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Langerhans cell Histiocytosis (LCH) and Erdheim-Chester disease (ECD) are clonal myeloid disorders, associated with MAP-Kinase activating mutations and an increased risk of neurodegeneration. Surprisingly, we found pervasive PU.1 + microglia mutant clones across the brain of LCH and ECD patients with and without neurological symptoms, associated with microgliosis, reactive astrocytosis, and neuronal loss. The disease predominated in the grey nuclei of the rhombencephalon, a topography attributable to a local proliferative advantage of mutant microglia. Presence of clinical symptoms was associated with a longer evolution of the disease and a larger size of PU.1 + clones (p= 0.0003). Genetic lineage tracing of PU.1 + clones suggest a resident macrophage lineage or a bone marrow precursor origin depending on patients. Finally, a CSF1R-inhibitor depleted mutant microglia and limited neuronal loss in mice suggesting an alternative to MAPK inhibitors. These studies characterize a progressive neurodegenerative disease, caused by clonal proliferation of inflammatory microglia (CPIM), with a decade(s)-long preclinical stage of incipient disease that represent a therapeutic window for prevention of neuronal death.
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GLI1-altered mesenchymal tumor is a recently described distinct pathologic entity with an established risk of malignancy, being defined molecularly by either GLI1 gene fusions or amplifications. The clinicopathologic overlap of tumors driven by the 2 seemingly distinct mechanisms of GLI1 activation is still emerging. Herein, we report the largest series of molecularly confirmed GLI1-altered mesenchymal neoplasms to date, including 23 GLI1-amplified and 15 GLI1-rearranged new cases, and perform a comparative clinicopathologic, genomic, and survival investigation. GLI1-rearranged tumors occurred in younger patients (42 vs. 52 y) and were larger compared with GLI1-amplified tumors (5.6 cm vs. 1.5 cm, respectively). Histologic features were overall similar between the 2 groups, showing a multinodular pattern and a nested architecture of epithelioid, and less commonly spindle cells, surrounded by a rich capillary network. A distinct whorling pattern was noted among 3 GLI1-amplified tumors. Scattered pleomorphic giant cells were rarely seen in both groups. The immunoprofile showed consistent expression of CD56, with variable S100, CD10 and SMA expression. Genomically, both groups had overall low mutation burdens, with rare TP53 mutations seen only in GLI1-amplified tumors. GLI1-amplified mesenchymal tumors exhibit mostly a single amplicon at the 12q13-15 locus, compared with dedifferentiated liposarcoma, which showed a 2-peak amplification centered around CDK4 (12q14.1) and MDM2 (12q15). GLI1-amplified tumors had a significantly higher GLI1 mRNA expression compared with GLI1-rearranged tumors. Survival pooled analysis of current and published cases (n=83) showed a worse overall survival in GLI1-amplified patients, with 16% succumbing to disease compared with 1.7% in the GLI1-rearranged group. Despite comparable progression rates, GLI1-amplified tumors had a shorter median progression-free survival compared with GLI1-rearranged tumors (25 mo vs. 77 mo). Univariate analysis showed that traditional histologic predictors of malignancy (mitotic count ≥4/10 high-power fields, presence of necrosis, and tumor size ≥5 cm) are associated with worse prognosis among GLI1-altered mesenchymal tumors.
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BACKGROUND AND PURPOSE: The aim of this study was to determine the diagnostic value of fractional plasma volume derived from dynamic contrast-enhanced perfusion MR imaging versus ADC, obtained from DWI in differentiating between grade 2 (low-grade) and grade 3 (high-grade) intracranial ependymomas. MATERIALS AND METHODS: A hospital database was created for the period from January 2013 through June 2022, including patients with histologically-proved ependymoma diagnosis with available dynamic contrast-enhanced MR imaging. Both dynamic contrast-enhanced perfusion and DWI were performed on each patient using 1.5T and 3T scanners. Fractional plasma volume maps and ADC maps were calculated. ROIs were defined by a senior neuroradiologist manually by including the enhancing tumor on every section and conforming a VOI to obtain the maximum value of fractional plasma volume (Vpmax) and the minimum value of ADC (ADCmin). A Mann-Whitney U test at a significance level of corrected P = .01 was used to evaluate the differences. Additionally, receiver operating characteristic curve analysis was applied to assess the sensitivity and specificity of Vpmax and ADCmin values. RESULTS: A total of 20 patients with ependymomas (10 grade 2 tumors and 10 grade 3 tumors) were included. Vpmax values for grade 3 ependymomas were significantly higher (P < .002) than those for grade 2. ADCmin values were overall lower in high-grade lesions. However, no statistically significant differences were found (P = .12114). CONCLUSIONS: As a dynamic contrast-enhanced perfusion MR imaging metric, fractional plasma volume can be used as an indicator to differentiate grade 2 and grade 3 ependymomas. Dynamic contrast-enhanced perfusion MR imaging plays an important role with high diagnostic value in differentiating low- and high-grade ependymoma.
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Neoplasias Encefálicas , Medios de Contraste , Imagen de Difusión por Resonancia Magnética , Ependimoma , Clasificación del Tumor , Humanos , Ependimoma/diagnóstico por imagen , Ependimoma/patología , Masculino , Femenino , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/patología , Adulto , Imagen de Difusión por Resonancia Magnética/métodos , Persona de Mediana Edad , Adulto Joven , Diagnóstico Diferencial , Imagen por Resonancia Magnética/métodos , Anciano , Sensibilidad y Especificidad , Adolescente , Niño , Estudios RetrospectivosRESUMEN
Histiocytic neoplasms are diverse clonal haematopoietic disorders, and clinical disease is mediated by tumorous infiltration as well as uncontrolled systemic inflammation. Individual subtypes include Langerhans cell histiocytosis (LCH), Rosai-Dorfman-Destombes disease (RDD) and Erdheim-Chester disease (ECD), and these have been characterized with respect to clinical phenotypes, driver mutations and treatment paradigms. Less is known about patients with mixed histiocytic neoplasms (MXH), that is two or more coexisting disorders. This international collaboration examined patients with biopsy-proven MXH with respect to component disease subtypes, oncogenic driver mutations and responses to conventional (chemotherapeutic or immunosuppressive) versus targeted (BRAF or MEK inhibitor) therapies. Twenty-seven patients were studied with ECD/LCH (19/27), ECD/RDD (6/27), RDD/LCH (1/27) and ECD/RDD/LCH (1/27). Mutations previously undescribed in MXH were identified, including KRAS, MAP2K2, MAPK3, non-V600-BRAF, RAF1 and a BICD2-BRAF fusion. A repeated-measure generalized estimating equation demonstrated that targeted treatment was statistically significantly (1) more likely to result in a complete response (CR), partial response (PR) or stable disease (SD) (odds ratio [OR]: 17.34, 95% CI: 2.19-137.00, p = 0.007), and (2) less likely to result in progression (OR: 0.08, 95% CI: 0.03-0.23, p < 0.0001). Histiocytic neoplasms represent an entity with underappreciated clinical and molecular diversity, poor responsiveness to conventional therapy and exquisite sensitivity to targeted therapy.
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Enfermedad de Erdheim-Chester , Mutación , Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Enfermedad de Erdheim-Chester/genética , Enfermedad de Erdheim-Chester/tratamiento farmacológico , Anciano , Adolescente , Terapia Molecular Dirigida , Adulto Joven , Histiocitosis de Células de Langerhans/genética , Histiocitosis de Células de Langerhans/tratamiento farmacológico , Niño , Histiocitosis Sinusal/genética , Histiocitosis Sinusal/tratamiento farmacológico , Histiocitosis Sinusal/patología , Proteínas Proto-Oncogénicas B-raf/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , PreescolarRESUMEN
Myxopapillary ependymoma (MPE) is an uncommon variant of ependymoma, almost exclusively seen in conus medullaris or filum terminale. MPE can be diagnostically challenging, especially when arising extra-axially. Here we report 5 cases of superficial soft tissue/cutaneous MPE, identified across three tertiary institutions. All patients were female and three of them (3/5, 60%) were children (median age 11 years, range 6-58 years). The tumors presented as slow-growing masses of the sacrococcygeal subcutaneous soft tissues, occasionally identified after minor trauma and clinically favored to be pilonidal sinuses. Imaging showed no neuraxis connection. Macroscopically, tumors were well-circumscribed, lobulated, and solid and microscopically they exhibited typical histopathology of MPE, at least focally. Two of the tumors (2/5, 40%) showed predominantly solid or trabecular architecture with greater cellular pleomorphism, scattered giant cells, and increased mitotic activity. All tumors (5/5, 100%) showed strong diffuse immunohistochemical expression of GFAP. One tumor clustered at the category "ependymoma, myxopapillary" by methylome analysis. Two patients (2/5, 40%) had local recurrence at 8 and 30 months after the initial surgery. No patients developed metastases during the follow-up period (median 60 months, range 6-116 months). Since a subset of extra-axial MPEs behaves more aggressively, timely and accurate diagnosis is of paramount importance.
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Cauda Equina , Ependimoma , Neoplasias de la Médula Espinal , Niño , Humanos , Femenino , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Masculino , Ependimoma/diagnóstico , Ependimoma/patología , Ependimoma/cirugía , Cauda Equina/patología , Cauda Equina/cirugía , Neoplasias de la Médula Espinal/patología , Neoplasias de la Médula Espinal/cirugíaRESUMEN
Fusions involving CRAF (RAF1) are infrequent oncogenic drivers in pediatric low-grade gliomas, rarely identified in tumors bearing features of pilocytic astrocytoma, and involving a limited number of known fusion partners. We describe recurrent TRAK1::RAF1 fusions, previously unreported in brain tumors, in three pediatric patients with low-grade glial-glioneuronal tumors. We present the associated clinical, histopathologic and molecular features. Patients were all female, aged 8 years, 15 months, and 10 months at diagnosis. All tumors were located in the cerebral hemispheres and predominantly cortical, with leptomeningeal involvement in 2/3 patients. Similar to previously described activating RAF1 fusions, the breakpoints in RAF1 all occurred 5' of the kinase domain, while the breakpoints in the 3' partner preserved the N-terminal kinesin-interacting domain and coiled-coil motifs of TRAK1. Two of the three cases demonstrated methylation profiles (v12.5) compatible with desmoplastic infantile ganglioglioma (DIG)/desmoplastic infantile astrocytoma (DIA) and have remained clinically stable and without disease progression/recurrence after resection. The remaining tumor was non-classifiable; with focal recurrence 14 months after initial resection; the patient remains symptom free and without further recurrence/progression (5 months post re-resection and 19 months from initial diagnosis). Our report expands the landscape of oncogenic RAF1 fusions in pediatric gliomas, which will help to further refine tumor classification and guide management of patients with these alterations.
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Astrocitoma , Neoplasias Encefálicas , Ganglioglioma , Glioma , Niño , Femenino , Humanos , Proteínas Adaptadoras del Transporte Vesicular , Astrocitoma/genética , Astrocitoma/patología , Neoplasias Encefálicas/patología , Ganglioglioma/patología , Glioma/genética , Glioma/patología , Fusión de OncogenesRESUMEN
PURPOSE: Brain metastases are rare in patients with prostate cancer and portend poor outcome. Prostate-specific membrane antigen positron emission tomography (PSMA PET)/CT scans including the brain have identified incidental tumors. We sought to identify the incidental brain tumor detection rate of PSMA PET/CT performed at initial diagnosis or in the setting of biochemical recurrence. METHODS: An institutional database was queried for patients who underwent 68Ga-PSMA-11 or 18F-DCFPyL (18F-piflufolastat) PET/CT imaging at an NCI-designated Comprehensive Cancer Center from 1/2018 to 12/2022. Imaging reports and clinical courses were reviewed to identify brain lesions and describe clinical and pathologic features. RESULTS: Two-thousand seven hundred and sixty-three patients underwent 3363 PSMA PET/CT scans in the absence of neurologic symptoms. Forty-four brain lesions were identified, including 33 PSMA-avid lesions: 10 intraparenchymal metastases (30%), 4 dural-based metastases (12%), 16 meningiomas (48%), 2 pituitary macroadenomas (6%), and 1 epidermal inclusion cyst (3%) (incidences of 0.36, 0.14, 0.58, 0.07, and 0.04%). The mean parenchymal metastasis diameter and mean SUVmax were 1.99 cm (95%CI:1.25-2.73) and 4.49 (95%CI:2.41-6.57), respectively. At the time of parenchymal brain metastasis detection, 57% of patients had no concurrent extracranial disease, 14% had localized prostate disease only, and 29% had extracranial metastases. Seven of 8 patients with parenchymal brain metastases remain alive at a median 8.8 months follow-up. CONCLUSION: Prostate cancer brain metastases are rare, especially in the absence of widespread metastatic disease. Nevertheless, incidentally detected brain foci of PSMA uptake may represent previously unknown prostate cancer metastases, even in small lesions and in the absence of systemic disease.
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Neoplasias Encefálicas , Neoplasias de la Próstata , Masculino , Humanos , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/patología , Tomografía de Emisión de Positrones , Neoplasias Encefálicas/diagnóstico por imagenRESUMEN
Vorasidenib and ivosidenib inhibit mutant forms of isocitrate dehydrogenase (mIDH) and have shown preliminary clinical activity against mIDH glioma. We evaluated both agents in a perioperative phase 1 trial to explore the mechanism of action in recurrent low-grade glioma (IGG) and select a molecule for phase 3 testing. Primary end-point was concentration of D-2-hydroxyglutarate (2-HG), the metabolic product of mIDH enzymes, measured in tumor tissue from 49 patients with mIDH1-R132H nonenhancing gliomas following randomized treatment with vorasidenib (50 mg or 10 mg once daily, q.d.), ivosidenib (500 mg q.d. or 250 mg twice daily) or no treatment before surgery. Tumor 2-HG concentrations were reduced by 92.6% (95% credible interval (CrI), 76.1-97.6) and 91.1% (95% CrI, 72.0-97.0) in patients treated with vorasidenib 50 mg q.d. and ivosidenib 500 mg q.d., respectively. Both agents were well tolerated and follow-up is ongoing. In exploratory analyses, 2-HG reduction was associated with increased DNA 5-hydroxymethylcytosine, reversal of 'proneural' and 'stemness' gene expression signatures, decreased tumor cell proliferation and immune cell activation. Vorasidenib, which showed brain penetrance and more consistent 2-HG suppression than ivosidenib, was advanced to phase 3 testing in patients with mIDH LGGs. Funded by Agios Pharmaceuticals, Inc. and Servier Pharmaceuticals LLC; ClinicalTrials.gov number NCT03343197.
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Neoplasias Encefálicas , Glioma , Humanos , Piridinas/efectos adversos , Isocitrato Deshidrogenasa/genética , Glioma/tratamiento farmacológico , Glioma/genética , Mutación/genética , Preparaciones Farmacéuticas , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/genéticaRESUMEN
Capicua transcriptional repressor (CIC)-rearranged sarcoma represents a distinct pathologic entity and constitutes the second most prevalent category of undifferentiated round cell sarcomas (URCSs) after Ewing sarcoma. The 2 most common translocations are t(4;19) and t(10;19), resulting in CIC fusions with either DUX4 and DUX4L paralog, respectively; however, other rare variant fusions have also been reported. In this study, we expand the molecular spectrum of CIC-gene partners, reporting on 5 cases of URCSs showing CIC fusions with AXL, CITED1, SYK, and LEUTX by targeted RNA or DNA sequencing. There were 4 female patients and 1 male patient with a wide age range (12-70 years; median, 36 years). Four cases occurred in the deep soft tissues (lower extremity, 3; neck, 1) and 1 case in the central nervous system (midbrain/thalamus). All cases showed similar histologic findings within the spectrum of URCSs. Immunohistochemistry, showed variable positivity for ETV4 in 4 of the 4 cases and positive results for ERG in 3 of the 4 cases and for WT1 in 1 of the 4 cases. CD31 showed positivity in 2 of the 3 cases, including one coexpressing ERG. Unsupervised clustering of methylation profiles by T-distributed stochastic neighborhood embedding performed in 4 cases showed that all clustered tightly together and along the CIC sarcoma methylation class. RNA-sequencing data showed consistent upregulation of ETV1 and ETV4 mRNA in all cases examined, at similar levels to CIC::DUX4 URCSs. Our study expands the molecular diversity of CIC-rearranged URCSs to include novel and rare partners, providing morphologic, immunohistochemical, gene expression, and methylation evidence supporting their classification within the family of tumors harboring the more common DUX4/DUX4L partner genes.
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Sarcoma de Ewing , Sarcoma de Células Pequeñas , Sarcoma , Humanos , Masculino , Femenino , Niño , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Sarcoma de Células Pequeñas/genética , Sarcoma de Ewing/genética , Sarcoma/genética , Sarcoma/patología , Reordenamiento Génico , ARN , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Biomarcadores de Tumor/genéticaRESUMEN
BACKGROUND: The incidence and biology of IDH1/2 mutations in pediatric gliomas are unclear. Notably, current treatment approaches by pediatric and adult providers vary significantly. We describe the frequency and clinical outcomes of IDH1/2-mutant gliomas in pediatrics. METHODS: We performed a multi-institutional analysis of the frequency of pediatric IDH1/2-mutant gliomas, identified by next-generation sequencing (NGS). In parallel, we retrospectively reviewed pediatric IDH1/2-mutant gliomas, analyzing clinico-genomic features, treatment approaches, and outcomes. RESULTS: Incidence: Among 851 patients with pediatric glioma who underwent NGS, we identified 78 with IDH1/2 mutations. Among patients 0-9 and 10-21 years old, 2/378 (0.5%) and 76/473 (16.1%) had IDH1/2-mutant tumors, respectively. Frequency of IDH mutations was similar between low-grade glioma (52/570, 9.1%) and high-grade glioma (25/277, 9.0%). Four tumors were graded as intermediate histologically, with one IDH1 mutation. Outcome: Seventy-six patients with IDH1/2-mutant glioma had outcome data available. Eighty-four percent of patients with low-grade glioma (LGG) were managed observantly without additional therapy. For low-grade astrocytoma, 5-year progression-free survival (PFS) was 42.9% (95%CI:20.3-63.8) and, despite excellent short-term overall survival (OS), numerous disease-related deaths after year 10 were reported. Patients with high-grade astrocytoma had a 5-year PFS/OS of 36.8% (95%CI:8.8-66.4) and 84% (95%CI:50.1-95.6), respectively. Patients with oligodendroglioma had excellent OS. CONCLUSIONS: A subset of pediatric gliomas is driven by IDH1/2 mutations, with a higher rate among adolescents. The majority of patients underwent upfront observant management without adjuvant therapy. Findings suggest that the natural history of pediatric IDH1/2-mutant glioma may be similar to that of adults, though additional studies are needed.
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Astrocitoma , Neoplasias Encefálicas , Glioma , Adulto , Adolescente , Humanos , Niño , Estudios Retrospectivos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/terapia , Glioma/genética , Glioma/terapia , Astrocitoma/genética , Mutación , Genómica , Isocitrato Deshidrogenasa/genéticaRESUMEN
Biallelic inactivation of NF2 represents the primary or sole oncogenic driver event in the vast majority of schwannomas. We report on a four-year-old female who underwent subtotal resection of a right medullary intraparenchymal schwannoma. RNA sequencing revealed an in-frame fusion between exon 5 of YAP1 and exon 2 of MAML2. YAP1-MAML2 fusions have previously been reported in a variety of tumor types, but not schwannomas. Our report expands the spectrum of oncogenic YAP1 gene fusions an alternative to NF2 inactivation to include sporadic schwannoma, analogous to what has recently been described in NF2-wildtype pediatric meningiomas. Appropriate somatic and germline molecular testing should be undertaken in all young patients with solitary schwannoma and meningioma given the high prevalence of an underlying tumor predisposition syndrome. In such patients, the identification of a somatic non-NF2 driver alteration such as this newly described YAP1 fusion, can help ascertain the diagnosis of a sporadic schwannoma.
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Neoplasias Meníngeas , Meningioma , Neurilemoma , Neurofibromatosis 2 , Tronco Encefálico/patología , Niño , Preescolar , Femenino , Fusión Génica , Humanos , Neoplasias Meníngeas/genética , Meningioma/genética , Neurilemoma/genética , Neurilemoma/patología , Neurilemoma/cirugía , Neurofibromatosis 2/genética , Transactivadores/genética , Factores de Transcripción/genética , Proteínas Señalizadoras YAPRESUMEN
BACKGROUND: The prognosis for patients with pediatric high-grade glioma (pHGG) is poor despite aggressive multimodal therapy. Objective responses to targeted therapy with BRAF inhibitors have been reported in some patients with recurrent BRAF-mutant pHGG but are rarely sustained. METHODS: We performed a retrospective, multi-institutional review of patients with BRAF-mutant pHGG treated with off-label BRAF +/- MEK inhibitors as part of their initial therapy. RESULTS: Nineteen patients were identified, with a median age of 11.7 years (range, 2.3-21.4). Histologic diagnoses included HGG (n = 6), glioblastoma (n = 3), anaplastic ganglioglioma (n = 4), diffuse midline glioma (n = 3), high-grade neuroepithelial tumor (n = 1), anaplastic astrocytoma (n = 1), and anaplastic astroblastoma (n = 1). Recurrent concomitant oncogenic alterations included CDKN2A/B loss, H3 K27M, as well as mutations in ATRX, EGFR, and TERT. Eight patients received BRAF inhibitor monotherapy. Eleven patients received combination therapy with BRAF and MEK inhibitors. Most patients tolerated long-term treatment well with no grade 4-5 toxicities. Objective and durable imaging responses were seen in the majority of patients with measurable disease. At a median follow-up of 2.3 years (range, 0.3-6.5), three-year progression-free and overall survival for the cohort were 65% and 82%, respectively, and superior to a historical control cohort of BRAF-mutant pHGG patients treated with conventional therapies. CONCLUSIONS: Upfront targeted therapy for patients with BRAF-mutant pHGG is feasible and effective, with superior clinical outcomes compared to historical data. This promising treatment paradigm is currently being evaluated prospectively in the Children's Oncology Group ACNS1723 clinical trial.
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Neoplasias Encefálicas , Glioblastoma , Glioma , Niño , Humanos , Preescolar , Adolescente , Adulto Joven , Adulto , Proteínas Proto-Oncogénicas B-raf/genética , Neoplasias Encefálicas/patología , Terapia Molecular Dirigida , Estudios Retrospectivos , Glioma/patología , Mutación , Inhibidores de Proteínas Quinasas/uso terapéutico , Glioblastoma/tratamiento farmacológico , Quinasas de Proteína Quinasa Activadas por MitógenosRESUMEN
The 2021 5th edition of the WHO Classification of Tumors of the Central Nervous System reflects the discovery of genetic alterations underlying many central nervous system (CNS) neoplasms. Insights gained from technologic advances and novel applications in molecular diagnostics, including next-generation sequencing and DNA methylation-based profiling, coupled with the recognition of clinicopathologic correlates, have prompted substantial changes to CNS tumor classification; this is particularly true for pediatric low-grade gliomas and glioneuronal tumors (pLGG/GNTs). The 2021 WHO now classifies gliomas, glioneuronal tumors and neuronal tumors into 6 families, three of which encompass pLGG/LGNTs: "Pediatric type diffuse low-grade gliomas," "circumscribed astrocytic gliomas," and "glioneuronal and neuronal tumors." Among these are six newly recognized tumor types: "diffuse astrocytoma, MYB or MYBL1-altered"; "polymorphous low grade neuroepithelial tumor of the young (PLNTY)"; "diffuse low-grade glioma-MAPK altered"; "Diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters (DGONC)"; "myxoid glioneuronal tumor (MGT)"; and "multinodular and vacuolating neuronal tumor (MVNT)." We review these newly recognized entities in the context of general changes to the WHO schema, discuss implications of the new classification for treatment of pLGG/LGNT, and consider strategies for molecular testing and interpretation.
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Astrocitoma , Neoplasias Encefálicas , Neoplasias del Sistema Nervioso Central , Glioma , Neoplasias Neuroepiteliales , Astrocitoma/patología , Neoplasias Encefálicas/patología , Sistema Nervioso Central/patología , Neoplasias del Sistema Nervioso Central/patología , Niño , Glioma/genética , Humanos , Neoplasias Neuroepiteliales/genética , Organización Mundial de la SaludRESUMEN
We describe a rare TPIT-positive corticotroph PitNET that is admixed with SF1-positive adrenocortical cells. This dimorphous population of cells showed no colocalisation between TPIT and SF1 by immunofluorescence, and an adrenocortical choristoma was favoured. Methylation array analysis revealed a novel methylation profile in relation to other pituitary neoplasms.
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Adenoma Hipofisario Secretor de ACTH/patología , Corticotrofos/patología , Metilación de ADN , Hipófisis/patología , Neoplasias Hipofisarias/patología , Adenoma Hipofisario Secretor de ACTH/genética , Adenoma Hipofisario Secretor de ACTH/metabolismo , Adulto , Corticotrofos/metabolismo , Humanos , Masculino , Hipófisis/metabolismo , Neoplasias Hipofisarias/genética , Neoplasias Hipofisarias/metabolismoRESUMEN
PURPOSE: The efficacy of salvage resection (SR) of recurrent brain metastases (rBrM) following stereotactic radiosurgery (SRS) is undefined. We sought to describe local recurrence (LR) and radiation necrosis (RN) rates in patients undergoing SR, with or without adjuvant post-salvage radiation therapy (PSRT). METHODS: A retrospective cohort study evaluated patients undergoing SR of post-SRS rBrM between 3/2003-2/2020 at an NCI-designated cancer center. Cases with histologically-viable malignancy were stratified by receipt of adjuvant PSRT within 60 days of SR. Clinical outcomes were described using cumulative incidences in the clustered competing-risks setting, competing risks regression, and Kaplan-Meier methodology. RESULTS: One-hundred fifty-five rBrM in 135 patients were evaluated. The overall rate of LR was 40.2% (95% CI 34.3-47.2%) at 12 months. Thirty-nine (25.2%) rBrM treated with SR + PSRT trended towards lower 12-month LR versus SR alone [28.8% (95% CI 17.0-48.8%) versus 43.9% (95% CI 36.2-53.4%), p = .07 by multivariate analysis]. SR as re-operation (p = .03) and subtotal resection (p = .01) were independently associated with higher rates of LR. On univariate analysis, tumor size (p = .48), primary malignancy (p = .35), and PSRT technique (p = .43) bore no influence on LR. SR + PSRT was associated with an increased risk of radiographic RN at 12 months versus SR alone [13.4% (95% CI 5.5-32.7%) versus 3.5% (95% CI 1.5-8.0%), p = .02], though the percentage with symptomatic RN remained low (5.1% versus 0.9%, respectively). Median overall survival from SR was 13.4 months (95% CI 10.5-17.7). CONCLUSION: In this largest-known series evaluating SR outcomes in histopathologically-confirmed rBrM, we identify a significant LR risk that may be reduced with adjuvant PSRT and with minimal symptomatic RN. Prospective analysis is warranted.
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Neoplasias Encefálicas , Traumatismos por Radiación , Radiocirugia , Reirradiación , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/cirugía , Humanos , Necrosis/etiología , Recurrencia Local de Neoplasia/radioterapia , Recurrencia Local de Neoplasia/cirugía , Radiocirugia/efectos adversos , Reirradiación/efectos adversos , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Neurocutaneous melanocytosis (NCM) is characterized by melanocyte deposition in the leptomeninges and brain parenchyma, primarily occurring in children with large or giant congenital melanocytic nevi (LCMN) or multiple congenital melanocytic nevi. Patients with NCM may develop hydrocephalus and increased intracranial pressure, which can be managed with ventriculoperitoneal (VP) shunting. We present the case of a 16-month-old girl who developed peritoneal carcinomatosis and malignant ascites following VP shunting for hydrocephalus secondary to NCM to increase awareness of this rare, but serious, complication of cerebrospinal fluid diversion.
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Melanoma , Melanosis , Síndromes Neurocutáneos , Nevo Pigmentado , Neoplasias Cutáneas , Niño , Femenino , Humanos , Lactante , Melanoma/complicaciones , Melanoma/diagnóstico , Melanosis/diagnóstico , Melanosis/etiología , Síndromes Neurocutáneos/complicaciones , Síndromes Neurocutáneos/diagnóstico , Nevo Pigmentado/diagnóstico , Neoplasias Cutáneas/diagnósticoRESUMEN
Cell-free DNA (cfDNA) from cerebrospinal fluid (CSF) offers unique opportunities for genomic profiling of tumors involving the central nervous system but remains uncommonly used in clinical practice. We describe our clinical experience using cfDNA from CSF for routine molecular testing using Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets (targeting 468 cancer-related genes). In all, 148 cfDNA samples were assessed, comparing results of cfDNA versus genomic DNA (gDNA; gDNA from cell pellets) derived from the same CSF sample and the primary tumor. Of these, 71.6% (106/148) were successfully sequenced. Somatic alterations (mutations and fusions) were observed in 70.8% (75/106) of the samples; 97.3% (73/75) comprised variants confirming central nervous system involvement by a previously diagnosed tumor, 14.7% (11/75) had additional variants consistent with a therapy-related resistance mechanism, and 2.7% (2/75) had variants that independently diagnosed a new primary. Among samples with paired cfDNA and gDNA sequencing results, cfDNA was more frequently positive for at least one mutation [43.6% (55/126) versus 19.8% (25/126)] and harbored 1.6× more mutations (6.94 versus 4.65; P = 0.005), with higher mean variant allele fractions (41.1% versus 13.0%; P < 0.0001). Among mutation-positive cfDNAs, the corresponding gDNA was frequently negative (44.6%; 25/55) or failed sequencing (17.8%; 9/55). Routine molecular profiling of cfDNA is superior to gDNA from CSF, facilitating the capture of mutations at high variant allele frequency, even in the context of a negative cytology.