Perry, Arie

AbstractOligodendroglioma 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.

Abstract 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 W orld H ealth O rganization ( WHO ) classification of central nervous system tumors. To address this question, a meeting of neuropathologists with expertise in molecular diagnosis was held in H aarlem, the N etherlands, under the sponsorship of the I nternational S ociety of N europathology ( 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 ‐ H aarlem” 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.

Abstract Purpose: Malignant peripheral nerve sheath tumors (MPNST) are highly aggressive sarcomas with variable patient survival and few known prognostically relevant genomic biomarkers. To identify survival-associated genomic biomarkers, we performed high-resolution array-based comparative genomic hybridization (aCGH) on a large set of MPNSTs. Experimental Design: Candidate gene alterations identified by aCGH in 38 MPNSTs were validated at the DNA, RNA, and protein levels on these same tumors and an independent set of 87 MPNST specimens. Results: aCGH revealed highly complex copy number alterations, including both previously reported and completely novel loci. Four regions of copy number gain were associated with poor patient survival. Candidate genes in these regions include SOX5 (12p12.1), NOL1 and MLF2 (12p13.31), FOXM1 and FKBP1 (12p13.33), and CDK4 and TSPAN31 (12q14.1). Alterations of these candidate genes and several others of interest (ERBB2, MYC and TP53) were confirmed by at least 1 complementary methodology, including DNA and mRNA quantitative real-time PCR, mRNA expression profiling, and tissue microarray-based fluorescence in situ hybridization and immunohistochemistry. Multivariate analysis showed that CDK4 gain/amplification and increased FOXM1 protein expression were the most significant independent predictors for poor survival in MPNST patients (P < 0.05). Conclusions: Our study provides new and independently confirmed candidate genes that could serve as genomic biomarkers for overall survival in MPNST patients. Clin Cancer Res; 17(7); 1924–34. ©2011 AACR.

✓ The authors report on a patient without neurofibromatosis Type 1 or 2 (NF1 or NF2) and without evidence of schwannomatosis, who was found to have an unusual combination of nerve sheath tumors—a large cellular schwannoma and multifascicular involvement of a plexiform neurofibroma arising from the same site within the radial nerve and posterior cord of the infraclavicular brachial plexus. This case broadens the spectrum of combined pathological features of nerve sheath tumors. Genetic studies revealed a combined loss of neurofibromin and merlin in both regions and chromosome arm 22q deletion within the neurofibroma component only. The latter finding supports the suggestion that these were two different clonal neoplasms, and is consistent with a collision tumor pattern.

Purpose High-grade gliomas (HGGs; WHO grades 3-4) are highly diverse, with survival times ranging from months to years. WHO 2000 grading criteria for high-grade oligodendroglial neoplasms [anaplastic oligoastrocytoma (AOA) and anaplastic oligodendroglioma (AO)] remain subjective, and the existence of grade 4 variants is controversial. Patients and Methods Overall survival (OS) of 1,093 adult patients with a cerebral HGG newly diagnosed between 1990 and 2005 was analyzed by univariate and multivariate models for significance of the following factors: patient age, surgery type, year of diagnosis, endothelial proliferation, necrosis, oligodendroglial histology, treatment center, and chromosome 1p, 19q, 7p (EGFR), and 10q (PTEN) abnormalities by fluorescence in situ hybridization (FISH). Results Necrosis was a statistically significant predictor of poor OS on univariate and multivariate analyses in AOA but not in AO. Median OS for patients with necrotic AOA (22.8 months) was significantly worse than for patients with non-necrotic AOA (86.9 months; P < .0001) but was better than conventional glioblastomas (9.8 months; P < .0001). In addition to patient age, the following were significant independent prognostic factors (P ≤ .001): grade and surgery type for the entire HGG cohort; modified grade for AOA (3 v 4); and modified grade, 1p/19q codeletion status, and oligodendroglial histology for the 586 HGGs analyzed by FISH. Conclusion Stratification of AOA, but not of pure AO, into grades 3 and 4 on the basis of necrosis is prognostically justified and is more powerful than the current approach. Both routine histology and genetic testing provide independent, prognostically useful information.

PurposeAlthough rare overall, marginal zone B-cell lymphoma (MZBCL) is the most common primary low-grade CNS lymphoma reported in the literature. The aim of this study is to elucidate the biology and genetic features of this unusual tumor.Patients and MethodsFifteen CNS MZBCLs were studied clinically, pathologically, and genetically, including fluorescent in situ hybridization analyses with commercially available MALT1 and IgH break-apart and centromere 3, 7, 12, and 18 probes.ResultsCNS MZBCLs preferentially affect middle-aged women (female-to-male ratio, 4:1), with 93% presenting as dural-based masses mimicking meningioma. Ten patients with 1 to 7.6 years of follow-up after diagnosis showed no evidence of disease after radiation and/or chemotherapy. Like MZBCLs outside of the CNS, they consisted of CD20+, CD3−small B lymphocytes with varying degrees of plasmacytic differentiation and predominantly κ light-chain restriction (78%). Lymphoid follicles with follicular colonization were seen in three patients and deposition of amyloid was noted in samples from two patients, one of which was tumefactive. Neither Bcl-6 protein nor Epstein-Barr virus–encoded RNA was expressed. Trisomy 3 was detected in six of 12 patients, with no rearrangements of MALT1 or IgH and no trisomies of 7, 12, or 18 detected.ConclusionOur data suggest that intracranial MZBCL is an indolent primary CNS lymphoma that typically presents as a meningioma-like dural-based mass. Trisomy 3, but not MALT1 or IgH translocation, is a common genetic abnormality that may contribute to the pathogenesis of this CNS lymphoma.

Abstract OBJECTIVE AND IMPORTANCE Melanocytic colonization of nonpigmented extracranial tumors has been reported in adenocarcinomas, squamous cell carcinomas, skin appendage tumors, and dermatofibrosarcoma protuberans. To our knowledge, melanocytic colonization of a meningioma has not previously been described. CLINICAL PRESENTATION We report an unusual case of a 70-year-old African-American woman who presented with a large frontoparietal meningioma that extended through the calvarium. INTERVENTION Craniotomy with gross total resection of the tumor was performed. Histochemistry, immunocytochemistry, ultrastructural analysis, and molecular genetic study via fluorescence in situ hybridization confirmed melanocytic colonization of a meningothelial meningioma. CONCLUSION With the inclusion of meningothelial meningioma, the spectrum of tumors affected by melanocytic colonization continues to expand.

Abstract OBJECTIVE AND IMPORTANCE We report the first case of combined oligodendroglioma and pleomorphic xanthoastrocytoma. CLINICAL PRESENTATION A female college student and competitive cross-country runner presented to the Mayo Clinic at age 18 years with complaints of progressive headache and visual disturbances. Neuroimaging revealed a heavily calcified left parieto-occipital mass with focal enhancement and remodeling of the overlying calvarium. INTERVENTION A histological examination of the nearly gross total resection specimen disclosed a low-grade oligodendroglioma discretely abutting a superficially situated focus of pleomorphic xanthoastrocytoma. Ten months thereafter, a recurrence was suspected on the basis of the detection of a new focus of nodular enhancement. This lesion stabilized after radiation therapy, and the patient is well, without apparent residual disease 2.8 years after surgery. CONCLUSION This unique neoplasm is presumed to represent a collision tumor, its biological behavior being similar to that of oligodendroglioma alone. However, the possibility of an unusual, mixed oligoastrocytoma with pleomorphic xanthoastrocytoma as the astrocytic component cannot be excluded entirely. Potentially, both components have the capacity for recurrence and anaplastic transformation.