Can morphology predict 1p/19q loss in oligodendroglial tumours?

AIMS: To investigate the relationship between phenotype and genotype in oligodendroglial tumours and evaluate whether 1p/19q status can be reliably predicted from histological findings. METHODS AND RESULTS: Three neuropathologists reviewed the association between 10 histological variables, location and genetic losses at 1p, 19q and 17p13 in 63 oligodendroglial tumours (cohort 1). Based on these findings, a multiple logistic regression model for prediction of 1p/19q status was constructed. The ability of this model to predict 1p/19q status was tested on cohort 2, comprising 20 oligodendroglial tumours. Loss of heterozygosity at 1p, 19q and 17p13 was analysed using polymerase chain reaction. Combined 1p/19q loss and losses at 17p13 were mutually exclusive (P < 0.001). The variable H1a (more or <50% of cells with round, uniform nuclei and perinuclear halos) demonstrated the strongest association with 1p/19q status (odds ratio 11.9, 95% confidence interval 3.6, 39.6, P < 0.001). Calcifications, absence of gemistocytic cells and a non-temporal/non-insular location were also associated. The correct 1p/19q status was predicted in 80% of cases in cohort 2. CONCLUSIONS: There is a strong association between phenotype and genotype in oligodendroglial tumours. However, even when all significant variables are accounted for, perfect prediction (100%) of 1p/19q status cannot be obtained.

Gliosarcoma with liposarcomatous component, bone infiltration and extracranial growth.

Gliosarcoma is a highly malignant brain tumor consisting of both a glioblastoma and a mesenchymal component. The latter typically resembles fibrosarcoma, but differentiation patterns resembling osteosarcoma, chondrosarcoma, angiosarcoma and rhabdomyosarcoma have also been described. Molecular-genetic studies have shown that both glioblastoma and the mesenchymal component share identical cytogenetic abnormalities or mutations, suggesting a monoclonal origin from glial cells. We report an unusual case of gliosarcoma that presented as a large intracerebral tumor with infiltration of the temporal bone and the soft tissues in the infratemporal fossa. Microscopically, the tumor consisted of alternating areas of glioblastoma and fibrosarcoma. Focally, areas ofosteosarcomatous and liposarcomatous differentiation were found. Although gliosarcoma with transcranial penetration is very rare, it should be suspected in case of intracranial tumor with glioblastoma-imaging features, infiltration of bone and extracranial growth. Our case of liposarcomatous differentiation in gliosarcoma--together with another very recently reported similar case--expands the morphologic heterogeneity of this peculiar brain tumor.

Neuropathological changes in ten cases of neuronal intermediate filament inclusion disease (NIFID): a study using alpha-internexin immunohistochemistry and principal components analysis (PCA).

Ten cases of neuronal intermediate filament inclusion disease (NIFID) were studied quantitatively. The alpha-internexin positive neurofilament inclusions (NI) were most abundant in the motor cortex and CA sectors of the hippocampus. The densities of the NI and the swollen achromatic neurons (SN) were similar in laminae II/III and V/VI but glial cell density was greater in V/VI. The density of the NI was positively correlated with the SN and the glial cells. Principal components analysis (PCA) suggested that PC1 was associated with variation in neuronal loss in the frontal/temporal lobes and PC2 with neuronal loss in the frontal lobe and NI density in the parahippocampal gyrus. The data suggest: 1) frontal and temporal lobe degeneration in NIFID is associated with the widespread formation of NI and SN, 2) NI and SN affect cortical laminae II/III and V/VI, 3) the NI and SN affect closely related neuronal populations, and 4) variations in neuronal loss and in the density of NI were the most important sources of pathological heterogeneity.

Cerebral thrombotic microangiopathy and antiphospholipid antibodies in Aicardi-Goutieres syndrome--report of two sisters.

Cerebral thrombotic microangiopathy was found at autopsy in one of two sisters with Aicardi-Goutieres syndrome, whereas the other revealed increased serum levels of anticardiolipin IgG antibodies (measured only in the living sister); both typical features of systemic lupus erythematosus. These findings add support to the suggestion that Aicardi-Goutieres syndrome and systemic lupus erythematosus are closely related disorders in which dysregulated production of interferon-alpha might play a crucial role.

Clinical and neuropathologic variation in neuronal intermediate filament inclusion disease.

BACKGROUND: Recently described neuronal intermediate filament inclusion disease (NIFID) shows considerable clinical heterogeneity. OBJECTIVE: To assess the spectrum of the clinical and neuropathological features in 10 NIFID cases. METHODS: Retrospective chart and comprehensive neuropathological review of these NIFID cases was conducted. RESULTS: The mean age at onset was 40.8 (range 23 to 56) years, mean disease duration was 4.5 (range 2.7 to 13) years, and mean age at death was 45.3 (range 28 to 61) years. The most common presenting symptoms were behavioral and personality changes in 7 of 10 cases and, less often, memory loss, cognitive impairment, language deficits, and motor weakness. Extrapyramidal features were present in 8 of 10 patients. Language impairment, perseveration, executive dysfunction, hyperreflexia, and primitive reflexes were frequent signs, whereas a minority had buccofacial apraxia, supranuclear ophthalmoplegia, upper motor neuron disease (MND), and limb dystonia. Frontotemporal and caudate atrophy were common. Histologic changes were extensive in many cortical areas, deep gray matter, cerebellum, and spinal cord. The hallmark lesions of NIFID were unique neuronal IF inclusions detected most robustly by antibodies to neurofilament triplet proteins and alpha-internexin. CONCLUSION: NIFID is a neuropathologically distinct, clinically heterogeneous variant of frontotemporal dementia (FTD) that may include parkinsonism or MND. Neuronal IF inclusions are the neuropathological signatures of NIFID that distinguish it from all other FTD variants including FTD with MND and FTD tauopathies.

Choroid plexus tumors in children and young adults: report of 16 consecutive cases.

Choroid plexus tumors are rare intraventricular tumors, and they represent 2-4% of brain tumors in children. This single-institution retrospective study involves 16 consecutive choroid plexus tumors: 13 papillomas and 3 carcinomas. Tumor locations were the lateral ventricles in 13 cases, the third ventricle in 2 cases and the fourth ventricle in 1 case. The mean age at presentation was 3.1 years. Two patients died of perioperative blood loss. Five-year survival was 85% with papillomas and 33% with carcinomas. None of the papillomas recurred after total tumor resection, and the functional outcome in long-term survivors after papilloma surgery was excellent in 92% of the cases. Two of the carcinoma patients had disseminated disease. Fifty percent of the patients had persistent hydrocephalus after tumor resection, and these required cerebrospinal fluid diversion.

Ependymoma in children and young adults (0-19 years): report of 25 consecutive cases.

The objective of this retrospective study was to evaluate the relative effect of surgery and radiotherapy (RT) on the survival of 25 consecutive children and young adults treated for ependymoma [18 in the posterior fossa (PF), 2 in supratentorial locations (ST) and 5 in intraspinal locations (IS)]. Five-year survival rates for patients with PF, ST and IS tumors were 28%, 0% and 100%, respectively. Total tumor resection was a positive prognostic factor in the case of PF tumors. No patients with subtotal removal of a PF tumor survived for longer than 5 years. The effect of RT on survival of patients with PF ependymomas in this series was uncertain. No patients with PF ependymoma had disseminated disease at diagnosis, and all tumor recurrences were local. Based on these observations, we see no indications for craniospinal RT of PF ependymomas, except in rare cases of disseminated disease. If RT is given, it should only be targeted to the tumor site. The two patients with ST ependymoma died within 3.8 years after primary treatment. Our series of ST ependymomas does not allow any specific treatment recommendations. One patient with IS ependymoma was cured by surgery alone. Four patients with IS ependymoma had documented residual tumor after surgery. RT induced remission in these patients. For IS ependymomas we recommend no RT if total tumor removal can be documented. In patients with subtotal removal of IS ependymomas local RT is effective and should be given.

Neuronal cell death in the visual cortex is a prominent feature of the X-linked recessive mitochondrial deafness-dystonia syndrome caused by mutations in the TIMM8a gene.

The Mohr-Tranebjaerg syndrome (MIM 304700) and the Jensen syndrome (MIM 311150) were previously reported as separate X-linked recessive deafness syndromes associated with progressive visual deterioration, dystonia, dementia, and psychiatric abnormalities. In the most extensively studied Norwegian family, the Mohr-Tranebjaerg syndrome was reported to be caused by a one-basepair deletion (151delT) in the deafness/dystonia peptide (DDP) gene at Xq22. This gene has been renamed TIMM8a. We identified a stop mutation (E24X) in the TIMM8a gene segregating with the disease in the original Danish family with the Jensen syndrome, which confirms that the two disorders are allelic conditions. We also report abnormal VEP examinations and neuropathological abnormalities in affected males from the two unrelated families with different mutations. The findings included neuronal cell loss in the optic nerve, retina, striate cortex, basal ganglia, and dorsal roots of the spinal cord. The demonstration of mitochondrial abnormalities in skeletal muscle biopsies in some patients is compatible with the suggestion from recent research that the TIMM8a protein is the human counterpart of an intermembrane mitochondrial transport protein, Tim8p, recently characterized in yeast. The clinical and neuropathological abnormalities associated with mutations in the TIMM8a gene support that this X-linked deafness-dystonia-optic neuropathy syndrome is an example of progressive neurodegeneration due to mutations in a nuclear gene necessary for some, yet unknown mitochondrial transport function. We recommend sequencing the TIMM8a gene, thorough ophthalmological examination, and measuring visual evoked potentials in clinically suspected male patients with either progressive hearing impairment, dystonia, or visual disability in order to establish an early diagnosis and provide appropriate genetic counselling.

Evidence that Alpers-Huttenlocher syndrome could be a mitochondrial disease.

We report an 11-year-old boy with a slight developmental delay and epilepsy. After he was placed on valproate, he developed hepatic failure and increasing neurologic symptoms, including epilepsia partialis continua, and died. Autopsy findings in liver and cerebrum were consistent with progressive neuronal degeneration of childhood with liver disease, also called Alpers-Huttenlocher syndrome. Ragged red fibers and cytochrome c oxidase negative fibers were present in muscle. These results suggest that Alpers-Huttenlocher syndrome, at least in some patients, is a mitochondrial disease.

[Long-term survival following surgery and radiotherapy of brain tumors in childhood]. / Langtidsoverlevelse etter kirurgi og strålebehandling av hjernesvulster i barnealder.

BACKGROUND: Brain tumours are seen in about one third of children with neoplastic disease. Treatment usually includes surgery and/or radiotherapy. Radiotherapy may have serious late effects, especially in children under the age of three; but is necessary for survival in children with medulloblastomas or high-grade gliomas. MATERIALS AND METHODS: We report ten and 20 years survival rates in 115 children with primary brain tumours (58 medulloblastoma, 14 high-grade gliomas, and 43 low-grade gliomas) operated at the National Hospital and given radiotherapy at the Norwegian Radium Hospital during the years 1970-1995. RESULTS: No patients with medulloblastomas or high-grade gliomas relapsed after ten years. Overall ten and 20 years survival in children treated with radiotherapy to tumour doses > 50 Gy for medulloblastoma was 51.5% and for high-grade gliomas 20%. Median survival for patients with low-grade gliomas was not reached at 20 years, but these patients were still at risk for late deaths. INTERPRETATION: Long-term survival in children with high-grade gliomas or medulloblastoma equals cure, while late relapses may occur in low-grade gliomas.

Significance of inflammatory changes in the brainstem in forensic autopsy cases.

Brain stem encephalitis is an uncommon disease. In order to assess the significance of inflammatory changes in the brain stem in a forensic autopsy material we reviewed the findings over a 12-year period. Between January 1st 1982-December 31st 1993, neuropathological examination of the brain was carried out in 29% of the autopsy cases from the Institute of Forensic Medicine, University of Oslo. Out of 4546 brains, 110 (2.2%) showed microglial nodules and perivascular lymphocytic cuffing in the lower brain stem. In 66 of the cases (60%), the abnormalities were limited to the nucleus and/or the spinal tract of the fifth cranial nerve. Only 16 of the 39 cases with more widespread changes, diagnosed as brain stem encephalitis, had a serious underlying or concomitant disease. Three particular cases of brain stem encephalitis are reported in more detail. In all three cases we suggest that the brain stem inflammatory changes may be either the direct or a contributory cause of death.

Hypoxic/ischaemic brain damage, especially pallidal lesions, in heroin addicts.

The occurrence of pallidal lesions with or without other hypoxic/ischaemic brain injuries was evaluated in 100 intravenous (i.v.) heroin addicts. The brains were collected consecutively from forensic autopsies during the period from January 1995 to June 1996. The autopsies were required by the police and performed at The Institute of Forensic Medicine, The National Hospital, Oslo. There were 21 women and 79 men, median age 32 (range 21-47) and 34 (19-60) years, respectively. Of 38 brains with abnormalities, twenty-five cases showed isolated or combined lesions of hypoxic/ischaemic origin. Pallidal lesions were found in nine brains; six lesions were old, one was subacute (a couple of weeks), and two were part of recent, generalized hypoxia/ischaemia. Six persons had old infarcts in the hippocampal formation, and one of them in combination with old pallidal infarcts. In seven brains small and old infarcts were found in watershed areas in the cerebellum. Between five and ten percent of i.v. heroin addicts might have pallidal infarcts, either as the sole lesion, or combined with other manifestations of hypoxic/ischaemic brain injury. This might give severe mental disturbances in the affected persons.

Prevalence and prognostic significance of epilepsy in patients with gliomas.

The aim of this study was to evaluate the prevalence and prognostic significance of epilepsy in 1028 patients diagnosed in the computer tomography (CT) era with histological low- or high-grade intracranial gliomas. Survival analysis included Kaplan-Meier plots, log-rank tests, logistic regression and Cox's analysis as implemented in the SPSS statistical package. Epilepsy was a positive univariate (P < 0.0001) and multivariate, (P < 0.03) prognostic factor for survival in the total patient group (n = 1028, relative risk of death 0.83, 95% confidence interval (CI) 0.70-0.98) as well as in the high-grade patient group (n = 649, relative risk of death 0.80, 95% CI 0.66-0.96), but not in the group of low-grade glioma patients (P > 0.2). The prevalence of epilepsy in glioblastoma patients was 251/512 (49%), 95/137 (69%) in anaplastic gliomas, and 322/379 (85%) in patients with low-grade gliomas, with 97 of the 102 T1 low-grade subgroup (95%) having epilepsy, indicating that the presence of epilepsy may select patients for early radiological diagnosis. The frequency of epilepsy at presentation decreased with age in high-grade glioma patients, and increased with age in low-grade glioma patients to a plateau in the fourth decade of life (P < 0.01). The prevalence of epilepsy in patients with histological intracranial gliomas varied with patient age and tumour histology, with low-grade patients having the highest prevalence. Epilepsy was a significant positive prognostic factor except in patients with low-grade gliomas, and may select low-grade patients for early diagnosis.

Diagnostic utility of the polymerase chain reaction in 2 cases of suspected Whipple disease.

We describe 2 patients with a diagnosis of Whipple disease in whom the usual antibiotic therapy failed. A polymerase chain reaction-based test was used to identify the recently described Whipple bacillus, Tropheryma whippelii. In one case, the diagnosis was confirmed, whereas in the second case, which had been histologically diagnosed as Whipple disease of the brain, the process was identified as a monocyte-derived histiocytosis. In conclusion, Whipple disease can be distinguished from other diseases with similar histological features with the use of a polymerase chain reaction-based test.

Prognostic significance of CT contrast enhancement within histological subgroups of intracranial glioma.

UNLABELLED: We report the prognostic significance of tumor CT contrast enhancement within histological subgroups in 831 consecutive adult glioma patients of high-grade (n = 516) and low-grade (n = 315) histology. In the present report, a negative prognostic factor is associated with shortened survival. METHODS: Survival analysis including Kaplan-Meier plots, log-rank tests, Cox analysis, and Aalen's linear model as implemented in SPSS and S-PLUS. RESULTS: Sensitivity and specificity of contrast enhancement as a test for high-grade glioma was 0.87 and 0.79, respectively. Enhancement was a strong negative prognostic factor comparable to high-grade histology in the total patient population. Enhancement was also a negative prognostic factor within the subgroups adult high-grade (Grade 3-4), anaplastic (Grade 3), and low-grade (Grade 1-2) gliomas (p < 0.001). The prognostic implications of initial enhancement declined in high-grade patients surviving beyond 36 months. Tumor contrast enhancement or calcifications (in parentheses) were present in 96% (3.6%) of glioblastomas, in 87% (7.4%) of high-grade gliomas, in 56.5% of anaplastic gliomas, and in 21% (16.2%) of low-grade gliomas. Calcification was a positive prognostic factor within the high-grade group of patients (p < 0.0001). CONCLUSION: Enhancement was a major prognostic factor comparable to high-grade histology in this glioma patient population. Enhancement was a negative prognostic factor within each of the adult subgroups high-grade, anaplastic (grade 3), and low-grade gliomas. Enhancement was strongly associated with but not pathognomonic for high-grade histology.

Focal, continuous spikes suggest cortical developmental abnormalities. Clinical, MRI and neuropathological correlates.

OBJECTIVES: Widespread use of MRI now gives us increased insights into the different expressions of malformations of cortical development (MCD). The heterogeneity of these disorders are reflected by their varied clinical and neuroimaging features. Characteristic and intense scalp EEG abnormalities have been described in some patients. MATERIAL AND METHODS: We report the MRI and clinical findings of 3 adult patients (age 32-36) with a peculiar EEG pattern of distinct, localized, fast, continuous spiking. These patients represent all patients with such EEG findings that have been recognized by the first author during 9 years. RESULTS: MRI showed MCDs in all, respectively hemimegalencephaly, a subcortical heterotopion, and a focal cortical dysgenesis. The EEG findings had been stable since childhood and were posteriorly located. Two patients had fairly well controlled epilepsy in adult age. The third patient was incapacitated by persistent seizures and was treated with surgery. Histologically cortical dysplasia with neuronal clusters was found in this patient. Variable degrees of cognitive dysfunction were present in all. CONCLUSION: Focal, continuous, fast spiking is an unusual scalp EEG pattern. It is not an inevitable sign of severe epilepsy. It may suggest an MCD. It is not yet clear to what extent such findings are predictive of a dysgenetic etiology of epilepsy.

Survival, prognostic factors, and therapeutic efficacy in low-grade glioma: a retrospective study in 379 patients.

PURPOSE: We report survival, prognostic factors, and treatment efficacy in low-grade glioma. PATIENTS AND METHODS: A total of 379 patients with histologic intracranial low-grade glioma received post-operative radiotherapy (n = 361) and intraarterial carmustine (BCNU) chemotherapy (n = 153). Overall survival and prognostic factors were evaluated with the SPSS statistical program (SPSS Inc, Chicago, IL). RESULTS: Median survival (all patients) was 100 months (95% confidence interval [CI], B7 to 113); in age group 0 to 19 years (n = 41), 226 months; in age group 20 to 49 years (n = 263), 106 months; in age group 50 to 59 years (n = 49), 76 months; and for older patients (n = 26), 39 months. Projected survival at 10 and 15 years was 42% and 29%, respectively. Patient age, World Health Organization (WHO) performance status, tumor computed tomography (CT) contrast enhancement, mental changes, or initial corticosteroid dependency were significant independent prognostic factors (p < .05), while histologic subgroup, focal deficits, presence of seizures, prediagnostic symptom duration, tumor category, and tumor stage were not. Patients aged 20 to 49 years with no independent negative prognostic factors (n = 132) had a median survival time of 139 months versus 41 months in patients with two or more factors (n = 33). Patients who presented with symptoms of expansion (n = 97) survived longer when resected (P < .03); otherwise no survival benefit was associated with initial tumor resection compared with biopsy. Intraarterial chemotherapy and radiation doses more than 55 Gy were not associated with prolonged survival. Among 66 reoperated patients, 45% progressed to high-grade histology within 25 months. CONCLUSION: Prognosis in low-grade glioma following postoperative radiotherapy seems largely determined by the inherent biology of the glioma and patient age at diagnosis.

Encephaloneuropathy with lysosomal zebra bodies and GM2 ganglioside storage.

An 11-year-old girl died of a neuronal storage disorder that clinically was characterized by failure to thrive and muscular hypotonia from birth, with the subsequent evolution of motor neuron disease, epilepsy, and dementia. A wide range of metabolic disorders, including all forms of GM2 gangliosidosis, could be excluded. Electron microscopy demonstrated neuronal zebra body inclusions, and immunohistochemistry demonstrated that GM2 ganglioside was a major constituent of the storage material. We suggest that the patient died of a lysosomal storage disease that is clinically and biochemically different from Tay-Sachs disease, Sandhoff disease, and other GM2 gangliosidoses described previously. This case also further demonstrates that significant accumulation of GM2 ganglioside, which is crucial for dendritic formation, may occur in neuronal storage diseases lacking known defects in ganglioside catabolism.