Localization of antibody in the central nervous system of a patient with paraneoplastic encephalomyeloneuritis.

We report a patient with severe paraneoplastic encephalomyeloneuritis, occult small-cell carcinoma of the lung, and high titers of circulating antineuronal antibody who died shortly after developing limbic encephalitis. The antibody was of IgG class and reacted specifically with nuclei and cytoplasm of all neurons in the pattern typical for encephalomyelitis and subacute sensory neuropathy associated with small-cell carcinoma (type II, anti-Hu). At autopsy, perivascular inflammatory infiltrates were prominent. All samples of serum, CSF, and postmortem peritoneal and pleural fluid contained high titers of antibody. Direct immunofluorescence of frozen tissue revealed IgG bound to most remaining neurons in multiple brain regions in a pattern similar to indirect immunofluorescence of normal brain tissue. IgG was also bound to tumor. Attempts to elute antibody from tissue decreased background staining but did not remove neuronal immunofluorescence. These results indicate that antibody can access and bind specifically to neuronal antigens in the brain during the course of paraneoplastic disease.

Cauda equina tumor with ependymal and paraganglionic differentiation.

We describe the case of a 31-year-old woman who was first treated for a pigmented choroid plexus papilloma of the fourth ventricle. Ten year later, she developed a new tumor in the region of the cauda equina. This second neoplasm contained areas of papillary ependymoma that displayed phosphotungstic acid hematoxylin-positive glial fibers and immunoreactivity for glial fibrillary acidic and S-100 proteins. Areas of ependymoma merged with others that displayed the appearance of a paraganglioma, including lobules and nests of chief cells immunoreactive for neuron-specific enolase, synaptophysin, chromogranin, and serotonin. Satellite cells, but not chief cells, stained for glial fibrillary acidic and S-100 proteins. Electron microscopy showed features of both ependymal and paraganglionic differentiation, including intercellular lumina with microvilli, junctional complexes, cell processes with closely packed filaments, and dense core granules. Our case represents a rare example of a cauda equina neoplasm with simultaneous ependymal and paraganglionic differentiation. To our knowledge, this is the first described example of a tumor of this region showing features of both ependymoma and paraganglioma.

Atypical and malignant meningiomas: a clinicopathological review.

There has been continuing debate on the subject of malignant meningiomas, but few studies of large series have been reported. We present our experiences with 25 atypical and malignant meningiomas operated on at Henry Ford Hospital between 1976 and 1990. A total of 319 primary intracranial meningiomas were operated on during this period; of these, 294 (92%) were benign, 20 (6.26%) atypical, and 5 (1.7%) malignant. We used a modified histological grading system, based primarily on World Health Organization criteria of malignancy (hypercellularity, loss of architecture, nuclear pleomorphism, mitotic index, tumor necrosis, and brain invasion), to define atypical and malignant meningiomas. Each of these criteria was given a score from 0 to 3, and then partial scores were added to obtain cumulative scores. These total scores were then used to determine what is benign, atypical, and malignant. The peak incidence of atypical and malignant meningiomas was in the seventh and sixth decades, respectively. The predominance of female patients with benign meningiomas was not observed in the nonbenign group. The male:female ratio for atypical and malignant meningiomas was 1:0.9 versus 1:2.3 for benign meningiomas (P = 0.024). The most common presenting symptom and physical sign in our patients was paresis. In reviewing their radiographic features, all patients showed moderate or marked edema on computed tomography. Calcification was exhibited by one patient only and "mushrooming" was seen in three cases. Of the 25 patients, 11 (44%) died during follow-up: 2 in the perioperative period, 8 within the first 5 years, and 1 died 11 years after the diagnosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Tenosynovial giant-cell tumor of the cervical spine. Case report.

A case of tenosynovial giant-cell tumor affecting the cervical spine is reported. The lesion is seen primarily in the fingers, knee, or ankle, and there are no previous reports of it occurring in the spine. The histological and radiological features of this tumor are discussed along with a brief description of the disease entity.

An immunohistochemical study of the primitive and maturing elements of human cerebral medulloepitheliomas.

Four examples of human cerebral medulloepithelioma were studied immunohistochemically with a panel of antibodies and antisera to neuronal and glial proteins. The tumors, in addition to primitive medullary epithelium, contained areas of neuroblastic, ganglionic, astrocytic, ependymoblastic and ependymal differentiation, and in one tumor, areas resembling polar spongioblastoma. Tumor cells throughout the primitive medullary epithelium displayed focal immunoreactivity for vimentin, glial fibrillary acidic (GFA) protein and for the neuron-associated class III beta-tubulin isotype. Neuroblasts showed immunoreactivity for the class III beta-tubulin isotype, microtubule-associated protein 2 and neuron-specific enolase. Immunoreactivity for neurofilament epitopes and synaptophysin was detected in areas of ganglionic differentiation and coincided with the demonstration of neurofibrils in Bielschowsky's silver impregnations. Vimentin was the only marker detected in ependymoblastic and ependymal rosettes or in areas of polar spongioblastoma, as well as in mesenchymal cells. The results indicate that, even in very primitive neoplastic neuroepithelium, immunocytochemical evidence of early commitment of some of the cells to a neuronal or glial lineage can be demonstrated. The neuron-associated class III beta-tubulin isotype appears to be one of the earliest markers indicative of neuronal differentiation in normal and neoplastic primitive neuroepithelium.

Isolated granulomatous angiitis of the spinal cord.

We describe a 31-year-old diabetic man, with granulomatous angiitis confined to the spinal cord, who developed rapidly progressive spastic paraplegia, clinically interpreted as being secondary to a spinal cord infarct. At the time of autopsy, vasculitis was limited to the spinal cord, without involvement of cerebral vessels. The inflammatory cells were predominantly CD4+ T lymphocytes, with few CD8+ T and B lymphocytes. The phenotypical composition of the inflammatory infiltrate is similar to that described in other granulomatous disorders such as sarcoidosis and tuberculin reaction.

Intracytoplasmic lumina in ependymomas: an ultrastructural study.

Intracytoplasmic lumina (ICL) are rarely described in tumors of the central nervous system. The morphogenesis of ICL remains incompletely characterized. Ultrastructural features of ICL in six ependymomas (one from lateral ventricle, three from fourth ventricle, and two from spinal cord) and three myxopapillary ependymomas of the filum terminale were analyzed. Two types of ICL were identified: ICL with both microvilli and cilia, and ICL with only microvilli. Some ICL also contained granulofibrillary or condensed material. Ciliated ICL were common in ependymomas of the ventricles, whereas nonciliated ICL were frequently seen in the myxopapillary variant. Various stages of formation and development were observed in ciliated ICL. They seemed to originate from distended periciliary cisterns, to enlarge by fusion with cytoplasmic vesicles or other ICL, and subsequently to open into the intercellular space. The last process may be the mechanism by which the intercellular microrosettes are formed. Ciliated ICL have not been described in other neoplasms. They may represent a characteristic ultrastructural feature of ependymomas. The morphogenesis of nonciliated ICL remains unknown. They may represent a degenerative form of ciliated ICL or pseudolumina resulting from invagination of the extracellular space within the cytoplasm.

Plasminogen activators and inhibitors in gliomas: an immunohistochemical study.

The tissue (tPA) and urokinase (uPA) types of plasminogen activator and the plasminogen activator inhibitor 1 (PAI-1) are enzymatic proteins that may play an important role in the degradation of the extracellular matrix in physiologic and neoplastic conditions. In particular, urokinase may underlie key properties of malignant cells, such as invasiveness and dissemination. We have studied the immunohistochemical distribution of tPA, uPA, and PAI-1 in 24 human gliomas, including seven well-differentiated astrocytomas, three oligodendrogliomas, six anaplastic astrocytomas, and eight glioblastomas multiforme. All anaplastic astrocytomas and glioblastomas showed numerous neoplastic cells immunoreactive for uPA, but not for tPA. In contrast, low-grade gliomas were negative for uPA, but contained some tPA-immunoreactive cells. Endothelial cells of vessels in non-neoplastic and neoplastic brain were immunoreactive for tPA, but not for uPA or PAI-1. Non-neoplastic glia were unreactive for tPA, uPA, and PAI-1. Small anaplastic cells present in three glioblastomas showed immunoreactivity for PAI-1. The presence of a large number of uPA-immunoreactive neoplastic cells in high-grade gliomas suggest that this fibrinolytic protein plays a significant role in the invasive properties of these neoplasms.

Proliferation indices of vestibular schwannomas by Ki-67 and proliferating cell nuclear antigen.

Two immunohistologic demonstrations of markers of proliferating cells, Ki-67 and proliferating cell nuclear antigen, were applied to tissues from 10 vestibular schwannomas. Each method demonstrated three distinct rates of positively stained cells (p < .01 and p < .015, respectively, for each method). There was a one-to-one correspondence between the two immunohistologic methods in the assignment of cases to each growth rate category except for two cases (Spearman rank correlation r = 0.76, p < .05). These data support the concept of distinct growth rates in vestibular schwannoma. Tissues were also sampled from different areas of the same tumor within nine samples. The results suggest that tumor growth is not homogeneous within a tumor, but that proliferation may be more active near the surface.

An immunohistochemical study of neuropeptides and neuronal cytoskeletal proteins in the neuroepithelial component of a spontaneous murine ovarian teratoma. Primitive neuroepithelium displays immunoreactivity for neuropeptides and neuron-associated beta-tubulin isotype.

Approximately one third of the female mice of the LTXBO strain develop spontaneous ovarian teratomas. These tumors contain a large neuroepithelial component, which includes primitive neural structures resembling embryonic neural tubes (medulloepithelial rosettes), ependymoblastic and ependymal rosettes, neuroblasts, mature ganglionic neurons, myelinated neurites, and astrocytes. The purpose of this study was to characterize these tumors according to the immunohistochemical location of some well-characterized trophic and regulatory neuropeptides and neurotransmitters, several neuronal-associated cytoskeletal proteins, and other proteins indicative of neuronal and glial differentiation. Medulloepithelial rosettes showed focal serotonin-like, opioid peptide-like and gamma-amino butyric acid-like immunoreactivity, and displayed immunostaining for the neuron-associated class III beta-tubulin isotype. The mature ganglion cells were also immunoreactive for these markers, and, in addition, for somatostatin, cholecystokinin, bombesin, glucagon, vasoactive intestinal peptide, and neuropeptide Y. Mature ganglion cells were also immunoreactive for proteins associated with the neuronal cytoskeleton (including microtubule-associated proteins, MAP2 and tau, and higher molecular weight phosphorylated and non-phosphorylated neurofilament subunits), neuron-specific enolase, and synaptophysin. Undifferentiated stem cells, ependymoblastic and ependymal rosettes, and astroglia all stained with a monoclonal antibody that recognizes all mammalian beta-tubulin isotypes, but did not react with antibodies to neuronal-associated cytoskeletal proteins or neuropeptides. Neuropeptide-like immunoreactivity and demonstration of the class III beta-tubulin isotype indicate early neuronal commitment in neoplastic primitive neuroepithelium. These patterns of immunoreactivity closely follow those encountered in the normal neurocytogenesis of the mammalian and avian forebrain, and increase the precision with which the early stages of progressive neuroepithelial differentiation can be analyzed in human embryonal tumors of the CNS.

An immunohistochemical characterization of the primitive and maturing neuroepithelial components in the OTT-6050 transplantable mouse teratoma.

The neuroepithelial component of the OTT-6050 mouse teratoma has previously been characterized as an experimental system for the study of differentiation and cytologic maturation in embryonal tumours of the human central nervous system. A number of transplantable tumours composed of primitive stem cells and of a neuroepithelial component displaying a spectrum of differentiation were previously produced by centrifugal elutriation of the dissociated OTT-6050 teratoma. These tumours have provided a reproducible cell population that has permitted the study of both the early and later stages of neoplastic neurocytogenesis. The purpose of the present study was to detect, by immunohistochemistry, the earliest stages of neurocytogenesis in these tumours as shown by the expression of neuron-associated microtubule proteins. This was correlated to the appearance and localization of other markers associated with neuronal and glial differentiation. The primitive neuroepithelial structures resembling neural tubes (medulloepithelial rosettes) contained single or small groups of cells which reacted with the monoclonal antibody TUJ1, specific for the neuron-associated class III beta-tubulin isotype. Immature neuroblasts and maturing polar neurons also showed immunoreactivity with TUJ1, whereas reactivity for microtubule-associated protein 2 (MAP2), tau, the 200 kilodalton isoform of neurofilament protein, neuron-specific enolase and synaptophysin was primarily seen in maturing neurons. By comparison, both medulloepithelial and ependymoblastic rosettes, neuroblasts and glial cells were immunopositive with monoclonal antibody TU27, which defines an antigenic site shared by most mammalian beta-tubulin isotypes. Astroglia were reactive with antisera to glial fibrillary acidic and S-100 proteins, but not with monoclonal antibody (MAb) TUJ1, or with MAbs to the other neuron-associated cytoskeletal proteins, MAP2, tau and the 200 kilodalton subunit of neurofilament protein. Our findings suggest that (1) expression of the class III beta-tubulin isotype is an early event during neoplastic neurocytogenesis, (2) this isotype is subsequently preserved in maturing neuronal populations, and (3) it is not present at detectable levels in stem cells or glial cells. The observation that morphologically undifferentiated neuroepithelial cells express a neuron-associated beta-tubulin isotype signifies the value of examining tubulin isotype expression in the characterization of normal and neoplastic neuroepithelial differentiation.

Kinetics and glial fibrillary acidic (GFA) protein production in a transplantable human giant cell glioblastoma (D-212 MG) of near haploid karyotype maintained in an organ culture system. An immunohistochemistry study.

A transplantable subcutaneous tumour (designated D-212 MG), sequentially passaged in athymic nude mice and originally derived from a human giant cell glioblastoma, was maintained in an organ culture (matrix) system and studied immunohistochemically after in vitro pulse-labelling with bromodeoxyuridine (BrdU) and for the presence of glial fibrillary acidic (GFA) protein, after 1, 2 and 3 weeks in culture. The histological characteristics of the tumour, showing two cell populations of giant multinucleated cells and small cells, were preserved in the explants. An increased percentage of multinucleated giant cells was found after 3 weeks in vitro. A small but constant fraction (4-6%) of these cells continued to synthesize DNA. The labelling index of the small cells was somewhat higher, but decreased slightly although significantly over the 3-week period in vitro (from approximately 10.5 to 8%). The percentage of small cells that were positive for GFA protein was in the region of 75% and that of the giant multinucleated cells was in the region of 45%; it did not change significantly during the 3 weeks in vitro. The in vitro results confirm the astrocytic nature of both the small cells and the giant multinucleated cells in this tumour, the capacity of both cell populations to synthesize DNA in culture and to demonstrate invasiveness, and suggest the possibility that some of the giant multinucleated cells may have originated from the conversion of a number of small tumour cells.