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.

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.

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.

Variations in the size of the human brain. Influence of age, sex, body length, body mass index, alcoholism, Alzheimer changes, and cerebral atherosclerosis.

The various factors which determine brain weight and volume of the lateral ventricles were studied in an autopsy material of 467 cases. The material consisted of 64 men and 17 women between 45-54 years and 196 men and 190 women between 70-79 years. The weights of the cerebral hemispheres and of the cerebellum and brainstem were determined separately. The volume of the lateral ventricles was determined by weighing the hemispheres with and without water in the lateral ventricles. The recorded variables were age, sex, body length, body weight, cerebral atherosclerosis, Alzheimer changes and alcoholism. Cerebral atherosclerosis and Alzheimer changes were quantitated by morphometric methods. The results were analysed by conventional and multivariate statistical methods. The following observations were made: In normal brains there was a significant correlation between the weight of the supra- and infratentorial parts. Similarly, there was a significant correlation between the size of the lateral ventricles and the weight of the cerebral hemispheres. Women had smaller brains than men even when the difference in body length was taken into account. The difference was approximately 110-115 g for the whole brain after correction for other variables. Women had also smaller lateral ventricles than men, but this difference was in proportion to the smaller size of their hemispheres. There was a physiologic decline in brain weight and a widening of the lateral ventricles with increasing age. This shrinkage probably started after the age of 55. There was a clear correlation between body length and brain weight. The estimated increase in brain weight was approximately 3 g per cm body length. There was a decreasing brain weight and an increasing ventricular size with a decreasing body mass index. This shows that emaciation leads to a decrease in brain size. Severe Alzheimer changes caused a statistically significant enlargement of the lateral ventricles both in men and women. There was a general trend for brain weight reduction in cases with severe Alzheimer changes but the decrease was statistically significant only in old women, and it could not be entirely excluded that the weight reduction in part was due to a concurrent emaciation rather than to the Alzheimer changes per se. In the majority of the cases, the Alzheimer changes were mild and had probably progressed slowly with age. A few cases had very severe changes.(ABSTRACT TRUNCATED AT 400 WORDS)

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.

VACTERL or MURCS association in a girl with neurenteric cyst and identical thoracic malformations in the father: a case of gonosomal mosaicism?

We report on a female infant with lethal congenital malformations including extreme hydrocephalus due to aqueductal stenosis, vertebral segmentation anomalies, fused costae, anal atresia, renal dysplasia, and bicornuate uterus with a double blind vagina. The VACTERL and the MURCS associations are possible diagnoses. Her father had a neurenteric cyst in infancy. He has identical vertebral and costal malformations as his daughter but is otherwise healthy. The possibility of dominant inheritance with gonosomal mosaicism in the father is discussed.

Slow progression to AIDS in intravenous drug users infected with HIV in Norway.

STUDY OBJECTIVE: To study the rate of progression to AIDS and to death, and the causes of death among intravenous drug users in Norway. DESIGN: This was a prospective study. The study population was followed from diagnosis of HIV seropositivity until death or the end of the study period. The mean follow up was 56 months (range 1-73 months). SETTING: Subjects were recruited from a public HIV test clinic and followed by linkage to the National AIDS Registry and the National Cause of Death Registry. PARTICIPANTS: A total of 131 HIV positive intravenous drug users were included. The study population represented 75% of all intravenous drug users who had been diagnosed as HIV positive in Norway before 1987. None were lost to follow up. MAIN RESULTS: Four years after study entry, 3% (95% confidence interval, 0, 6%) had developed AIDS, while 15% (95% CI, 9, 21%) had died. Of the 25 subjects who died during the follow up period, 21 died from unnatural causes. Drug overdose accounted for 17 of these deaths. AIDS was the cause of death of three subjects only. Age more than 30 years at entry to the study was associated with short survival. CONCLUSIONS: These results suggest that the progression rate to AIDS in intravenous drug users is slow.

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.

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.

Watershed infarcts in the brain caused by microemboli.

Multiple vascular occlusions are frequently found in the leptomeningeal arteries over watershed infarcts in the brain. These occlusions have largely been interpreted as thrombi secondary to slowing of the blood flow. This report suggests that most of the occlusions are microemboli, which may lodge preferentially in these areas, and that they are the cause of the infarcts rather than secondary events. These suggestions are based upon the analysis of three groups of patients. The first group consists of four cases, two of which had atheromatous masses and the other two, tumor emboli in the overlying leptomeningeal arteries. These cases prove beyond doubt that microemboli can lodge preferentially in the watershed areas and cause infarcts in the brain. The second group consists of the cases of watershed infarcts that were precipitated by hypotensive episodes. Only one of these showed occlusion of the overlying arteries, although all of them obviously had slowing of the blood flow during the acute phase. These cases thus discredit the concept that stagnation thrombosis is a frequent event. Finally, three cases with watershed infarcts and vascular occlusions interpreted as platelet microemboli are presented to demonstrate different pathogenetic mechanisms effective in the process of embolization.

Pleomorphic xanthoastrocytoma: report of 5 cases.

Five cases of pleomorphic xanthoastrocytoma are described. The favorable prognosis of these tumors is confirmed. Thus, two patients had postoperative survival of 9 and 12 years, respectively, and three others are still alive and well, one of them 6 years after the operation. All the cases described until now (17 including the ones described here) have involved patients under 30 years of age. Most of the tumors have been located superficially in the brain with extensive adhesions to the meninges. Usually they have been well demarcated from the brain. Histologically, the tumors showed a marked cellular pleomorphism, including bizarre giant cells, but there were few mitoses and only a slight tendency to necrosis. The tumor tissue contained a dense network of reticulin fibers and many cells contained lipid vacuoles. Glial fibrillary acidic protein (GFAP) was demonstrated in the cytoplasm of the tumor cells.

Intracranial primary leiomyosarcoma arising in a teratoma of the pineal area.

The case of a 33-year-old man with a primary leiomyosarcoma arising in a mature teratoma in the pineal area is presented. The tumor extended into the posterior part of the third ventricle and caused hydrocephalus. Its smooth muscle derivation was confirmed by immunohistochemistry and electron microscopy. The patient has been followed for more than 2 years after surgery and postoperative radiotherapy. He has full working capacity and there are no signs of tumor recurrence. To our knowledge this is the first presentation of a leiomyosarcoma derived from a teratoma in the pineal area.

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.

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.

Neurocutaneous melanosis. Case report and a brief review.

Neurocutaneous melanosis is a rare congenital syndrome characterised by large or numerous congenital pigmented naevi and excessive proliferation of melanin-containing cells in the leptomeninges. The process is diffuse or multifocal, and has a tendency to infiltrate the neural tissue and the cerebrospinal cord; remote metastases may occur. There is usually histological evidence of malignancy (cellular pleomorphism and mitotic activity). Involvement of the basal cisterns is apt to cause internal hydrocephalus, and the prognosis is grave even when there is no histological evidence of malignancy. We present the case history and necropsy findings of a baby boy with neurocutaneous melanosis, followed by a brief review.

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.

[Brain injuries after transient circulatory and/or respiratory failure (cerebral hypoxic injury) in newborn infants]. / Hjerneskader etter forbigående sirkulasjonsog/eller respirasjonsstans (cerebral hypoksiskade) hos nyfødte.

A clinico-pathological survey of different types of cerebral hypoxic/ischemic injuries in foetuses and infants is presented. The lesions may occur before, during and after the birth. Some of them occur only in foetuses and infants less than two months old. The topic has been simplified in order to be useful as a basis for evaluating these lesions in daily diagnostic work. Cerebral hypoxic/ischemic injuries are frequently seen in preterm infants and term infants with severe cardiac anomalies. Extensive damage may be fatal or may involve severe permanent psychomotoric deficits in the survivors. The severity of the deficiencies depends on the type, location, and extent of damage. A severe lesion is a common cause of cerebral palsy, and a mild lesion is probably one cause of minimal brain dysfunction. Recent studies indicate that the lesions seen in preterm infants frequently occurred in utero. Thus, autopsies of perinatal deaths should include neuropathological examination of the brain to disclose possible cerebral/hypoxic damage, and its distribution, severity and age.