF and NFs occurring at other locations. Further investigation may be warranted, given that orbitofacial NF are notoriously difficult to treat and associated with disproportionate morbidity.
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http://dx.doi.org/10.1111/bpa.13007DOI Listing
July 2021

Predicting BRAF V600E mutation in glioblastoma: utility of radiographic features.

Brain Tumor Pathol 2021 Jul 3;38(3):228-233. Epub 2021 Jul 3.

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

Detection of BRAF V600E mutation in glioblastomas (GBMs) is important because of potential therapeutic implications. Still, the relative paucity of these mutations makes molecular detection in all GBMs controversial. In the present study, we analyzed clinical, radiographic and pathologic features of 12 BRAF V600E-mutant GBMs and 12 matched controls from 2 institutions. We found that a majority of BRAF V600E-mutant GBMs displayed a combination of well-circumscribed lesions, large cystic components with thin walls and solid cortical component on MRI, but with some overlap with matched BRAF wildtype controls (p = 0.069). BRAF V600E-mutant GBMs were also apt to gross total resection (83% vs 17%, p = 0.016) and morphologically displayed epithelioid features (83% vs 0%, p < 0.0001). Identification of these clinical, radiographic, and pathologic characteristics should prompt testing for BRAF V600E in IDH-wildtype GBM.
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http://dx.doi.org/10.1007/s10014-021-00407-0DOI Listing
July 2021

Reimagining pilocytic astrocytomas in the context of pediatric low-grade gliomas.

Neuro Oncol 2021 10;23(10):1634-1646

Department of Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.

Pediatric low-grade gliomas (pLGGs) are the most common brain tumor in children and are associated with lifelong clinical morbidity. Relative to their high-grade adult counterparts or other malignant childhood brain tumors, there is a paucity of authenticated preclinical models for these pLGGs and an incomplete understanding of their molecular and cellular pathogenesis. While large-scale genomic profiling efforts have identified the majority of pathogenic driver mutations, which converge on the MAPK/ERK signaling pathway, it is now appreciated that these events may not be sufficient by themselves for gliomagenesis and clinical progression. In light of the recent World Health Organization reclassification of pLGGs, and pilocytic astrocytoma (PA), in particular, we review our current understanding of these pediatric brain tumors, provide a conceptual framework for future mechanistic studies, and outline the challenges and pressing needs for the pLGG clinical and research communities.
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http://dx.doi.org/10.1093/neuonc/noab138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8485452PMC
October 2021

SMARCAL1 loss and alternative lengthening of telomeres (ALT) are enriched in giant cell glioblastoma.

Mod Pathol 2021 Oct 8;34(10):1810-1819. Epub 2021 Jun 8.

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

Subsets of high-grade gliomas, including glioblastoma (GBM), are known to utilize the alternative lengthening of telomeres (ALT) pathway for telomere length maintenance. However, the telomere maintenance profile of one subtype of GBM-giant cell GBM-has not been extensively studied. Here, we investigated the prevalence of ALT, as well as ATRX and SMARCAL1 protein loss, in a cohort of classic giant cell GBM and GBM with giant cell features. To determine the presence of ALT, a telomere-specific fluorescence in situ hybridization assay was performed on 15 cases of classic giant cell GBM, 28 additional GBMs found to have giant cell features, and 1 anaplastic astrocytoma with giant cell features. ATRX, SMARCAL1, and IDH1 protein status were assessed in a proportion of cases by immunohistochemistry and were compared to clinical-pathologic and molecular characteristics. In the overall cohort of 44 cases, 19 (43%) showed evidence of ALT. Intriguingly, of the ALT-positive cases, only 9 (47.4%) displayed loss of the ALT suppressor ATRX by immunohistochemistry. Since inactivating mutations in SMARCAL1 have been identified in ATRX wild-type ALT-positive gliomas, we developed an immunohistochemistry assay for SMARCAL1 protein expression using genetically validated controls. Of the 19 ALT-positive cases, 6 (31.5%) showed loss or mis-localization of SMARCAL1 by immunohistochemistry. Of these cases, four retained ATRX protein expression, while two cases also displayed ATRX loss. Additionally, we assessed five cases from which multiple temporal samples were available and ALT status was concordant between both tumor biopsies. In summary, we have identified a subset of giant cell GBM that utilize the ALT telomere maintenance mechanism. Importantly, in addition to ATRX loss, ALT-positive tumors harboring SMARCAL1 alterations are prevalent in giant cell GBM.
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http://dx.doi.org/10.1038/s41379-021-00841-7DOI Listing
October 2021

Histopathologic findings in malignant peripheral nerve sheath tumor predict response to radiotherapy and overall survival.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa131. Epub 2020 Oct 1.

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

Background: Malignant peripheral nerve sheath tumor (MPNST) is an aggressive and poorly understood malignant neoplasm. Even in the setting of multimodal therapy, the clinical course of MPNST is frequently marked by metastatic conversion and poor overall prognosis, with optimal treatment paradigms for this rare tumor unknown.

Methods: We reviewed the medical records and histopathology of 54 consecutive patients who were treated at University of California San Francisco between 1990 and 2018.

Results: Our cohort consisted of 24 male and 30 female patients (median age 38 years). Fédération Nationale des Centres de Lutte Contre Le Cancer (FNCLCC) sarcoma grading criteria segregated patients into groups with differences in overall survival (OS) ( = .02). Increasing Ki-67 labeling index was associated with poor OS (hazard ratio [HR] 1.36 per 10%, = .0002). Unsupervised hierarchical clustering-based immunohistochemical staining patterns identified 2 subgroups of tumors with differences in H3K27me3, Neurofibromin, S100, SOX10, p16, and EGFR immunoreactivity. In our cohort, cluster status was associated with improved locoregional failure-free rate ( = .004) in response to radiation.

Conclusions: Our results lend support to the FNCLCC sarcoma grading criteria as a prognostic scheme for MPNST, although few cases of grade 1 were included. Further, we identify increased Ki-67 labeling as a strong predictor of poor OS from MPNST. Finally, we identify a subset of MPNSTs with a predictive immunohistochemical profile that has improved local control with adjuvant radiotherapy. These data provide insights into the grading and therapy for patients with MPNST, although further studies are needed for independent validation.
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http://dx.doi.org/10.1093/noajnl/vdaa131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044670PMC
October 2020

Chromosome 8 gain is associated with high-grade transformation in MPNST.

JCI Insight 2021 03 22;6(6). Epub 2021 Mar 22.

Department of Internal Medicine, Division of Oncology, Washington University in St. Louis, St. Louis, Missouri, USA.

One of the most common malignancies affecting adults with Neurofibromatosis type 1 (NF1) is the malignant peripheral nerve sheath tumor (MPNST), an aggressive and often fatal sarcoma that commonly arises from benign plexiform neurofibromas. Despite advances in our understanding of MPNST pathobiology, there are few effective therapeutic options, and no investigational agents have proven successful in clinical trials. To further understand the genomic heterogeneity of MPNST, and to generate a preclinical platform that encompasses this heterogeneity, we developed a collection of NF1-MPNST patient-derived xenografts (PDX). These PDX were compared with the primary tumors from which they were derived using copy number analysis, whole exome sequencing, and RNA sequencing. We identified chromosome 8 gain as a recurrent genomic event in MPNST and validated its occurrence by FISH in the PDX and parental tumors, in a validation cohort, and by single-cell sequencing in the PDX. Finally, we show that chromosome 8 gain is associated with inferior overall survival in soft-tissue sarcomas. These data suggest that chromosome 8 gain is a critical event in MPNST pathogenesis and may account for the aggressive nature and poor outcomes in this sarcoma subtype.
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http://dx.doi.org/10.1172/jci.insight.146351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026192PMC
March 2021

Diagnostic Pathology of Tumors of Peripheral Nerve.

Neurosurgery 2021 02;88(3):443-456

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

Neoplasms of the peripheral nervous system represent a heterogenous group with a wide spectrum of morphological features and biological potential. They range from benign and curable by complete excision (schwannoma and soft tissue perineurioma) to benign but potentially aggressive at the local level (plexiform neurofibroma) to the highly malignant (malignant peripheral nerve sheath tumors [MPNST]). In this review, we discuss the diagnostic and pathologic features of common peripheral nerve sheath tumors, particularly those that may be encountered in the intracranial compartment or in the spine and paraspinal region. The discussion will cover schwannoma, neurofibroma, atypical neurofibromatous neoplasms of uncertain biological potential, intraneural and soft tissue perineurioma, hybrid nerve sheath tumors, MPNST, and the recently renamed enigmatic tumor, malignant melanotic nerve sheath tumor, formerly referred to as melanotic schwannoma. We also discuss the diagnostic relevance of these neoplasms to specific genetic and familial syndromes of nerve, including neurofibromatosis 1, neurofibromatosis 2, and schwannomatosis. In addition, we discuss updates in our understanding of the molecular alterations that represent key drivers of these neoplasms, including neurofibromatosis type 1 and type 2, SMARCB1, LZTR1, and PRKAR1A loss, as well as the acquisition of CDKN2A/B mutations and alterations in the polycomb repressor complex members (SUZ12 and EED) in the malignant progression to MPNST. In summary, this review covers practical aspects of pathologic diagnosis with updates relevant to neurosurgical practice.
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http://dx.doi.org/10.1093/neuros/nyab021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884141PMC
February 2021

Predictors of Postoperative Visual Outcome After Surgical Intervention for Craniopharyngiomas.

World Neurosurg 2021 04 20;148:e589-e599. Epub 2021 Jan 20.

Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. Electronic address:

Background: Because of involvement of the optic apparatus, craniopharyngiomas frequently present with visual deterioration. Although visual improvement is a primary goal of surgical intervention, prediction models are lacking.

Methods: We retrospectively reviewed all patients undergoing craniopharyngioma surgery at a single institution (2014-2019). Preoperative, intraoperative, and postoperative variables of interest were collected. Visual acuity and visual fields (VFs) were standardized into Visual Impairment Scores (VISs), defined by the German Ophthalmological Society. VIS ranged from 0 (normal vision) to 100 (complete bilateral blindness). Visual improvement/deterioration was defined as a postsurgical decrease/increase of ≥5 VIS points, respectively.

Results: Complete ophthalmologic assessments were available for 61 operations, corresponding to 41 patients (age, 4-73 years). Vision improved after 28 operations (46%), remained stable after 27 (44%), and deteriorated after 6 (10%). In bivariate analysis, significant predictors of visual improvement included worse preoperative VIS (odds ratio [OR], 1.058; P < 0.001), worse preoperative VF mean deviation (OR, 1.107; P = 0.032), preoperative vision deficits presenting for longer than 1 month (OR, 6.050; P = 0.010), radiographic involvement of the anterior cerebral arteries (OR, 3.555; P = 0.019), and gross total resection (OR, 4.529; P = 0.022). The translaminar surgical approach was associated with visual deterioration (OR, 6.857; P = 0.035). In multivariate analysis, worse preoperative VIS remained significantly associated with postoperative visual improvement (OR, 1.060; P = 0.011). Simple linear correlation (R=0.398; P < 0.001) suggests prediction of postoperative VIS improvement via preoperative VIS.

Conclusions: Patients with reduced preoperative vision, specific radiographic vascular involvement, and gross total resection showed increased odds of visual improvement, whereas the translaminar approach was associated with visual deterioration. Such characteristics may facilitate patient-surgeon counseling and surgical decision making.
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http://dx.doi.org/10.1016/j.wneu.2021.01.044DOI Listing
April 2021

Preoperative BMI Predicts Postoperative Weight Gain in Adult-onset Craniopharyngioma.

J Clin Endocrinol Metab 2021 03;106(4):e1603-e1617

Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Context: Craniopharyngiomas, while benign, have the highest morbidity of all nonmalignant sellar tumors. Studies on weight and metabolic outcomes in adult-onset craniopharyngioma (AOCP) remain sparse.

Objective: To examine postsurgical weight and metabolic outcomes in AOCP and to identify any clinical predictors of weight gain.

Methods: Retrospective chart review of patients with AOCP who underwent surgery between January 2014 and May 2019 in a single pituitary center. The study included 45 patients with AOCP with a minimum follow-up of 3 months. Median follow-up time was 26 months (interquartile range [IQR] 10-44). Main outcome measures were the changes in weight/body mass index (BMI), metabolic comorbidities, and pituitary deficiencies between preoperative and last follow-up.

Results: Both weight and BMI were higher at last follow-up, with a mean increase of 3.4 kg for weight (P = .015) and 1.15 kg/m2 for BMI (P = .0095). Median % weight change was 2.7% (IQR -1.1%, 8.8%). Obesity rate increased from 37.8% at baseline to 55.6% at last follow-up. One-third of patients had ~15% median weight gain. The prevalence of metabolic comorbidities at last follow-up was not different from baseline. Pituitary deficiencies increased postoperatively, with 58% of patients having ≥3 hormonal deficiencies. Preoperative BMI was inversely associated with postoperative weight gain, which remained significant after adjusting for age, sex, race, tumor, and treatment characteristics. Patients with ≥3 hormonal deficiencies at last follow-up also had higher postoperative weight gain.

Conclusion: In this AOCP cohort, those with a lower BMI at the preoperative visit had higher postoperative weight gain. Our finding may help physicians better counsel patients and provide anticipatory guidance on postoperative expectations and management.
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http://dx.doi.org/10.1210/clinem/dgaa985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993568PMC
March 2021

Conditional reprogramming culture conditions facilitate growth of lower-grade glioma models.

Neuro Oncol 2021 05;23(5):770-782

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

Background: The conditional reprogramming cell culture method was developed to facilitate growth of senescence-prone normal and neoplastic epithelial cells, and involves co-culture with irradiated fibroblasts and the addition of a small molecule Rho kinase (ROCK) inhibitor. The aim of this study was to determine whether this approach would facilitate the culture of compact low-grade gliomas.

Methods: We attempted to culture 4 pilocytic astrocytomas, 2 gangliogliomas, 2 myxopapillary ependymomas, 2 anaplastic gliomas, 2 difficult-to-classify low-grade neuroepithelial tumors, a desmoplastic infantile ganglioglioma, and an anaplastic pleomorphic xanthoastrocytoma using a modified conditional reprogramming cell culture approach.

Results: Conditional reprogramming resulted in robust increases in growth for a majority of these tumors, with fibroblast conditioned media and ROCK inhibition both required. Switching cultures to standard serum containing media, or serum-free neurosphere conditions, with or without ROCK inhibition, resulted in decreased proliferation and induction of senescence markers. Rho kinase inhibition and conditioned media both promoted Akt and Erk1/2 activation. Several cultures, including one derived from a NF1-associated pilocytic astrocytoma (JHH-NF1-PA1) and one from a BRAF p.V600E mutant anaplastic pleomorphic xanthoastrocytoma (JHH-PXA1), exhibited growth sufficient for preclinical testing in vitro. In addition, JHH-NF1-PA1 cells survived and migrated in larval zebrafish orthotopic xenografts, while JHH-PXA1 formed orthotopic xenografts in mice histopathologically similar to the tumor from which it was derived.

Conclusions: These studies highlight the potential for the conditional reprogramming cell culture method to promote the growth of glial and glioneuronal tumors in vitro, in some cases enabling the establishment of long-term culture and in vivo models.
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http://dx.doi.org/10.1093/neuonc/noaa263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099469PMC
May 2021

GLI3 Is Associated With Neuronal Differentiation in SHH-Activated and WNT-Activated Medulloblastoma.

J Neuropathol Exp Neurol 2021 01;80(2):129-136

Department of Pathology, Brain Research Institute, Niigata University.

Glioma-associated oncogene homolog 3 (GLI3), whose main function is to inhibit GLI1, has been associated with neuronal differentiation in medulloblastoma. However, it is not clear what molecular subtype(s) show increased GLI3 expression. GLI3 levels were assessed by immunohistochemistry in 2 independent cohorts, including a total of 88 cases, and found to be high in both WNT- and SHH-activated medulloblastoma. Analysis of bulk mRNA expression data and single cell RNA sequencing studies confirmed that GLI1 and GLI3 are highly expressed in SHH-activated medulloblastoma, whereas GLI3 but not GLI1 is highly expressed in WNT-activated medulloblastoma. Immunohistochemical analysis has shown that GLI3 is expressed inside the neuronal differentiated nodules of SHH-activated medulloblastoma, whereas GLI1/2 are expressed in desmoplastic areas. In contrast, GLI3 is diffusely expressed in WNT-activated medulloblastoma, whereas GLI1 is suppressed. Our data suggest that GLI3 may be a master regulator of neuronal differentiation and morphology in these subgroups.
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http://dx.doi.org/10.1093/jnen/nlaa141DOI Listing
January 2021

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 Case of Metastatic Giant Cell Tumor of Soft Tissue of the Orbit Associated With PALB2 Variant.

JAMA Ophthalmol 2020 12;138(12):1322-1324

Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland.

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http://dx.doi.org/10.1001/jamaophthalmol.2020.4308DOI Listing
December 2020

Combined Inhibition of SHP2 and MEK Is Effective in Models of NF1-Deficient Malignant Peripheral Nerve Sheath Tumors.

Cancer Res 2020 12 8;80(23):5367-5379. Epub 2020 Oct 8.

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Loss of the RAS GTPase-activating protein (RAS-GAP) NF1 drives aberrant activation of RAS/MEK/ERK signaling and other effector pathways in the majority of malignant peripheral nerve sheath tumors (MPNST). These dysregulated pathways represent potential targets for therapeutic intervention. However, studies of novel single agents including MEK inhibitors (MEKi) have demonstrated limited efficacy both preclinically and clinically, with little advancement in overall patient survival. By interrogation of kinome activity through an unbiased screen and targeted evaluation of the signaling response to MEK inhibition, we have identified global activation of upstream receptor tyrosine kinases (RTK) that converges on activation of RAS as a mechanism to limit sensitivity to MEK inhibition. As no direct inhibitors of pan-RAS were available, an inhibitor of the protein tyrosine phosphatase SHP2, a critical mediator of RAS signal transduction downstream of multiple RTK, represented an alternate strategy. The combination of MEKi plus SHP099 was superior to MEKi alone in models of NF1-MPNST, including those with acquired resistance to MEKi. Our findings have immediate translational implications and may inform future clinical trials for patients with MPNST harboring alterations in . SIGNIFICANCE: Combined inhibition of MEK and SHP2 is effective in models of NF1-MPNST, both those naïve to and those resistant to MEKi, as well as in the MPNST precursor lesion plexiform neurofibroma.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739379PMC
December 2020

Low-Grade Gemistocytic Morphology in H3 G34R-Mutant Gliomas and Concurrent K27M Mutation: Clinicopathologic Findings.

J Neuropathol Exp Neurol 2020 10;79(10):1038-1043

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.

Mutations in histone H3 are key molecular drivers of pediatric and young adult high-grade gliomas. Histone H3 G34R mutations occur in hemispheric high-grade gliomas and H3 K27M mutations occur in aggressive, though histologically diverse, midline gliomas. Here, we report 2 rare cases of histologically low-grade gliomas with gemistocytic morphology and sequencing-confirmed histone H3 G34R mutations. One case is a histologically low-grade gemistocytic astrocytoma with a G34R-mutation in H3F3A. The second case is a histologically low-grade gemistocytic astrocytoma with co-occurring K27M and G34R mutations in HIST1H3B. Review of prior histone H3-mutant gliomas sequenced at our institution shows a divergent clinical and immunohistochemical pattern in the 2 cases. The first case is similar to prior histone H3 G34R-mutant tumors, while the second case most closely resembles prior histone H3 K27M-mutant gliomas. These represent novel cases of sequencing-confirmed histone H3 G34R-mutant gliomas with low-grade histology and add to the known rare cases of G34R-mutant tumors with gemistocytic morphology. Although K27M and G34R mutations are thought to be mutually exclusive, we document combined K27M and G34R mutations in HIST1H3B and present evidence suggesting the K27M-mutation drove tumor phenotype in this dual mutant glioma.
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http://dx.doi.org/10.1093/jnen/nlaa101DOI Listing
October 2020

Imaging of non-neurogenic peripheral nerve malignancy-a case series and systematic review.

Skeletal Radiol 2021 Jan 23;50(1):201-215. Epub 2020 Jul 23.

The Russell H. Morgan Department of Radiology & Radiological Science, The Johns Hopkins Medical Institutions, 600 North Wolfe Street, Baltimore, MD, 21287, USA.

Objective: To evaluate the frequency, clinico-pathologic and imaging features of malignant tumors in peripheral nerves which are of non-neurogenic origin (non-neurogenic peripheral nerve malignancy-PNM).

Materials And Methods: We retrospectively reviewed our pathology database for malignant peripheral nerve tumors from 07/2014-07/2019 and performed a systematic review. Exclusion criteria were malignant peripheral nerve sheath tumor (MPNST). Clinico-pathologic and imaging features, apparent diffusion coefficient (ADC), and standard uptake values (SUV) are reported.

Results: After exclusion of all neurogenic tumors (benign = 196, MPNST = 57), our search yielded 19 non-neurogenic PNMs (7%, n = 19/272), due to primary intraneural malignancy (16%, n = 3/19) and secondary perineural invasion from an adjacent malignancy (16%, n = 3/19) or metastatic disease (63%, n = 12/19). Non-neurogenic PNMs were located in the lumbosacral plexus/sciatic nerves (47%, n = 9/19), brachial plexus (32%, n = 6/19), femoral nerve (5%, n = 1/19), tibial nerve (5%, n = 1/19), ulnar nerve (5%, n = 1/19), and radial nerve (5%, n = 1/19). On MRI (n = 14/19), non-neurogenic PNM tended to be small (< 5 cm, n = 10/14), isointense to muscle on T1-W (n = 14/14), hyperintense on T2-WI (n = 12/14), with enhancement (n = 12/12), low ADC (0.5-0.7 × 10-3 mm/s), and variable metabolic activity (SUV range 2.1-13.1). A target sign was absent (n = 14/14) and fascicular sign was rarely present (n = 3/14). Systematic review revealed 89 cases of non-neurogenic PNM.

Conclusion: Non-neurogenic PNMs account for 7% of PNT in our series and occur due to metastases and primary intraneural malignancy. Although non-neurogenic PNMs exhibit a non-specific MRI appearance, they lack typical signs of neurogenic tumors such as the target sign. Quantitative imaging features identified by DWI (low ADC) and F-FDG PET/CT (high SUV) may be helpful clues to the diagnosis.
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http://dx.doi.org/10.1007/s00256-020-03556-zDOI Listing
January 2021

Assessing interobserver variability and accuracy in the histological diagnosis and classification of cutaneous neurofibromass.

Neurooncol Adv 2020 Jul 5;2(Suppl 1):i117-i123. Epub 2019 Dec 5.

Department of Pathology, Neuropathology Division, Massachusetts General Hospital, Boston, Massachusetts.

Background: Cutaneous neurofibromas (cNFs) are the most common tumors in people with neurofibromatosis type 1 (NF1) and are associated with reduced quality of life. There is currently no widely accepted standardized language for describing cNFs clinically or histopathologically. The objective of this study was to evaluate interobserver agreement across pathologists in describing and reporting of neurofibromas involving the skin.

Methods: Twenty-eight (H&E)-stained slides of cNF were scanned using an Aperio XT scanner. The digital images were reviewed by 6 pathologists, who entered free text of up to a 200 word description for each case into a REDcap database. Responses were analyzed for the most commonly used terms based on frequency, as well as agreement (reported as concordance) between reviewers.

Results: A set of the terms most commonly used by pathologists for the histological classification of cNF along with areas of agreement and disagreement have been identified. The study shows that there was strong agreement across reviewers that not all neurofibromas involving the skin are cutaneous neurofibromas and regarding the presence or absence of atypical features and heterologous elements. Areas of less concordance were identified and include cNF subtypes, definition of extension and pattern of growth, as well as the distinction of a cNF from a plexiform without an intraneural component involving skin.

Conclusions: This work is the first step towards development of a robust classification system and devising "gold standard" histopathologic diagnostic criteria for cutaneous neurofibromas.
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http://dx.doi.org/10.1093/noajnl/vdz050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7317056PMC
July 2020

Biology and grading of pleomorphic xanthoastrocytoma-what have we learned about it?

Brain Pathol 2021 01 4;31(1):20-32. Epub 2020 Aug 4.

Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.

Pleomorphic xanthoastrocytoma (PXA) is a rare astrocytoma predominantly affecting children and young adults. We performed comprehensive genomic characterization on a cohort of 67 patients with histologically defined PXA (n = 53, 79%) or anaplastic PXA (A-PXA, n = 14, 21%), including copy number analysis (ThermoFisher Oncoscan, n = 67), methylation profiling (Illumina EPIC array, n = 43) and targeted next generation sequencing (n = 32). The most frequent alterations were CDKN2A/B deletion (n = 63; 94%) and BRAF p.V600E (n = 51, 76.1%). In 7 BRAF p.V600 wild-type cases, alternative driver alterations were identified involving BRAF, RAF1 and NF1. Downstream phosphorylation of ERK kinase was uniformly present. Additional pathogenic alterations were rare, with TERT, ATRX and TP53 mutations identified in a small number of tumors, predominantly A-PXA. Methylation-based classification of 46 cases utilizing a comprehensive reference tumor allowed assignment to the PXA methylation class in 40 cases. A minority grouped with the methylation classes of ganglioglioma or pilocytic astrocytoma (n = 2), anaplastic pilocytic astrocytoma (n = 2) or control tissues (n = 2). In 9 cases, tissue was available from matched primary and recurrent tumors, including 8 with anaplastic transformation. At recurrence, two tumors acquired TERT promoter mutations and the majority demonstrated additional non-recurrent copy number alterations. Methylation class was preserved at recurrence. For 62 patients (92.5%), clinical follow-up data were available (median follow-up, 5.4 years). Overall survival was significantly different between PXA and A-PXA (5-year OS 80.8% vs. 47.6%; P = 0.0009) but not progression-free survival (5-year PFS 59.9% vs. 39.8%; P = 0.05). WHO grade remained a strong predictor of overall survival when limited to 38 cases defined as PXA by methylation-based classification. Our data confirm the importance of WHO grading in histologically and epigenetically defined PXA. Methylation-based classification may be helpful in cases with ambiguous morphology, but is largely confirmatory in PXA with well-defined morphology.
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http://dx.doi.org/10.1111/bpa.12874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018001PMC
January 2021

A clinically and genomically annotated nerve sheath tumor biospecimen repository.

Sci Data 2020 06 19;7(1):184. Epub 2020 Jun 19.

Sidney Kimmel Comprehensive Cancer Center and Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, USA.

Nerve sheath tumors occur as a heterogeneous group of neoplasms in patients with neurofibromatosis type 1 (NF1). The malignant form represents the most common cause of death in people with NF1, and even when benign, these tumors can result in significant disfigurement, neurologic dysfunction, and a range of profound symptoms. Lack of human tissue across the peripheral nerve tumors common in NF1 has been a major limitation in the development of new therapies. To address this unmet need, we have created an annotated collection of patient tumor samples, patient-derived cell lines, and patient-derived xenografts, and carried out high-throughput genomic and transcriptomic characterization to serve as a resource for further biologic and preclinical therapeutic studies. In this work, we release genomic and transcriptomic datasets comprised of 55 tumor samples derived from 23 individuals, complete with clinical annotation. All data are publicly available through the NF Data Portal and at http://synapse.org/jhubiobank.
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http://dx.doi.org/10.1038/s41597-020-0508-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305302PMC
June 2020

Neurogenic Tumors of the Mediastinum.

Semin Diagn Pathol 2020 Jul 21;37(4):179-186. Epub 2020 May 21.

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

Neurogenic tumors represent a broad ill-defined category of neoplasms that includes tumors of Schwann cell and/or neuroblastic derivation, as well as neoplasms that typically develop in the central nervous system, but rarely present in ectopic sites including the mediastinum. Neurogenic tumors may occur at many different anatomic sites, but the mediastinum represents a uniquely challenging site given the complex anatomy. Additionally, some of these neoplasms may present with multicentric involvement in the context of genetic syndromes, including NF1, NF2 and schwanomatosis. Most of these develop in posterior structures, often in association with paraspinal structures. Fine needle biopsy/small biopsies play an important role in the diagnosis of these neoplasms, given its record of safety and the increased applicability of ancillary testing to these smaller samples at the present time. In this review we focus on the major categories of neurogenic tumors that may be encountered in the mediastinum, including schwannoma, neurofibroma, malignant peripheral nerve sheath tumors, ganglioneuroma and ganglioneuroblastoma, as well as rarer members of this category. We discuss diagnostic approaches applicable to small cytologic and tissue samples and relevant differential diagnoses.
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http://dx.doi.org/10.1053/j.semdp.2020.04.004DOI Listing
July 2020

Correction to: Differential gene methylation and expression of HOX transcription factor family in orbitofacial neurofibroma.

Acta Neuropathol Commun 2020 05 14;8(1):69. Epub 2020 May 14.

Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.

An amendment to this paper has been published and can be accessed via the original article.
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http://dx.doi.org/10.1186/s40478-020-00944-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222592PMC
May 2020

Localized Hypertrophic Neuropathy as a Neoplastic Manifestation of KRAS-Mediated RASopathy.

J Neuropathol Exp Neurol 2020 06;79(6):647-651

Department of Pathology, Baltimore, Maryland.

Localized hypertrophic neuropathy is a rare Schwann cell proliferation that usually affects single nerves from the extremities, and it is of unclear etiology in its pure form. RASopathies are a defined group of genetic diseases with overlapping clinical features, usually secondary to germline mutations in genes encoding either components or regulators of the RAS/MAPK pathway. Herein, we report an 11-year-old boy presenting with café au lait spots and right leg length discrepancy. A fascicular nerve biopsy of the tibial nerve demonstrated a Schwann cell proliferation with prominent onion-bulb formation, satisfying criteria for localized hypertrophic neuropathy. Molecular genetic analysis demonstrated identical KRAS mutations (c38_40dupGCG) in the peripheral nerve lesion and melanocytes from café au lait spots, but not in blood, supporting a diagnosis of a KRAS-mediated rasopathy with mosaicism. Immunohistochemical staining in the peripheral nerve lesion demonstrated strong pERK staining consistent with downstream MAPK pathway activation. This report suggests that at least a subset of localized hypertrophic neuropathies are bonafide, well-differentiated Schwann cell neoplasms developing through oncogenic RAS signaling, which provides new insights into the controversial entity historically known as localized hypertrophic neuropathy.
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http://dx.doi.org/10.1093/jnen/nlaa034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241937PMC
June 2020

Differential gene methylation and expression of HOX transcription factor family in orbitofacial neurofibroma.

Acta Neuropathol Commun 2020 05 4;8(1):62. Epub 2020 May 4.

Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, United States.

Although most commonly benign, neurofibromas (NFs) can have devastating functional and cosmetic effects in addition to the possibility of malignant transformation. In orbitofacial neurofibromatosis type 1, NFs may cause progressive, disfiguring tumors of the lid, brow, temple, face and orbit. The purpose of this study was to identify biological differences between orbitofacial NFs and those occurring at other anatomic sites. We used Illumina Methylation EPIC BeadChip to study DNA methylation differences between orbitofacial NFs (N = 20) and NFs at other sites (N = 4). Global methylation differences were detected between the two groups and the top differentially methylated genes were part of the HOX (Homebox) family of transcription factors (HOXC8, HOXC4, HOXC6, HOXA6 and HOXD4), which were hypomethylated in orbitofacial NFs compared to the non-orbital NFs. Conversely, LTF (lactoferrin) was relatively hypermethylated in orbitofacial NF compared to non-orbitofacial NF. HOXC8 protein levels were higher in orbitofacial plexiform NFs (p = 0.04). We found no significant differences in the expression of HOXC4, HOXA6, or HOXD4 between the two groups. HOXC8 mRNA levels were also higher in orbitofacial NFs and HOXC8 overexpression in a non-neoplastic human Schwann cell line resulted in increased growth. In summary, we identified gene methylation and expression differences between orbitofacial NF and NFs occurring at other locations. Further investigation may be warranted, given that the HOX family of genes play an important role during development, are dysregulated in a variety of cancers, and may provide novel insights into therapeutic approaches.
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http://dx.doi.org/10.1186/s40478-020-00940-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7197183PMC
May 2020

Intraneural perineurioma in neurofibromatosis type 2 with molecular analysis.

Clin Neuropathol 2020 Jul/Aug;39(4):167-171

Intraneural perineuriomas are rare benign neoplasms. The gene associated with neurofibromatosis 2 (NF2) is located on chromosome 22q12, and mutations in are commonly seen in soft tissue perineuriomas. However, an association between mutations and intraneural perineuriomas (INPs) has not been well established. We present a 20-year-old male with NF2, multiple schwannomas and an intraneural perineurioma in the radial nerve at the spiral groove. Sequencing of , , and was performed and demonstrated loss of the long arm of chromosome 22 including , , and , and a constitutional alteration. We review the literature supporting two mutually exclusive pathways involving and mutations that lead to the development of INPs.
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http://dx.doi.org/10.5414/NP301245DOI Listing
April 2021

Telomere length alterations and ATRX/DAXX loss in pituitary adenomas.

Mod Pathol 2020 08 18;33(8):1475-1481. Epub 2020 Mar 18.

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

Telomeres are nucleoprotein complexes located at the termini of eukaryotic chromosomes that prevent exonucleolytic degradation and end-to-end chromosomal fusions. Cancers often have critically shortened, dysfunctional telomeres contributing to genomic instability. Telomere shortening has been reported in a wide range of precancerous lesions and invasive carcinomas. However, the role of telomere alterations, including the presence of alternative lengthening of telomeres (ALT), has not been studied in pituitary adenomas. Telomere length and the presence of ALT were assessed directly at the single cell level using a telomere-specific fluorescence in situ hybridization assay in tissue microarrays. Tumors were characterized as either ALT-positive or having short, normal, or long telomere lengths and then these categories were compared with clinicopathological characteristics. ATRX and DAXX expression was studied through immunohistochemistry. We characterized a discovery set of 106 pituitary adenomas including both functional and nonfunctional subsets (88 primary, 18 recurrent). Telomere lengths were estimated and we observed 64 (59.4%) cases with short, 39 (36.8%) cases with normal, and 0 (0%) cases with long telomeres. We did not observe significant differences in the clinicopathological characteristics of the group with abnormally shortened telomeres compared to the group with normal telomeres. However, three pituitary adenomas were identified as ALT-positive of which two were recurrent tumors. Two of these three ALT-positive cases had alterations in either of the chromatin remodeling proteins, ATRX and DAXX, which are routinely altered in other ALT-positive tumor subtypes. In a second cohort of 32 recurrent pituitary adenomas from 22 patients, we found that the tumors from 36% of patients (n = 8) were ALT-positive. This study demonstrates that short telomere lengths are prevalent in pituitary adenomas and that ALT-positive pituitary adenomas are enriched in recurrent disease.
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http://dx.doi.org/10.1038/s41379-020-0523-2DOI Listing
August 2020

Implications of new understandings of gliomas in children and adults with NF1: report of a consensus conference.

Neuro Oncol 2020 06;22(6):773-784

Department of Neurology; Washington University, St Louis, Missouri, USA.

Gliomas are the most common primary central nervous system tumors occurring in children and adults with neurofibromatosis type 1 (NF1). Over the past decade, discoveries of the molecular basis of low-grade gliomas (LGGs) have led to new approaches for diagnosis and treatments. However, these new understandings have not been fully applied to the management of NF1-associated gliomas. A consensus panel consisting of experts in NF1 and gliomas was convened to review the current molecular knowledge of NF1-associated low-grade "transformed" and high-grade gliomas; insights gained from mouse models of NF1-LGGs; challenges in diagnosing and treating older patients with NF1-associated gliomas; and advances in molecularly targeted treatment and potential immunologic treatment of these tumors. Next steps are recommended to advance the management and outcomes for NF1-associated gliomas.
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http://dx.doi.org/10.1093/neuonc/noaa036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283027PMC
June 2020

alterations in anaplastic ependymoma progression to ependymosarcoma.

Clin Neuropathol 2020 Jul/Aug;39(4):179-187

Ependymosarcomas are rare, biphasic tumors composed of ependymal and sarcomatous components. Due to their rarity, their biologic basis is not well understood. We report the case of a 38-year-old male with anaplastic ependymoma (WHO grade III) that progressed to ependymosarcoma in less than 2 years after multiple resections, chemoradiotherapy, and anti-PD1 immunotherapy. Next-generation sequencing was performed on both high-grade anaplastic ependymoma and ependymosarcoma samples to detect small base changes, insertions, and deletions in exons and splice junctions from a panel of over 400 genes. We identify genetic variants in the tumor suppressors , , and in these samples and discuss the potential significance of an additional genetic variant in the progression to ependymosarcoma.
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http://dx.doi.org/10.5414/NP301240DOI Listing
April 2021

Astrocytic trans-Differentiation Completes a Multicellular Paracrine Feedback Loop Required for Medulloblastoma Tumor Growth.

Cell 2020 02 23;180(3):502-520.e19. Epub 2020 Jan 23.

Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22908, USA. Electronic address:

The tumor microenvironment (TME) is critical for tumor progression. However, the establishment and function of the TME remain obscure because of its complex cellular composition. Using a mouse genetic system called mosaic analysis with double markers (MADMs), we delineated TME evolution at single-cell resolution in sonic hedgehog (SHH)-activated medulloblastomas that originate from unipotent granule neuron progenitors in the brain. First, we found that astrocytes within the TME (TuAstrocytes) were trans-differentiated from tumor granule neuron precursors (GNPs), which normally never differentiate into astrocytes. Second, we identified that TME-derived IGF1 promotes tumor progression. Third, we uncovered that insulin-like growth factor 1 (IGF1) is produced by tumor-associated microglia in response to interleukin-4 (IL-4) stimulation. Finally, we found that IL-4 is secreted by TuAstrocytes. Collectively, our studies reveal an evolutionary process that produces a multi-lateral network within the TME of medulloblastoma: a fraction of tumor cells trans-differentiate into TuAstrocytes, which, in turn, produce IL-4 that stimulates microglia to produce IGF1 to promote tumor progression.
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http://dx.doi.org/10.1016/j.cell.2019.12.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7259679PMC
February 2020

Genomic Landscape of Intramedullary Spinal Cord Gliomas.

Sci Rep 2019 12 10;9(1):18722. Epub 2019 Dec 10.

Ludwig Center for Cancer Genetics, Sidney Kimmel Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.

Intramedullary spinal cord tumors (IMSCTs) are rare neoplasms that have limited treatment options and are associated with high rates of morbidity and mortality. To better understand the genetic basis of these tumors we performed whole exome sequencing on 45 tumors and matched germline DNA, including twenty-nine spinal cord ependymomas and sixteen astrocytomas. Though recurrent somatic mutations in IMSCTs were rare, we identified NF2 mutations in 15.7% of tumors (ependymoma, N = 7; astrocytoma, N = 1), RP1 mutations in 5.9% of tumors (ependymoma, N = 3), and ESX1 mutations in 5.9% of tumors (ependymoma, N = 3). We further identified copy number amplifications in CTU1 in 25% of myxopapillary ependymomas. Given the paucity of somatic driver mutations, we further performed whole-genome sequencing of 12 tumors (ependymoma, N = 9; astrocytoma, N = 3). Overall, we observed that IMSCTs with intracranial histologic counterparts (e.g. glioblastoma) did not harbor the canonical mutations associated with their intracranial counterparts. Our findings suggest that the origin of IMSCTs may be distinct from tumors arising within other compartments of the central nervous system and provides the framework to begin more biologically based therapeutic strategies.
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http://dx.doi.org/10.1038/s41598-019-54286-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904446PMC
December 2019

Clinicopathologic Features of Diencephalic Neuronal and Glioneuronal Tumors.

J Neuropathol Exp Neurol 2020 01;79(1):67-73

Department of Pathology and Neurology, University of Maryland School of Medicine, Baltimore, Maryland (C-YH).

Neuronal/mixed glioneuronal tumors are central nervous system neoplasms composed of neoplastic neuronal cell components or a mixture of glial and neuronal elements. They occur in cerebral hemispheres, posterior fossa, and spinal cord. Compared with other tumors at these locations, diencephalic neuronal/glioneuronal tumors are very rare and therefore not well characterized. We hereby performed clinicopathologic evaluation on 10 neuronal/glioneuronal tumors arising from the diencephalic region. Morphologically, these tumors resemble their histologic counterparts in other locations, except that lymphocytic infiltrates and microcalcifications are more common than Rosenthal fibers or eosinophilic granular bodies. The BRAFV600 mutation rate is 75%. Given the high percentage of samples being small biopsy specimens, the subtle histologic features and molecular findings greatly aided in establishing the pathologic diagnosis in several cases. At a median follow-up of 42 months, 71% of the tumors demonstrated radiological recurrence or progression, with median progression-free survival of 18 months. Recurrence/progression is observed in tumors across different histologic subtypes, necessitating additional therapies in 56% of the cases. Despite their bland histology, diencephalic neuronal/glioneuronal tumors are not clinically indolent. Their frequent recurrences warrant a close follow-up, and the prevalent BRAF mutation makes MAPK pathway inhibition a plausible treatment option when conventional therapies fail.
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http://dx.doi.org/10.1093/jnen/nlz115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850088PMC
January 2020
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