Scheithauer, Bernd W.

Object In clinical practice, schwannomas are among the most common types of nerve sheath tumors. Their clinical presentation, imaging characteristics, and operative features are well known. Over the past 20 years, clinical outcomes have improved due to resection of these tumors at a fascicular level. Despite these advances, a subgroup of patients with schwannomas is associated with a disappointing neurological outcome following resection. The purpose of this study was to correlate the imaging and histological features in this group of patients with more anatomically complex forms of schwannomas. Methods In a retrospective review performed at their institution over a 10-year period, the authors found a subgroup of patients with complex multinodular/plexiform schwannomas affecting major peripheral nerves. Eleven patients were identified, and the clinical, imaging, and pathological features of their disease were reviewed. Results The clinical presentation of multinodular/plexiform schwannomas of major peripheral nerves may be similar to that of conventional schwannomas, but their imaging features, operative appearance, and outcomes differ. Conclusions Preoperatively and intraoperatively, the distinguishing features of multinodular/plexiform schwannomas of major peripheral nerves may be subtle and can easily go unrecognized, thus explaining the often suboptimal surgical results. Familiarity with the imaging and operative features of multinodular/plexiform schwannomas will no doubt alter treatment approaches and improve neurological function in this subgroup of patients.

Purpose Vorinostat, a histone deacetylase inhibitor, represents a rational therapeutic target in glioblastoma multiforme (GBM). Patients and Methods Patients with recurrent GBM who had received one or fewer chemotherapy regimens for progressive disease were eligible. Vorinostat was administered at a dose of 200 mg orally twice a day for 14 days, followed by a 7-day rest period. Results A total of 66 patients were treated. Grade 3 or worse nonhematologic toxicity occurred in 26% of patients and consisted mainly of fatigue (17%), dehydration (6%), and hypernatremia (5%); grade 3 or worse hematologic toxicity occurred in 26% of patients and consisted mainly of thrombocytopenia (22%). Pharmacokinetic analysis showed lower vorinostat maximum concentration and area under the curve (0 to 24 hours) values in patients treated with enzyme-inducing anticonvulsants, although this did not reach statistical significance. The trial met the prospectively defined primary efficacy end point, with nine of the first 52 patients being progression-free at 6 months. Median overall survival from study entry was 5.7 months (range, 0.7 to 28+ months). Immunohistochemical analysis performed in paired baseline and post-vorinostat treatment samples in a separate surgical subgroup of five patients with recurrent GBM showed post treatment increase in acetylation of histones H2B and H4 (four of five patients) and of histone H3 (three of five patients). Microarray RNA analysis in the same samples showed changes in genes regulated by vorinostat, such as upregulation of E-cadherin (P = .02). Conclusion Vorinostat monotherapy is well tolerated in patients with recurrent GBM and has modest single-agent activity. Histone acetylation analysis and RNA expression profiling indicate that vorinostat in this dose and schedule affects target pathways in GBM. Additional testing of vorinostat in combination regimens is warranted.

Biologically malignant pilocytic astrocytomas are rare. Precise morphologic criteria permitting their identification and clinically meaningful distinction from more ordinary pilocytic astrocytomas have not been developed. The histologic grading schemes applied to fibrillary astrocytomas—ones based on nuclear atypia, increased cellularity, mitotic activity, endothelial proliferation, and necrosis—are thought not to correlate with prognosis in pilocytic astrocytomas. Nonetheless, these features were systematically sought in 107 cerebellar pilocytic astrocytomas, four of which were histologically malignant. The clinical, morphologic, and flow cytometric features of these cases were studied. The incidence of histologic malignancy occurring spontaneously in otherwise typical pilocytic astrocytomas was 0.9%; that occurring after radiation was 1.8%. The four histologically malignant tumors occurred in two males and two females, ages 6 to 18 years. All showed increased mitotic activity (three to five mitoses per high-power microscopic field [250×]). Endothelial proliferation and necrosis were present in three and two cases each. DNA ploidy analysis showed the spontaneously occurring malignant-appearing tumors to be aneuploid, whereas both previously radiated tumors were tetraploid; 5% to 11% of cells were in S phase. The appearance of histologic malignancy in pilocytic astrocytoma is rare and less reliably correlated with prognosis than in patients with fibrillary astrocytomas. Essential features of such tumors include a high mitotic index and perhaps a high percentage of cells in S phase. (J Child Neurol 1994;9:301-310).

The pathobiology of medulloblastoma is reviewed in light of emerging data regarding its immunocytochemical and cytobiologic, as well as molecular biologic, characteristics. The nature of the lesion, particularly its nosologic relation to primitive neuroectodermal tumor, is discussed, as is its place in the World Health Organization classification of tumors of the central nervous system. ( J Child Neurol 1992;7:240-252).

Medulloblastoma, the most common embryonal tumor of the central nervous system, affects both children and adults. It poses a significant therapeutic challenge in that age-dependent differences exist, not only in their pathobiology, but in the efficacy of chemotherapy and radiotherapy. This is particularly the case in very young children, whose still developing nervous system exhibits a low tolerance to radiotherapy. We review the epidemiology, clinical presentation, radiologic features, and current therapeutic concepts relative to this unique neoplasm. Efforts are made to highlight clinical controversies. ( J Child Neurol 1992;7:142-155).

Purpose Epidermal growth factor receptor (EGFR) amplification in glioblastoma multiforme (GBM) is a common occurrence and is associated with treatment resistance. Erlotinib, a selective EGFR inhibitor, was combined with temozolomide (TMZ) and radiotherapy (RT) in a phase I/II trial. Patients and Methods Adults not taking enzyme-inducing anticonvulsants after resection or biopsy of GBM were treated with erlotinib (150 mg daily) until progression. Erlotinib was delivered alone for 1 week, then concurrently with TMZ (75 mg mg/m2 daily) and RT (60 Gy), and finally, concurrently with up to six cycles of adjuvant TMZ (200 mg/m2 daily for 5 days every 28 days). The primary end point was survival at 1 year. Results Ninety-seven eligible patients were accrued with a median follow-up time of 22.2 months. By definition, the primary end point was successfully met with a median survival time of 15.3 months. However, there was no sign of benefit in overall survival when comparing N0177 with the RT/TMZ arm of the European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada trial 26981/22981 (recursive partitioning analysis [RPA] class III, 19 v 21 months; RPA class IV, 16 v 16 months; RPA class V, 8 v 10 months, respectively). Presence of diarrhea, rash, and EGFRvIII, p53, phosphatase and tensin homolog (PTEN), combination EGFR and PTEN, and EGFR amplification status were not predictive (P > .05) of survival. Conclusion Although the primary end point was successfully met using nitrosourea-based (pre-TMZ) chemotherapy era historic controls, there was no sign of benefit compared with TMZ era controls. Analyses of molecular subsets did not reveal cohorts of patients sensitive to erlotinib. TMZ chemotherapy combined with RT resulted in improved outcomes compared with historical controls who received nitrosourea-based chemotherapies.

✓ As a rule, normal human nerve does not contain glomus bodies. Nonetheless, rare examples of glomus tumors do arise in peripheral nerves of various sizes. Their pathobiological characteristics are poorly understood, but reported examples have been small and clinically benign. The authors identified in 1 patient each a glomus tumor and a glomangioma involving nerve. Clinical histories as well as imaging and surgical findings were reviewed. All available H & E–stained slides were examined in both cases. Immunohistochemical stains and electron microscopy, as appropriate, were also performed. The lesions were subtotally and completely resected, respectively. An uneventful postoperative recovery was noted in both patients. Glomus tumors and glomangiomas can involve major nerves on rare occasions. They seem to follow a favorable clinical course, and conservative resection can be of benefit.

Object Spontaneous intracerebral hemorrhage is an uncommon but recognized initial presenting sign of both primary and metastatic brain tumors. The rate of tumor-related intracranial hemorrhage is variably reported from < 1 to 14.6%. Hemorrhage in primary gliomas occurs in 3.7–7.2% of gliomas, mainly in glioblastoma muliforme and oligodendroglioma with low-grade astrocytomas accounting for < 1%. Hemorrhage associated with pilocytic astrocytomas (PAs) is only sporadically reported. The authors report on a series of patients in whom PAs presenting as hemorrhages prompted them to examine the incidence of bleeding in these tumors. Methods Cases involving a confirmed tissue diagnosis of PA from 1994–2005 were reviewed retrospectively. The authors included only patients with evidence of hemorrhage on computed tomography and/or magnetic resonance imaging seen prior to biopsy or resection and in the absence of trauma or other vascular pathological entities. Results In 138 patients with histologically proven PAs, the mean age at diagnosis was 23 years. In 11 patients (8%; 5 male and 6 female) there was evidence of hemorrhage at presentation. There were no locations more susceptible to hemorrhage than any other, although no bleeding occurred within the cerebellum. All but 1 patient was treated with a gross-total resection. Conclusions Hemorrhage in association with PAs likely results from the frequently observed abnormal vasculature in these tumors, occurs with a greater frequency than previously thought, and should be considered in the differential diagnosis of spontaneous intracerebral hemorrhage.

✓ 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.