Multiple Intraspinal Gangliogliomas in a Child With Neurofibromatosis Type 1: Case Report and Literature Review.

Neurofibromatosis type 1 (NF1)-associated primary intramedullary spinal cord ganglioglioma has only rarely been reported. Because of frequent nonresectability, they pose significant management challenges despite clinical indolence. This report describes a 4-year-old girl with NF1 who was found to have multiple discrete, infiltrative intramedullary cord masses, and biopsy demonstrated World Health Organization grade I ganglioglioma. Panel-based next-generation sequencing showed her previously identified germline NF1 mutation and a second somatic NF1 mutation. This represents the first report of multiple primary intramedullary gangliogliomas in a child with NF1 and demonstrates how biopsy with panel-based next-generation sequencing provides potential targets for MAPK/MEK/BRAF pathway inhibitor therapy.

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

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.

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

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.

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

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.

RNA Binding Proteins and the Pathogenesis of Frontotemporal Lobar Degeneration.

Frontotemporal dementia is a group of early onset dementia syndromes linked to underlying frontotemporal lobar degeneration (FTLD) pathology that can be classified based on the formation of abnormal protein aggregates involving tau and two RNA binding proteins, TDP-43 and FUS. Although elucidation of the mechanisms leading to FTLD pathology is in progress, recent advances in genetics and neuropathology indicate that a majority of FTLD cases with proteinopathy involving RNA binding proteins show highly congruent genotype-phenotype correlations. Specifically, recent studies have uncovered the unique properties of the low-complexity domains in RNA binding proteins that can facilitate liquid-liquid phase separation in the formation of membraneless organelles. Furthermore, there is compelling evidence that mutations in FTLD genes lead to dysfunction in diverse cellular pathways that converge on the endolysosomal pathway, autophagy, and neuroinflammation. Together, these results provide key mechanistic insights into the pathogenesis and potential therapeutic targets of FTLD.

Characterization of gliomas: from morphology to molecules.

This article reviews the histologic and molecular characterization of gliomas, including the new "integrated diagnoses" of the World Health Organization Classification, 2016 edition. The entities reviewed within include diffuse gliomas (astrocytoma, oligodendroglioma, glioblastoma), as well as circumscribed and low-grade gliomas (angiocentric glioma, pilocytic astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma, pilomyxoid astrocytoma, ependymoma, myxopapillary ependymoma, and subependymoma). Diagnostic, prognostic, and predictive biomarkers are discussed for each entity. We review how molecular testing for IDH1 and ATRX and detection of chromosome 1p/19q codeletion can be used to categorize glioblastomas as IDH-wildtype or IDH-mutant, and lower grade diffuse gliomas into three molecular groups that correlate better with patient outcomes than histologic subtyping. Pediatric diffuse gliomas are highlighted, including diffuse midline glioma, H3 K27M-mutant, and inherited germline mutations that predispose to pediatric gliomas. The utility of genomic profiling of certain gliomas is discussed, including identifying candidates for experimental therapies. This review is meant to be a concise summary of glioma characterization for the practicing pathologist.

Reduced expression of MYC increases longevity and enhances healthspan.

MYC is a highly pleiotropic transcription factor whose deregulation promotes cancer. In contrast, we find that Myc haploinsufficient (Myc(+/-)) mice exhibit increased lifespan. They show resistance to several age-associated pathologies, including osteoporosis, cardiac fibrosis, and immunosenescence. They also appear to be more active, with a higher metabolic rate and healthier lipid metabolism. Transcriptomic analysis reveals a gene expression signature enriched for metabolic and immune processes. The ancestral role of MYC as a regulator of ribosome biogenesis is reflected in reduced protein translation, which is inversely correlated with longevity. We also observe changes in nutrient and energy sensing pathways, including reduced serum IGF-1, increased AMPK activity, and decreased AKT, TOR, and S6K activities. In contrast to observations in other longevity models, Myc(+/-) mice do not show improvements in stress management pathways. Our findings indicate that MYC activity has a significant impact on longevity and multiple aspects of mammalian healthspan.

Epidermotropic Merkel cell carcinoma: a case series with histopathologic examination.

BACKGROUND: Merkel cell carcinoma (MCC), an aggressive malignancy that has been increasing in incidence, rarely presents with an epidermotropic pattern. OBJECTIVE: We conducted an immunohistochemical evaluation of 6 previously unpublished cases of epidermotropic MCC, focusing particularly on the staining characteristics of epithelial membrane antigen and cytokeratin-20 in the hope of providing insight into the mechanism of epidermotropism in MCC. METHODS: This study is a retrospective evaluation using light microscopy and immunohistochemistry. RESULTS: Forty cases of MCC with pathology at Rhode Island Hospital and the Miriam Hospital in Providence, RI, from 1983 through 2009 were reviewed. Following exclusion criteria, 6 patients (5 men, 1 woman) with a mean age of 82.5 years (range, 72-92) demonstrated epidermotropism. Three of 6 patients had MCC of the eyelid. In cases 1, 3, and 6, the perinuclear dot pattern observed with cytokeratin-20 in the epidermotropic MCC cells was less pronounced than the pattern observed in the dermis, and in all 6 of the tumors, the epidermal staining pattern observed with epithelial membrane antigen was not more or less prominent than the staining observed in the dermis. LIMITATIONS: The small total number of cases of epidermotropic MCC is a limitation. CONCLUSION: The data presented reinforce the differential diagnosis of tumors with an epidermotropic growth pattern and the importance of immunohistochemical staining in the histologic workup of such tumors: squamous cell carcinoma in situ, melanoma, mycosis fungoides, eccrine porocarcinoma, sebaceous carcinoma of the eyelid, mammary and extramammary Paget disease, MCC, and epidermotropic metastases. It is notable that 3 of 6 identified tumors were located on the eyelid; further study of epidermotropic MCC may shed more light on this finding, either as an unusual coincidence or a finding with unexplained significance.