Walter Schachenmayr

Prognostic implication of histopathological, immunohistochemical and clinical features of oligodendrogliomas: a study of 89 cases

Abstract Histopathological, immunohistochemical and clinical parameters were correlated with survival in 89 cases of oligodendroglioma (65 patients with grade II and 24 patients with grade III of the WHO classification). Median survival time and 5-year survival rate were 3.5 years and 76% for patients with oligodendroglioma grade II and 0.875 years and 23% for patients with oligodendroglioma grade III. The tumor biopsy specimens were immunohistochemically analyzed for Ki 67 (MIB-1), vimentin, glial fibrillary acidic protein (GFAP), neuron-specific enolase (NSE) and synaptophysin. MIB-1 nuclear labeling index ranged from 0.0% to 33.4%; vimentin-immunoreactive tumor cells were found in 25 cases. MIB-1 nuclear labeling index and vimentin immunoreaction showed a significant statistical correlation to the 5-year survival rate of the patients. Tumors with vimentin expression (n = 25) and/ or high MIB-1 labeling index (n = 26) had a poorer prognosis than tumors lacking vimentin expression (n = 57) and/or displaying a low MIB-1 labeling index (n = 56). The expression of immunoreactivity for GFAP (n = 53), NSE (n = 23) and synaptophysin (n = 15) appeared to be of no prognostic relevance. Patients with gross total tumor resection (n = 47) had a median survival time and 5-year survival rate of 3.3 years and 84% compared to 1.2 years and 42% for patients with subtotal resection (n = 41). The comparison between patients who underwent surgery alone (n = 53) and those who had surgery plus postoperative radiation therapy showed no significant survival benefit from postoperative radiation therapy. In conclusion, tumor grade, MIB-1 labeling index, expression of vimentin and the extent of surgery are shown to be of prognostic relevance for patients with oligodendroglioma.

VACTERL with the mitochondrial NP 3243 point mutation

The VACTERL association of vertebral, anal, cardiovascular, tracheo-esophageal, renal, and limb defects is one of the more common congenital disorders with limb deficiency arising during blastogenesis. The cause is probably heterogeneous; a molecular basis has not yet been defined. We report on a family in which a female infant with VACTERL was born in 1977 and died at age 1 month due to renal failure. Because her mother and sister later developed classical mitochondrial cytopathy associated with the A-G point mutation at nucleotide position (np) 3243 of mitochondrial (mt) DNA, we performed a molecular analysis of mt DNA in preserved kidney tissue from the VACTERL case. We discovered 100% mutant mt DNA in multicystic and 32% mutant mt DNA in normal kidney tissue. Mild deficiency of complex I respiratory chain enzyme activity was found in the mothers muscle biopsy. Other maternal relatives were healthy but had low levels of mutant mt DNA in blood. This is the first report to provide a precise molecular basis for a case of VACTERL. The differing tissue pathology depending on the percentage of mutant mt DNA suggests a causal connection between the mutation and symptoms. VACTERL, and this type of multicystic renal dysplasia, are new phenotypes for the np 3243 point mutation. The possibility of a mitochondrial disorder should be born in mind and also that VACTERL may occur as a first manifestation of a mutation that has been present for generations. This would have major implications for patient management and for genetic counselling regarding both the risk of recurrence and risk of other mitochondrial syndromes in affected families.

Fine Structure of Arachnoid Cysts

Recent studies of the fine structure of the cranial meanings of laboratory animals and man have shown that there is no subdural space. The latter is formed artificially by the tendency of meningeal tissues to cleave along a collagen-free zone, the dura-arachnoid interface layer. This layer is composed of an outer zone of dural border cells and an inner arachnoid barrier layer. The fine structure of nine arachnoid cysts was studied to determine the derivation of the cysts wall from the various components of normal human meanings. A cleaved dura-arachnoid interface layer covered only the dome of the cyst where the latter had abutted the dura mater. The interface layer did not partake in forming the cysts wall. The dominant phenomenon of the cysts wall was an absence of the normal trabeculation of the subarachnoid space, the trabecules being replaced by tightly packed collagen fibrils and a few scattered cells in between. Some cells were layered discontinuously at the inner face of the cyst wall, but there was no organized inner lining. No evidence was found for either a tight sealing of the extracellular spaces in the cysts wall, nor for the existence of an active transcellular fluid movement.

Cranial neuronavigation with direct integration of (11)C methionine positron emission tomography (PET) data -- results of a pilot study in 32 surgical cases.

Summary.Summary. Background: MRI detects small intracranial lesions, but has difficulties in differentiating between tumour, gliosis and edema. 11C methionine-PET may help to overcome this problem. For its appropriate intra-operative use, it must be integrated into neuronavigation. We present the results of our pilot study with this method. Method: 32 patients with 34 intracranial lesions detected by MRI underwent additional 11C methionine-PET, because the pathophysiological behaviour or the tumour delineation was unclear. All lesions were treated surgically. In 25 patients PET data could be integrated directly into cranial neuronavigation. Findings:11C methionine uptake was observed in 27/34 lesions, 26 of them were tumours: 14 malignant and 7 benign gliomas, 3 gliomas without further histological typing, one Ewing sarcoma and one non-Hodgkin lymphoma. Only one 11C methionine positive lesion was non-tumourous: it was staged as post-irradiation necrosis in a patient operated on for a malignant glioma. 3/7 11C-methionine negative lesions were classified as gliosis (n=2) and M. Whipple (n=1), but 4/7 were tumours: 2 astrocytomas WHO°II, 1 DNT and one astrocytoma WHO°III. The sensitivity of 11C methionine-PET was 87%, the specifity 75%, the positive predictive value 96% and the negative predictive value 43%. In all tumourous cases with positive tracer uptake the borderline area of the tumour was better defined by 11C methionine-PET than by MRI. Interpretation: A positive 11C methionine-PET is highly suspicious of a tumour, a negative one does not exclude it. 11C methionine-PET seems to be more sensitive than MRI for differentiating between tumour and edema or gliosis. Simultaneous integration MRI and 11C methionine-PET into cranial neuronavigation can facilitate cross total tumour removal in glioma surgery.

S-antigen-like immunoreactivity in a human pineocytoma

SummaryA pineocytoma was investigated by means of immunocytochemistry with the use of a polyclonal antibody against bovine retinal S-antigen. Several cells of this tumor displayed strong S-antigen-like immunoreaction in analogy to certain pinealocytes in normal human pineal organs. This study indicates that S-antigen immunocytochemistry may be applied to characterize tumors of the pineal region.

Immunocytochemical evidence of molecular photoreceptor markers in cerebellar medulloblastomas

With the use of antisera against bovine retinal S‐antigen and bovine opsin the authors demonstrate that in cerebellar medulloblastomas certain tumor cells display immunocytochemical properties characteristic of retinal photoreceptors and pinealocytes. S‐antigen‐like and opsin‐like immunoreactions occur in nine of 28 medulloblastomas investigated. All tumors displaying S‐antigen‐like immunoreactive neoplastic cells also contain opsin‐like immunoreactive cells; however, the opsin‐like immunoreactive cells were less frequent than the S‐antigen‐like immunoreactive cells throughout all positive cases. The immunoreactive cells displayed several long processes. Generally, both S‐antigen and opsin‐like immunoreactive cells considerably vary in number among individual tumors. The results indicate that certain neoplastic cells of medulloblastoma are capable of expression of photoreceptor‐specific proteins and, thus, may be closely related to tumor cells of retinoblastoma and pineocytomas previously shown to bind antisera against retinal S‐antigen and opsin. No S‐antigen and opsin‐like immununoreaction was found in malignant teratomas and germinomas of the pineal gland, oat cell tumors, astrocytomas, ependymomas, oligodendrogliomas, glioblastomas, gangliogliomas, gangliocytoma, ganglioneuroblastomas, neuroblas‐tomas, and esthesioneuroblastoma.

A new model of reversible sinus sagittalis superior thrombosis in the rat: magnetic resonance imaging changes.

OBJECTIVE: The causes of cerebral sinus and vein occlusion and the accompanying parenchymal changes remain largely unexplained. The clinical variability and low incidence of the disease complicate systematic clinical investigations. Animal studies are indispensable; however, existing animal models of sinus thrombosis do not allow for long-term follow-up studies and are not suitable for pharmacological recanalization because sinus thrombosis is induced by ligation and injection of thrombogenic substances and does not resemble sinus thrombosis in humans. METHODS: We induced thrombosis of the superior sagittal sinus (SSS) by careful topical application of ferric chloride onto the SSS of rats, leading to highly reproducible occlusions. Magnetic resonance imaging was performed immediately after initiation of thrombosis and on postoperative Days 1, 2, and 7. Diffusion- and T2-weighted images allowed for calculation of the apparent diffusion coefficient and T2 relaxation time. Vascular status was assessed by venous magnetic resonance angiography. Neurological deficits were assessed with the rotarod test. RESULTS: Seven days after induction of thrombosis, partial recanalization (50.7% of the SSS remaining occluded) was accompanied by a resolution of early generalized changes of the apparent diffusion coefficient and of T2 relaxation time, indicating edema of the entire brain parenchyma. Compared with sham-treated animals, clinical skills in the experimental group improved over time, which was statistically independent from the degree of recanalization. Histopathological analysis revealed no signs of cerebral infarction. CONCLUSION: This is the first animal model of SSS thrombosis that offers the possibility to investigate pathophysiological aspects of the disease as well as the influence of therapy on the nature of disease progression.

Differentiation in medulloblastomas: correlation between the immunocytochemical demonstration of photoreceptor markers (S-antigen, rod-opsin) and the survival rate in 66 patients

SummaryBiopsy specimens of 66 medulloblastomas were investigated by means of S-antigen and rod-opsin immunocytochemistry. The patients were operated between 1969 and 1988 and the medical records were retrospectively evaluated to correlate the immunocytochemical features of the tumors to the course of the disease. S-antigen- and rod-opsin-immunoreactive tumor cells were found in 19 out of 66 cases. Since in the normal non-neoplastic state immunoreactive S-antigen and rod-opsin are restricted to retinal photoreceptors and a class of pinealocytes derived from photoreceptor cells, the occurrence of these proteins in certain tumor cells of medulloblastomas suggests a differentiation of these cells along the photoreceptor cell lineage and allows the identification of a special subtype of medulloblastoma displaying photoreceptor-specific characteristics. This subtype appears to be closely related to retinoblastomas and pineal cell tumors. The incidence of this subtype corresponds to approximately 30% of all medulloblastomas. Correlation between the demonstration of immunoreactive S-antigen and rod-opsin and the course of the disease revealed a 10-year survival rate of 50.6% for patients with medulloblastomas displaying photoreceptor-specific characteristics and maximally 11% for patients suffering from medulloblastomas devoid of these markers. Although the statistical evaluation does not provide a significant result, the estimatedP-value of 0.085 indicates a distinct trend toward a better prognosis for patients suffering from medulloblastomas with photoreceptor-specific features. The validity of this trend needs to be proven in further studies with a greater number of patients.

S-antigen and rod-opsin immunoreactions in midline brain neoplasms of transgenic mice: Similarities to pineal cell tumors and certain medulloblastomas in man.

Transgenic mice expressing the large T-antigen of the simian virus 40 (SV 40) under the control of 1) the enhancer of Moloney murine sarcoma virus (MSV) and 2) the SV 40 promoter develop undifferentiated neuroectodermal tumors located in the midline of the dorsal brain surface, abnormalities in lens fiber differentiation and retinal dysplasia. In this study the brain neoplasms of six adult animals and the brain of one 11-day old mouse were examined by conventional histology and immunocytochemical demonstration of S-antigen, rod-opsin, neuron-specific enolase, neurofilaments (160 and 200 kDa) and glial fibrillary acidic protein. According to histologic criteria the neoplasms were characterized as “primitive” neuroectodermal tumors composed mainly of small cells with scanty and ill-defined cytoplasm. Neoplastic cells displaying immunoreactive S-antigen were found in five brain tumors; three of these tumors also contained a limited number of rod-opsin immunoreactive neoplastic cells. Some tumor cells had neurite-like processes containing immunoreactive neurofilament (200 kDa). No pathologic lesions were found in the brain of the 11-day old animal. Tumors in transgenic mice may resemble pineal cell tumors and a special subtype of medulloblastoma in man. These neoplasms contain S-antigen immunoreactive and also rod-opsin immunoreactive tumors cells in certain cases. The findings suggest that transgenic mice expressing the large T-antigen of SV 40 may become a valuable animal model for analysing the origin, histogenesis and development of primitive neuroectodermal tumors with photoreceptor-like features (pineal cell tumors and certain medulloblastomas).

Immunocytochemical demonstration of interphotoreceptor retinoid-binding protein in cerebellar medulloblastoma

SummaryPreviously, immunoreactive rod-opsin and S-antigen (arrestin), two highly characteristic markers of retinal photoreceptors and pinealocytes, were shown to be present in certain medulloblastoma cells. It, thus, has been suggested that such cells differentiate along the photoreceptor lineage. This is corroborated in the present immunocytochemical investigation using antibodies against another photoreceptor-cell marker, the interphotoreceptor retinoid-binding protein (IRBP). As shown in preparations of human retina and pineal organ, IRBP can be successfully demonstrated in formalinfixed and paraffin-embedded tissue: the IRBP immunoreaction is located to the outer and inner segments of retinal photoreceptor cells and to perikarya of certain pinealocytes. Examination of formalin-fixed, paraffinembedded biopsy specimens of 66 cerebellar medulloblastomas revealed varying numbers of IRBP-immunoreactive tumor cells in 19 cases that were formerly shown to contain rod-opsin and S-antigen immunoreaction. IRBP-immunoreactive tumor cells were also found in a retinoblastoma and a pineocytoma, but not in neuroblastoma, ganglioneuroblastoma, glioblastoma, oligodendroglioma and astrocytoma. The results indicate: (1) cerebellar medulloblastomas are heterogeneous in their differentiation potential; (2) one type of medulloblastoma displays photoreceptor characteristics; (3) this type appears to be closely related to retinoblastoma and pineal cell tumors; and (4) all three types of tumors may display additional common features to be explored in future studies.