Presenile Alzheimer dementia characterized by amyloid angiopathy and large amyloid core type senile plaques in the APP 692Ala-->Gly mutation.

Mutations at codons 717 and 670/671 in the amyloid precursor protein (APP) are rare genetic causes of familial Alzheimer's disease (AD). A mutation at codon 693 of APP has also been described as the genetic defect in hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D). We have reported a APP692Ala-->Gly (Flemish) mutation as a cause of intracerebral hemorrhage and presenile dementia diagnosed as probable AD in a Dutch family. We now describe the post-mortem examination of two demented patients with the APP692 mutation. The neuropathological findings support the diagnosis of AD. Leptomeningial and parenchymal vessels showed extensive deposition of Abeta amyloid protein. Numerous senile plaques consisted of large Abeta amyloid cores, often measuring more than 30 microm in diameter and were surrounded by a fine meshwork of dystrophic neurites. In addition, there were a large number of paired helical filaments in pyramidal neurons and dystrophic neurites. Our findings show that the APP692 mutation leads to morphological abnormalities that are similar to AD, but the morphology of senile plaques is clearly distinct from that described in sporadic and chromosome 14-linked AD patients, in patients with APP717 mutations causing familial, presenile AD and in patients with the APP693 mutation causing HCHWA-D.

Signet-ring cell oligodendroglioma--report of two cases and discussion of the differential diagnosis.

Two cases of oligodendroglioma consisting largely of signet-ring cells were analyzed histopathologically, immunohistochemically and at the ultrastructural level. The signet-ring cells were negative for a panel of tumor lineage markers including glial fibrillary acidic protein, and were negative for Ki-67 (MIB-1 immunohistochemistry). In contrast with the abundance of lysosomal structures reportedly present in the so-called eosinophilic granular cells in oligodendrogliomas, degenerating mitochondria were mainly seen in the cytoplasm of the signet-ring cells. The differential diagnosis of the oligodendroglial signet-ring cell tumors occurring in children and in adults is discussed.

Cytogenetic, molecular genetic and pathological analyses in 126 meningiomas.

In a series of 126 meningiomas, tumor and patient characteristics were investigated and statistically analyzed. A combined cytogenetic and molecular genetic approach was used to study chromosomal abnormalities and loss of markers on chromosome 22q. This approach was successfully applied to 93 meningiomas. In 66 cases, complete or partial loss of chromosome 22 was observed and in at least 12 of them this chromosome was involved in structural aberrations. In addition to chromosome 22 changes, chromosomes 1, 6, 11, 13, 14, 18, 19, X, and Y were also frequently involved in structural and numerical aberrations. Statistical analysis revealed a significant association between the number of chromosomal abnormalities and tumor grade. Complex karyotypes predominated in the group of grade II/III meningiomas. Furthermore, other variables showed statistically (or marginally statistically) significant differences. Meningiomas from the convexity were more often grade II/III, displayed predominantly (partial) loss of chromosome 22 and had complex karyotypes more often. These features were frequently found in meningiomas from males. Base meningiomas, on the other hand, occurred more often in females; they were usually grade I, showed loss of (parts of) chromosome 22 less often and displayed fewer additional chromosomal abnormalities.

Familial occurrence of polymorphous oligodendroglioma.

A case of familial polymorphous oligodendroglioma, occurring in a brother and sister, is presented. Polymorphous oligodendrogliomas have a characteristic histopathology consisting of scattered multinucleated giant cells against a typical oligodendroglial background. The oligodendroglial character of the tumors was underlined by positive immunostaining for antigalactocerebroside, anticarbonic anhydrase, and anti-leu-7, without expression of glial fibrillary acidic protein. Both tumors were immunopositive for p53, suggesting a mutation in the p53 gene. No incidence of cancer was recorded in the family. This is the first report of familial occurrence of this particular subtype of oligodendroglioma.

Nasopharyngeal presentation of pituitary tumors. Differential diagnosis and treatment.

The intranasal presentation of pituitary tumors is rare. We describe six patients with supposedly intranasal carcinomas, treated by surgery, local chemotherapy, and/or radiotherapy. Because of the favorable clinical course, immunohistochemical reexamination of tumor tissue was done, which showed a macroprolactinoma in four and a nonfunctioning pituitary adenoma in two patients. Interestingly, anterior pituitary function was normal in four and only slightly disturbed in two of them. The radiological appearance of the sellar region was completely normal in two patients. Routine immuno-histochemistry would have prevented inappropriately aggressive therapy. Dopamine agonist therapy was effective in the four macroprolactinoma patients, but the nasopharyngeal localization of the tumor seems to increase the risk of rhinorrhea and/or meningitis.

The pleomorphic xanthoastrocytoma and its differential diagnosis: a study of five cases.

Five brain tumors with the histopathologic features of pleomorphic xanthoastrocytomas (PXAs) are presented. Computed tomography scans showed a remarkable homology. Two cases had atypical localizations for a PXA, while one 46-year-old patient did not conform to the normal age distribution of this tumor. Nevertheless, in these cases, the histopathology was always characteristic for PXA, a remarkable pleomorphism, in addition to simultaneous expression of glial fibrillary acidic protein and histiocytic markers in the various tumor cells. In one of the presented tumors, however, clusters of neoplastic neuronal cells were also found. In this particular case, differential diagnostic criteria to distinguish between a PXA and a desmoplastic infantile ganglioglioma are lacking.

Ultrastructural and immunohistochemical segregation of gemistocytic subsets.

Gemistocytes are frequently encountered in cases of reactive gliosis as well as in glial tumors. Recently, miniature forms of gemistocytes (minigemistocytes) were recognized as cellular constituents of oligodendrogliomas. Antibodies specific for the intermediate filaments glial fibrillary acidic protein and vimentin are reactive with gemistocytic cells, but do not react specifically with these cells. In a study of 23 glial tumors we found the monoclonal antibody Pm43 selectively reactive with the classical gemistocytes as well as with the minigemistocytes. Nevertheless, at the ultrastructural level a striking difference in the arrangement of the glial filaments between both gemistocytic cell types was found. Immunoelectron microscopy showed that the reactivity for the newly discovered gemistocytic marker Pm43 was confined to identical intermediate filaments. Despite immunohistochemical homology, a clearly different ultrastructure divides classic gemistocytes and minigemistocytes into two subsets.

Prognostic implications of glial fibrillary acidic protein containing cell types in oligodendrogliomas.

In oligodendroglial tumors the intermediate filament glial fibrillary acidic protein (GFAP) may be expressed by cells with the morphologic characteristics of typical oligodendrocytes (gliofibrillary oligodendrocytes [GFOC]) and by miniature forms of gemistocytes (minigemistocytes) as well. These latter cell types have been regarded as transitional cells that represent intermediate forms between an oligodendroglial and an astrocytic phenotype. Furthermore, in oligodendrogliomas GFAP may be expressed by intermingled classic large gemistocytes, which are not considered transitional cells. In a retrospective study of 111 oligodendrogliomas, the presence of the various GFAP-positive cell types was correlated with the survival rates of the patients. Therefore, GFAP expression was visualized with the use of an indirect conjugated peroxidase method. The survival times of the patients were recorded and statistical comparisons were made. The percentage of GFAP-positive tumor cells is increased in oligodendrogliomas of 28 patients who underwent a second biopsy (all these patients had been treated with radiation therapy as well). It was found that neither the presence of GFOC nor that of minigemistocytes is predictive of the survival. In contrast, patients with classic gemistocytes had survival lengths approximately twice as short as those of patients who did not have these cells in their tumors. No clear correlation was found between tumor grading or any of the individual histopathologic features with the presence of the various GFAP-positive cell types. The ominous sign of the presence of gemistocytes in oligodendrogliomas confirms some earlier reports about the prognostic significance of this cell type in astrocytomas.

Computed tomography-guided and stereotactic techniques in the diagnosis and treatment of cerebral tuberculoma.

The advantages of computed tomography-guided preoperative localization of brain lesions are illustrated in four cases of solitary tuberculoma and in one case of tuberculous abscess of both the cerebrum and the cerebellum. The role of stereotactic diagnostic techniques is emphasized. The clinical presentation and the computed tomography findings in these patients were equivalent to those from glial or metastatic tumors. Synchronous pulmonary tuberculosis was not present in these patients, but in three patients there was metachronous tuberculosis. Tuberculous meningitis had not developed in any of the patients.

The influence of the extent of surgery on the neurological function and survival in malignant glioma. A retrospective analysis in 243 patients.

A retrospective analysis was performed on 66 patients with anaplastic astrocytoma (AA) and 177 patients with glioblastoma multiforme (GM). The prognostic importance of age, performance status, tumour location, extent of surgery and radiation treatment was studied. Radiation therapy gave a significant improvement in survival in both AA (p less than 0.003) and GM (p less than 0.002), but was given only to patients in a good neurological condition. Both younger age (p less than 0.003), and good preoperative performance status (p less than 0.002) were associated with a longer survival in AA, but not in GM. Extensive surgery was correlated with a better immediate postoperative performance, a lower one-month mortality rate and a longer survival, in both AA and GM. There was no relationship between preoperative neurological function status and the extent of surgery. Because of the retrospective nature of this study, the conclusion is that performing extensive surgery instead of limited surgery does not lead to more deterioration in postoperative neurological function.

[Intracranial tuberculoma, a special space-occupying process]. / Intracranieel tuberculoom, een bijzonder ruimte-innemend proces.

In four men and in one woman we found an intracranial local tuberculous infection (4 tuberculomas and 1 tuberculous abscess) in the period 1982-1988. Clinical presentation and computer tomography do not allow discrimination of intracranial tuberculomas from other space-occupying lesions. The value of the stereotactic biopsy for the diagnosis is emphasized and some characteristics of this intracranial process are discussed.

Heterogeneity of growth hormone (GH) release by individual pituitary adenoma cells from acromegalic patients, as determined by the reverse hemolytic plaque assay: effects of SMS 201-995, GH-releasing hormone and thyrotropin-releasing hormone.

We used the reverse hemolytic plaque assay to study the dynamics of GH secretion by individual pituitary adenoma cells from eight acromegalic patients. There was a considerable variation between the adenomas with respect to the percentages of GH-secreting cells (25-78.5%) and also with respect to the amount of GH released per individual pituitary adenoma cell (mean plaque areas varying from 901-3559 micron 2). The GH plaque area frequency distributions from the adenoma cells were not normally distributed, but revealed a preponderance of small plaques, defined as those with areas smaller than the mean plaque area. The large plaques, that is those with areas larger than the mean plaque area, constituted 24-38% of the total cell population from different tumors and accounted for a large fraction (63-80%) of the total plaque area (the total amount of GH released by the adenoma cells). The somatostatin analog SMS 201-995 caused a shift in the GH plaque area frequency distributions toward smaller plaques, but had no effect on the overall percentages of GH plaque-forming cells in three of the five adenomas in which it was studied. This finding suggests that the adenoma cells from these patients that formed large plaques were preferentially inhibited by SMS 201-995. GHRH (studied in two adenomas) and TRH (studied in one adenoma) had no preferential effect on any subpopulation of adenoma cells. We conclude that GH secretion by individual somatotroph adenoma cells is highly variable both within and between adenomas and that SMS 201-995 has a preferential inhibitory effect on a subpopulation of adenoma cells in some adenomas.

Basilar artery giant fusiform aneurysms caused by congenital defect of the internal elastic lamina and media.

Giant fusiform aneurysms of the basilar artery were found in a 6-year-old boy who subsequently died after rupture of the aneurysm, and in a 64-year-old man who showed signs of ischemia and compression of the brain stem. Autopsy disclosed strikingly similar abnormalities of the wall of the basilar artery, consisting of a defect of the internal elastic lamina and absence of the media. A congenital anomaly may play a role in the pathogenesis of this abnormality, in both young and some elderly patients.

The effects of bromocriptine, thyrotropin-releasing hormone, and gonadotropin-releasing hormone on hormone secretion by gonadotropin-secreting pituitary adenomas in vivo and in vitro.

The characteristics and dynamics of hormone secretion in vivo and in vitro were investigated in six patients with gonadotropin-secreting pituitary adenomas. All six tumors secreted and contained FSH and different combinations of LH, beta-LH, and alpha-subunit. In addition, immunohistochemical examination of the pituitary tumor tissue showed staining with both LH and FSH in three and either LH or FSH in the other three tumors. TRH and GnRH stimulated hormone secretion in vivo and in vitro, and they also increased the hormone content of the cultured tumor cells. Bromocriptine significantly inhibited hormone release and reduced the hormone content of the tumor cells. In vivo, 2.5 mg bromocriptine significantly suppressed plasma hormone levels; the inhibiting effect on alpha-subunit concentrations was in general more marked than that on LH and FSH. We conclude that hormone release by gonadotropin-secreting pituitary adenomas can be stimulated by TRH and GnRH and inhibited by bromocriptine. Most of these tumors synthesize FSH, but there is a wide variation in the production of LH, beta-LH, and alpha-subunits. The sensitivity of hormone release to bromocriptine suggests that chronic therapy with this drug might have a beneficial effect on pituitary tumor size.

The sensitivity of growth hormone and prolactin secretion to the somatostatin analogue SMS 201-995 in patients with prolactinomas and acromegaly.

The somatostatin analogue SMS 201-995 has recently been shown to be effective in suppressing GH secretion in most acromegalic patients. In the present study it was investigated whether PRL release in prolactinoma and acromegalic patients might also be sensitive to SMS 201-995 and whether co-secretion of PRL in acromegaly plays a role in determining the sensitivity of GH secretion to SMS 201-995. The s.c. administration of 50 micrograms SMS 201-995 did not affect high plasma PRL levels in four microprolactinoma patients. Therapy of one of these patients for 3 d with 50 micrograms three times a day also did not affect PRL levels. The single administration of 50 micrograms SMS 201-995 in 22 acromegalic patients lowered plasma GH levels for 2-6 h to less than 5 micrograms/l in 14 patients and to less than 50% of control values in 16 patients. In 18 of these 22 patients the immunohistochemical picture of the pituitary tumour was known. Eleven patients had pure GH-containing tumours and in seven patients there were mixed GH/PRL-containing tumours. In two of these latter patients there was evidence for GH and PRL being secreted by the same tumour cells. The sensitivity of GH secretion to SMS 201-995 did not differ between the patients with pure GH or mixed GH/PRL-containing adenomas. Plasma PRL levels were not affected by SMS 201-995 in the patients with pure GH-secreting tumours, but were significantly suppressed in four of the seven patients with mixed GH/PRL containing tumours. Chronic treatment for 16 weeks of one patient with a mixed GH/PRL-containing tumour with SMS 201-995 (100 micrograms three times a day) resulted in normalization of both the increased GH and PRL levels. It is concluded that SMS 201-995 does not affect tumorous PRL secretion in patients with pure prolactinomas. In acromegalic patients with mixed GH/PRL-containing tumours PRL secretion in some patients is sensitive to SMS 201-995, making these patients good candidates for chronic treatment with the analogue. The simultaneous presence of PRL in the GH-secreting pituitary tumour or the presence of hyperprolactinaemia in acromegalics does not play a role in the sensitivity of GH secretion to the somatostatin analogue.

High incidence of somatostatin receptors in human meningiomas: biochemical characterization.

Thirteen human meningiomas were tested for their content of specific somatostatin (SRIH) receptors using an in vitro binding assay with meningioma homogenates as well as receptor autoradiography. All tumors had measurable amounts of somatostatin receptors. Receptor density, however, greatly varied among the tumors, ranging from low levels to more than 400 fmol/mg protein. Seven tumors, biochemically characterized in detail, had saturable and high affinity receptors [mean Kd, 1.10 +/- 0.42 (+/- SEM) nM], with pharmacological specificity for SRIH resembling the noncentral nervous system type of SRIH receptor. There was no correlation between the density of SRIH receptors and the density of progestin receptors measured in parallel. The presence of SRIH receptors in meningiomas was completely unexpected, and their role unknown. If the receptors can mediate antiproliferative properties in meningiomas, as has been suggested to be the case for such receptors in other endocrine tumors, the present data could be of potential therapeutic interest.

Monoclonal antibody selectively reactive with myelin sheaths of the peripheral nervous system in paraffin-embedded material.

We have produced a monoclonal antibody (PM43) selectively reactive with formalin-fixed paraffin-embedded peripheral nervous system (PNS) myelin. The hybridomas were generated by fusion of mouse myeloma cell line Sp2/0 with spleen cells of BALB/c mice immunized with cultured human melanocytes. Hybridomas were screened by the indirect immunoperoxidase assay. Ouchterlony analysis showed the immunoclass of PM43 to be IgM. By the immunoaffinity chromatography technique, among others a 43-kDa protein was isolated from PNS myelin. The antigenic determinant of PM43 in the mouse is expressed with a similar tissue distribution as observed in man. Expression of the antigenic determinant does not become visible until after birth in mice. PM43 opens further possibilities for the use of anti-myelin antibodies in the study of myelination and demyelination processes in the PNS and remyelination processes in the central nervous system.

Pyruvate kinase inhibition in the diagnosis of gliomas with an intermediate degree of malignancy.

The aim of the investigation was to see if the histological diagnosis of brain tumors showing an intermediate degree of malignancy can be improved by the measurement of L-alpha-alanine inhibition of pyruvate kinase isoenzymes. The inhibition of pyruvate kinase activity was measured in 51 gliomas with different grades of malignancy. It was confirmed that benign tumors have a low level of inhibition (less than 50%) and that the more malignant the tumor, the higher the level of inhibition became, reaching more than 75%. However, when grade II and III astrocytomas and grade II and III oligodendrogliomas were analyzed, their level of inhibition was found to be variable. Grade II showed low and moderate levels of inhibition and grade III moderate and high levels. In turn, inhibition levels ranging from 50 to 75% were not only found in brain tumors with an intermediate grade of malignancy, but also in a number of benign and malignant tumors. When the survival times of patients with brain tumors were compared with both the histological diagnosis and pyruvate kinase inhibition, the prediction of the survival time on the basis of low and high levels of inhibition correlated well with the histological diagnosis. In contrast, when moderate levels of inhibition were measured, the prediction of the patients' survival remained uncertain and no improvement was found in the prediction for tumors showing an intermediate degree of malignancy on the basis of histology.

Congenital malformations of the spinal cord without early symptoms.

Description of 11 patients with congenital malformations of the spinal cord. Six of them were males, five females and the age varied from 7 to 70 years. Most of these cases produced clinical neurological signs indicating spinal cord disease in later life during an intercurrent disease. It was thought that changes in the bloodvessels and/or perfusion of the area of the spinal cord malformation was the ultimate cause of the neurological symptoms. An exact explanation of the origin of these developmental disturbances of the spinal cord remains unknown. Different hypotheses proposed in the literature, concerning these malformations, are not satisfactory.

Intracerebral malignant schwannoma.

A case of highly malignant primary intracerebral schwannoma is presented in a boy aged 15 years. The histological, ultrastructural and immunocytochemical properties were consistent with a partly epithelioid schwannoma. All reports so far published of 18 intracerebral schwannomas were of benign tumors, one case was semi-malignant. As far as we know, this is the first report of a highly malignant intracerebral schwannoma.