Grey matter pathology in multiple sclerosis.

Although multiple sclerosis (MS) has been considered a white matter disease, MS lesions are known to occur in grey matter. Recent immunohistochemical studies have demonstrated extensive grey matter demyelination in chronic MS. The most common lesion type consists of purely cortical lesions extending inward from the surface of the brain, this lesion subgroup is grossly underestimated by standard histochemical myelin staining methods. Some MS patients have subpial demyelination in all cortical areas of the brain; this pattern has been termed ''general cortical subpial demyelination''. Extensive cortical demyelination is associated with the progressive phases of disease, as less cortical demyelination has been detected in relapsing-remitting MS. The pathology of grey matter lesions differs from that of white matter lesions; grey matter lesions are less inflammatory, with less macrophage and lymphocyte infiltration. In purely cortical lesions there is no significant increase in lymphocytes compared with non-demyelinated adjacent cortical areas in MS patients or cerebral cortex in control patients. Significant axonal transection and neuronal loss have been demonstrated in grey matter MS lesions. Current magnetic resonance imaging (MRI) methods are not sensitive for purely cortical MS lesions. The clinical significance of cortical MS lesions may not be characterised until more sensitive MRI methods are developed.

Leptomeningeal tissue: a barrier against brain tumor cell invasion.

BACKGROUND: Primary brain tumors are characterized by an extensive infiltrative growth into the surrounding brain tissue. This process is confined to the central nervous system, and tumor cell metastasis to other organs is rare. However, other tumors of non-neural origin may frequently metastasize to the central nervous system. PURPOSE: The purpose of the present study was to examine the invasive behavior of different glioma cells into tissues of neural (brain aggregates) as well as non-neural origin (leptomeningeal tissue). Using the same target tissues, the invasive characteristics of two neural metastatic tumors (one malignant melanoma and one small-cell lung carcinoma) were also studied. This direct comparison of the invasive behavior between tumors of neural and non-neural origin provides valuable information regarding the mechanisms of glioma cell dissemination in the central nervous system. METHODS: The in vitro invasive behavior of human tumors of the central nervous system into human leptomeningeal tissue as well as into normal rat brain tissue was studied. For this purpose, a co-culture system consisting of tumor biopsy specimens, human leptomeningeal cell aggregates, and brain cell aggregates was established. Three glioblastomas, one oligodendroglioma, one meningioma, one small-cell lung carcinoma, and one malignant melanoma were studied. RESULTS: In co-cultures of gliomas and leptomeningeal cell aggregates, a well-defined border between the two tissues was observed. The brain cell aggregates, in contrast, were consistently invaded by the glioma cells. The brain metastases showed a different invasion pattern. The metastatic cells invaded and progressively destroyed leptomeningeal cell aggregates, whereas they did not invade the brain cell aggregates. Upon confrontation of the leptomeningeal tissue with the meningioma, a fusion of the two tissues was observed. Immunostaining of the leptomeningeal tissue showed a strong expression of the basement membrane components fibronectin, collagen type IV, and laminin with no expression of glial fibrillary acidic protein, neuron-specific enolase, or S-100 protein. CONCLUSIONS: The present study indicates that there may be important biologic differences between the invasive behavior of gliomas and non-neuroepithelial tumors. Our co-culture experiments suggest that leptomeningeal cells and associated acellular components may constitute a barrier against glioma cell invasion. However, this barrier may not be functional for metastatic tumors to the brain. The presence of glioma cells within the leptomeninges should not necessarily be taken as evidence of aggressive growth or as an indicator of malignancy.

Patterns of epithelial metaplasia in malignant gliomas. I. Papillary formations mimicking medulloepithelioma.

Adenoid-like formations resembling ducts and glands or forming a cribriform pattern have previously been described in malignant gliomas, resulting in some cases in a confusion with metastatic adenocarcinoma. The interpretation of these structures as being composed of anaplastic glial cells rests partly on the presence of transitions to more differentiated neoplastic astrocytes and partly on the positivity of some of these cells for glial fibrillary acidic protein. In this report two cases are presented in which the adenoid pattern was associated with papillary formations mimicking the arrangement of a medulloepithelioma. These structures represent a form of aberrant neoplastic differentiation in a malignant glioma rather than the expression of an embryonal neuroepithelial neoplasm.

Oligodendroglioma. Histologic evaluation and prognosis.

All oligodendrogliomas registered in Norway during a 25-year period (1953-1977) were studied to establish the frequency of different histologic features and to compare them with survival data of the patients. The minimum observation time was five years. The original tumor specimens from 208 patients were independently reexamined by two pathologists. The characteristic oligodendroglioma of this series was of medium cell density (53% of lesions), with moderate nuclear atypia, with vascular endothelial proliferation (53%), calcification (56%), with from one to five mitotic figures per ten high power fields, and without microcystic degenerative changes (58%). Subpial tumor cell infiltration, perivascular lymphocytic infiltration and local leptomeningeal invasion were present in a minority of cases. In 11 cases autopsy material was the only source of diagnosis. Microcysts, necrosis, and cell density were the only histologic features of prognostic significance. Subpial infiltrative growth was of suggestive prognostic value. There was no significant association between the number of mitotic figures and survival. Vascular endothelial proliferation, calcification, pronounced nuclear atypia, perivascular lymphocytic infiltration and local leptomeningeal invasion were of no significant prognostic value. Age at operation did not alter these conclusions, neither did sex nor duration of preoperative symptoms.

Patterns of epithelial metaplasia in malignant gliomas. II. Squamous differentiation of epithelial-like formations in gliosarcomas and glioblastomas.

Six cases are reported (four gliosarcomas and two glioblastomas) in which the epithelial-like areas of glial anaplasia showed focal squamous cell differentiation, characterized by the development of epithelial whorls, keratin pearls and immunopositivity for cytokeratin. The expression of glial fibrillary acidic protein and the development of squamous metaplasia usually were mutually exclusive. Autopsy findings in two patients and clinical work-up in five failed to disclose a primary extraneural malignancy. It is suggested that squamous differentiation may represent an extreme form of epithelial metaplasia in a malignant glioma. This possibility should be kept in mind in the diagnostic evaluation of such cases, especially in view of the current emphasis on the immunomorphologic demonstration of intermediate filament tumor markers.

Neoplasms of the central nervous system in Norway. III. Epidemiological characteristics of intracranial gliomas according to histology.

Data were analysed from 4859 patients with different histological types of intracranial glioma registered by the Norwegian Cancer Registry between 1955 and 1984. Glioblastoma comprised 57.9% of all cases. The second most common primary brain tumour was astrocytoma (19.0%), then mixed glioma (9.2%), oligodendroglioma (7.9%), medulloblastoma (3.1%) and ependymoma (2.9%). A primary brain tumour in a child is approximately twice as likely to be an astrocytoma as a medulloblastoma. The age-specific incidence for glioblastoma increases with age, whereas the incidence of astrocytoma and oligodendroglioma peaks at middle age. Both glioblastoma and astrocytoma showed increased incidence rates over the study period and this was most pronounced in the age-group above 60 years. The prognosis for gliomas varied with age at time of diagnosis, generally being better the younger the patient. For oligodendroglioma patients, survival prospects were independent of age at time of diagnosis. The best prognosis was seen in patients up to 30 years with astrocytoma. Applied in epidemiology, the data indicate that astrocytoma, oligodendroglioma, mixed glioma and ependymoma may be treated as a group which should be separated from both glioblastoma and medulloblastoma.

Neoplasms of the central nervous system in Norway. II. Descriptive epidemiology of intracranial neoplasms 1955-1984.

A population-based study of 8480 patients - 4508 (53%) males and 3972 females - with primary intracranial neoplasms reported to the Norwegian Cancer Registry during the period 1955-84, is presented. 81% of the cases were histologically verified. The peak age-specific incidence rate in the total series occurred in the age-group 55-64 years. Gliomas constituted the largest histological group with an age-adjusted incidence rate of 5.0 cases per 100,000 population per year for males and 3.5 for females. Case ascertainment of primary intracranial neoplasms is reduced above the age of 60 in Norway, mostly due to a a low autopsy rate. The major impact of the introduction of computer tomography (CT) in the case ascertainment of intracranial neoplasms has been a raised incidence, in patients over the age of 60, of neoplasms which are not histologically verified.

Neoplasms of the central nervous system in Norway. I. Quality control of the registration in the Norwegian Cancer Registry.

The Norwegian Cancer registry includes reports on 8,933 cases of primary central nervous system neoplasms diagnosed in the period 1955-1984. Before submitting this data set to epidemiological analysis, errors were searched out and subsequently corrected, and a quality control was performed. First, seven categories of neoplasm records likely to be faulty were defined. In this way 109 cases (1.2% of the total) were identified for extensive study. Minor or major errors were found and corrected in 86 cases. The main source of error was misinterpretation of data by cancer registry staff (67 out of 109 cases). The second approach was to evaluate the quality of the corrected data set by a random draw of 300 cases. Errors concerning total incidence rates and rates for main groups of gliomas, meningiomas and neurilemmomas represented 0.3% of the total, and altogether 9.3% of errors of varying severity were revealed. The series is discussed with regard to prerequisites for serving as reliable data on CNS neoplasm epidemiology. The results indicate that the data from the Norwegian Cancer Registry is sufficiently valid for a thorough study of CNS neoplasms.

Neoplasms of the central nervous system in Norway. V. Meningioma and cancer of other sites. An analysis of the occurrence of multiple primary neoplasms in meningioma patients in Norway from 1955 through 1986.

The association between meningioma and a primary malignant neoplasm at another site was studied. The data from the population-based Norwegian Cancer Registry were analysed according to whether the meningioma occurred before or after the malignant neoplasm. Male patients with meningioma showed a raised risk for developing a subsequent renal cancer. A significant association was found between meningioma and subsequent breast cancer in females 50-64 years old at time of meningioma diagnosis and between breast cancer and subsequent occurrence of meningioma. Breast cancer patients with symptoms of an intracranial neoplasm may therefore have a potentially curable meningioma and female meningioma patients over 50 years should be considered for breast cancer screening programmes.

Neoplasms of the central nervous system in Norway. IV. A population-based epidemiological study of meningiomas.

All 1632 cases of meningioma reported to the Norwegian Cancer Registry from 1955 to 1986 have been studied: a) 96% appeared in patients over 30 years of age, b) 95% were histologically benign, c) 88% were located intracranially, and d) 66% occurred in females. The female predominance manifested itself in the middle age period. Eighty-seven percent of the intraspinal meningiomas presented in females, but the ratio between intracranial and intraspinal meningiomas was significantly lower in females (5.4) than in males (20.4). Increased incidence rates of meningioma in females are revealed for the birth-cohorts after 1930. The reason for this change is unclear so both environmental and hormonal factors should be explored. Based upon the epidemiological data, it appears that female sex hormone(s) could act as a growth stimulus in the development of meningiomas, but are neither sufficient nor necessary for tumourigenesis.

Modal DNA content of human intracranial neoplasms studied by flow cytometry.

The relative DNA content in 56 human intracranial tumors was investigated by flow cytometry and correlated to their histological type. Tumors with a modal DNA content within the diploid value (2c) +/- 1/2c were divided from those with heteroploidy. Of the "benign non-neuroepithelial tumors," the meningiomas (five), neurilemomas (two), pituitary adenomas (three), and one hemangioblastoma had a unimodal diploid/near-diploid DNA content. The "malignant non-neuroepithelial tumors" were both heteroploid (two metastatic carcinomas) and diploid/near-diploid (three meningeal fibrosarcomas and one primary malignant lymphoma). Of the neuroepithelial tumors, the highly differentiated gliomas all had a diploid/near-diploid DNA mode except one recurrent oligodendroglioma. The majority of the poorly differentiated gliomas also presented near-diploid DNA modes. Heteroploidy of primary brain tumors was not correlated with a more malignant clinical/biological behavior in the individuals in this study.

Primary intraspinal neoplasms in Norway, 1955 to 1986. A population-based survey of 467 patients.

A survey of all patients (173 males and 294 females) registered with primary intraspinal neoplasms in the Norwegian Cancer Registry from 1955 through 1986 is presented. Annual age-adjusted incidence rates of new tumors per one million population were three for males and five for females. Altogether, 89% of the tumors were verified histologically. Meningioma was the most common tumor type, followed by ependymoma and neurilemoma. Intraspinal ependymomas accounted for 34.5% of all 223 ependymomas of the central nervous system, whereas only 0.2% of the 3046 glioblastomas were found intraspinally. Patients with intraspinal meningioma had a better life expectancy than those with intracranial meningioma. The 5-year relative survival rate for patients with intraspinal ependymoma was 88.9% in contrast to 24.4% for patients with intracranial ependymoma.

Cerebellar ganglioglioma. Case report.

This report presents clinicopathological documentation of a nerve-cell tumor in the right cerebellar hemisphere in a young woman. The nomenclature and some other aspects of tumors containing neuronal cells are discussed.

Oligodendroglioma: incidence and biological behavior in a defined population.

The cases of 208 patients with histologically confirmed oligodendrogliomas were studied. The incidence represents 4.2% of all primary brain tumors diagnosed in the Norwegian population over a 25-year period. All of these tumors were cerebral and the majority affected the frontal lobe. The patients' median age at diagnosis was 47 years, with a range from 3 to 76 years; 6% of the oligodendrogliomas occurred in children. The median duration of symptoms before diagnosis was 20.5 months (mean 43 months). Plain skull x-ray films showed calcified deposits in 28% of the tumors. At operation, most of the tumors were poorly defined, without cyst formation, hematoma necrosis, or calcification. The median duration of disease from onset of symptoms until death was 14 months in nine untreated cases. In surgically treated oligodendroglioma patients the median survival time from onset of symptoms was 74 months. The median postoperative survival time was 35 months (mean 52 months). Tumor calcification, as seen on plain skull x-ray films, was associated with a significantly longer survival period. The surgical findings of gross necrosis, gross hypervascularity, and soft tumor consistency were all related to a shorter total duration of disease. Grossly well demarcated lesions were associated with a significantly longer postoperative survival. The length of postoperative survival correlated with the preoperative clinical status. The cumulative proportion of patients surviving 5 years was 0.342. The patient's age and sex did not have a statistically significant influence on survival time. The extent of surgical excision only seemed to play a role when the neurosurgeon considered that he had removed the whole lesion: these patients had a median postoperative survival period 14 months longer than the other oligodendroglioma patients. The ABO blood group of the oligodendroglioma patient was of prognostic value. In particular, patients with blood group A had a distinctly poorer prognosis than patients with O or B blood. The survival data from this unselected series indicate that cerebral oligodendrogliomas have a less favorable prognosis than has generally been believed.

Statistical analysis of clinicopathological features, radiotherapy, and survival in 170 cases of oligodendroglioma.

The postoperative survival time of 170 nonrandomized patients treated for cerebral oligodendrogliomas in Norway from 1953 to 1977 was studied. Survival times were significantly prolonged if postoperative irradiation was performed in addition to surgery (median survival time 26.5 vs. 38 months, p = 0.039). In the group without postoperative radiotherapy, the 5-year rate of survival was 27% compared with 36% in the irradiated patients. The respective survival rates after 8 years were 14% versus 17%; thus, there was little effect on long-term survival. Irradiation appears not to be of benefit after "total" removal. Patients with partly resected lesions appeared to benefit from postoperative radiotherapy; the median survival period after subtotal tumor resection was 37 months with and 26 months without radiotherapy (p = 0.0089). The findings also indicate that irradiation doses between 40 and 50 Gy were as effective as doses between 50 and 60 Gy in increasing the patients' probability of surviving 5 years after subtotal tumor resection. Since the risk of radiation necrosis is proportional to the dose applied, the lower dose is recommended. These conclusions were also valid when adjustments were made for prognostically significant histological and clinical features.

Characterization of premalignant neurogenic rat cells in vitro.

In long term culture of N-ethyl-N-nitrosourea (ENU) exposed fetal BD IX-rat brains, cells proliferate and form aggregates (nodules) in vitro, starting 2-3 months after the transplacental carcinogen injection in vivo. Cell nodules of cultures from 3-6 months after ENU exposure were investigated for the presence of organoid structures, signs of differentiation, and differentiation products. Organoid structures were absent as were signs of differentiation into more mature neuroglial cells since a relatively uniform immature cell population was typical for the nodules studied. Nuclear changes in form of nuclear envelope dilatation, margination and condensation of chromatin were present. The S-100 protein was generally expressed by the neuroglial cells in this premalignant phase; GFA and 14.3.2. protein were expressed to a variable degree. The cells showed enhanced proliferation. In conclusion there was a gradual change of differentiation accompanied by the acquisition of atypical nuclear structure in the premalignant phase studied.

Transmission electron microscopy of malignant neurogenic rat cells during invasion into embryonic chick heart fragments in vitro.

Invasion of chemically induced brain tumour cells from BD IX-rats into precultured fragments of embryonic chick heart (PHF) was studied by transmission electron microscopy. The malignant cells from monolayer cultures were suspended and allowed to form aggregates for 24 hours on a gyratory shaker. The single aggregates were allowed ro attach to a single PHF and thereafter incubated in a confronting culture on a gyratory shaker. Invasion into the PHF started with cytoplasmic cell extensions between PHF cells and vanishing of heart cell junctions. Irreversible intracellular alterations in heart cells followed the disruption of intracellular contact by the malignant neurogenic cells. The latter exhibited fewer microvilli when invading the PHF than when located at the periphery. No junctions connecting heart cells with neurogenic cells were observed. Malignant cells were lying between the PHF and no extensions were seen in PHF cells. Hetero/autophagosomes were regularly present in the malignant cells and also in PHF cells. The aggregates of the 13 tumourigenic neurogenic cell lines tested, all produced the same alterations in the PHF cells.

Trans fatty acids. 1. Growth, fertility, organ weights and nerve histology and conduction velocity in sows and offspring.

Effects of dietary trans fatty acids on the pre- and postnatal growth and development in pigs were studied with special emphasis on nervous tissue. In experiment 1, female pigs were fed partially hydrogenated fish oil (PHFO) (28% trans) or soybean oil (PHSBO) (36% trans), in comparison with lard (0% trans) from weaning (3 wk) through the first reproduction cycle (up to 2 yr). In experiment 2, female pigs were fed two fish oils (33 and 19% trans) in comparison with coconut oil (0% trans) in diets with low and high levels of linoleic acid (18:2n-6 cis, cis) from gestation until their offspring were three wk old. Compared with the trans-free fats, the trans-containing fats had no effect on growth and development, feed consumption and utilization or on the weight of the brain, heart, kidneys, liver, lungs or spleen in the adult sows and their offspring. No effects from the experimental fats were found on histology and conduction velocity of the peroneal nerve. An increased number of the sows fed PHFO had fertility problems compared with those fed lard and PHSBO in Expt. 1, but no similar effects were seen in Expt. 2. It is concluded that consumption of trans fatty acids with 18-22 carbon atoms from PHFO and with 18 carbon atoms from PHSBO at levels that were 5 to 12 times higher than those normally consumed by humans had no detrimental effects on female pigs or their offspring during pregnancy and lactation.

Subependymoma and unexpected death.

A previously healthy 53-year-old man died suddenly and unexpected. The main finding at the post mortem examination was a large 4th ventricle subependymoma, a rare brain tumour related to the ventricles of the brain. The salient features of subependymoma are described with emphasis on the microscopic picture and distinction from subependymal giant cell astrocytoma, as the tumour harboured large, bizarre astrocytes. Coronary atherosclerosis and mild cardiac hypertrophy were present as the only pathologic changes outside the central nervous system. The cause of death is discussed in light of earlier reports on brain tumours and sudden fatal incidents.

Tumour volume reduction following gamma knife radiosurgery: the relationship between X-ray and histological findings.

The case histories of two young ladies with Cushing's disease are described. Both patients were treated first with Gamma Knife radiosurgery and subsequently by microsurgery. The radiosurgery caused a marked reduction in tumour volume but only a partial relief of the endocrinopathy. Comparison of the histological findings with the radiological findings following radiosurgery indicates that confluent necrosis is not a prerequisite for a reduction in tumour volume. It seems more likely that the reduction in tumour volume is related to changes in cellular dynamics.