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IDH1 mutation is the earliest genetic alteration in low-grade gliomas (LGGs), but its role in tumor recurrence is unclear. Mutant IDH1 drives overproduction of the oncometabolite d-2-hydroxyglutarate (2HG) and a CpG island (CGI) hypermethylation phenotype (G-CIMP). To investigate the role of mutant IDH1 at recurrence, we performed a longitudinal analysis of 50 IDH1 mutant LGGs. We discovered six cases with copy number alterations (CNAs) at the IDH1 locus at recurrence. Deletion or amplification of IDH1 was followed by clonal expansion and recurrence at a higher grade. Successful cultures derived from IDH1 mutant, but not IDH1 wild type, gliomas systematically deleted IDH1 in vitro and in vivo, further suggestive of selection against the heterozygous mutant state as tumors progress. Tumors and cultures with IDH1 CNA had decreased 2HG, maintenance of G-CIMP, and DNA methylation reprogramming outside CGI. Thus, while IDH1 mutation initiates gliomagenesis, in some patients mutant IDH1 and 2HG are not required for later clonal expansions.

Familial melanoma-astrocytoma syndrome is a tumor predisposition syndrome caused by inactivating germline alteration of the CDKN2A tumor suppressor gene on chromosome 9p21. While some families with germline CDKN2A mutations are prone to development of just melanomas, other families develop both melanomas, astrocytomas, and occasionally other nervous-system neoplasms including peripheral nerve sheath tumors and meningiomas. The histologic spectrum of the astrocytomas that arise as part of this syndrome is not well described, nor are the additional genetic alterations that drive these astrocytomas apart from the germline CDKN2A inactivation. Herein, we report the case of a young man with synchronous development of a pleomorphic xanthoastrocytoma, diffuse astrocytoma, and paraspinal mass radiographically consistent with a peripheral nerve sheath tumor. His paternal family history is significant for melanoma, glioblastoma, and oral squamous cell carcinoma. Genomic profiling revealed that he harbors a heterozygous deletion in the germline of chromosome 9p21.3 encompassing the CDKN2A and CDKN2B tumor suppressor genes. Both the pleomorphic xanthoastrocytoma and diffuse astrocytoma were found to have homozygous deletion of CDKN2A/B due to somatic loss of the other copy of chromosome 9p containing the remaining intact alleles. Additional somatic alterations included BRAF p.V600E mutation in the pleomorphic xanthoastrocytoma and PTPN11, ATRX, and NF1 mutations in the diffuse astrocytoma. The presence of germline CDKN2A/B inactivation together with the presence of multiple anatomically, histologically, and genetically distinct astrocytic neoplasms, both with accompanying somatic loss of heterozygosity for the CDKN2A/B deletion, led to a diagnosis of familial melanoma-astrocytoma syndrome. This remarkable case illustrates the histologic and genetic diversity that astrocytomas arising as part of this rare glioma predisposition syndrome can demonstrate.
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Patients with neurofibromatosis 1 (NF1) develop multiple neurofibromas, with 8% to 15% of patients experiencing malignant peripheral nerve sheath tumor (MPNST) during their lifetime. Prediction of transformation, typically from plexiform neurofibroma, is clinically and histologically challenging. In this overview, after a consensus meeting in October 2016, we outline the histopathologic features and molecular mechanisms involved in the malignant transformation of neurofibromas. Nuclear atypia alone is generally insignificant. However, with atypia, loss of neurofibroma architecture, high cellularity, and/or mitotic activity >1/50 but

BackgroundActivation of the mitogen-activated protein kinase pathway is important for growth of pediatric low-grade gliomas (LGGs). The aim of this study was to determine the recommended phase II dose (RP2D) and the dose-limiting toxicities (DLTs) of the MEK inhibitor selumetinib in children with progressive LGG.MethodsSelumetinib was administered orally starting at 33 mg/m2/dose b.i.d., using the modified continual reassessment method. Pharmacokinetic analysis was performed during the first course. BRAF aberrations in tumor tissue were determined by real-time polymerase chain reaction and fluorescence in situ hybridization.ResultsThirty-eight eligible subjects were enrolled. Dose levels 1 and 2 (33 and 43 mg/m2/dose b.i.d.) were excessively toxic. DLTs included grade 3 elevated amylase/lipase (n = 1), headache (n = 1), mucositis (n = 2), and grades 2-3 rash (n = 6). At dose level 0 (25 mg/m2/dose b.i.d, the RP2D), only 3 of 24 subjects experienced DLTs (elevated amylase/lipase, rash, and mucositis). At the R2PD, the median (range) area under the curve (AUC0-∞) and apparent oral clearance of selumetinib were 3855 ng*h/mL (1780 to 7250 ng × h/mL) and 6.5 L × h-1 × m-2 (3.4 to 14.0 L × h-1 × m-2), respectively. Thirteen of 19 tumors had BRAF abnormalities. Among the 5 (20%) of 25 subjects with sustained partial responses, all at the RP2D, 4 had BRAF aberrations, 1 had insufficient tissue. Subjects received a median of 13 cycles (range: 1-26). Fourteen (37%) completed all protocol treatment (26 cycles [n = 13], 13 cycles [n = 1]) with at least stable disease; 2-year progression-free survival at the RP2D was 69 ± SE 9.8%.ConclusionSelumetinib has promising antitumor activity in children with LGG. Rash and mucositis were the most common DLTs.

The "integrated diagnosis" for infiltrating gliomas in the 2016 revised World Health Organization (WHO) classification of tumors of the central nervous system requires assessment of the tumor for IDH mutations and 1p/19q codeletion. Since TERT promoter mutations and ATRX alterations have been shown to be associated with prognosis, we analyzed whether these tumor markers provide additional prognostic information within each of the five WHO 2016 categories. We used data for 1206 patients from the UCSF Adult Glioma Study, the Mayo Clinic and The Cancer Genome Atlas (TCGA) with infiltrative glioma, grades II-IV for whom tumor status for IDH, 1p/19q codeletion, ATRX, and TERT had been determined. All cases were assigned to one of 5 groups following the WHO 2016 diagnostic criteria based on their morphologic features, and IDH and 1p/19q codeletion status. These groups are: (1) Oligodendroglioma, IDH-mutant and 1p/19q-codeleted; (2) Astrocytoma, IDH-mutant; (3) Glioblastoma, IDH-mutant; (4) Glioblastoma, IDH-wildtype; and (5) Astrocytoma, IDH-wildtype. Within each group, we used univariate and multivariate Cox proportional hazards models to assess associations of overall survival with patient age at diagnosis, grade, and ATRX alteration status and/or TERT promoter mutation status. Among Group 1 IDH-mutant 1p/19q-codeleted oligodendrogliomas, the TERT-WT group had significantly worse overall survival than the TERT-MUT group (HR: 2.72, 95% CI 1.05-7.04, p = 0.04). In both Group 2, IDH-mutant astrocytomas and Group 3, IDH-mutant glioblastomas, neither TERT mutations nor ATRX alterations were significantly associated with survival. Among Group 4, IDH-wildtype glioblastomas, ATRX alterations were associated with favorable outcomes (HR: 0.36, 95% CI 0.17-0.81, p = 0.01). Among Group 5, IDH-wildtype astrocytomas, the TERT-WT group had significantly better overall survival than the TERT-MUT group (HR: 0.48, 95% CI 0.27-0.87), p = 0.02). Thus, we present evidence that in certain WHO 2016 diagnostic groups, testing for TERT promoter mutations or ATRX alterations may provide additional useful prognostic information.

The authors report the case of a 5-year-old boy in whom extraneural metastases developed 5 years after he underwent an occipitocervical fusion and transoral approach to treat a clival chordoma without local recurrence. Following primary resection, the patient's postoperative course was complicated by recurrent meningitis secondary to CSF leak, which responded to antibiotics, and communicating hydrocephalus, for which a ventriculoperitoneal shunt was placed. The patient then underwent postoperative proton beam radiotherapy. Five years following his initial presentation, surveillance imaging revealed a new asymptomatic lung mass for which the patient underwent thoracotomy and resection of the mass. Histological examination of the lung mass revealed findings consistent with a de-differentiated chordoma, confirming extraneural metastasis from the original tumor without evidence of local recurrence. Chest wall and scalp metastases subsequently developed, and the patient was started on an adjuvant chemotherapy regimen that included imatinib and rapamycin followed by subsequent nivolumab and an EZH2 inhibitor for recurrent, disseminated disease. Despite this patient's remote and distant metastases, primary gross-total resection for chordoma remains a critical treatment objective, followed by proton beam radiotherapy. This case illustrates the importance of interval posttreatment imaging and the emerging potential to treat chordoma with molecularly targeted therapies.

Molecular profiling is revolutionizing cancer diagnostics and leading to personalized therapeutic approaches. Herein we describe our clinical experience performing targeted sequencing for 31 pediatric neuro-oncology patients.We sequenced 510 cancer-associated genes from tumor and peripheral blood to identify germline and somatic mutations, structural variants, and copy number changes.Genomic profiling was performed on 31 patients with tumors including 11 high-grade gliomas, 8 medulloblastomas, 6 low-grade gliomas, 1 embryonal tumor with multilayered rosettes, 1 pineoblastoma, 1 uveal ganglioneuroma, 1 choroid plexus carcinoma, 1 chordoma, and 1 high-grade neuroepithelial tumor. In 25 cases (81%), results impacted patient management by: (i) clarifying diagnosis, (ii) identifying pathogenic germline mutations, or (iii) detecting potentially targetable alterations. The pathologic diagnosis was amended after genomic profiling for 6 patients (19%), including a high-grade glioma to pilocytic astrocytoma, medulloblastoma to pineoblastoma, ependymoma to high-grade glioma, and medulloblastoma to CNS high-grade neuroepithelial tumor with BCOR alteration. Multiple patients had pathogenic germline mutations, many of which were previously unsuspected. Potentially targetable alterations were identified in 19 patients (61%). Additionally, novel likely pathogenic alterations were identified in 3 cases: an in-frame RAF1 fusion in a BRAF wild-type pleomorphic xanthoastrocytoma, an inactivating ASXL1 mutation in a histone H3 wild-type diffuse pontine glioma, and an in-frame deletion within exon 2 of MAP2K1 in a low-grade astrocytic neoplasm.Our experience demonstrates the significant impact of molecular profiling on diagnosis and treatment of pediatric brain tumors and confirms its feasibility for use at the time of diagnosis or recurrence.

BackgroundMalignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that arise at an estimated frequency of 8% to 13% in individuals with neurofibromatosis type 1 (NF1). Compared with their sporadic counterparts, NF1-associated MPNSTs (NF1-MPNSTs) develop in young adults, frequently recur (approximately 50% of cases), and carry a dismal prognosis. As such, most individuals affected with NF1-MPNSTs die within 5 years of diagnosis, despite surgical resection combined with radiotherapy and chemotherapy.MethodsClinical genomic profiling was performed using 1000 ng of DNA from 7 cases of NF1-MPNST, and bioinformatic analyses were conducted to identify genes with actionable mutations.ResultsA total of 3 women and 4 men with NF1-MPNST were identified (median age, 38 years). Nonsynonymous mutations were discovered in 4 genes (neurofibromatosis type 1 [NF1], ROS proto-oncogene 1 [ROS1], tumor protein p53 [TP53], and tyrosine kinase 2 [TYK2]), which in addition were mutated in other MPNST cases in this sample set. Consistent with their occurrence in individuals with NF1, all tumors had at least 1 mutation in the NF1 gene. Whereas TP53 gene mutations are frequently observed in other cancers, ROS1 mutations are common in melanoma (15%-35%), another neural crest-derived malignancy. In contrast, TYK2 mutations are uncommon in other malignancies (

BackgroundPatients with meningiomas have widely divergent clinical courses. Some entirely recover following surgery alone, while others have relentless tumor recurrences. This clinical conundrum is exemplified by rhabdoid meningiomas, which are designated in the World Health Organization Classification of Tumours as high grade, despite only a subset following an aggressive clinical course. Patient management decisions are further exacerbated by high rates of interobserver variability, biased against missing possibly aggressive tumors. Objective molecular determinants are needed to guide classification and clinical decision making.MethodsTo define genomic aberrations of rhabdoid meningiomas, we performed sequencing of cancer-related genes in 27 meningiomas from 18 patients with rhabdoid features and evaluated breast cancer [BRCA]1-associated protein 1 (BAP1) expression by immunohistochemistry in 336 meningiomas. We assessed outcomes, germline status, and family history in patients with BAP1-negative rhabdoid meningiomas.ResultsThe tumor suppressor gene BAP1, a ubiquitin carboxy-terminal hydrolase, is inactivated in a subset of high-grade rhabdoid meningiomas. Patients with BAP1-negative rhabdoid meningiomas had reduced time to recurrence compared with patients with BAP1-retained rhabdoid meningiomas (Kaplan-Meier analysis, 26 mo vs 116 mo, P < .001; hazard ratio 12.89). A subset of patients with BAP1-deficient rhabdoid meningiomas harbored germline BAP1 mutations, indicating that rhabdoid meningiomas can be a harbinger of the BAP1 cancer predisposition syndrome.ConclusionWe define a subset of aggressive rhabdoid meningiomas that can be recognized using routine laboratory tests. We implicate ubiquitin deregulation in the pathogenesis of these high-grade malignancies. In addition, we show that familial and sporadic BAP1-mutated rhabdoid meningiomas are clinically aggressive, requiring intensive clinical management.

Low-grade gliomas can vary widely in disease course and therefore patient outcome. While current characterization relies on both histological and molecular analysis of tissue resected during surgery, there remains high variability within glioma subtypes in terms of response to treatment and outcome. In this study we hypothesized that parameters obtained from magnetic resonance data would be associated with progression-free survival for patients with recurrent low-grade glioma. The values considered were derived from the analysis of anatomic imaging, diffusion weighted imaging, and 1H magnetic resonance spectroscopic imaging data. Metrics obtained from diffusion and spectroscopic imaging presented strong prognostic capability within the entire population as well as when restricted to astrocytomas, but demonstrated more limited efficacy in the oligodendrogliomas. The results indicate that multi-parametric imaging data may be applied as a non-invasive means of assessing prognosis and may contribute to developing personalized treatment plans for patients with recurrent low-grade glioma.

BackgroundOptimal adjuvant management of adult low-grade gliomas is controversial. Recently described tumor classification based on molecular subtype has the potential to individualize adjuvant therapy but has not yet been evaluated as part of a prospective trial.MethodsPatients aged 18 or older with newly diagnosed World Health Organization grade II low-grade gliomas and gross residual disease after surgical resection were enrolled in the study. Patients received monthly cycles of temozolomide for up to 1 year or until disease progression. For patients with available tissue, molecular subtype was assessed based upon 1p/19q codeletion and isocitrate dehydrogenase-1 R132H mutation status. The primary outcome was radiographic response rate; secondary outcomes included progression-free survival (PFS) and overall survival (OS).ResultsOne hundred twenty patients were enrolled with median follow-up of 7.5 years. Overall response rate was 6%, with median PFS and OS of 4.2 and 9.7 years, respectively. Molecular subtype was associated with rate of disease progression during treatment (P

Background:Worse chemotherapy response for neurofibromatosis type 1- (NF1-) associated compared to sporadic malignant peripheral nerve sheath tumors (MPNST) has been reported. Methods:We evaluated the objective response (OR) rate of patients with AJCC Stage III/IV chemotherapy-naive NF1 MPNST versus sporadic MPNST after 4 cycles of neoadjuvant chemotherapy, 2 cycles of ifosfamide/doxorubicin, and 2 cycles of ifosfamide/etoposide. A Simon optimal two-stage design was used (target response rate 40%). Results:34 NF1 (median age 33 years) and 14 sporadic (median age 40 years) MPNST patients enrolled. Five of 28 (17.9%) evaluable NF1 MPNST patients had a partial response (PR), as did 4 of 9 (44.4%) patients with sporadic MPNST. Stable disease (SD) was achieved in 22 NF1 and 4 sporadic MPNST patients. In both strata, results in the initial stages met criteria for expansion of enrollment. Only 1 additional PR was observed in the expanded NF1 stratum. Enrollment was slower than expected and the trial closed before full accrual. Conclusions:This trial was not powered to detect differences in response rates between NF1 and sporadic MPNST. While the OR rate was lower in NF1 compared to sporadic MPNST, qualitative responses were similar, and disease stabilization was achieved in most patients.

While immunotherapy may offer promising new approaches for high grade meningiomas, little is currently known of the immune landscape in meningiomas. We sought to characterize the immune microenvironment and a potentially targetable antigen mesothelin across WHO grade I-III cases of meningiomas, and how infiltrating immune populations relate to patient outcomes. Immunohistochemistry was performed on tissue microarrays constructed from 96 meningioma cases. The cohort included 16 WHO grade I, 62 WHO grade II, and 18 WHO grade III tumors. Immunohistochemistry was performed using antibodies against CD3, CD8, CD20, CD68, PD-L1, and mesothelin. Dual staining using anti-PD-L1 and anti-CD68 antibodies was performed, and automated cell detection and positive staining detection algorithms were utilized. Greater degree of PD-L1 expression was found in higher grade tumors. More specifically, higher grade tumors contained increased numbers of intratumoral CD68-, PD-L1+ cells (p = 0.022), but did not contain higher numbers of infiltrating CD68+, PD-L1+ cells (p = 0.30). Higher PD-L1+/CD68- expression was independently predictive of worse overall survival in our cohort when accounting for grade, performance status, extent of resection, and recurrence history (p = 0.014). Higher expression of PD-L1+/CD68- was also present in tumors that had undergone prior radiotherapy (p = 0.024). Approximately quarter of meningiomas overexpressed mesothelin to levels equivalent to those found in pancreatic carcinomas and malignant mesotheliomas. The association with poor survival outcomes in our study suggests that PD-L1 may play a significant biologic role in the aggressive phenotype of higher grade meningiomas. Thus, immunotherapeutic strategies such as checkpoint inhibition may have clinical utility in PD-L1 overexpressing meningiomas.

Mutations in the isocitrate dehydrogenase gene IDH1 are common in low-grade glioma, where they result in the production of 2-hydroxyglutarate (2HG), disrupted patterns of histone methylation, and gliomagenesis. IDH1 mutations also cosegregate with mutations in the ATRX gene and the TERT promoter, suggesting that IDH mutation may drive the creation or selection of telomere-stabilizing events as part of immortalization/transformation process. To determine whether and how this may occur, we investigated the phenotype of pRb-/p53-deficient human astrocytes engineered with IDH1 wild-type (WT) or R132H-mutant (IDH1mut) genes as they progressed through their lifespan. IDH1mut expression promoted 2HG production and altered histone methylation within 20 population doublings (PD) but had no effect on telomerase expression or telomere length. Accordingly, cells expressing either IDH1WT or IDH1mut entered a telomere-induced crisis at PD 70. In contrast, only IDH1mut cells emerged from crisis, grew indefinitely in culture, and formed colonies in soft agar and tumors in vivo Clonal populations of postcrisis IDH1mut cells displayed shared genetic alterations, but no mutations in ATRX or the TERT promoter were detected. Instead, these cells reactivated telomerase and stabilized their telomeres in association with increased histone lysine methylation (H3K4me3) and c-Myc/Max binding at the TERT promoter. Overall, these results show that although IDH1mut does not create or select for ATRX or TERT promoter mutations, it can indirectly reactivate TERT, and in doing so contribute to astrocytic immortalization and transformation. Cancer Res; 76(22); 6680-9. ©2016 AACR.

Molecular profiling is revolutionizing cancer diagnostics and leading to personalized therapeutic approaches. Herein we describe our clinical experience performing targeted sequencing for 31 pediatric neuro-oncology patients.We sequenced 510 cancer-associated genes from tumor and peripheral blood to identify germline and somatic mutations, structural variants, and copy number changes.Genomic profiling was performed on 31 patients with tumors including 11 high-grade gliomas, 8 medulloblastomas, 6 low-grade gliomas, 1 embryonal tumor with multilayered rosettes, 1 pineoblastoma, 1 uveal ganglioneuroma, 1 choroid plexus carcinoma, 1 chordoma, and 1 high-grade neuroepithelial tumor. In 25 cases (81%), results impacted patient management by: (i) clarifying diagnosis, (ii) identifying pathogenic germline mutations, or (iii) detecting potentially targetable alterations. The pathologic diagnosis was amended after genomic profiling for 6 patients (19%), including a high-grade glioma to pilocytic astrocytoma, medulloblastoma to pineoblastoma, ependymoma to high-grade glioma, and medulloblastoma to CNS high-grade neuroepithelial tumor with BCOR alteration. Multiple patients had pathogenic germline mutations, many of which were previously unsuspected. Potentially targetable alterations were identified in 19 patients (61%). Additionally, novel likely pathogenic alterations were identified in 3 cases: an in-frame RAF1 fusion in a BRAF wild-type pleomorphic xanthoastrocytoma, an inactivating ASXL1 mutation in a histone H3 wild-type diffuse pontine glioma, and an in-frame deletion within exon 2 of MAP2K1 in a low-grade astrocytic neoplasm.Our experience demonstrates the significant impact of molecular profiling on diagnosis and treatment of pediatric brain tumors and confirms its feasibility for use at the time of diagnosis or recurrence.

We present the case of a patient with a left frontal glioblastoma with primitive neuroectodermal tumor features and hypermutated genotype in the setting of a POLE germline alteration. During standard-of-care chemoradiation, the patient developed a cervical spine metastasis and was subsequently treated with pembrolizumab. Shortly thereafter, the patient developed an additional metastatic spinal lesion. Using whole-exome DNA sequencing and clonal analysis, we report changes in the subclonal architecture throughout treatment. Furthermore, a persistently high neoantigen load was observed within all tumors. Interestingly, following initiation of pembrolizumab, brisk lymphocyte infiltration was observed in the subsequently resected metastatic spinal lesion and an objective radiographic response was noted in a progressive intracranial lesion, suggestive of active central nervous system (CNS) immunosurveillance following checkpoint blockade therapy.SignificanceIt is unclear whether hypermutated glioblastomas are susceptible to checkpoint blockade in adults. Herein, we provide proof of principle that glioblastomas with DNA-repair defects treated with checkpoint blockade may result in CNS immune activation, leading to clinically and immunologically significant responses. These patients may represent a genomically stratified group for whom immunotherapy could be considered. Cancer Discov; 6(11); 1230-6. ©2016 AACR.See related commentary by Snyder and Wolchok, p. 1210This article is highlighted in the In This Issue feature, p. 1197.

Somatic mutations of the H3F3A and HIST1H3B genes encoding the histone H3 variants, H3.3 and H3.1, were recently identified in high-grade gliomas arising in the thalamus, pons and spinal cord of children and young adults. However, the complete range of patients and locations in which these tumors arise, as well as the morphologic spectrum and associated genetic alterations remain undefined. Here, we describe a series of 47 diffuse midline gliomas with histone H3-K27M mutation. The 25 male and 22 female patients ranged in age from 2 to 65 years (median = 14). Tumors were centered not only in the pons, thalamus, and spinal cord, but also in the third ventricle, hypothalamus, pineal region and cerebellum. Patients with pontine tumors were younger (median = 7 years) than those with thalamic (median = 24 years) or spinal (median = 25 years) tumors. A wide morphologic spectrum was encountered including gliomas with giant cells, epithelioid and rhabdoid cells, primitive neuroectodermal tumor (PNET)-like foci, neuropil-like islands, pilomyxoid features, ependymal-like areas, sarcomatous transformation, ganglionic differentiation and pleomorphic xanthoastrocytoma (PXA)-like areas. In this series, histone H3-K27M mutation was mutually exclusive with IDH1 mutation and EGFR amplification, rarely co-occurred with BRAF-V600E mutation, and was commonly associated with p53 overexpression, ATRX loss (except in pontine gliomas), and monosomy 10.

Low-grade neuroepithelial tumors (LGNTs) are diverse CNS tumors presenting in children and young adults, often with a history of epilepsy. While the genetic profiles of common LGNTs, such as the pilocytic astrocytoma and 'adult-type' diffuse gliomas, are largely established, those of uncommon LGNTs remain to be defined. In this study, we have used massively parallel sequencing and various targeted molecular genetic approaches to study alterations in 91 LGNTs, mostly from children but including young adult patients. These tumors comprise dysembryoplastic neuroepithelial tumors (DNETs; n = 22), diffuse oligodendroglial tumors (d-OTs; n = 20), diffuse astrocytomas (DAs; n = 17), angiocentric gliomas (n = 15), and gangliogliomas (n = 17). Most LGNTs (84 %) analyzed by whole-genome sequencing (WGS) were characterized by a single driver genetic alteration. Alterations of FGFR1 occurred frequently in LGNTs composed of oligodendrocyte-like cells, being present in 82 % of DNETs and 40 % of d-OTs. In contrast, a MYB-QKI fusion characterized almost all angiocentric gliomas (87 %), and MYB fusion genes were the most common genetic alteration in DAs (41 %). A BRAF:p.V600E mutation was present in 35 % of gangliogliomas and 18 % of DAs. Pathogenic alterations in FGFR1/2/3, BRAF, or MYB/MYBL1 occurred in 78 % of the series. Adult-type d-OTs with an IDH1/2 mutation occurred in four adolescents, the youngest aged 15 years at biopsy. Despite a detailed analysis, novel genetic alterations were limited to two fusion genes, EWSR1-PATZ1 and SLMAP-NTRK2, both in gangliogliomas. Alterations in BRAF, FGFR1, or MYB account for most pathogenic alterations in LGNTs, including pilocytic astrocytomas, and alignment of these genetic alterations and cytologic features across LGNTs has diagnostic implications. Additionally, therapeutic options based upon targeting the effects of these alterations are already in clinical trials.

BackgroundThe colony stimulating factor 1 receptor (CSF1R) ligands, CSF1 and interleukin-34, and the KIT ligand, stem cell factor, are expressed in glioblastoma (GB). Microglia, macrophages, blood vessels, and tumor cells also express CSF1R, and depletion of the microglia reduces tumor burden and invasive capacity. PLX3397 is an oral, small molecule that selectively inhibits CSF1R and KIT, penetrates the blood-brain barrier in model systems, and represents a novel approach for clinical development.MethodsWe conducted a phase II study in patients with recurrent GB. The primary endpoint was 6-month progression-free survival (PFS6). Secondary endpoints included overall survival response rate, safety, and plasma/tumor tissue pharmacokinetics. Exploratory endpoints included pharmacodynamic measures of drug effect in blood and tumor tissue.ResultsA total of 37 patients were enrolled, with 13 treated prior to a planned surgical resection (Cohort 1) and 24 treated without surgery (Cohort 2). PLX3397 was given at an oral dose of 1000 mg daily and was well tolerated. The primary efficacy endpoint of PFS6 was only 8.6%, with no objective responses. Pharmacokinetic endpoints revealed a median maximal concentration (Cmax) of 8090 ng/mL, with a time to attain Cmax of 2 hour in plasma. Tumor tissue obtained after 7 days of drug exposure revealed a median drug level of 5500 ng/g. Pharmacodynamic changes included an increase in colony stimulating factor 1 and reduced CD14(dim)/CD16+ monocytes in plasma compared with pretreatment baseline values.ConclusionPLX3397 was well tolerated and readily crossed the blood-tumor barrier but showed no efficacy. Additional studies are ongoing, testing combination strategies and potential biomarkers to identify patients with greater likelihood of response.

Oligodendroglioma represents a distinctive neoplasm in adults but similar neoplasms occur rarely in children. We studied 20 cases of pediatric oligodendroglioma by SNP array (median age 9 years, range 1-19; 15 grade II and 5 grade III). Cytogenetic abnormalities were present in 8 (53%) grade II and all five anaplastic oligodendrogliomas. Most changes were in the form of deletion and copy neutral loss of heterozygosity (LOH). The most common abnormality was 1p deletion (n = 5). Whole arm 1p19q co-deletion was present in three cases from adolescent patients and 9p loss in 3, including one low-grade oligodendroglioma with CDKN2A homozygous deletion. Common losses were largely limited to the anaplastic subset (n = 5) and included 3q29 (n = 3), 11p (n = 3), 17q (n = 3), 4q (n = 2), 6p (n = 2), 13q (n = 2), 14q (n = 2), 17p (n = 2) and whole Ch 18 loss (n = 2). Gains were non-recurrent except for whole Ch 7 (n = 2) and gain on 12q (n = 2) including the MDM2 locus. Possible germ line LOH (or uniparental disomy) was present in seven cases (35%), with one focal abnormality (22q13.1-13.2) in two. BRAF-KIAA1549 fusions and BRAF p.V600E mutations were absent (n = 13 and 8). In summary, cytogenetic alterations in pediatric oligodendrogliomas are characterized mostly by genomic losses, particularly in anaplastic tumors.

Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein, we demonstrate that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors. From the remaining fraction of CNS-PNETs, we identify four new CNS tumor entities, each associated with a recurrent genetic alteration and distinct histopathological and clinical features. These new molecular entities, designated "CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2)," "CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC)," "CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1)," and "CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR)," will enable meaningful clinical trials and the development of therapeutic strategies for patients affected by poorly differentiated CNS tumors.

The behavior of rhabdoid meningiomas otherwise lacking malignant features remains unknown as most of the originally reported aggressive cases showed anaplastic histologic features independently of rhabdoid phenotype. We studied 44 patients with rhabdoid meningiomas lacking anaplastic features. Median age at diagnosis was 48.6 years (range 10-79). Location was supratentorial in 28 (63.6%), skull base in 15 (34.1%), and spinal in 1 (2.3%). Tumor grade was otherwise World Health Organization grade I (n = 22, 50%) or II (n = 22, 50%). Rhabdoid cells represented 50% in 14 (31.8%). Median clinical follow-up, available for 38 patients, was 5.0 years (range 0.17-14.2). Recurrence occurred in 9 patients (5-year recurrence-free survival, 73.7%) with a significantly higher risk in subtotally resected tumors (p = 0.043). Rhabdoid cell percentage was not associated with recurrence. Six patients died (4 of disease, 2 of unclear causes); 5-year overall survival was 86.7%, a mortality in excess of that expected in grade I-II meningiomas but much lower than originally reported. Review of 50 similar previously reported cases confirmed our findings. We suggest that rhabdoid meningiomas be graded analogously to nonrhabdoid tumors, with caution that some may still behave aggressively and close follow-up is recommended.

* Context.--Standards for pathology reporting of cancer are foundational to national and international benchmarking, epidemiology, and clinical trials, with international standards for pathology reporting of cancer being undertaken through the International Collaboration on Cancer Reporting (ICCR). Objective.--To develop standardized templates for brain tumor diagnostic pathology reporting. Design.--As a response to the 2016 updated 4th edition of the WHO (World Health Organization) Classification of Tumours of the Central Nervous System (2016 CNS WHO), an expert ICCR committee developed data sets to facilitate reporting of brain tumors that are classified histologically and molecularly by the 2016 CNS WHO; as such, this represents the first combined histologic and molecular ICCR data set, and required a novel approach with 3 highly related data sets that should be used in an integrated manner. Results.--The current article and accompanying ICCR Web site describe reporting data sets for central nervous system tumors in the hope that they provide easy-to-use and highly reproducible means to issue diagnostic reports in consort with the 2016 CNS WHO. Conclusions.--The consistent use of these templates will undoubtedly prove useful for patient care, clinical trials, epidemiologic studies, and monitoring of neuro-oncologic care around the world. (Arch Pathol Lab Med. 2020;144:196-206; doi: 10.5858/arpa.2018-0565-OA), The value of a structured or synoptic approach to cancer reporting, leading to improvement in the quality and completeness of pathology cancer reports, has been recognized through many studies (1-4) [...]

PurposeMalignant peripheral nerve sheath tumors (MPNST) occur at increased frequency in individuals with neurofibromatosis type 1 (NF1), where they likely arise from benign plexiform neurofibroma precursors. While previous studies have used a variety of discovery approaches to discover genes associated with MPNST pathogenesis, it is currently unclear what molecular events are associated with the evolution of MPNST from plexiform neurofibroma.Experimental designWhole-exome sequencing was performed on biopsy materials representing plexiform neurofibroma (n = 3), MPNST, and metastasis from a single individual with NF1 over a 14-year period. Additional validation cases were used to assess candidate genes involved in malignant progression, while a murine MPNST model was used for functional analysis.ResultsThere was an increasing proportion of cells with a somatic NF1 gene mutation as the tumors progressed from benign to malignant, suggesting a clonal process in MPNST development. Copy number variations, including loss of one copy of the TP53 gene, were identified in the primary tumor and the metastatic lesion, but not in benign precursor lesions. A limited number of genes with nonsynonymous somatic mutations (βIII-spectrin and ZNF208) were discovered, several of which were validated in additional primary and metastatic MPNST samples. Finally, increased βIII-spectrin expression was observed in the majority of MPNSTs, and shRNA-mediated knockdown reduced murine MPNST growth in vivo.ConclusionsCollectively, the ability to track the molecular evolution of MPNST in a single individual with NF1 offers new insights into the sequence of genetic events important for disease pathogenesis and progression for future mechanistic study.

Glioblastoma (GBM) is the most common and aggressive human brain tumor. Human cytomegalovirus (HCMV) immediate-early (IE) proteins that are endogenously expressed in GBM cells are strong viral transactivators with oncogenic properties. Here, we show how HCMV IEs are preferentially expressed in glioma stem-like cells (GSC), where they colocalize with the other GBM stemness markers, CD133, Nestin, and Sox2. In patient-derived GSCs that are endogenously infected with HCMV, attenuating IE expression by an RNAi-based strategy was sufficient to inhibit tumorsphere formation, Sox2 expression, cell-cycle progression, and cell survival. Conversely, HCMV infection of HMCV-negative GSCs elicited robust self-renewal and proliferation of cells that could be partially reversed by IE attenuation. In HCMV-positive GSCs, IE attenuation induced a molecular program characterized by enhanced expression of mesenchymal markers and proinflammatory cytokines, resembling the therapeutically resistant GBM phenotype. Mechanistically, HCMV/IE regulation of Sox2 occurred via inhibition of miR-145, a negative regulator of Sox2 protein expression. In a spontaneous mouse model of glioma, ectopic expression of the IE1 gene (UL123) specifically increased Sox2 and Nestin levels in the IE1-positive tumors, upregulating stemness and proliferation markers in vivo. Similarly, human GSCs infected with the HCMV strain Towne but not the IE1-deficient strain CR208 showed enhanced growth as tumorspheres and intracranial tumor xenografts, compared with mock-infected human GSCs. Overall, our findings offer new mechanistic insights into how HCMV/IE control stemness properties in GBM cells.

BackgroundThe prediction of clinical behavior, response to therapy, and outcome of infiltrative glioma is challenging. On the basis of previous studies of tumor biology, we defined five glioma molecular groups with the use of three alterations: mutations in the TERT promoter, mutations in IDH, and codeletion of chromosome arms 1p and 19q (1p/19q codeletion). We tested the hypothesis that within groups based on these features, tumors would have similar clinical variables, acquired somatic alterations, and germline variants.MethodsWe scored tumors as negative or positive for each of these markers in 1087 gliomas and compared acquired alterations and patient characteristics among the five primary molecular groups. Using 11,590 controls, we assessed associations between these groups and known glioma germline variants.ResultsAmong 615 grade II or III gliomas, 29% had all three alterations (i.e., were triple-positive), 5% had TERT and IDH mutations, 45% had only IDH mutations, 7% were triple-negative, and 10% had only TERT mutations; 5% had other combinations. Among 472 grade IV gliomas, less than 1% were triple-positive, 2% had TERT and IDH mutations, 7% had only IDH mutations, 17% were triple-negative, and 74% had only TERT mutations. The mean age at diagnosis was lowest (37 years) among patients who had gliomas with only IDH mutations and was highest (59 years) among patients who had gliomas with only TERT mutations. The molecular groups were independently associated with overall survival among patients with grade II or III gliomas but not among patients with grade IV gliomas. The molecular groups were associated with specific germline variants.ConclusionsGliomas were classified into five principal groups on the basis of three tumor markers. The groups had different ages at onset, overall survival, and associations with germline variants, which implies that they are characterized by distinct mechanisms of pathogenesis. (Funded by the National Institutes of Health and others.).

Lower-grade (World Health Organization Grades II and III) gliomas vary widely in clinical behavior and are classified as astrocytic, oligodendroglial, or mixed. Anaplasia depends greatly on mitotic activity, with CDKN2A loss considered as the most common mechanism for cell cycle dysregulation. We investigated whether loss of the CDKN2A gene is associated with overall survival across pathologically and genetically defined glioma subtypes. After adjustment for IDH mutation, sex, and age, CDKN2A deletion was strongly associated with poorer overall survival in astrocytomas but not in oligodendrogliomas or oligoastrocytomas. Molecular classification of astrocytomas by IDH mutation, TP53 mutation, and /or ATRX loss of expression revealed that CDKN2A loss in IDH/TP53 mutated tumors was strongly associated with worse overall survival. CDKN2A loss in IDH mutated tumors with ATRX loss was only weakly associated with worse overall survival. These findings suggest that CDKN2A testing may provide further clinical aid in lower-grade glioma substratification beyond IDH mutation and 1p19q codeletion status, particularly in IDH/TP53 mutated astrocytomas.

Intravascular large cell lymphoma (IVLCL) is a rare disease characterized by proliferation of malignant lymphocytes within the small blood vessel lumens. The association of IVLCL with autoimmune hemolytic anemia (AIHA) has been described in a single case report, but the true prevalence of this co-occurrence is not known because of declining autopsy rates. Here, we report a case of a 41-year-old woman who carried a diagnosis of AIHA for 2 years, with repeated hemolytic episodes that were initially well controlled with immunomodulatory treatment. At her last presentation, the patient developed rapidly progressive neurologic symptoms and leukoencephalopathy on MRI; she died 4 weeks later with a clinical impression of thrombotic microangiopathy, a known complication of AIHA. At autopsy, the brain showed widespread platelet thrombi and intraparenchymal hemorrhages characteristic of this disorder. In addition, there was evidence of a clinically unsuspected IVLCL, most likely of B-cell lineage. This case illustrates a potential association between IVLCL and AIHA, highlights the need for broad differential diagnosis in cases with atypical disease presentation or progression, and underlines the importance of autopsy in establishing the full cause of morbidity and mortality.

Cellular schwannoma is an uncommon, but well-recognized, benign peripheral nerve sheath tumor, which can be misdiagnosed as malignant peripheral nerve sheath tumor. To develop consensus diagnostic criteria for cellular schwannoma, we reviewed 115 malignant peripheral nerve sheath tumor and 26 cellular schwannoma cases from two institutions. Clinical data were retrieved from the electronic medical records, and morphologic features, maximal mitotic counts, Ki67 labeling indices, and immunohistochemical profiles (SOX10, SOX2, p75NTR, p16, p53, EGFR, and neurofibromin) were assessed. Several features distinguish cellular schwannoma from malignant peripheral nerve sheath tumor. First, in contrast to patients with malignant peripheral nerve sheath tumor, no metastases or disease-specific deaths were found in patients with cellular schwannoma. More specifically, 5-year progression-free survival rates were 100 and 18%, and 5-year disease-specific survival rates were 100 and 32% for cellular schwannoma and malignant peripheral nerve sheath tumor, respectively. Second, the presence of Schwannian whorls, a peritumoral capsule, subcapsular lymphocytes, macrophage-rich infiltrates, and the absence of fascicles favored the diagnosis of cellular schwannoma, while the presence of perivascular hypercellularity, tumor herniation into vascular lumens, and necrosis favor malignant peripheral nerve sheath tumor. Third, complete loss of SOX10, neurofibromin or p16 expression, or the presence of EGFR immunoreactivity was specific for malignant peripheral nerve sheath tumor (P

Light chain deposition disease (LCDD) is a rare clinicopathologic entity first described in 1976 and is characterized by a monoclonal gammopathy resulting in nonamyloid immunoglobulin light chain tissue deposition. Only four cases of intracerebral LCDD have been previously reported, all in the setting of a known plasma cell dyscrasia or in the presence of local mature plasma cells. We present the first case of intracranial LCDD in the absence of a known plasma cell dyscrasia or local mature plasma cells.

Germ-line RB-1 mutations predispose to pineoblastoma (PinB), but other predisposing genetic factors are not well established. We recently identified a germ-line DICER1 mutation in a child with a PinB. This was accompanied by loss of heterozygosity (LOH) of the wild-type allele within the tumour. We set out to establish the prevalence of DICER1 mutations in an opportunistically ascertained series of PinBs. Twenty-one PinB cases were studied: Eighteen cases had not undergone previous testing for DICER1 mutations; three patients were known carriers of germ-line DICER1 mutations. The eighteen PinBs were sequenced by Sanger and/or Fluidigm-based next-generation sequencing to identify DICER1 mutations in blood gDNA and/or tumour gDNA. Testing for somatic DICER1 mutations was also conducted on one case with a known germ-line DICER1 mutation. From the eighteen PinBs, we identified four deleterious DICER1 mutations, three of which were germ line in origin, and one for which a germ line versus somatic origin could not be determined; in all four, the second allele was also inactivated leading to complete loss of DICER1 protein. No somatic DICER1 RNase IIIb mutations were identified. One PinB arising in a germ-line DICER1 mutation carrier was found to have LOH. This study suggests that germ-line DICER1 mutations make a clinically significant contribution to PinB, establishing DICER1 as an important susceptibility gene for PinB and demonstrates PinB to be a manifestation of a germ-line DICER1 mutation. The means by which the second allele is inactivated may differ from other DICER1-related tumours.

Major discoveries in the biology of nervous system tumors have raised the question of how non-histological data such as molecular information can be incorporated into the next World Health Organization (WHO) classification of central nervous system tumors. To address this question, a meeting of neuropathologists with expertise in molecular diagnosis was held in Haarlem, the Netherlands, under the sponsorship of the International Society of Neuropathology (ISN). Prior to the meeting, participants solicited input from clinical colleagues in diverse neuro-oncological specialties. The present "white paper" catalogs the recommendations of the meeting, at which a consensus was reached that incorporation of molecular information into the next WHO classification should follow a set of provided "ISN-Haarlem" guidelines. Salient recommendations include that (i) diagnostic entities should be defined as narrowly as possible to optimize interobserver reproducibility, clinicopathological predictions and therapeutic planning; (ii) diagnoses should be "layered" with histologic classification, WHO grade and molecular information listed below an "integrated diagnosis"; (iii) determinations should be made for each tumor entity as to whether molecular information is required, suggested or not needed for its definition; (iv) some pediatric entities should be separated from their adult counterparts; (v) input for guiding decisions regarding tumor classification should be solicited from experts in complementary disciplines of neuro-oncology; and (iv) entity-specific molecular testing and reporting formats should be followed in diagnostic reports. It is hoped that these guidelines will facilitate the forthcoming update of the fourth edition of the WHO classification of central nervous system tumors.

Major discoveries in the biology of nervous system tumors have raised the question of how non-histological data such as molecular information can be incorporated into the next World Health Organization (WHO) classification of central nervous system tumors. To address this question, a meeting of neuropathologists with expertise in molecular diagnosis was held in Haarlem, the Netherlands, under the sponsorship of the International Society of Neuropathology (ISN). Prior to the meeting, participants solicited input from clinical colleagues in diverse neuro-oncological specialties. The present "white paper" catalogs the recommendations of the meeting, at which a consensus was reached that incorporation of molecular information into the next WHO classification should follow a set of provided "ISN-Haarlem" guidelines. Salient recommendations include that (i) diagnostic entities should be defined as narrowly as possible to optimize interobserver reproducibility, clinicopathological predictions and therapeutic planning; (ii) diagnoses should be "layered" with histologic classification, WHO grade and molecular information listed below an "integrated diagnosis"; (iii) determinations should be made for each tumor entity as to whether molecular information is required, suggested or not needed for its definition; (iv) some pediatric entities should be separated from their adult counterparts; (v) input for guiding decisions regarding tumor classification should be solicited from experts in complementary disciplines of neuro-oncology; and (iv) entity-specific molecular testing and reporting formats should be followed in diagnostic reports. It is hoped that these guidelines will facilitate the forthcoming update of the fourth edition of the WHO classification of central nervous system tumors.

Three histological variants are known within the family of embryonal rosette-forming neuroepithelial brain tumors. These include embryonal tumor with abundant neuropil and true rosettes (ETANTR), ependymoblastoma (EBL), and medulloepithelioma (MEPL). In this study, we performed a comprehensive clinical, pathological, and molecular analysis of 97 cases of these rare brain neoplasms, including genome-wide DNA methylation and copy number profiling of 41 tumors. We identified uniform molecular signatures in all tumors irrespective of histological patterns, indicating that ETANTR, EBL, and MEPL comprise a single biological entity. As such, future WHO classification schemes should consider lumping these variants into a single diagnostic category, such as embryonal tumor with multilayered rosettes (ETMR). We recommend combined LIN28A immunohistochemistry and FISH analysis of the 19q13.42 locus for molecular diagnosis of this tumor category. Recognition of this distinct pediatric brain tumor entity based on the fact that the three histological variants are molecularly and clinically uniform will help to distinguish ETMR from other embryonal CNS tumors and to better understand the biology of these highly aggressive and therapy-resistant pediatric CNS malignancies, possibly leading to alternate treatment strategies.

Individuals harboring germ-line DICER1 mutations are predisposed to a rare cancer syndrome, the DICER1 Syndrome or pleuropulmonary blastoma-familial tumor and dysplasia syndrome [online Mendelian inheritance in man (OMIM) #601200]. In addition, specific somatic mutations in the DICER1 RNase III catalytic domain have been identified in several DICER1-associated tumor types. Pituitary blastoma (PitB) was identified as a distinct entity in 2008, and is a very rare, potentially lethal early childhood tumor of the pituitary gland. Since the discovery by our team of an inherited mutation in DICER1 in a child with PitB in 2011, we have identified 12 additional PitB cases. We aimed to determine the contribution of germ-line and somatic DICER1 mutations to PitB. We hypothesized that PitB is a pathognomonic feature of a germ-line DICER1 mutation and that each PitB will harbor a second somatic mutation in DICER1. Lymphocyte or saliva DNA samples ascertained from ten infants with PitB were screened and nine were found to harbor a heterozygous germ-line DICER1 mutation. We identified additional DICER1 mutations in nine of ten tested PitB tumor samples, eight of which were confirmed to be somatic in origin. Seven of these mutations occurred within the RNase IIIb catalytic domain, a domain essential to the generation of 5p miRNAs from the 5' arm of miRNA-precursors. Germ-line DICER1 mutations are a major contributor to PitB. Second somatic DICER1 "hits" occurring within the RNase IIIb domain also appear to be critical in PitB pathogenesis.

BackgroundGrades II and III gliomas have unpredictable rates of progression, making management decisions difficult. Currently, several clinical and radiological characteristics are utilized to predict progression and survival but collectively are suboptimal.MethodsIn this study, we analyzed a set of 108 nonenhancing hemispheric grade II-III gliomas. Demographic variables, including patient age, tumor diameter, extent of resection, and performance status, were combined with molecular data (IDH mutation status [mIDH], 1p/19q codeletion, PTEN deletion, and EGFR amplification). A complete dataset for all variables was compiled for 70 of the 108 patients. Both univariable and multivariable analyses were performed to determine whether the molecular data singly or in combination offer advantages over tumor type and grade for prediction of overall survival (OS) and/or progression-free rate (PFR).ResultsPatient age, clinical variables (tumor diameter, extent of resection, performance status), and pathology (tumor type and grade) were not predictive of OS or PFR. IDH mutation status alone was predictive of longer OS and PFR for the entire group of tumors; 1p/19q deletion alone was predictive of OS but not PFR. In the multivariable analysis, none of the clinical or demographic factors were predictive of OS or PFR. IDH mutation status, 1p/19q codeletion, and PTEN deletion were predictive of OS (P = .003, P = .005, P = .02, respectively). Both mIDH (P < .001) and the interaction term of 1p/19q and PTEN (P < .001) were found to be predictive of PFR.ConclusionsWe conclude that the combination of mIDH, 1p/19q codeletion, and PTEN deletion may be particularly effective in discriminating good prognosis from poor prognosis hemispheric gliomas. We propose that such a scheme merits testing on larger prospective cohorts. Should our findings be confirmed, routine clinical analysis of hemispheric gliomas for mIDH, 1p/19q codeletion, and PTEN deletion would be justified.

Meningiomas with prominent inflammation are traditionally classified as "lymphoplasmacyte-rich meningioma" (LPM). Both inflammatory and neoplastic meningeal proliferations have recently been linked to IgG4 disease, although a potential association with LPM has not been previously explored. Sixteen meningiomas with inflammatory cells outnumbering tumor cells were further characterized by CD3, CD20, CD68 and/or CD163, CD138, kappa, lambda, IgG and IgG4 immunostains. There were 11 female and 4 male patients, ranging from 22 to 78 (median 59) years of age. Tumors consisted of 10 World Health Organization (WHO) grade I, 5 grade II and 1 grade III LPMs. Immunohistochemically, the most numerous cell type was the macrophage in all cases followed by CD3-positive T cells and fewer CD20-positive B cells. Plasma cells ranged from moderate-marked (N = 5) to rare (N = 7), or absent (N = 4). Maximal numbers of IgG4 plasma cells per high power field (HPF) ranged from 0 to 32, with only two cases having counts exceeding 10/HPF. The IgG4/IgG ratio was increased focally in only two cases (30% and 31%). Additionally, plasma cells represented only a minor component in most examples, whereas macrophages predominated, suggesting that "inflammation-rich meningioma" may be a more accurate term. The inflammatory stimulus for most cases remains to be elucidated.

BackgroundBoth the epidermal growth factor receptor and vascular endothelial growth factor pathways are frequently overexpressed in glioblastoma multiforme. This study combined bevacizumab, a vascular endothelial growth factor inhibitor, and erlotinib, an epidermal growth factor receptor inhibitor, with standard radiation and temozolomide (TMZ), with the goal of improving overall survival (OS).MethodsTreatment consisted of fractionated radiotherapy to 60 Gy, with daily TMZ at 75 mg/m²/d and erlotinib 150-200 mg/d (or 500-600 mg/d for patients on enzyme-inducing antiepileptic drugs). Bevacizumab was given at 10 mg/kg every 2 weeks, starting ≥4 weeks after surgery. After radiotherapy, adjuvant TMZ was given at 200 mg/m²/d × 5d per 28-day cycle, with unchanged erlotinib and bevacizumab doses. Treatment continued until progression or for 12 months. Efficacy was compared against an institutional historical control. A sample of 55 patients was calculated to provide 85% power to detect a hazard ratio of 0.67 for OS.ResultsFifty-nine patients were enrolled for efficacy analysis after a 15-patient safety lead-in. For the efficacy group, median age was 54 years; median KPS was 90. Gross total and subtotal resections were achieved in 33% and 53%, respectively. The most frequent related grade 3/4 adverse effects were lymphopenia, thrombocytopenia, neutropenia, diarrhea, weight loss, and fatigue. One patient died of disseminated aspergillosis. Median OS was 19.8 months (vs 18 mo for HC, P = .33) and median progression-free survival was 13.5 months (vs 8.6 mo for HC, P = .03).ConclusionsThe combination of bevacizumab, erlotinib, TMZ, and radiotherapy appears to be well tolerated and improved progression-free survival but did not reach the primary endpoint of improved OS.

Amplification of the C19MC oncogenic miRNA cluster and high LIN28 expression has been linked to a distinctly aggressive group of cerebral CNS-PNETs (group 1 CNS-PNETs) arising in young children. In this study, we sought to evaluate the diagnostic specifici