World Health Organization Grade II-III Research Articles

208 Proposed Revision to Meningioma Classification System to Utilize Methylation Status of EGFR

INTRODUCTION: Meningiomas are among the most common brain tumors, making up about 13-26% of all intracranial tumors. They arise from the arachnoid cap and most commonly appear along the lining of the skull base and the venous cavities. The current classification system for meningiomas was established by the World Health Organization (WHO) and designates tumors as WHO grades I-III depending on histological characteristics. While WHO grade does strongly correlate with tumor recurrence, it has serious shortcomings. In particular, some WHO grade I tumors, which are supposedly benign, end up becoming highly aggressive and recurrent. A more accurate method of classifying tumors to provide better insight into prognosis is needed. Epidermal growth factor receptor (EGFR) is a highly expressed protein in meningiomas that has been linked to angiogenesis and other tumor-promoting properties. METHODS: A retrospective chart analysis was first performed to gather clinical and demographic information for 291 patients diagnosed with meningioma and treated with surgical intervention. Primary tissue samples were available for 25 patients and an analysis of EGFR promoter methylation status was performed. RESULTS: A significant association was found between EGFR promoter methylation and tumor recurrence (p = 0.02176*). Of note, there was a 100% positivity rate for EGFR hypermethylation in patients with tumor progression within 10 months post-surgery (n =9). Every tumor sample classified as WHO grade II-III had EGFR hypermethylation (n = 10), as well as 7 out of the 15 WHO grade I tumors. In total, over half of the meningioma patients with EGFR hypermethylation had tumor progression within 10 months of surgery. CONCLUSION: These findings suggest that assessing methylation status of EGFR could be a valuable tool for identifying highly aggressive meningiomas and determining patient prognosis early in the game. This would allow for improved postoperative treatment regimens to be developed, reducing the chances of tumor progression.

Effect of Postoperative Radiation Therapy Timing on Survival in Pediatric and Young Adult Ependymoma

PurposePostoperative radiation therapy (RT) is commonly used for World Health Organization grade II-III intracranial ependymoma. Clinicians generally aim to begin RT ≤5 weeks after surgery, but postoperative recovery and need for second look surgery can delay the initiation of adjuvant therapy. On ACNS 0831, patients were required to enroll ≤8 weeks after initial surgery and begin adjuvant therapy within 3 weeks after enrollment. The purpose of this study was to determine the optimal timing of RT after surgery. Methods and MaterialsThe National Cancer Database was queried for patients (aged 1-39 years) with localized World Health Organization grade II-III intracranial ependymoma treated with surgery and postoperative RT. Overall survival (OS) curves were plotted based on RT timing (≤5 weeks, 5-8 weeks, and >8 weeks after surgery) and were compared by log-rank test. Factors associated with OS were identified by multivariate analysis. After 2009, complete data were available on whether patients underwent gross total resection or subtotal resection. Planned subset analysis was performed to examine the effect of RT timing on OS in patients with known extent of resection. ResultsIn the final analytical data set of 1043 patients, no difference in 3-year OS was observed in patients who initiated RT ≤5 weeks, 5 to 8 weeks, and >8 weeks after surgery (89.8% vs 89.1% vs 88.4%; P = .796). On multivariate analysis, grade III tumors (hazard ratio, 2.752; 95% confidence interval, 1.969-3.846, P < .001) and subtotal resection (hazard ratio, 2.253; 95% confidence interval, 1.405-3.611, P < .001) were significantly associated with reduced OS. Timing of RT, total RT dose, age, and other factors were not significant. These findings were affirmed in the subset of patients treated between 2010 and 2016, when extent of resection was routinely recorded. ConclusionsDelayed postoperative RT was not associated with inferior survival in patients with intracranial ependymoma. Delayed RT initiation may be acceptable in patients who require longer postoperative recovery or referral to an appropriate RT center, but should be minimized whenever practical.

PATH-35. A SCALABLE MOLECULARLY INTEGRATED CLASSIFIER FOR MENINGIOMA OUTPERFORMS WHO CLASSIFICATION

Abstract The clinical behavior of meningiomas often belies their histopathologic grade. Increasing data suggest that molecular features augment classic World Health Organization (WHO) classification in predicting recurrent risk. We investigated the influence of histopathology, chromosome copy number, and treatment on meningioma outcome to construct a simple, scalable, molecularly integrated classifier. METHODS: We analyzed 684 meningiomas with genome-wide chromosomal copy-number profiling for clinical features, pre-/post-operative tumor volume, histopathology, and recurrence. We devised a point-based molecularly-integrated classification system (IC 1-3), incorporating mitotic count and nine common molecular alterations consistently associated with risk of recurrence across four independent statistical tests. We used brier curves, time-dependent area-under-the-curve, and average precision to assess model performance. We added treatment variables, including primary or recurrent status, tumor size, and extent of resection, to the Integrated class to formulate a nomogram of recurrence risk at 5 years. RESULTS: The Integrated Class significantly associated with recurrence in a multivariate model (IC Class 2 vs 1: HR 3.60, 95% CI 2.19-5.91; Class 3 vs 1: HR 5.15, 95% CI 3.28-8.09) and outperformed WHO grade in predicting recurrence (by integrated brier score, 0.093 vs 0.178, internally and independently validated). WHO Grade I and IC-1 exhibited 86% concordance, 31.5% between Grade II and IC-2, and 64% between Grade III and IC-3. WHO grade I meningiomas with IC 2-3 fared significantly worse than WHO grade II-III meningiomas with IC-1 designation. Each additional molecular feature incrementally strengthens the classifier, allowing for application of single-arm FISH or combinatorial genome-wide signatures based on available resources. Intriguingly, receipt of adjuvant radiation in newly diagnosed WHO Grade II-III or IC 2-3 meningiomas was associated with greater propensity for recurrence, after controlling for extent of resection. CONCLUSION: We present a scalable, molecularly-integrated classification for meningioma that better predicts recurrence compared to classic histopathologic grades to aid in clinical management.

TMOD-04. CHARACTERIZATION OF MUTANT IDH1 OLIGODENDROGLIOMAS

Abstract Gliomas are the most common primary central nervous system malignancy in adults, but the molecular mechanisms responsible for their development and progression are not fully understood. Recent genomic analysis of World Health Organization grade II-III gliomas identifies 3 molecular subtypes of low grade glioma: no IDH mutation; IDH mutation without 1p/19q co-deletion; and IDH mutation with 1p/19q co-deletion. The latter, categorized as oligodendroglioma, commonly expresses loss of function mutations in CIC, FUBP1, and activation of PIK3CA. However, it is unknown if any of these mutations are sufficient to promote glioma development in cooperation with mutant IDH. Furthermore, research in oligodendroglioma is hampered by the lack of in vivo models of this specific glioma subtype. By utilizing the established RCAS/TVA somatic cell gene delivery method, mutant IDH1 can be expressed in the brains of mice. The tumorgenicity of other mutated genes associated with oligodendroglioma can be determined using additional methods such as conditional gene knockout and in vivo CRISPR-Cas9 mediated deletion. A mouse model for oligodendroglioma may identify new targetable genetic drivers of oligodendroglioma that will be useful for testing novel therapeutic strategies.

Meningiomas Display a Specific Immunoexpression Pattern in a Rostrocaudal Gradient: An Analysis of 366 Patients

Meningiomas are heterogeneous, with differences in anatomical, histopathological, and clinical characteristics. Such spatial variability in meningioma biology is thought to result from differences in the expression of critical developmental regulators. We hypothesized that the variability in meningioma biology would follow gradients such as in embryology and tested a cohort of 366 meningiomas for histopathological and immunohistochemical gradients. The medical records from 366 patients treated for meningiomas from 2003 to 2016 were retrospectively analyzed for age, gender, anatomical localization, recurrence-free survival, overall survival, histopathological diagnosis, and immunohistochemistry findings for 6 markers: epithelial membrane antigen (EMA), progesterone receptor (PR), CD34, S100, p53, and Ki-67 labeling index. EMA, PR, S100, p53, and CD34 were expressed in 94%, 73%, 49%, 26%, and 23% of the tumors, respectively. p53 expression correlated positively with Ki-67 and World Health Organization (WHO) grade (rτ= 0.31 and rτ= 0.4, respectively). PR positivity correlated inversely with S100, p53, Ki-67, and WHO grade (rτ=-0.19, rτ=-0.14, rτ=-0.15, and rτ=-0.16, respectively). All secretory meningiomas were positive for EMA and PR and negative for S100, and this pattern exhibited a rostrocaudal gradient. The overall proportion of EMA+PR+S100- cases was significantly lower in the cranial vault (30.3%) than in the skull base (45.89%; P= 0.021). The proportion of WHO grade II-III tumors was greater in cranial vault than in skull base meningiomas. Unsupervised methods detected an association between the anatomical location and tumor biology in meningiomas. Unlike the categorical associations that former studies had indicated, the present study revealed a rostrocaudal gradient in both the cranial vault and the skull base, correlating with human developmental biology.

Rapid progression to glioblastoma in a subset of IDH-mutated astrocytomas: a genome-wide analysis.

According to the recently updated World Health Organization (WHO) classification (2016), grade II-III astrocytomas are divided into IDH-wildtype and IDH-mutant groups, the latter being significantly less aggressive in terms of both progression-free and total survival. We identified a small cohort of WHO grade II-III astrocytomas that harbored the IDH1 R132H mutation, as confirmed by both immunohistochemistry and molecular sequence analysis, which nonetheless had unexpectedly rapid recurrence and subsequent progression to glioblastoma. Among these four cases, the mean time to recurrence as glioblastoma was only 16months and the mean total survival among the three patients who have died during the follow-up was only 31months. We hypothesized that these tumors had other, unfavorable genetic or epigenetic alterations that negated the favorable effect of the IDH mutation. We applied genome-wide profiling with a methylation array (Illumina Infinium Human Methylation 450k) to screen for genetic and epigenetic alterations in these tumors. As expected, the methylation profiles of all four tumors were found to match most closely with IDH-mutant astrocytomas. Compared with a control group of four indolent, age-similar WHO grade II-III astrocytomas, the tumors showed markedly increased levels of overall copy number changes, but no consistent specific genetic alterations were seen across all of the tumors. While most IDH-mutant WHO grade II-III astrocytomas are relatively indolent, a subset may rapidly recur and progress to glioblastoma. The precise underlying cause of the increased aggressiveness in these gliomas remains unknown, although it may be associated with increased genomic instability.

Aberrations in the Iron Regulatory Gene Signature Are Associated with Decreased Survival in Diffuse Infiltrating Gliomas.

Iron is a tightly regulated micronutrient with no physiologic means of elimination and is necessary for cell division in normal tissue. Recent evidence suggests that dysregulation of iron regulatory proteins may play a role in cancer pathophysiology. We use public data from The Cancer Genome Atlas (TCGA) to study the association between survival and expression levels of 61 genes coding for iron regulatory proteins in patients with World Health Organization Grade II-III gliomas. Using a feature selection algorithm we identified a novel, optimized subset of eight iron regulatory genes (STEAP3, HFE, TMPRSS6, SFXN1, TFRC, UROS, SLC11A2, and STEAP4) whose differential expression defines two phenotypic groups with median survival differences of 52.3 months for patients with grade II gliomas (25.9 vs. 78.2 months, p< 10−3), 43.5 months for patients with grade III gliomas (43.9 vs. 87.4 months, p = 0.025), and 54.0 months when considering both grade II and III gliomas (79.9 vs. 25.9 months, p < 10−5).

Phantosmia During Radiation Therapy

Phantosmia is an infrequently reported and poorly understood qualitative olfactory disorder characterized by the perception of a frequently unpleasant odor in the absence of an odorant stimulus. Peripheral phantosmia is hypothesized to involve abnormally active olfactory receptor neurons while central phantosmia is theorized to be the result of hyperactive neurons in the cortex. The authors present a case report that describes 2 patients with incomparable tumors and radiation fields who both experienced phantosmia featuring a halitosis-like odor during their courses of radiation therapy. Both the 6-year-old with diffuse intrinsic pontine glioma and the 15-year-old with World Health Organization grade II-III astrocytoma in the bifrontal lobes experienced significant distress and decreased quality of life during treatment because of the phantosmia, which resolved after completion of radiation therapy. To the best of the authors' knowledge, these are the first descriptions of phantosmia during focal or whole-brain radiation therapy.

Whole Genome Analysis From Microdissected Tissue Revealed Adult Supratentorial Grade II-III Gliomas Are Divided Into Clinically Relevant Subgroups by Genetic Profile

Gliomas are classified into pathologically defined subgroups. However, the tumors in the same entity could show varied 'clinical courses. Recently, various studies revealed that genetic analyses of gliomas can provide clinically relevant information. To investigate the correlation between genetic characterization and clinical information of adult supratentorial grade II-III gliomas to establish a genetic classification of these tumors. We analyzed the genetic profile of tumor samples microdissected from formalin-fixed archival tissue sections based on the defined selection criteria of tumor region using a comparative genomic hybridization method. We collected genetic and clinical data from 140 adult supratentorial gliomas of World Health Organization grade II-III and classified the tumors analyzed into subgroups according to chromosomal copy number aberrations. The relationship between histologic or genetic subclassification and clinical features was analyzed. The tumors were classified into subgroups based on the genetic profiles. Tumors with +7q and those with -1p/19q showed long progression-free survival, and loss of 10q in association with gain of 7p (+7/-10q) appeared to predict poor outcome. Most tumors with histologic diagnosis of glioblastoma showed +7/-10q; however, World Health Organization grade II-III gliomas contained a variety of genetic subgroups that correlated well with the clinical course, and this might explain why these tumors do not respond uniformly to therapies. Our pilot study suggests that care must be taken in clinical studies of these tumors because, unlike glioblastoma, grade II-III tumors may contain genetically distinct subgroups with different sensitivity to the therapies.

Metabolism and regional cerebral blood volume in autoimmune inflammatory demyelinating lesions mimicking malignant gliomas

Dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) and MR spectroscopy are thought to differentiate tumefactive autoimmune inflammatory demyelinating lesions from glial brain tumours. The aim of this work is to evaluate whether regional cerebral blood volume (rCBV), as well as choline (Cho), N-acetyl-aspartate (NAA) and myo-inositol (mIns) concentrations differ between tumefactive lesions and World Health Organization (WHO) grade II-III gliomas. Five patients with single autoimmune inflammatory demyelinating lesions and nine patients with WHO grade II and III gliomas were examined by DSC-MRI and by two-dimensional (2D) 1H MR spectroscopic imaging (1H-MRSI). rCBV values and metabolite concentrations were normalised to the respective values of the contralateral hemisphere. Normalised rCBV in the tumefactive lesions (mean 2.89, range 1.98-6.74) was in the some high level as in gliomas (mean 2.77, range 1.43-6.22). 1H-MRSI revealed increased normalised choline concentrations in five of six examinations of autoimmune lesions (mean 1.4, range 1.06-1.8) and in eight of nine gliomas (mean 1.35, range 0.92-1.73). Tumefactive autoimmune inflammatory demyelinating lesions not only have imaging appearance of gliomas but may also imitate marked increase of rCBV and Cho in WHO grade II-III gliomas.

Real-Time Quantitative PCR Analysis of Gene Dosages Reveals Gene Amplification in Low-Grade Oligodendrogliomas

Proto-oncogene amplification is an important alteration that is present in about 45% to 50% of high-grade human gliomas. We studied this mechanism in 8 genes (cyclin-dependent kinase-4 [CDK4], MDM2, MDM4, renin-angiotensin system-1, ELF3, GAC1, human epidermal growth factor receptor-2, and platelet-derived growth factor receptor-A gene) in a series of 40 oligodendrogliomas (World Health Organization (WHO) grade II, 21; WHO grade III, 13; and WHO grade II-III oligoastrocytomas, 6) using real-time quantitative polymerase chain reaction. Amplification of at least 1 of these genes was detected in 58% of samples (23/40). By histopathologic grade, 67% of grade II oligodendrogliomas (14/21), 46% of grade III anaplastic oligodendrogliomas (6/13), and 50% of mixed oligoastrocytomas (3/6) were positive for amplification of at least 1 gene. CDK4, MDM2, and GAC1 were the most frequently involved genes (12/40 [30%], 12/40 [30%], and 13/40 [33%], respectively). Our findings demonstrate gene amplification in low-grade samples indicating that it is an important alteration in the early steps of oligodendroglioma development and, therefore, might be considered a molecular mechanism leading to malignant progression toward anaplastic forms.