Helmut K. Wolf

NeuN: a useful neuronal marker for diagnostic histopathology.:

The monoclonal antibody A60 specifically recognizes the DNA-binding, neuron-specific protein NeuN, which is present in most neuronal cell types of vertebrates. In this study we demonstrate the potential use of NeuN as a diagnostic neuronal marker using a wide range of formalin-fixed, paraffin-embedded human surgical and autopsy specimens from the central and peripheral nervous system. After microwave antigen retrieval, almost all neuronal populations revealed strong immunoreactivity for NeuN in nuclei, perikarya, and some proximal neuronal processes, whereas more distal axon cylinders and dendritic ramifications were not stained. The stain greatly enhanced the gray matter architecture. NeuN immunoreactivity was not detected in Purkinje cells, most neurons of the internal nuclear layer of the retina, and in sympathetic chain ganglia. We examined nine gangliogliomas and 14 dysembryoplastic neuroepithelial tumors, one ganglioneuroma, and one dysplastic cerebellar gangliocytoma. The neuronal component of all of these lesions showed marked immunoreactivity for NeuN. In addition, NeuN immunoreactivity was focally seen in one of seven medulloblastomas with prominent neuronal differentiation. There was no staining of non-neuronal structures. The results indicate that NeuN immunoreactivity is a sensitive and specific neuronal marker in formalin-fixed, paraffin-embedded tissues, and may be useful in diagnostic histopathology.

Gangliogliomas: clinical, radiological, and histopathological findings in 51 patients.

Clinical, radiological, and histopathological features of 51 surgically treated gangliogliomas were evaluated retrospectively. The most common presenting symptoms were epileptic seizures (47 patients (92%)). Focal neurological deficits occurred in 8% of the patients. The duration of symptoms at the time of operation ranged from three months to 45 years, mean 11 years. The temporal lobe was affected in 43 patients (84%), the frontal lobe in five patients (10%), and the occipital lobe in one patient (2%). Two of the tumours (4%) were localised infratentorially. On MRI, solid tumour parts usually showed a pronounced signal increase on proton density images and a less pronounced signal increase on T2 weighted images, whereas solid components were mainly isointense on T1 weighted images. Contrast enhancement was noted in 16 of 36 patients (44%). Cystic tumour parts were found in 23 of 40 patients (57%), all characterised by signal increase on T2 weighted images and decreased T1 signals. Signal deviation of cystic tumour parts on proton density images was variable. Computed tomography was performed in 17 patients and showed hypodense lesions in 10 (59%), and calcifications in seven (41%) cases. Surgery included complete tumour removal in 44 patients (86%) and partial resection in seven (14%). In six patients (12%) there were transient postoperative complications. One patient (2%) died postoperatively due to pulmonary embolism. Histopathological examination of the surgical specimens showed low grade gangliogliomas in 49 cases (96%) and anaplastic gangliogliomas in two (4%). Control MRI of 31 patients with a mean follow up period of 16 months was uneventful in all but one case of an anaplastic ganglioglioma. In all patients in whom the ganglioglioma was associated with medically intractable seizures the operation resulted in complete relief of seizures or a noticeable improvement of the epilepsy.

Surgical treatment of extratemporal epilepsy: clinical, radiologic, and histopathologic findings in 60 patients.

Summary: Purpose and Methods: The aim of this study was to analyze clinical, radiologic, and histopathologic findings in 60 consecutive patients with medically intractable extratemporal epilepsy who were operated on between November 1987 and May 1993.

Surgical Pathology of Temporal Lobe Epilepsy. Experience with 216 Cases

The surgical treatment of chronic epilepsies is increasing rapidly. Here we report the histopathologic findings in 216 consecutive surgical specimens of patients with chronic pharmacoresistant temporal lobe epilepsy. In 75 cases (34.7%) there were tumors, all but two of which were of low histopathological grade (WHO grade I or II). The most common tumors were gangliogliomas (34 cases), pilocytic astrocytomas (17 cases), oligodendrogliomas (9 cases), fibrillary astrocytomas (6 cases), and dysembryoplastic neuroepithelial tumors (6 cases). There were 51 cases with non-neoplastic focal lesions and an additional 13 cases with tumors and non-neoplastic focal lesions within the same specimen. The most frequent non-neoplastic focal lesions were microscopic glioncuronal hamartias (32 cases), glioneuronal hamartomas (7 cases), and vascular malformations (13 cases). The hippocampal formation was structurally well preserved in 71 specimens. In 51 of these (71.8%) there was Ammons horn sclerosis. Presurgical placement of depth electrodes was invariably associated with circumscribed defects of the brain parenchyma. The implantation of subdural electrodes was sometimes followed by chronic inflammatory changes of the leptomeninges. Our findings indicate that in the majority of patients with medically intractable temporal lobe epilepsy there are significant histopathologic findings, many of which are only rarely encountered otherwise.

Ganglioglioma: a detailed histopathological and immunohistochemical analysis of 61 cases

Gangliogliomas are tumors composed of intimately admixed neuronal and glial components and account for approximately 1% of all brain tumors. Here we report the histopathological findings in 61 gangliogliomas. Epilepsy was the most common presenting symptom. Most gangliogliomas were located in the temporal lobes (74%). Thirteen percent of the gangliogliomas were associated with glioneuronal hamartias. There was considerable variation in neuronal size and density, presence of binucleated neurons, calcifications, desmoplasia, lymphocytic infiltrate, pilocytic differentiation, Rosenthal fibers, location, or histological uniformity. Fifteen percent of the gangliogliomas contained areas of purely astrocytic differentiation. All tumors were examined immunohistochemically for an aberrant p53 tumor suppressor gene product and for the presence of nuclear antigens associated with cell proliferation (Ki-67, Ki-S1, proliferating cell nuclear antigen). In 45 of 61 cases (74%) labeling indices for Ki-67 were less than 1%. Nuclear labeling for Ki-67 was observed exclusively in the astrocytic component. Gangliogliomas with very large neurons had higher Ki-67 labeling indices and occurred in younger patients than gangliogliomas with small-or intermediate-sized neurons. None of the tumors had an aberrant expression of p53. The observations suggest that gangliogliomas may arise from glioneuronal hamartias through neoplastic transformation of the astrocytic component.

Surgical treatment of temporal lobe epilepsy: clinical, radiological, and histopathological findings in 178 patients.

The surgical treatment of pharmacoresistant temporal lobe epilepsy is increasing rapidly. The correlation of preoperative MRI, histopathological findings, and postoperative seizure control is reported for 178 patients with chronic medically intractable temporal lobe epilepsy who were operated on between November 1987 and January 1993. Histopathologically there were distinct structural abnormalities in 97.2% of the surgical specimens. Signal abnormalities on MRI were present in 98.7% of patients with neoplastic lesions (n = 79), 76.6% of patients with non-neoplastic focal lesions (n = 55), and 69.2% of patients with Ammons horn sclerosis (n = 39). Overall, structural abnormalities were detected by MRI in 82.7% of all patients. The mean postoperative follow up period was three years. Some 92% of the patients benefited from surgery: 103 patients (61.7%) were seizure free, 26 (15.5%) had no more than two seizures a year, and 24 (14.4%) showed a reduction of seizure frequency of at least 75%. Fourteen patients (8.4%) had a < 75% reduction of seizure frequency. The percentage of patients who were completely free of seizures after operation was 68.5% for patients with neoplastic lesions, 66.7% for Ammons horn sclerosis, and 54.0% for patients with non-neoplastic focal lesions. By contrast, none of the patients in whom histopathological findings were normal became seizure free postoperatively. The data show that the presence of focal lesions or Ammons horn sclerosis as determined by histopathological examination is associated with improved postoperative seizure control compared with patients without specific pathological findings. Brain MRI was very sensitive in detecting neoplasms; however, its sensitivity and specificity were limited with respect to non-neoplastic focal lesions and Ammons horn sclerosis. Improvement of imaging techniques may provide a more precise definition of structural lesions in these cases and facilitate limited surgical resections of the epileptogenic area rather than standardised anatomical resections.

Expression and distribution of vascular endothelial growth factor protein in human brain tumors

Abstract Marked neovascularization is a hallmark of many neoplasms in the nervous system. Recent reports indicate that the endothelial mitogen vascular endothelial growth factor (VEGF) may play a critical role in the regulation of vascular endothelial proliferation in malignant gliomas. Using novel monoclonal antibodies to the VEGF polypeptide we have determined the expression and cellular distribution of VEGF protein in a representative series of 171 human central nervous system (CNS) tumors by immunohistochemistry and immunoblotting. In agreement with previous in situ hybridization data, 19 out of 20 glioblastomas (95%) showed immunoreactivity for VEGF, whereas both the percentage of immunoreactive tumors and the extent of immunoreactivity for VEGF were significantly lower in astrocytomas. Of the pilocytic astrocytomas (WHO grade I) 44% were immunoreactive for VEGF, but we observed several cases with pronounced vascular proliferates in the absence of VEGF. In ependymomas, meningiomas, hemangioblastomas, and primitive neuroectodermal tumors, there was no correlation between VEGF expression, vascular endothelial proliferation and the grade of malignancy. Oligodendrogliomas and the oligodendroglial component of mixed gliomas lacked immunoreactive VEGF, indicating that endothelial growth factors other than VEGF may regulate tumor angiogenesis in these neoplasms. Western blot analysis showed a predominant VEGF protein species of 23 kDa and confirmed the immunohistochemical data in all cases. Our findings demonstrate that VEGF is expressed in a wide spectrum of brain tumors in which it may induce neovascularization. However, other angiogenic factors also appear to contribute to the vascularization of CNS neoplasms.

The CD34 epitope is expressed in neoplastic and malformative lesions associated with chronic, focal epilepsies.

Abstract The etiology and pathogenesis of complex focal lesions associated with chronic, intractable epilepsy are largely unknown. Some data indicate that malformative changes of the central nervous system may preceed the development of gangliogliomas and other epilepsy-associated neoplasms. In the present immunhistochemical study, we have examined epilepsy-associated lesions for CD34, a stem cell marker transiently expressed during early neurulation. Surprisingly, most tissue samples from patients with chronic epilepsy (n = 262) revealed neural cells immunoreactive for CD34. Prominent immunoreactivity was detected in gangliogliomas (74%), low-grade astrocytomas (62%) and oligodendrogliomas (59%). Only 52% of non-neoplastic, malformative pathologies, such as glio-neuronal hamartias or hamartomas showed solitary or small clusters of CD34-immunoreactive cells. None of the adult control tissues (n = 22), none of the specimens obtained from the developing human brain (n = 44) and none of those tumor samples from patients without epilepsy (n = 63) contained CD34-immunoreactive neural cells. However, a malignant teratoma with microscopic features of early neural differentiation displayed a focal CD34-immunoreactive staining pattern. The majority of CD34-immunoreactive cells co-localized with S-100 protein and a small subpopulation was also immunoreactive for neuronal antigens. CD34 may, thus, represent a valuable marker for the diagnostic evaluation of neoplastic and/or malformative pathological changes in epilepsy patients. The CD34 immunoreactivity of these lesions indicates an origin from dysplastic or atypically differentiated neural precursors. Further studies may elucidate the functional significance of CD34 expression during the pathogenesis of epilepsy-related focal lesions as well as during neurogenesis.

Surgical treatment of neoplasms associated with medically intractable epilepsy.

OBJECTIVE Surgical treatment in patients with brain tumors and medically intractable epilepsy is aimed at the removal of the neoplasm and complete seizure control. However, an adequate surgical approach is still controversial. This study was designed to analyze the factors for the optimum surgical treatment of these patients. METHODS The clinical, electrophysiological, operative, and histopathological data of 146 consecutive patients who underwent surgery between November 1987 and May 1995 for intrinsic brain tumors and pharmacoresistant epilepsy were evaluated. RESULTS The majority of the tumors were located in the temporal lobe (n = 116) and involved the cortical gray matter. The most frequent tumors were gangliogliomas (n = 65), pilocytic astrocytomas (n = 21), and dysembryoplastic neuroepithelial tumors (n = 19). All but three tumors (98%) were of low histopathological grade (World Health Organization Grades I or II). The biological behavior of the tumors was strikingly indolent, as indicated by a long preoperative history of chronic seizures (mean, 14 yr). In all cases, complete resection of the tumor, including the epileptogenic area (as determined by noninvasive and/or invasive recordings of the zone of seizure onset and persistent interictal activity), was intended. Complications were encountered in 11 cases (8%). However, no patient died and there was no permanent morbidity. Of the 124 patients who had postoperative follow-up examinations more than 6 months after resection, 71% were seizure-free, 11% had no more than two seizures per year, 13% showed a reduction of seizure frequency of at least 75%, and 5% had no appreciable reduction in seizure frequency. CONCLUSION The data indicate that neoplasms associated with medically intractable epilepsy constitute a distinct clinicopathological group of tumors that arise in young hosts, involve the cortex, and exhibit indolent biological behavior for many years. Complete surgical removal of these tumors, including the epileptogenic area, can achieve excellent seizure control.

Surgical pathology of chronic epileptic seizure disorders.

The surgical treatment of chronic epilepsies is increasing rapidly and involves neuropathologists in the care of patients with chronic and medically intractable seizure disorders. Herein we review the histopathologic findings in 279 consecutive surgical specimens of patients with chronic pharmaco‐resistant epileptic disorders. Aspects that are relevant to the diagnostic surgical pathologist such as the terminology of developmental lesions and Amnions horn sclerosis are discussed. In 87 cases (31.2%), there were tumors in which all but two were of low histopathological grade (WHO grade I or grade II). The most common tumors were gan‐gliogliomas, pilocytic astrocytomas, oligodendrogliomas, fibrillary astrocytomas and dysembryo‐plastic neuroepithelial tumors. Among the most frequent non‐neoplastic focal lesions, microscopic glioneuronal hamartias, circumscribed vascular malformations, glioneuronal hamartomas and porencephalic defects were most frequent. The hippocampal formation was structurally well preserved in 71 specimens of patients with temporal lobe epilepsy. In 51 of these (71.8%) cases. Amnions horn sclerosis was present. The findings suggest that the structural lesions observed in the great majority of the specimens are closely related to the pathogenesis of intractable seizures.