Ultrastructure of capillary endothelium in pilocytic astrocytomas

The aim of this study was to assess the capillary ultrastructure of pilocytic astrocytomas with gadolinium contrast enhancement on magnetic resonance imaging (MRI). Cysts were identified in all cases with pilocytic astrocytoma. Histological investigation focusing on the vascular structure was performed by light microscopy and electron microscopy in four pilocytic astrocytomas. In the pilocytic astrocytomas, light microscopic examination demonstrated vascular abnormalities (fibrosis, hyalinization, and vascular proliferation), and electron microscopic examination revealed fenestration and vesicles in the capillary endothelium. Fenestration of the vessels and vascular abnormalities with degeneration are suggested to develop both contrast enhancement on neuroimaging and cystic formation in pilocytic astrocytomas.     

Magnetic resonance spectroscopy in gliomas

Magnetic resonance spectroscopy (MRS), that may be added to conventional magnetic resonance imaging (MRI) exam exhibit an increasing role in the management of brain tumors. These technique allow quantitative analysis of metabolites, either cell specific, either reflecting physiological and/or pathological process. With a rigorous approach, MRS explore brain metabolism that may improve MRI data in clinical practice in neuro-oncology. Positive diagnosis of brain tumor, differential diagnosis between infiltrative glioma (grade II) and gliomatosis, determination of the limits of tumor infiltration, and distinction between tumor and post-therapeutic images are some of the potential applications of MRS. Ongoing and future studies may also precise the place of MRS in the differential diagnosis between high grade glioma, metastasis and CNS lymphoma, as well as in monitoring therapy in glioma.     

Reimagining pilocytic astrocytomas in the context of pediatric low-grade gliomas

Pediatric low-grade gliomas (pLGGs) are the most common brain tumor in children and are associated with lifelong clinical morbidity. Relative to their high-grade adult counterparts or other malignant childhood brain tumors, there is a paucity of authenticated preclinical models for these pLGGs and an incomplete understanding of their molecular and cellular pathogenesis. While large-scale genomic profiling efforts have identified the majority of pathogenic driver mutations, which converge on the MAPK/ERK signaling pathway, it is now appreciated that these events may not be sufficient by themselves for gliomagenesis and clinical progression. In light of the recent World Health Organization reclassification of pLGGs, and pilocytic astrocytoma (PA), in particular, we review our current understanding of these pediatric brain tumors, provide a conceptual framework for future mechanistic studies, and outline the challenges and pressing needs for the pLGG clinical and research communities.     

Magnetic resonance spectroscopy in clinical oncology

The combination of magnetic resonance spectroscopy (MRS) and imaging (MRI) has led to mapping metabolites from normal and neoplastic tissue within the time limits of a routine study. MRSI (magnetic resonance spectroscopy imaging) detects metabolites that contain protons, phosphorus, fluorine, or other nuclei. The uniqueness of the information available in vivo and in a non-invasive manner encouraged radiologists and oncologists to apply MRSI in research and clinical practice. Both (1)H- and (31)P-MRS have revealed significant disturbances in amino acids, lipids, and phosphorus-containing metabolites within tumors. Phosphocreatine is often diminished in neoplasms compared to their primary host or surrounding tissues. However, the reduction of the compound does not appear to be closely correlated to the degree of malignancy. Moreover, abnormalities in (31)P spectra from neoplasms are shared by other disorders. Changes in high-energy phosphate levels almost invariably occur with radio- and chemotherapy of tumors. The spectroscopic alterations are often seen before any variations in tumor size and shape can be detected. However, opposite responses can be associated with the same clinical outcome. (1)H-MRS has been successfully used to quantify the extent of neuronal cell loss imposed on the brain during radiotherapy. Recently, MRSI was successfully integrated into radiotherapy planning in prostate cancer patients. (19)F-MRS opens access to artificially induced fluorocompounds such as 5-fluorouracil and its metabolites.     

Magnetic resonance spectroscopy in cancer diagnostics

Magnetic resonance spectroscopy (MRS) is one of the most powerful analytical techniques, being frequently used to derive physical, chemical, electronic, and structural information about molecules. Considering its potentialities and its evolution as cell/tissue response predictor, it can be used to detect changes in the tumor pathophysiology before, during, and after treatment. Of particular relevance to this analysis, due to its higher sensitivity, is proton magnetic resonance spectroscopy (¹H-MRS) either applied directly in vivo or by using tumor biopsies and high-rotation magic angle spinning (HRMAS). Several metabolites have been quantified in several tumors, including creatine and phosphocreatine, choline, lactate and myoinositol, and used for distinguishing different cancer types. Several advantages characterize this technique including swiftness and ability to support the characterization of tumoral lesions on the basis of their biochemical composition, which may provide additional diagnostic and prognostic information as an adjunct to routine histological assessment. Many tumors have already been studied by ¹H-MRS, and there is growing interest in studying others in order to establish extended metabolite databases which could help in their identification and characterization.     

Magnetic resonance spectroscopy of brain tumors

Magnetic resonance spectroscopy provides metabolic information about brain tumors beyond what can be obtained from anatomic images. In contrast to other metabolism-based imaging techniques such as single photon emission computed tomography and positron-emission tomography, magnetic resonance spectroscopy yields multiparametric data, does not require radio-labeled tracers or ionizing radiation, and can be performed in conjunction with other magnetic resonance imaging studies. Magnetic resonance spectral patterns have been shown to be distinct for different tumor types and grades. Response to radiation therapy is also reflected by magnetic resonance spectral patterns. Although there are quantitative issues still to be addressed, correlation of in vivo spectral patterns with ex vivo spectral patterns obtained from actual biopsy samples indicates that magnetic resonance spectroscopy is a fundamentally valid tool for monitoring disease progression and therapeutic response in patients with brain tumors.     

Diffusion differences between pilocytic astrocytomas and grade II ependymomas

Background

The aim of our study was to differentiate between cerebellar pilocytic astrocytomas and grade II ependymomas on the basis of their diffusion properties.

Patients and methods

The study prospectively included 12 patients with pilocytic astrocytomas and 5 with ependymomas. Apparent diffusion coefficients (ADC) were compared between tumour types.

Results

ADC values were significantly higher in pilocytic astrocytomas than ependymomas, with almost no overlapping of the range of measured ADCs between the two tumour types.

Conclusions

Significant diffusion differences between pilocytic astrocytomas and grade II ependymomas enable their preoperative distinction, in combination with conventional magnetic resonance images.     

Adult pilocytic astrocytomas: clinical features and molecular analysis

Background

Adult pilocytic astrocytomas (PAs) are rare and have an aggressive clinical course compared with pediatric patients. Constitutive Ras/RAF/MAPK signaling appears to be an important oncogenic event in sporadic PA. We evaluated clinical data and molecular profiles of adult PAs at our institution.

Methods

We identified 127 adult PAs in our institutional database. Cases with available tissue were tested for BRAF-KIAA1549 fusion/duplication (B-K fusion) by fluorescence in situ hybridization and submitted for mutation profiling using the Sequenom mutation profiling panel. Subgroup analyses were performed based on clinical and molecular data.

Results

The majority of adult PAs are supratentorial. Twenty-two percent of cases had an initial pathologic diagnosis discordant with the diagnosis made at our institution. Recurrence was seen in 42% of cases, and 13% of patients died during follow-up. Adjuvant radiotherapy following surgical resection was associated with a statistically significant decrease in progression-free survival (P = .004). B-K fusion was identified in 20% (9 of 45) of patients but was not associated with outcome. No BRAF V600E mutations (0 of 40 tested) were found.

Conclusion

This was the largest single institution series of adult PA. A significant proportion of adult PAs follow an aggressive clinical course. Our results support a period of observation following biopsy or surgical resection. B-K fusion in adult PA does not influence outcome, and BRAF V600E mutation appears to be a very rare event. Further study of tumor biology and optimal treatment is needed, given a more aggressive clinical behavior.     

Imaging in breast cancer: Magnetic resonance spectroscopy

A technique called in vivo magnetic resonance spectroscopy (MRS) can be performed along with magnetic resonance imaging (MRI) to obtain information about the chemical content of breast lesions. This information can be used for several clinical applications, such as monitoring the response to cancer therapies and improving the accuracy of lesion diagnosis. Initial MRS studies of breast cancer show promising results, and a growing number of research groups are incorporating the technique into their breast MRI protocols. This article introduces ¹H-MRS of the breast, reviews the literature, discusses current methods and technical issues, and describes applications for treatment monitoring and lesion diagnosis.     

Stereotactic radiosurgery for pilocytic astrocytomas part 2: outcomes in pediatric patients

To assess outcomes after stereotactic radiosurgery (SRS) for newly diagnosed or recurrent pilocytic astrocytomas in pediatric patients. Fifty patients (28 male and 22 females) with juvenile pilocytic astrocytomas (JPA) underwent Gamma knife SRS between 1987 and 2006. The median patient age was 10.5 years (range, 4.2–17.9 years). Three patients had failed prior fractionated radiation therapy (RT) and two had failed RT and chemotherapy. The median radiosurgery target volume was 2.1 cc (range, 0.17–14.4 cc) and the median margin dose was 14.5 Gy (range, 11–22.5 Gy). At a median follow-up of 55.5 months (range 6.0–190 months), one patient died and 49 were alive. The progression free survival after SRS (including tumor growth and cyst enlargement) for the entire series was 91.7, 82.8 and 70.8% at 1, 3 and 5 years, respectively. Stereotactic radiosurgery for pediatric pilocytic astrocytomas should be considered when resection is not feasible, or if there is an early recurrence. The best response was observed in small volume residual solid tumors.     

Preliminary observations on genetic alterations in pilocytic astrocytomas associated with neurofibromatosis 1

Neurofibromatosis 1 (NF1) is an autosomal dominant disorder that predisposes sufferers to various forms of neoplasia. Among affected individuals, 15%-20% develop astrocytomas, especially pilocytic astrocytomas (PA), which are benign and classified as grade I by the World Health Organization. They are generally well circumscribed, and their progression is slow. NF1-associated PAs (NF1-PAs) occasionally behave as aggressive tumors. To elucidate underlying genetic events in clinically progressive NF1-PAs, we performed molecular genetic analysis on 12 PAs, including 3 NF1-PAs, for pS3, p16, and epidermal growth factor receptor genes, as well as loss of heterozygosity (LOH) on chromosome 1p, 10, 17, and 19q. None of the obvious genetic alterations typically seen in higher grade astrocytomas were found in 9 sporadic PAs. However, in 2 of 3 NF1-PAs, microsatellite analysis showed LOH10, including the PTEN (phosphatase and tensin homolog deleted on chromosome 10) gene locus, despite the diagnosis of pilocytic astrocytoma;one of these also manifested homozygous deletion of the p16 gene. The other NF1-PA harbored only LOH of the NF1 gene locus (17q). Our preliminary results support the hypothesis that some NF1-PAs differ genetically from sporadic PAs.     

Stereotactic radiosurgery for pilocytic astrocytomas part 1: outcomes in adult patients

To assess outcomes when stereotactic radiosurgery (SRS) is used during multimodality management of pilocytic astrocytomas in adult patients. Fourteen patients (six male and eight females) with pilocytic astrocytomas underwent SRS between 1994 and 2006. The median patient age was 32 years (range, 19–52 years). Initial surgical management included stereotactic biopsy (N = 4), gross total resection (N = 1), and partial resection (N = 9). Fractionated radiation therapy had failed in six patients. The median radiosurgery target volume was 4.7 cc (range, 0.6–33.7 cc) and the median margin dose was 13.3 Gy (range, 10–20 Gy). At a median follow-up of 36.3 months (range 6.1–109 months), three patients died and 11 were alive. The overall survival after SRS for the entire series was 100%, 88.9% and 88.9% at 1, 3 and 5 years, respectively. Localized solid tumor progression was seen in two patients. Cyst progression was noted in three of nine patients with cystic tumors and mixed solid and cyst progression was noted in two with cystic tumors. The progression free survival after SRS (including tumor growth and cyst enlargement) for the entire series was 83.9%, 31.5% and 31.5% at 1, 3 and 5 years, respectively. Prior surgical resection was associated with better progression free survival after SRS (P = 0.027). Despite their purported benign nature, pilocytic astrocytomas in adult patients often do not behave benignly. Unresectable pilocytic astrocytomas that are located in critical or deep areas of the brain require additional management approaches. In this preliminary experience obtained over a 12 year interval, SRS is most valuable for patients after maximal feasible surgical resection. Delayed cyst progression contributes to late loss of tumor control.     

Distinct genetic signatures among pilocytic astrocytomas relate to their brain region origin

Pilocytic astrocytomas (PAs) are the most common glioma in children. Whereas many PAs are slow-growing or clinically indolent, others exhibit more aggressive features with tumor recurrence and death. To identify genetic signatures that might predict PA clinical behavior, we did gene expression profiling on 41 primary PAs arising sporadically and in patients with neurofibromatosis type 1 (NF1). Whereas no expression signature was found that could discriminate clinically aggressive or recurrent tumors from more indolent cases, PAs arising in patients with NF1 did exhibit a unique gene expression pattern. In addition, we identified a gene expression signature that stratified PAs by location (supratentorial versus infratentorial). Lastly, we also identified a gene expression pattern common to PAs and normal mouse astrocytes and neural stem cells from these distinct brain regions as well as a gene expression pattern shared between PAs and another human glial tumor (ependymoma) arising supratentorially compared with those originating in the posterior fossa. These results suggest that glial tumors share an intrinsic, lineage-specific molecular signature that reflects the brain region in which their nonmalignant predecessors originated.     

Adult patients with supratentorial pilocytic astrocytomas: a prospective multicenter clinical trial

PURPOSE: Supratentorial pilocytic astrocytomas in adults are uncommon. A prospective clinical trial was conducted to obtain clinical and outcome data in these patients. METHODS AND MATERIALS: Between 1986 and 1994, 20 eligible adults with supratentorial pilocytic astrocytomas were enrolled in a prospective intergroup trial of radiotherapy (RT) after biopsy (3 patients) or observation after gross (11 patients) or subtotal (6 patients) resection. RESULTS: At the time of analysis (median follow-up, 10 years), 1 patient (5%) had died and 19 patients (95%) were alive. The 5-year progression-free and overall survival rates were 95%. The cause of death in the patient who died (2.1 years after enrollment) was unknown; a radiographic examination obtained shortly before the patient's demise revealed no signs of progression. Progression in 1 patient approximately 1 month after enrollment required injection of (32)P into an enlarging cyst. The patient required RT approximately 18 months later because of further progression. This patient was alive without evidence of progression 9 years after RT. No toxic effects had been recorded at the latest follow-up examinations. CONCLUSION: With follow-up comparable or superior to that in many retrospective studies, the results of this prospective trial confirm that adults with pilocytic astrocytomas have a favorable prognosis with regard to survival and neurologic function. The vast majority of patients remained stable after gross or subtotal resection and no adjuvant therapy. RT need not be offered to adults with supratentorial pilocytic astrocytoma after gross or subtotal resection; instead, close observation is recommended. Because only 3 patients received RT after biopsy, it is difficult to comment on the effect of RT on their outcome as a group.     

Magnetic resonance spectroscopy suggests key differences in the metastatic behaviour of medulloblastoma

BackgroundMetastatic medulloblastoma has a poorer prognosis than localised disease in part due to inherent properties of the tumour. ¹H magnetic resonance spectroscopy (MRS) provides a powerful method for investigating tumour metabolism in vivo.MethodsMagnetic resonance imaging and short echo time (Te 30 ms) single voxel MRS were performed on the primary tumour of 16 children with medulloblastoma prior to surgical resection. Tumour volumes were calculated using a segmentation technique and the MRS was analysed using LCModel™.ResultsPatients with metastatic disease had primary tumours which were smaller (p = 0.01), had higher levels of total choline (p = 0.03) and lower levels of mobile lipids (p = 0.04).ConclusionMetastatic medulloblastomas have metabolite profiles indicative of increased cell growth and decreased cell death compared with localised tumours reflecting intrinsic differences in underlying biology. Localised tumours with an MRS metabolite profile similar to those with metastatic disease may be at increased risk of metastatic relapse.     

Expression analysis of juvenile pilocytic astrocytomas by oligonucleotide microarray reveals two potential subgroups

Juvenile pilocytic astrocytoma (JPA) is one of the most common brain tumors in children. The expression profiles of 21 JPAs, determined using Affymetrix GeneChip U133A, were compared with subjects with normal cerebella. The genes involved in neurogenesis, cell adhesion, synaptic transmission, central nervous system development, potassium ion transport, protein dephosphorylation, and cell differentiation were found to be significantly deregulated in JPA. These 21 JPAs were further clustered into two major groups by unsupervised hierarchical clustering using a set of 848 genes with high covariance (0.5-10). Supervised analysis with Significance Analysis of Microarrays software between these two potential subgroups identified a list of significant differentially expressed genes involved in cell adhesion, regulation of cell growth, cell motility, nerve ensheathment, and angiogenesis. Immunostaining of myelin basic protein on paraffin sections derived from 18 incompletely resected JPAs suggests that JPA without myelin basic protein-positively stained tumor cells may have a higher tendency to progress.     

Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas

Brain tumors are the most common solid tumors of childhood, and pilocytic astrocytomas (PA) are the most common central nervous system tumor in 5 to 19 year olds. Little is known about the genetic alterations underlying their development. Here, we describe a tandem duplication of approximately 2 Mb at 7q34 occurring in 66% of PAs. This rearrangement, which was not observed in a series of 244 higher-grade astrocytomas, results in an in-frame fusion gene incorporating the kinase domain of the BRAF oncogene. We further show that the resulting fusion protein has constitutive BRAF kinase activity and is able to transform NIH3T3 cells. This is the first report of BRAF activation through rearrangement as a frequent feature in a sporadic tumor. The frequency and specificity of this change underline its potential both as a therapeutic target and as a diagnostic tool.