Citations

OBJECTIVE Intracranial germ cell tumors (iGCTs) often arise at the neurohypophysis, their second most common origination, following the pineal region. Neurohypophyseal iGCTs present with stereotypical symptoms, including pituitary dysfunction and visual field deficit, due to their suprasellar location. The goal of this study was to present a large, longitudinal single-institution experience with neurohypophyseal iGCTs to better understand their natural history and identify opportunities for further improvement in treatment outcomes. METHODS This is a retrospective, single-institution cohort study of neurohypophyseal iGCTs treated between 1988 and 2017, with a focus on the epidemiology, presentation, natural history, and treatment. RESULTS Thirty-five neurosurgically managed patients met inclusion criteria; the median age was 18 years (3 months to 49 years), and 74% of patients were male (n = 26). Thirty-one tumors were germinomas, and 4 were nongerminomatous iGCTs. Presenting symptoms included pituitary insufficiency in 76% (n = 25), visual deficit in 45% (n = 15), and diabetes insipidus (DI) in 61% (n = 20) of patients. Index symptoms included isolated DI in 10 (36%), isolated hormone deficiency in 14 (50%), and concomitant DI and hormone deficiency symptoms in 4 (14%). Radiographic diagnostic latency was common, occurring at a median of 363 days (range 9–2626 days) after onset of the first symptoms and was significantly associated with both DI and hormone deficiency as the index symptoms (no DI vs DI: 360 vs 1083 days, p = 0.009; no hormone deficiency vs hormone deficiency: 245 vs 953 days, p = 0.004). Biochemical abnormalities were heterogeneous; each pituitary axis was dysfunctional in at least 1 patient, with most patients demonstrating at least 2 abnormalities, and pretreatment dysfunction demonstrating a nonsignificant trend toward association with long-term posttreatment hormone supplementation. Among germinomas, whole-brain or whole-ventricle radiotherapy demonstrated significantly improved progression-free and overall survival compared with local therapy (p = 0.009 and p = 0.004, respectively). CONCLUSIONS Neurohypophyseal iGCTs are insidious tumors that may pose a diagnostic dilemma, as evidenced by the prolonged latency before radiographic confirmation. Serial imaging and close endocrine follow-up are recommended in patients with a characteristic clinical syndrome and negative imaging, due to the propensity for radiographic latency. Pretreatment biochemical abnormalities may indicate higher risk of posttreatment pituitary insufficiency, and all patients should receive careful endocrine follow-up. Local radiotherapy is prone to treatment failure, while whole-ventricle treatment is associated with improved survival in germinomas.

OBJECTIVE Central nervous system (CNS) germ cell tumors (GCTs) are rare malignant neoplasms that arise predominantly in adolescents and young adults. CNS GCTs demonstrate characteristic trends in national associations, with implications for both tumor incidence and genetics. Although the incidence of CNS GCTs is markedly higher in East Asia than Western countries, direct comparative analyses between these CNS GCT populations are limited. METHODS In Japan, to facilitate the genomic analyses of CNS GCTs, the Intracranial Germ Cell Tumor Genome Analysis Consortium was established in 2011, and more than 200 cases of GCTs are available for both tumor tissue and clinical data, which is organized by the National Cancer Center (NCC) Japan. At the Mayo Clinic, there have been 98 cases of intracranial GCTs treated by the Department of Neurologic Surgery since 1988. In this paper, the authors compared the epidemiology, clinical presentation including location and histology, and prognosis between cases treated in the US and Japan. RESULTS There was no significant difference in age and sex distributions between the databases. However, there was a significant difference in the tumor locations; specifically, the frequency of basal ganglia was higher in the NCC database compared with the Mayo Clinic (8.4% vs 0%, p = 0.008), and bifocal location (neurohypophysis and pineal gland) was higher at the Mayo Clinic than at the NCC (18.8% vs 5.8%, p = 0.002). There was no difference in histological subdivisions between the databases. There was no difference in progression-free survival (PFS) and overall survival (OS) of germinoma cases and OS of nongerminomatous GCT (NGGCT) cases treated with chemotherapy and radiation therapy covering whole ventricles. However, PFS of NGGCTs differed significantly, and was better in the NCC cohorts (p = 0.04). CONCLUSIONS There appears to be a differential distribution of GCTs by neuroanatomical location between major geographic and national groups. Further study is warranted to better characterize any underlying genomic, epigenetic, or environmental factors that may be driving the phenotypic differences.

Abstract Purpose: Glioblastoma is the most frequent and lethal primary brain tumor. Development of novel therapies relies on the availability of relevant preclinical models. We have established a panel of 96 glioblastoma patient-derived xenografts (PDX) and undertaken its genomic and phenotypic characterization. Experimental Design: PDXs were established from glioblastoma, IDH-wildtype (n = 93), glioblastoma, IDH-mutant (n = 2), diffuse midline glioma, H3 K27M-mutant (n = 1), and both primary (n = 60) and recurrent (n = 34) tumors. Tumor growth rates, histopathology, and treatment response were characterized. Integrated molecular profiling was performed by whole-exome sequencing (WES, n = 83), RNA-sequencing (n = 68), and genome-wide methylation profiling (n = 76). WES data from 24 patient tumors was compared with derivative models. Results: PDXs recapitulate many key phenotypic and molecular features of patient tumors. Orthotopic PDXs show characteristic tumor morphology and invasion patterns, but largely lack microvascular proliferation and necrosis. PDXs capture common and rare molecular drivers, including alterations of TERT, EGFR, PTEN, TP53, BRAF, and IDH1, most at frequencies comparable with human glioblastoma. However, PDGFRA amplification was absent. RNA-sequencing and genome-wide methylation profiling demonstrated broad representation of glioblastoma molecular subtypes. MGMT promoter methylation correlated with increased survival in response to temozolomide. WES of 24 matched patient tumors showed preservation of most genetic driver alterations, including EGFR amplification. However, in four patient–PDX pairs, driver alterations were gained or lost on engraftment, consistent with clonal selection. Conclusions: Our PDX panel captures the molecular heterogeneity of glioblastoma and recapitulates many salient genetic and phenotypic features. All models and genomic data are openly available to investigators.

Objective. We explore the clinicopathologic features of Ewing sarcoma (ES) presenting in older adulthood. Methods. Cases of molecularly confirmed ES arising in patients aged ≥40 years were evaluated. Results. Fifty patients were identified (33 males/17 females; 41-86 years). The majority of tumors (41) arose at extraskeletal sites, while 9 were bone primaries. Twenty-eight cases showed nested architecture, while the remaining cases showed sheet-like growth. Tumor cytology was categorized as conventional (n = 39), crushed (n = 5), clear cell (n = 4), rhabdoid (n = 3), and epithelioid (n = 2). Fifty percent had necrosis, while rosettes were noted in 1 case. Immunostains performed ranged from 1 to 28 (median = 10). Follow-up (n = 43, 1-147 months) revealed 15 patients with metastasis. Conclusion. Although rare, ES should be considered in the differential diagnosis for round cell malignancies in older adult patients. In this cohort, ES is most often extraskeletal, and may show unusual morphologic features, closely simulating more common neoplasms in this age group.

Abstract Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a recently described epileptogenic tumor characterized by oligodendroglioma-like components, aberrant CD34 expression, and genetic MAPK pathway activation through alterations such as BRAF V600E mutation, and FGFR2-KIAA1598/CTNNA3 and FGFR3-TACC3 fusions. We report the molecular profiling of PLNTY in 9 patients, 7 female: 2 male, median age at diagnosis of 16 years (range, 5–34). All tumors were supratentorial with diagnostic morphological features of PLNTY including oligodendroglioma-like areas and strong diffuse CD34 immunostaining. Four (of 9; 44%) tumors were positive for BRAF V600E immunostain, indicating the presence of a BRAF V600E mutation. The 6 cases evaluated for IDH status were negative by IDH1-R132H immunostain (n=5; 3 BRAF V600E-negative and 2 BRAF V600E-positive) or by NGS (n=1; BRAF V600E-negative). Oncoscan chromosomal microarray performed in 5 BRAF V600E-negative tumors showed recurrent copy number changes including gain of whole chromosomes 5, 7, 8, 9, 12, 18, 19, 20, 21 and X, and loss of chromosomes 1, 2, 10q, 13, 22 and Xq. The 10q losses (n=2) were highly suggestive of an FGFR2-KIAA1598 and of a potentially novel FGFR2 underlying fusion event in one case each. Custom targeted neuro-oncology DNA and RNA NGS panel performed in 2 cases revealed a fusion similar to fusions previously reported in pilocytic astrocytoma: one with a KIAA1549-BRAF (exon 15-exon 9) fusion associated with a 7q34 ~785 kilobase deletion rather than the characteristic ~2 megabase duplication seen in pilocytic astrocytoma, and another with a QKI-NTRK2 (exon 6-exon 15) fusion associated with a 9q21 ~191 kilobase duplication disrupting NTRK2. The KIAA1549-BRAF fusion-positive case also had a TP53 mutation with loss of whole chromosome 17, suggesting TP53 complete inactivation. This study confirms that PLNTY is a low-grade neuroepithelial tumor with frequent MAPK pathway activation and expands the spectrum of MAPK activating alterations observed in PLNTY.

Abstract BACKGROUND Oligodendrogliomas are classified as either WHO grade II or III depending on histologic features. Grade often influences treatment decisions. However, there is variability in patient outcome within tumors of similar grade. We hypothesized that copy number burden (CNB) and specific copy number variants (CNV) might be associated with oligodendroglioma grade and prognosis. METHODS Copy number array analyses were performed on 285 molecular oligodendrogliomas (IDH-mutant, 1p/19q-whole arm-codeleted) from the Mayo Clinic internal and consult neuropathology practice and 167 TCGA molecular oligodendrogliomas. CNB was defined as the total number of copy number alterations. The association of CNB and CNV with grade and overall survival (when available) was assessed. All Mayo and TCGA data were evaluated using the ChAS software suite (Thermo- Fisher) and blindly reviewed by a clinical cytogeneticist (RBJ). RESULTS The mean CNB was 5.0 and 10.4 in the Mayo WHO grade II and III oligodendrogliomas, respectively (p = 5.4 x 10–17). Among the TCGA WHO grade II and III oligodendrogliomas the mean CNB was 4.4 and 5.3, respectively (p = 0.034). Common CNVs (occurring in at least 5% of cases) were -4/4q-, +8/8q+, -9/9p-/cnLOH 9p, +11/11q+, -14/14q-, -15 and -18/18q-. Of these, -9/9p-/cnLOH 9p was significantly associated with higher grade in both the Mayo and TCGA cohorts (p = 8.3 x 10-10 and 0.018, respectively). In the TCGA cohort the presence of >10 CNVs or +11/11q+ was associated with a poorer survival (p = 0.016 and 0.006, respectively). CONCLUSIONS CNB is significantly associated with WHO grade in IDH-mutant, 1p/19q co-deleted oligodendrogliomas. The presence of a significantly elevated CNB in some WHO grade II tumors may be suspicious for the presence of unappreciated grade III histologic features. Longer follow-up will be necessary to determine if CNB or single CNVs are associated with survival.

The specific effect of TDP-43 pathology on grey matter volume in individuals without frontotemporal lobar degeneration is unclear. Bejanin et al. reveal a major and independent contribution of TDP-43 to neurodegeneration and shed light on the regional distribution of TDP-43-related atrophy in older adults.