Annexin-1 is no useful surrogate marker of multiple sclerosis - an immunocytochemical study of the cerebrospinal fluid.

OBJECTIVE: Annexin-1 is a calcium-binding protein with anti-inflammatory properties, which has previously been described in MS plaque tissue. We investigated the feasibility and specificity of annexin-1-immuncytochemistry of CSF cells to test its potential as a surrogate marker for MS. MATERIALS AND METHODS: CSF-specimens of 49 MS cases with different courses and 94 control cases were immunocytochemically studied with a monoclonal antibody to annexin-1. RESULTS: The highest level of cytoplasmic immunoreaction was seen in the most acute inflammatory disorders, such as bacterial meningitis and neuroborreliosis. CIS-, RR-MS-, and viral meningoencephalitis cases came next. The lowest annexin-1 expression was observed in neurosyphilis and SP-MS. In PP-MS and non-inflammatory control cases, annexin-1 expression was entirely lacking. CONCLUSION: Immunocytochemical staining of CSF cells with an antibody to annexin-1 is feasible. This may be helpful in further study of its role in the pathophysiology of inflammatory CNS diseases. The expression pattern seems to rather reflect the acuteness of the inflammatory process than specifying a certain underlying pathology. Although differences were observed between diverse disease groups, because of considerable overlap, a certain diagnosis of an individual case cannot be achieved. Thus, at present, we cannot recommend annexin-1 as a reliable surrogate marker of MS.

Primary intradural chordoma: report on three cases and review of the literature.

OBJECTIVE: Chordomas are rare malignant bone tumors of the skull base or sacrococcygeal region. They derive from notochordal remnants and usually have a chronic progressive course. Even rarer, intradural chordomas with a better biological behavior have also been reported. We present 3 further primary intradural extraosseous chordomas with a favorable clinical outcome. CLINICAL PRESENTATION: Two patients, a 38-year-old man and a 44-year-old woman, presented with neck pain. In these, intradural extraspinal tumors within intervertebral foramina were found. Both tumors were totally removed and the patients have been free of disease for 7 years and 1 year, respectively. The other patient, a 76-year-old man suffered from an unspecific gait disorder and diplopia as a result of a prepontine space-occupying lesion. In this case, only an incomplete tumor resection was possible but progression has not occurred for 5 years. MATERIALS AND METHODS: Paraffin blocks from all cases were examined with classical histopathological stainings and immunohistochemistry for pancytokeratin, CK7, CK8/18, CK19, EMA, CEA, vimentin, S100, aktin, desmin, GFAP, CD117, PDGF-receptor alpha and beta, collagen-type-IV, p63, and Ki67. Fluorescent in situ hybridization was used to exclude EWS translocation. RESULTS: All cases showed the typical histological picture with physaliphorous cells in a myxoid matrix and the characteristic immunohistochemical profile with positivity for vimentin, pancytokeratin, CK19, EMA, and S100. Staining for P63 and type IV collagen was consistently negative. Myxoid extraskeletal chondrosarcoma was excluded by in-situ-hybridization of the EWS gene. CONCLUSION: Considering our cases in context with so far published literature, we conclude that intradural chordomas are rare and in this location usually have a better prognosis compared to classical intraosseous chordomas.

[Muscle biopsy : Indications and techniques]. / Muskelbiopsie : Indikationen und Technik.

Various histological techniques were introduced for the analysis of muscle biopsy specimens in recent decades. During the 1960s, cryosections and enzyme histochemistry were established as the main techniques for evaluating muscle biopsies. Subsequently, immunohistochemistry was able to show normal components of muscle fibre, its damage, as well as accumulation or maldistribution in the presence of myopathies. In this way, structure myopathies, muscle dystrophies and inflammatory myopathies can be reliably diagnosed today. For the diagnosis of certain entities, semithin sections and electron microscopy of resin-embedded tissue, as well as molecular pathological techniques including immunoblotting and PCR are useful. To apply these and other methods optimally with the goal of achieving a diagnosis some prerequisites need to be met: a moderately affected muscle has to be chosen and a 3x1x1 cm biopsy should be taken by an experienced surgeon in an atraumatic way and transported immediately in a moist chamber to the nearest specialized laboratory. The muscle specimen is divided into four pieces, two of which are snap frozen in liquid nitrogen (one with OCT mounting medium on a cork plate, the other without mounting medium); the third piece is fixed in formalin and embedded in paraffin. The fourth is fixed in glutaraldehyde and embedded in resin. The logistical problems of a muscle biopsy need to be solved between clinicians and the analysis center prior to removal.

Spinocerebellar ataxia type 2 with glial cell cytoplasmic inclusions.

Glial cell cytoplasmic inclusions were identified in a case of spinocerebellar ataxia type 2. These have not been reported before. The inclusions were found in low frequency in the dentate nucleus, cerebellar white matter, pontine transverse fibres, and the inferior olivary nucleus. They were of variable size and shape and expressed ubiquitin, thus resembling glial cytoplasmic inclusions in multiple system atrophy. However, their immunohistochemical profile was different as they did not show immunoreactivity for either tau protein or alpha-synuclein. There was no evidence of expanded polyglutamine tracts in these inclusions, which also failed to label with silver stains. As in many other neurodegenerative diseases, in spinocerebellar ataxia type 2 there may be pathogenic contributions of glial cells other than the common astrogliotic response to neuronal damage.

Expression of annexin-1 in multiple sclerosis plaques.

This study describes the distribution and identity of annexin-1 positive cells in the central nervous system in patients with multiple sclerosis (MS). Glucocorticoid-inducible, anti-inflammatory properties have been ascribed to annexin-1, a member of a family of calcium-binding proteins that are referred to collectively as annexins. We have found annexin-1 to be spatially associated with active MS lesions and demonstrated a stage-dependent expression of annexin-1 in MS plaques. All of the most important pathogenetically involved cells of MS lesions showed a strong annexin-1 reactivity. Both correlation analysis and double staining procedures suggested annexin-1 expression in macrophages and perivascular lymphocytes, where a cytoplasmic reactivity was displayed, whereas in activated, gemistocytic astrocytes it was also concentrated close to the plasma membrane. Although the exact roles of annexin-1 in this setting are still to be determined, a possible contribution to anti-inflammatory processes might be suggested.

C-MYC expression in medulloblastoma and its prognostic value.

To identify prognostic factors in medulloblastoma, a common malignant brain tumor of childhood, expression of the oncogene c-myc was examined at the mRNA level by in situ hybridization. c-myc mRNA expression was observed in 30 of 72 tumors (42%). The c-myc gene copy number was determined by quantitative PCR from genomic DNA of paraffin-embedded tumors. c-myc gene amplification was present in 5 of 62 cases (8.3%). Therefore, c-myc amplification was obviously not the cause of c-myc mRNA expression in most samples. Kaplan-Meier estimation revealed a significant correlation between c-myc mRNA expression and survival (total mean follow-up 4.6 +/- 3.6 years, log-rank p = 0.02). Multivariate logistic regression analysis including sex, age, histological type, degree of surgical resection and expression of synaptophysin, GFAP and c-myc, was carried out on 54 patients who received both radiotherapy and chemotherapy. The analysis identified expression of c-myc as an independent predictive factor of death from disease.

Muscle hypertrophy due to scarring of the S1 nerve root.

Segmental muscle enlargement occurs in a variety of neurogenic conditions. We present a patient with calf hypertrophy, likely produced by continuous neuromuscular irritability and compensatory type 1 and type 2 muscle fiber hypertrophy. The underlying lesion of the S1 nerve root was caused by scarring, which could be demonstrated by Gadolinum enhanced, fat saturated magnetic resonance imaging. Thus, the application of this technique is recommended in otherwise etiologically unclear cases of neurogenic muscular lesions in order to detect chronic nerve root pathology.

Cell death in vasculitic neuropathy.

Vasculitic neuropathy shows cluster of differentiation (CD)4+ and CD8+ perivascular infiltrates. CD8+ cells kill the target by different ways. Some mechanisms require the release of granzymes and T-cell restricted intracellular antigen (TIA-1) which induce cell death by apoptosis. A nonsecretory ligand-mediated mechanism has been proposed for apoptosis and requires the interaction of Fas and Fas-ligand. We studied apoptosis by immunohistochemistry and terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) in nerve biopsy specimens in 19 cases of vasculitic neuropathy and 8 controls. In vasculitic neuropathy, perivascular mononuclear cells expressed TIA-1, granzyme A, and granzyme B. Regarding the ligand-mediated mechanism, we observed Fas+ and Fas-ligand+ mononuclear cells in an epineurial-perivascular distribution. Cells undergoing apoptosis, as demonstrated by TUNEL, represented mononuclear cells. In vasculitic neuropathy, apoptosis by both a secretory and a nonsecretory mechanism is suspected. However, apoptosis seems to be restricted to inflammatory mononuclear cells, suggesting that it may play a critical role in recovery from vasculitic neuropathy.

[30 years multiple system atrophy concept: retrospect and overview of multiple system atrophy]. / 30 Jahre MSA-Konzept: Ein Rück- und Uberblick über die Multisystematrophie.

Multiple system atrophy represents an enigmatic, clinico-pathologically defined neurodegenerative disease. According to findings of the last three decades, the historically derived, previously used terms olivopontocerebellar atrophy, striatonigral degeneration, and Shy-Drager-syndrome should be avoided in clinical use because of both the clinical and morphological overlap between these syndromes. Complex neurodegenerative syndromes other than multiple system atrophy according to recently developed criteria, should rather be referred to as multiple system degenerations.

Melanotic progonoma of the brain: a case report and review.

So far, only 25 melanotic progonomas have been found in the central nervous system (male/female ratio 3.5), mostly located in the cerebellum. The average age is 8 years (range 3.5 months to 69 years) with 85% becoming clinically apparent in the first decade of life; 73.7% of the patients reported succumbed to their disease at a mean age of 2.8 years, with a postoperative survival time of just 9 months. Systemic metastases were reported in 9 cases and had mostly spread via cerebrospinal fluid. In contrast to peripheral melanotic progonomas usually found in the maxilla, cerebral progonomas have a much worse outcome and have to be regarded as malignant. We present the case of a 1-year-old boy suffering from a melanotic progonoma of the pineal gland, who died at the age of 22 months with extensive spinal and abdominal metastases 10 months after partial removal of the tumor.

Cell death mechanisms in multiple system atrophy.

The presence and distribution of apoptotic cell death in multiple system atrophy (MSA) and morphologically related diseases were investigated by means of a modified terminal deoxynucleotidyl transferase-mediated nick end labeling method, comparing their distribution with that of glial cytoplasmic inclusions, immunohistochemically demonstrated bcl-2 protein, bax protein, CD95, TNFalpha, and p53-protein expression, as well as activated microglia. Apoptosis occurred almost exclusively in oligodendrocytes in multiple system atrophy and its general distribution was comparable to the already known oligodendroglial pathology in this disorder. Additionally, in about a quarter of glial cytoplasmic inclusions, there was upregulation of bcl-2-protein and coexpression with ubiquitin, suggesting a final attempt of involved cells to counteract apoptotic cell death. Bax protein was also demonstrated in oligodendroglial cells. A significant neuronal apoptosis was not observed in MSA; these cells might be destroyed secondarily to oligodendroglial apoptosis by necrosis or other forms of programmed cell death. These results emphasize the central role of oligodendroglial pathology in multiple system atrophy, making this disease unique among neurodegenerative diseases.

A unique case of cerebral spleen.

We present the first case of cerebral splenosis, occurring in a 20-year-old man 15 years after posttraumatic splenectomy. He became symptomatic through seizures and was operated on for suspected meningioma of the right occipital pole. Histologic evaluation of the lesion revealed splenic tissue with matching immunohistochemical results. Because no penetrating head injuries were reported at the time of trauma, a hematogenous spread of splenic tissue has to be assumed.

High amino acid uptake in a low-grade desmoplastic infantile ganglioglioma in a 14-year-old patient.

Amino acid uptake is higher in high-grade than in low-grade gliomas; this is the rationale for using radioactively labelled amino acids for the non-invasive grading of brain neoplasms. We present a 14-year-old boy with a low-grade desmoplastic infantile ganglioglioma (DIG) that exhibited marked contrast enhancement on magnetic resonance imaging (MRI), but no signs of infiltration and only minimal surrounding edema. In this benign neoplasm the relative uptake of the radioactively labelled amino acid I-123-alpha-methyl tyrosine (IMT), determined using single-photon emission computed tomography (SPECT), was 3.24; it was considerably higher than that of eleven other pretherapeutic low-grade gliomas where it ranged from 1.06 to 1.94 and also markedly above that average value of 2.37 found in 20 high-grade gliomas. This case report illustrates that results from emission tomography with radioactively labelled amino acids must be interpreted with caution, particularly when rare tumor entities are considered in view of uncommon clinical or radiological findings.

Factor XIIIa-immunoreactivity in tumors of the central nervous system.

The clotting factor XIIIa (FXIIIa) has been shown to be present both in tumor cells and in tumor-associated macrophages of different neoplasms such as Hodgkin's disease, giant cell tumor of bone, malignant fibrous histiocytoma, meningeal tumors, and hemangiopericytoma. The biological significance of these findings, however, are still unclear. This study investigates the immunohistochemical distribution of FXIIIa in 186 tumors of the central nervous system (CNS) in order to evaluate its possible diagnostic or prognostic significance in neuro-oncology. High-grade gliomas such as glioblastoma, gliosarcoma, astrocytoma (grade III WHO), and ependymoma (III) as well as meningiomas and meningeal hemangiopericytomas consistently contained factor XIIIa-positive cells, whereas low-grade glial tumors did not do so. One desmoplastic medulloblastoma and one anaplastic schwannoma also showed FXIIIa-positive cells. With the exception of hemangiopericytomas, however, the major source of FXIIIa expression in all these tumors consisted of a subpopulation of tumor-associated macrophages, the exact role of which still remains unclear. Because of its non-discriminatory staining in a wide variety of CNS tumors, the differential diagnostic contribution of FXIIIa in neuro-oncology seems to be limited.

Primary intracranial neoplasms of infancy and early childhood.

We investigated the age-related location, gender distribution, and histology of 107 brain tumors in children under 4 years of age seen in our department between 1984 and 1997. The male-to-female ratio was 1.4 (62/45 cases) with a prevalence of supratentorial tumors (60/47 = 1.3); the main histological entity was astrocytoma (33.6%), followed by ependymoma (14.0%). In the 1st year of life 22 cerebral neoplasms became clinically apparent. A higher ratio for supratentorial tumors was revealed (17/5 = 3.4), but without gender preference, and primitive neuroectodermal tumors (PNET) were the most frequent (5/22). In the 2nd year 25 tumors were found. The male-to-female ratio was 1.5 (15/10) and the supratentorial-to-infratentorial ratio, 1.1 (13/12). The two most common entities were astrocytoma and ependymoma (6 cases each). In addition, a survey of previously published investigations into this subject was performed and a compilation of data on 1960, 545 and 1084 tumors in children below the age of 1, 2 and 4 years, respectively, was prepared, which makes it the most extensive review of brain tumors of infancy and early childhood yet undertaken.

Congenital immature teratoma of the fetal brain.

Congenital intracranial tumors are very rare and only account for 0.5-1.5% of all childhood brain tumors. Even rarer are those with prenatal manifestation. The most common of these present at birth are teratomas, which show divergent differentiation with 90% of them containing tissues from all three germ layers. We report a rare case of an intrauterine congenital immature teratoma in a female fetus at 23 weeks of gestation, which was sonographically diagnosed in vivo by detection of the tumor and associated craniomegaly. Because of the poor prognosis, termination of the pregnancy was induced by Rivanol instillation. The cerebral tumor was confirmed at autopsy and was not associated with any other malformations. Histological and immunohistochemical features of this tumor are presented.

Iodine-123-alpha-methyl tyrosine in gliomas: correlation with cellular density and proliferative activity.

UNLABELLED: Amino acid transport rate in gliomas can be assessed using SPECT and the amino acid L-123I-alpha-methyl tyrosine (IMT). This study attempted to correlate the uptake of IMT by gliomas with the proliferative activity and cellular density of these neoplasms. METHODS: The study used 27 patients with gliomas, including 18 patients with high-grade tumors and nine patients with low-grade neoplasms. Amino acid transport rate was determined using IMT and the triple-headed SPECT camera. Proliferative activity was immunohistochemically assessed as the relative number of cells expressing the Ki-67 nuclear antigen; cellular density was evaluated using light microscopy. RESULTS: Relative IMT uptake correlated significantly with the proliferative fraction of tumor cells (r = 0.6, p < 0.001). There was no significant correlation between IMT uptake and cellular density (r = 0.25, p > 0.05). CONCLUSION: The uptake of the SPECT radiopharmaceutical IMT is related to proliferative activity rather than to the cellular density of gliomas.

Malignant peripheral nerve sheath tumor with extensive miliary metastases: a case report.

We report the course of a 19-year-old female who presented with a 13-year history of an occipital dermal tumor. Only five weeks after excision, the patient succumbed to cerebral dysregulation due to extensive miliary cerebral, hepatic, and pulmonary metastasis. The histologic features of the surgical specimen and the autopsy material differed suspiciously: a peculiar malignant progression of the tumor seemed to have occurred within five weeks.