Characterization of pseudoprogression in patients with glioblastoma: is histology the gold standard?

Pseudoprogression (psPD) refers to an increase in size or appearance of new areas of MRI contrast enhancement soon after completing chemoradiation, timely diagnosis of which has been a challenge. Given that tissue sampling of the MRI changes would be expected to accurately distinguish psPD from true progression when MRI changes are first seen, we examined the utility of surgery in diagnosing psPD and influencing patient outcome. We retrospectively reviewed data from adults with GBM who had MRI changes suggestive of progression within 3 months of chemoRT; of these, 34 underwent surgical resection. Three subsets-tumor, psPD or mixed-were identified based on histology and immunohistochemistry in the surgical group and by imaging characteristics in the nonsurgical group. A cohort of patients with stable disease post-chemoRT served as control. PFS and OS were determined using the Kaplan-Meier method and log rank analysis. Concordance for psPD between radiological interpretation and subsequent histological diagnosis was seen in only 32% of cases (11/34) 95%CI 19-49%. A large proportion of patients had a histologically "mixed" pattern with tumor and treatment effect. No significant differences in PFS or OS were seen among the three subtypes. Surgical sampling and histologic review of MRI changes after chemoRT may not serve as a gold standard to distinguish psPD from true progression in GBM patients. Refinement of the histological criteria, careful intraoperative selection of regions of interest and advanced imaging modalities are needed for early differentiation of PsPD from progression to guide clinical management.

Anaplastic oligodendroglioma involving the subcutaneous tissue of the scalp: report of an exceptional case and review of the literature.

Anaplastic oligodendroglioma [AO, World Health Organization (WHO) grade III] is an uncommon but aggressive tumor of the central nervous system that typically arises in adults. Clinically, patients present with seizures, and the prognosis is considered poor. Metastatic spread is extremely rare. We report an exceptional case of AO with extracranial scalp involvement, which arose in a patient with recurrent primary AO of the brain after chemoradiation, multiple cranial surgical resections, and subsequent scalp reconstruction. On histopathology, the subcutaneous tissue of the scalp contained several clusters and infiltrating cords of relatively small, epithelioid cells with hyperchromatic nuclei, scant eosinophilic cytoplasm, and perinuclear halos, which gave the cells a characteristic fried-egg appearance. By immunohistochemistry, the lesional cells were positive for glial fibrillary acidic protein and S-100. It is likely that surgical implantation and direct extracranial extension after craniotomy were the mechanisms responsible for dissemination of the patient's tumor.

IGFBP2 is a candidate biomarker for Ink4a-Arf status and a therapeutic target for high-grade gliomas.

The levels of insulin-like growth factor-binding protein 2 (IGFBP2) are elevated during progression of many human cancers. By using a glial-specific transgenic mouse system (RCAS/Ntv-a), we reported previously that IGFBP2 is an oncogenic factor for glioma progression in combination with platelet-derived growth factor-beta (PDGFB). Because the INK4a-ARF locus is often deleted in high-grade gliomas (anaplastic oligodendroglioma and glioblastoma), we investigated the effect of the Ink4a-Arf-null background on IGFBP2-mediated progression of PDGFB-initiated oligodendroglioma. We demonstrate here that homozygous deletion of Ink4a-Arf bypasses the requirement of exogenously introduced IGFBP2 for glioma progression. Instead, absence of Ink4a-Arf resulted in elevated endogenous tumor cell IGFBP2. An inverse relationship between p16(INK4a) and IGFBP2 expression was also observed in human glioma tissue samples and in 90 different cancer cell lines by using Western blotting and reverse-phase protein lysate arrays. When endogenous IGFBP2 expression was attenuated by an RCAS vector expressing antisense IGFBP2 in our mouse model, a decreased incidence of anaplastic oligodendroglioma as well as prolonged survival was observed. Thus, p16(INK4a) is a negative regulator of the IGFBP2 oncogene. Loss of Ink4a-Arf results in increased IGFBP2, which contributes to glioma progression, thereby implicating IGFBP2 as a marker and potential therapeutic target for Ink4a-Arf-deleted gliomas.

Aligning the Central Brain Tumor Registry of the United States (CBTRUS) histology groupings with current definitions.

Background: The Central Brain Tumor Registry of the United States (CBTRUS) uses a histology grouping model based on the World Health Organization (WHO) classifications to group records for clinically relevant statistical reporting. Newly identified genetic markers more accurately stratify patients than histology alone and were incorporated into the 2016 update to the WHO Classification. Methods: CBTRUS and consulting neuropathologists reviewed and aligned histology groupings with the 2016 WHO update. "Obsolete" (terms not currently in use) histology nomenclature along with their International Classification of Disease, Oncology 3rd edition (ICD-O-3) codes were identified, some histologies were reclassified to 2016 WHO, and new codes found in 2016 WHO were incorporated. An evaluation of the frequency of histology codes affected in the realignment process, and incidence and survival pre- and post-realignment was conducted. Results: After review, 67 codes were noted as obsolete, 51 codes were reclassified, and 12 new codes were incorporated. Histology groups most affected were mesenchymal tumors and neuronal/mixed neuronal-glial tumors. Reorganization resulted in 2588 (0.65%) cases with grouping reassignment or reporting change, indicating that the 2016 WHO Classification revision has impacted the collection and reporting of primary brain and other CNS tumors. Conclusion: This work demonstrates the need to be responsive to changes in classification and coding in order to ensure the most up-to-date and accurate statistics for brain and CNS tumors. This will require collaboration from all stakeholders within the brain tumor community, so to have the ability to reconcile clinical practices and surveillance requirements.

IIp45 inhibits cell migration through inhibition of HDAC6.

IIp45 (aka MIIP) is a newly discovered gene whose protein product inhibits cell migration. HDAC6 is a class IIb deacetylase that specifically deacetylates alpha-tubulin, modulates microtubule dynamics, and promotes cell migration. A yeast two-hybrid assay using IIp45 as bait identified HDAC6 protein as a binding partner of IIp45. This physical interaction of the two functionally antagonistic proteins was confirmed by glutathione S-transferase pulldown assay and co-immunoprecipitation assay in human cells. Serial deletion constructs of HDAC6 were used to characterize the interaction of HDAC6 and IIp45, and this analysis found that the two catalytic domains of HDAC6 protein are required for IIp45 binding. We examined the protein expression patterns of IIp45 and HDAC6 in glioma tissues. Elevated protein levels of HDAC6 were found in high grade glioma samples, in contrast to the decreased protein expression of IIp45. The potential negative regulation of HDAC6 expression by IIp45 was confirmed in cell lines with altered IIp45 expression by constitutive overexpression or small interfering RNA knockdown. Protein turnover study revealed that overexpression of IIp45 significantly reduces the intracellular protein stability of endogenous HDAC6, indicating a possible mechanism for the negative regulation of HDAC6 by IIp45. Results from the HDAC activity assay demonstrated that overexpressed IIp45 effectively decreases HDAC6 activity, increases acetylated alpha-tubulin, and reduces cell migration. The increased cell migration resulting from siIIp45 knockdown was significantly reversed by co-transfection of siHDAC6. Thus, we report here for the first time a novel mechanism by which IIp45 inhibits cell motility through inhibition of HDAC6.

99mTc-sestamibi scan differentiates tumor from other contrast enhancing tissue in choroid plexus tumors.

Choroid plexus tumors are rare brain tumors which account for 0.4% to 0.6% among brain tumors. Tumor resection is known to be of large prognostic impact, and re-resection of residual tumors is a part of standard care. However, after multiple resections it can become difficult to differentiate tumor from reactive tissue. 99mTC-sestamibi scans may assist in differentiating neoplastic (99mTC-sestamibi positive) from non-neoplastic tissue (99mTC-sestamibi negative). Previous literature showed sestamibi to be helpful in detecting residual choroid plexus tumors resulting in further resection. Here, we report the first case to show that sestamibi scans can also help with the opposite decision.

Evaluating quality in clinical cancer research: the M.D. Anderson Cancer Center experience.

BACKGROUND: Despite the unquestionable importance of clinically oriented research designed to test the safety and efficacy of new therapies in patients with malignant disease, there is limited information regarding strategies to evaluate the quality of such efforts at academic institutions. METHODS: To address this issue, a committee of senior faculty at the University of Texas M.D. Anderson Cancer Center established specific criteria by which investigators from all departments engaged in clinical research could be formally evaluated. Scoring criteria were established and revised based on the results of a pilot study. Beginning in January 2004, the committee evaluated all faculty involved in clinical research within 35 departments. Scores for individual faculty members were assigned on a scale of 1 (outstanding) to 5; a score of 3 was set as the standard for the institution. Each department also received a score. The results of the evaluation were shared with departmental chairs and the Chief Academic Officer. RESULTS: 392 faculty were evaluated. The median score was 3. Full professors more frequently received a score of 1, but all faculty ranks received scores of 4 and 5. As a group, tenure/tenure track faculty achieved superior scores compared to nontenure track faculty. CONCLUSIONS: Based on our experience, we believe it is possible to conduct a rigorous consensus-based evaluation of the quality of clinical cancer research being conducted at an academic medical center. It is reasonable to suggest such evaluations can be used as a management tool and may lead to higher-quality clinical research.

Issues of diagnostic review in brain tumor studies: from the Brain Tumor Epidemiology Consortium.

Epidemiologists routinely conduct centralized single pathology reviews to minimize interobserver diagnostic variability, but this practice does not facilitate the combination of studies across geographic regions and institutions where diagnostic practices differ. A meeting of neuropathologists and epidemiologists focused on brain tumor classification issues in the context of protocol needs for consortial studies (http://epi.grants.cancer.gov/btec/). It resulted in recommendations relevant to brain tumors and possibly other rare disease studies. Two categories of brain tumors have enough general agreement over time, across regions, and between individual pathologists that one can consider using existing diagnostic data without further review: glioblastomas and meningiomas (as long as uniform guidelines such as those provided by the WHO are used). Prospective studies of these tumors benefit from collection of pathology reports, at a minimum recording the pathology department and classification system used in the diagnosis. Other brain tumors, such as oligodendroglioma, are less distinct and require careful histopathologic review for consistent classification across study centers. Epidemiologic study protocols must consider the study specific aims, diagnostic changes that have taken place over time, and other issues unique to the type(s) of tumor being studied. As diagnostic changes are being made rapidly, there are no readily available answers on disease classification issues. It is essential that epidemiologists and neuropathologists collaborate to develop appropriate study designs and protocols for specific hypothesis and populations.

The Utility of Expert Diagnosis in Surgical Neuropathology: Analysis of Consultations Reviewed at 5 National Comprehensive Cancer Network Institutions.

The aim of this study was to characterize the type and degree of discrepancies between non-expert and expert diagnoses of CNS tumors to identify the value of consultations in surgical neuropathology. Neuropathology experts from 5 National Comprehensive Cancer Network (NCCN) member institutions participated in the review of 1281 consultations selected based on inclusion criteria. The consultation cases were re-reviewed at the NCCN headquarters to determine concordance with the original diagnoses. Among all consultations, 249 (19.4%) were submitted for expert diagnoses without final diagnoses from the submitting institution. Within the remaining 1032 patients, the serious/major discrepancy rate was 4.8%, and less serious and minor discrepancies were seen in 19.4% of the cases. The discrepancy rate was higher among patients who were referred to NCCN institutions for consultation compared to those who were referred for treatment only. The discrepancy rates, patient demographics, type of consultations and submitting institutions varied among participating NCCN institutions. Expert consultations identified a subset of cases with significant diagnostic discrepancies, and constituted the initial diagnoses in some cases. These data indicate that expert consultations in glial tumors and all types of pediatric CNS tumors can improve accurate diagnosis and enable appropriate management.

Glioblastoma-infiltrated innate immune cells resemble M0 macrophage phenotype.

Glioblastomas are highly infiltrated by diverse immune cells, including microglia, macrophages, and myeloid-derived suppressor cells (MDSCs). Understanding the mechanisms by which glioblastoma-associated myeloid cells (GAMs) undergo metamorphosis into tumor-supportive cells, characterizing the heterogeneity of immune cell phenotypes within glioblastoma subtypes, and discovering new targets can help the design of new efficient immunotherapies. In this study, we performed a comprehensive battery of immune phenotyping, whole-genome microarray analysis, and microRNA expression profiling of GAMs with matched blood monocytes, healthy donor monocytes, normal brain microglia, nonpolarized M0 macrophages, and polarized M1, M2a, M2c macrophages. Glioblastoma patients had an elevated number of monocytes relative to healthy donors. Among CD11b+ cells, microglia and MDSCs constituted a higher percentage of GAMs than did macrophages. GAM profiling using flow cytometry studies revealed a continuum between the M1- and M2-like phenotype. Contrary to current dogma, GAMs exhibited distinct immunological functions, with the former aligned close to nonpolarized M0 macrophages.

Phase I trial of adenovirus-mediated p53 gene therapy for recurrent glioma: biological and clinical results.

PURPOSE: Advances in brain tumor biology indicate that transfer of p53 is an alternative therapy for human gliomas. Consequently, we undertook a phase I clinical trial of p53 gene therapy using an adenovirus vector (Ad-p53, INGN 201). MATERIALS AND METHODS: To obtain molecular information regarding the transfer and distribution of exogenous p53 into gliomas after intratumoral injection and to determine the toxicity of intracerebrally injected Ad-p53, patients underwent a two-stage approach. In stage 1, Ad-p53 was stereotactically injected intratumorally via an implanted catheter. In stage 2, the tumor-catheter was resected en bloc, and the postresection cavity was treated with Ad-p53. This protocol provided intact Ad-p53-treated biologic specimens that could be analyzed for molecular end points, and because the resection cavity itself was injected with Ad-p53, patients could be observed for clinical toxicity. RESULTS: Of fifteen patients enrolled, twelve underwent both treatment stages. In all patients, exogenous p53 protein was detected within the nuclei of astrocytic tumor cells. Exogenous p53 transactivated p21CIP/WAF and induced apoptosis. However, transfected cells resided on average within 5 mm of the injection site. Clinical toxicity was minimal and a maximum-tolerated dose was not reached. Although anti-adenovirus type 5 (Ad5) titers increased in most patients, there was no evidence of systemic viral dissemination. CONCLUSION: Intratumoral injection of Ad-p53 allowed for exogenous transfer of the p53 gene and expression of functional p53 protein. However, at the dose and schedule evaluated, transduced cells were only found within a short distance of the injection site. Although toxicity was minimal, widespread distribution of this agent remains a significant goal.

Preradiation chemotherapy in primary high-risk brainstem tumors: phase II study CCG-9941 of the Children's Cancer Group.

PURPOSE: This Children's Cancer Group group-wide phase II trial evaluated the efficacy and toxicity of two chemotherapy arms administered before hyperfractionated external-beam radiotherapy (HFEBRT). PATIENTS AND METHODS: Thirty-two patients with newly diagnosed brainstem gliomas were randomly assigned to regimen A and 31 to regimen B. Regimen A comprised three courses of carboplatin, etoposide, and vincristine; regimen B comprised cisplatin, etoposide, cyclophosphamide, and vincristine. Both arms included granulocyte colony-stimulating factor. Patients were evaluated by magnetic resonance imaging after induction chemotherapy and HFEBRT at a dose of 72 Gy. RESULTS: Ten percent +/- 5% of regimen A patients objectively responded to chemotherapy. For combined induction and radiotherapy, 27% +/- 9% of patients improved. The neuroradiographic response rate for regimen B was 19% +/- 8% for chemotherapy and 23% +/- 9% after HFEBRT. Response rates were not statistically significant between regimens after induction or chemotherapy/HFEBRT. Event-free survival was 17% +/- 5% (estimate +/- SE) at 1 year and 6% +/- 3% at 2 years. Survival was significantly longer among patients who responded to chemotherapy (P <.05). Among patients who received regimen A induction, grades 3 and 4 leukopenia were observed in 50% to 65%, with one toxicity-related death. For regimen B, severe leukopenia occurred in 86% to 100%, with febrile neutropenia in 48% to 60% per course. CONCLUSION: Neither chemotherapy regimen meaningfully improved response rate, event-free survival, or overall survival relative to previous series of patients with brainstem gliomas who received radiotherapy with or without chemotherapy.

Molecular voting for glioma classification reflecting heterogeneity in the continuum of cancer progression.

Gliomas, the most common brain tumors, are generally categorized into two lineages (astrocytic and oligodendrocytic) and further classified as low-grade (astrocytoma and oligodendroglioma), mid-grade (anaplastic astrocytoma and anaplastic oligodendroglioma), and high-grade (glioblastoma multiforme) based on morphological features. A strict classification scheme has limitations because a specific glioma can be at any stage of the continuum of cancer progression and may contain mixed features. Thus, a more comprehensive classification based on molecular signatures may reflect the biological nature of specific tumors more accurately. In this study, we used microarray technology to profile the gene expression of 49 human brain tumors and applied the k-nearest neighbor algorithm for classification. We first trained the classification gene set with 19 of the most typical glioma cases and selected a set of genes that provide the lowest cross-validation classification error with k=5. We then applied this gene set to the 30 remaining cases, including several that do not belong to gliomas such as atypical meningioma. The results showed that not only does the algorithm correctly classify most of the gliomas, but the detailed voting results also provide more subtle information regarding the molecular similarities to neighboring classes. For atypical meningioma, the voting was equally split among the four classes, indicating a difficulty in placement of meningioma into the four classes of gliomas. Thus, the actual voting results, which are typically used only to decide the winning class label in k-nearest neighbor algorithms, provide a useful method for gaining deeper insight into the stage of a tumor in the continuum of cancer development.

Phase III randomized study of postradiotherapy chemotherapy with combination alpha-difluoromethylornithine-PCV versus PCV for anaplastic gliomas.

PURPOSE: In the current study, we sought to determine whether the addition of DFMO (alpha-difluoromethyl ornithine; eflornithine), an inhibitor of ornithine decarboxylase, to a nitrosourea-based therapy procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, vincristine (PCV) would be more effective as a postirradiation adjuvant therapy for anaplastic gliomas (AG) than PCV alone. PATIENTS AND METHODS: After conventional radiation therapy, 249 AG patients were randomized to receive either DFMO-PCV (125 patients) or PCV alone (124 patients), with survival being the primary endpoint and progression-free survival being an important secondary endpoint. The starting dosage of DFMO was 3 grams/m(2) p.o. q. 8 h for 14 days before and 4 weeks after 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea; PCV was administered as described previously (1). Clinical and radiological (gadolinium-enhanced magnetic resonance imaging) follow-ups were nominally at the end of each 6- or 8-week cycle (PCV at 6 weeks; DFMO-PCV at 8 weeks). Laboratory evaluations for hematological and other adverse effects were at 2-week intervals. RESULTS: In the DFMO-PCV arm, there were 114 evaluable patients with 78.1% anaplastic astrocytoma (AA), 3.5% anaplastic oligoastrocytoma (AOA), 14% anaplastic oligodendroglioma (AO), and 4.4% other malignant gliomas. These histological groupings were comparable with those of the 114 patients in the PCV arm: (a) 69.3% AA; (b) 7% AOA; (c) 21.1% AO; and (d) 2.6% malignant gliomas. Although improved survival estimates for the DFMO-PCV treatment group persisted over the course of the study, analysis of survival differences over the entire follow-up period did not yield significance (P = 0.11). However, careful analysis of the corresponding hazard and hazard ratio functions indicated that the real treatment difference was limited to the first 24 months of follow-up (P = 0.02). The median progression-free survival for the two treatment groups, as measured from postradiotherapy registration, was 71.1 months for the DFMO-PCV arm and 37.5 months for the PCV-only arm. Median survival, measured from registration, was 75.8 and 61.1 months, respectively, for the DFMO-PCV and PCV arms. The treatment effect persisted when the AA histology was separated from AO and AOA histologies. This effect persisted even after adjusting for the covariates of age, Karnofsky performance status, and extent of surgery. There was a statistically significant increase in grade 3 adverse events for diarrhea and anemia associated with DFMO-PCV. Grade 3 or 4 adverse events of nausea, ototoxicity, and thrombocytopenia were not significantly increased among groups. CONCLUSIONS: The addition of DFMO to the nitrosourea-based PCV regimen in this Phase III study demonstrated a sustained benefit in survival probabilities for AG patients but not in the corresponding hazard rates. Survival analysis from registration found a DFMO-PCV median survival of 6.3 years (49 of 114 events), whereas that for PCV alone was 5.1 years (55 of 114 events). The hazard function demonstrated a difference over the first 2 years of study (hazard ratio 0.53, P = 0.02) but not after 2 years (hazard ratio 1.06, P = 0.84), supporting the conclusion that DFMO adds to the survival advantage of PCV chemotherapy for AG patients by direct temporal interaction with PCV.

Adult brainstem gliomas: Correlation of clinical and molecular features.

BACKGROUND: Brainstem gliomas are rare in adults and overall have superior survival outcomes compared to pediatric brainstem gliomas. PATIENTS AND METHODS: We conducted a retrospective data and tissue analysis of all adult patients (≥ 18 years old) with World Health Organization (WHO) Grade II, III, and IV brainstem gliomas in the University of Texas MD Anderson Cancer Center institutional database from 1990 to 2012. RESULTS: We identified 143 cases in adults ages 18 and over. There were 28 glioblastomas, 43 anaplastic astrocytomas, 15 diffuse astrocytomas, and 11 gliomas not otherwise specified, and in 46 cases the diagnosis was made radiographically. 128 (89.5%) cases were classified radiographically as diffuse and of the focal tumors, 9 of the 15 were WHO Grade III or IV tumors. Increasing tumor grade and contrast enhancement were associated with significantly reduced overall survival. The median overall survival for the entire cohort was 32.1 months similar to previously published studies. Two of 25 grade II and III tumors, and 1 of 17 glioblastomas had IDH1 mutations on immunohistochemical testing. Nine cases had sufficient tissue for mutation profiling, 1 case had a BRAF V600E mutation and 2 had 2 PIK3CA mutations. CONCLUSIONS: Survival outcomes for adult WHO Grade II to IV brainstem gliomas were similar to supratentorial IDH1 wild-type tumors of similar grade and histology. Potentially actionable mutations can be identified from small biopsy samples in a subset of adult brainstem gliomas.

Molecular classification of human diffuse gliomas by multidimensional scaling analysis of gene expression profiles parallels morphology-based classification, correlates with survival, and reveals clinically-relevant novel glioma subsets.

There are several currently employed classification systems for diffuse gliomas that sort tumors based on histological features. Contemporary molecular techniques, however, offer the promise of improved tumor classification and resultant patient stratification for treatment and prognosis. In particular, gene expression profiling has shown exceptional promise for providing an alternative and more objective molecular approach to glioma classification. In this study, we used cDNA array technology to profile the gene expression of 30 primary human glioma tissue samples comprising 4 different glioma subtypes as defined by current World Health Organization (WHO 2000) criteria: glioblastoma (GM, WHO grade IV), anaplastic astrocytoma (AA, WHO grade III), anaplastic oligodendroglioma (AO, WHO grade III), and oligodendroglioma (OL, WHO grade II). Gene expression data alone were used to group the tumors using multidimensional scaling, which is an unsupervised statistical method. Results show that impressive separation of the 4 glioma subtypes can be achieved solely on the basis of molecular data. In addition, a subcluster of 3 glioblastomas was identified as distinct from other GMs and from the oligodendroglial tumors. These 3 patients have shown extended survival compared to other GMs in the study. Survival analysis of the full data set revealed a good correlation with the molecular classification. Results of this proof-of-principle study demonstrate that molecular profiling alone can recapitulate conventional histologic classification and grading with high fidelity. In addition, results show that the molecular approach to tumor classification can generate clinically meaningful patient stratification, and, more importantly, is an efficient class-discovery tool for human gliomas, permitting the identification of previously unrecognized, clinically relevant tumor subsets.

Consensus Conference on Brain Tumor Definition for registration. November 10, 2000.

The Consensus Conference on Brain Tumor Definition was facilitated by the Central Brain Tumor Registry of the United States and held on November 10, 2000, in Chicago, Illinois, to reach multidisciplinary agreement on a standard definition of brain tumors for collecting and comparing data in the U.S. The Brain Tumor Working Group, convened in 1998 to determine the status of brain tumor collection in the U.S., outlined 4 recommendations of which the first 2 guided the discussion for the Consensus Conference: (1) standardization of a definition of primary brain tumors that is based on site alone, rather than on site and behavior, and that can be used by surveillance organizations in collecting these tumors; and (2) development of a reporting scheme that can be used for comparing estimates of primary brain tumors across registries. Consensus was reached on the collection of all primary brain tumor histologies found and reported in the brain or CNS ICD-O site codes (C70.0-C72.9 and C75.1-C75.3), including those coded benign and uncertain as well as those coded malignant. In addition, a comprehensive listing of histologies occurring in the brain and CNS, based on the CBTRUS grouping scheme, was formulated to provide a template for reporting in accordance with the second recommendation of the Brain Tumor Working Group. With consensus achieved on the first 2 recommendations, the stage is set to move forward in estimating additional resources necessary for the collection of these tumors, including funding, training for cancer registrars, identifying quality control measures, and developing computerized edit checks, as outlined in the last 2 recommendations of the Brain Tumor Working Group.

The mitosis-specific antibody anti-phosphohistone-H3 (PHH3) facilitates rapid reliable grading of meningiomas according to WHO 2000 criteria.

Mitotic figure (MF) counting is the most objective criterion for grading of meningiomas according to the 2000 World Health Organization (WHO) classification. However, the search for the area(s) of highest mitotic activity is tedious, and there is high interobserver variability in differentiating MF from apoptotic cells. We tested the utility of the mitosis-specific marker phosphohistone-H3 (PHH3) to enhance rapid recognition of MFs and quick reliable grading of meningioma. Fifty-four archival meningiomas (26 benign, 20 atypical, 8 anaplastic) were reclassified according to current WHO criteria. PHH3-immunostained MFs were counted the same way as in hematoxylin and eosin-stained sections. Anti-PHH3-labeled MFs were easily seen and permitted quick identification of the area(s) of highest mitotic activity. Count results (mean) show a strong correlation between both methods: benign, hematoxylin and eosin 1.4, PHH3 2.2; atypical, hematoxylin and eosin 9.0, PHH3 15.9; anaplastic, hematoxylin and eosin 22.4, PHH3 34.1. PHH3 counting yielded greater sensitivity and in 12 cases (22.2%) suggested a change in grade (increased 9; lowered 3). All cases in which PHH3 lowered the grade were from older blocks, suggesting a loss of antigen preservation. PHH3 immunostaining facilitates the rapid reliable grading of meningiomas by focusing attention on the most mitotically active areas and by allowing easy and objective differentiation of MFs from apoptotic nuclei.

Unusual small choroid plexus cyst obstructing the foramen of monroe: case report.

This is a case report of unusual case of choroid plexus cyst at the right foramen of Monro in the anterior third ventricle that caused unilateral obstructive hydrocephalus. The value of small-FOV thin-section MR imaging in the diagnosis of small lesions of the foramen of Monroe is demonstrated. The immunohistochemical findings in choroid epithelial cysts in comparison with those of other types of cysts at this location are discussed.