Improved long term survival after intracavitary interleukin-2 and lymphokine-activated killer cells for adults with recurrent malignant glioma.

BACKGROUND: The median survival for adults with glioblastoma multiforme (GBM) is 12 months, despite surgery, radiation, and chemotherapy. Regimens using interleukin-2 (IL-2) plus lymphokine-activated killer (LAK) cells have been beneficial against systemic cancers, albeit with significant toxicity. METHODS: Nineteen adults with recurrent malignant glioma (5 GBMs, and 4 anaplastic astrocytomas (AA)), Karnofsky performance status 60 or greater, were treated with intracavitary autologous LAK cells plus IL-2 after reoperation. Lymphokine-activated killer cells and IL-2 were given on day 1, and IL-2 alone was given 5 times during a 2-week cycle. This cycle was repeated at 2 weeks to constitute one 6-week course of therapy. Each two-cycle course of treatment was repeated at 3-month intervals for patients with stable disease or response to therapy. At the conclusion of immunotherapy, all patients were offered chemotherapy, generally carmustine or procarbazine, including responders. Corticosteroids were strictly limited during immunotherapy. Sequential reservoir aspirates were obtained for microbiologic and cytologic analyses. RESULTS: The maximal tolerated dose for a 12-dose course of therapy was 1.2 million international units (MIU) per dose. Dose-limiting, cumulative IL-2-related central nervous system (CNS) toxicity was observed at 2.4 MIU per dose. Three responses were confirmed by computed tomography scan during therapy: one complete response (CR) (1 AA), and two partial responses (PR) (2 GBM); as well as a significant increase in GBM survival. One additional CR (GBM) was observed at 17 months. The median survival for immunotherapy patients with GBM was 53 weeks after reoperation (N = 15) (mean, 87.9 +/- 21.4 weeks, standard error for the mean), with 8 of 15 surviving more than 1 year (53%). The median survival for 18 contemporary patients with GBM reoperated and treated with chemotherapy was 25.5 weeks (mean, 27.4 +/- 3.7 weeks), with 1/18 alive at 1 year (> 6%). Six of the 15 patients with GBM had additional surgery or biopsy, and chemotherapy after immunotherapy. The contribution of subsequent chemotherapy to survival cannot be discounted. CONCLUSIONS: Lymphokine-activated killer cells and IL-2 can be administered safely within the CNS resulting in improved long term survival in patients with recurrent glioblastoma. Increased survival was associated with significant biologic changes characterized by a regional eosinophilia, and extensive lymphocytic infiltration. A prospective randomized clinical trial is warranted.

Neuropathology of AIDS in surgical biopsy specimens.

In this brief review of the surgical neuropathology of AIDS we have emphasized that, although there are obvious and meaningful similarities between the autopsy descriptions of AIDS-related CNS disease and those we have seen in surgical specimens, there are also some clear differences in terms of which types of lesions are likely to undergo biopsy. It is also clear that the smaller samples allowed by neurosurgical procedures, particularly in stereotaxic biopsies, can limit the expression of the full pathologic pattern of these entities as expected from autopsy evaluations. Nevertheless, useful diagnostic information is readily and routinely obtained when the surgical sampling is carefully planned and when the tissues obtained are properly handled. There is a role, however, a limited one, for frozen sections in intraoperative consultations. The best diagnostic study is a careful perusal of a good hematoxylin and eosin stain, but judicious use of histochemical and immunohistochemical methods can be essential to a proper diagnosis in selected cases.

Late radiation necrosis of the brain: case report.

We report a case of radiation necrosis occurring 47 years after resection and radiotherapy for a juvenile pilocystic cerebellar astrocytoma, the longest yet reported. The patient presented with progressive lower cranial nerve dysfunction, and eventually died from cardiopulmonary arrest secondary to aspiration. The presentation, diagnosis, pathological features, and management of radiation necrosis are discussed.

Demyelinating disease versus tumor in surgical neuropathology. Clues to a correct pathological diagnosis.

Clinical presentations as well as radiological and histopathological findings in biopsies from patients with multiple sclerosis (MS) or other demyelinating disorders of the central nervous system are sometimes misleading, resulting in an erroneous diagnosis of brain or spinal cord tumor. We report 17 patients who presented with symptoms mimicking those of brain (14 cases) or spinal cord (three cases) tumors. Computerized tomography or magnetic resonance imaging studies or both were interpreted as consistent with a tumor in each case. All patients underwent surgery, and all 17 pathological specimens were eventually diagnosed as showing demyelinating disease, usually consistent with MS. In each case we examined a variety of histological features and immunohistochemical studies and addressed their relative importance in considering the diagnosis of MS. All cases showed perivascular lymphocytic inflammation with variable amounts of macrophage infiltration, necrosis, and edema. The hypercellularity of the lesions and the presence of atypical reactive astrocytes with mitotic figures were the disturbing features that might have led to the erroneous diagnosis of an astrocytic neoplasm. Immunohistochemistry for astrocytic (glial fibrillary acidic protein) and macrophage (HAM-56) markers are helpful in evaluating biopsies. Our results emphasize the need to perform special stains (i.e., for myelin and axons) that demonstrate myelin loss and relative preservation of axons and allow a correct diagnosis.

Prognostic relevance of epidermal growth factor receptor (EGF-R) and c-neu/erbB2 expression in glioblastomas (GBMs).

Seventeen untreated primary adult glioblastomas were analyzed using immunocytochemistry for the expression of EGF-R, c-neu/erbB2, TGF-alpha, and phosphotyrosine. Patients were divided by median survival into long-term or short-term survivors (LTS, N = 10, median > 4 years; versus STS, N = 7, median 61 weeks). There were no significant differences between the two groups in terms of age, extent of resection, post-operative Karnofsky status, or treatment. Diagnostic sections from each tumor were stained with antibodies to EGF-R, c-neu/erbB2, TGF-alpha and phosphotyrosine. Double-labelling for TGF-alpha and EGF-R was also performed. All 10/10 LTS were considered to be EGF-R negative/scant, while 4/7 STS were EGF-R positive. EGF-R negativity significantly correlated with long-term survival. The differences in c-neu/erbB2 expression did not reach significance. However, 4/7 STS were positive for both proteins and 76% of the 17 cases were either double negative or positive for EGF-R and c-neu/erbB2. TGF-alpha and phosphotyrosine were frequently expressed, but neither were prognostic. Recurrent tumors were studied in 7 STS. EGF-R expression was increased in 4/7 of these cases and c-neu/erbB2 was increased in all 7 cases, compared to the pretreatment baselines. Increased expression of these proteins in glioblastomas may be associated with aggressive clinical behavior and treatment resistance.

Treatment and survival of low-grade astrocytoma in adults--1977-1988.

A retrospective review of the records of the Division of Neuropathology at the New York University Medical Center between 1977 and 1988 revealed 53 cases of adult supratentorial astrocytomas. Fifty were fibrillary, and three were gemistocytic. Two additional patients had pilocytic tumors and were not included in the study. The majority of patients had either a subtotal (64%) or gross total resection (19%). Biopsy (17%) was performed for deep-seated lesions and for those lesions confined to eloquent cortex. Forty-eight patients (91%) received postoperative radiation therapy. The median survival was 7 1/4 years with a 5-year survival of 64%. Multivariate regression analysis demonstrated that the most important prognosticators for improved survival were young age, absence of contrast enhancement of the original tumor on computed tomography (CT) and the performance status of the patient. Patients with hemispheric tumors died from dedifferentiation into an anaplastic astrocytoma or a glioblastoma multiforme, with a median time to recurrence of 4.5 years from the original surgery. Survival from the time of recurrence was 12 months. Subsequent operations confirmed progression towards malignancy in six of seven (86%) recurrent tumors. CT contrast enhancement of the original tumor was associated with a 6.8-fold increase in risk for later recurrence. Patients with thalamic tumors (six patients) had a poor prognosis with a median survival of less than 2 years. A review of their CT scans suggest that four died of progressive low-grade disease; however, confirmatory autopsy data were available for only one patient. This study supports others that have shown improved survival for adult patients with astrocytomas treated in the CT era.

Intramedullary abscess associated with a spinal cord ependymoma: case report.

Intramedullary spinal cord abscesses are relatively uncommon. We report the first case of an intramedullary spinal cord abscess in a preexisting spinal cord ependymoma. The clinical features and pathogenesis are discussed. Salient features of the management of intramedullary spinal cord abscesses are outlined.

The lipid-rich epithelioid glioblastoma.

The authors add to the literature an account of four aggressive glial neoplasms characterized by diffuse cytoplasmic lipidization and a cohesive architectural disposition in epithelioid nests and sheets. These neoplasms arose in the cerebral hemispheres of adults and tended to a circumscribed neuroradiologic presentation that in two instances prompted an unrewarding preoperative search for an extracranial primary. One represented recurrent disease in a patient being followed for a biopsy-proven low-grade astrocytoma. Three cases were collected by way of consultation from pathologists uncertain as to their primary versus metastatic derivation. The apparent expression of cytokeratins and epithelial membrane antigen further conspired to obscure the glial lineage of these peculiar neoplasms, which are best regarded as tumors of the astrocytic series.

Glioneurofibroma: renaming the pediatric "gliofibroma": a neoplasm composed of Schwann cells and astrocytes.

Three children had central nervous system tumors with histologic and ultrastructural features corresponding to those of tumors previously described as "gliofibromas." These features, which include a composite appearance with glial and mesenchymal elements, with glial fibrillary acidic protein (GFAP)-containing and GFAP-immunonegative cells, diffuse S-100 immunoreactivity, and basal lamina wrapping processes of both cell types, suggest that the "mesenchymal" cells are Schwann cells, not fibroblasts. We therefore propose to rename this entity "glioneurofibroma." The clinical behavior of these lesions is uncertain but is more often indolent or benign.

Brain and spinal cord hemorrhage in long-term survivors of malignant pediatric brain tumors: a possible late effect of therapy.

Three children with malignant primary CNS tumors treated with craniospinal radiotherapy developed intraparenchymal hemorrhages a median of 5 years following therapy in sites distant from the primary tumor. Radical surgical procedures disclosed fresh and old hematoma, gliosis, and necrosis in all 3 patients and an aggregation of abnormal microscopic blood vessels in two. No tumor was found. All 3 patients remain in long-term (greater than 10 years) continuous remission.

Melanotic ependymoma and subependymoma.

We report two examples of melanin production by human gliomas. One was a grossly pigmented, well-differentiated ependymoma resected from the left frontoparietal region of a 13-year-old girl. The patient received radiotherapy and was free of tumor 12 years after operation. The second example was a pigmented subependymoma incidentally discovered at the autopsy of a 52-year-old man. Neoplastic cells containing an intracytoplasmic pigment satisfying histochemical criteria for melanin were present in both cases. Electron microscopic study of the melanotic ependymoma revealed electron-dense granules in the cytoplasm of cells forming rosettes. Premelanosomes were not detected. While the mechanism of melanogenesis in these cases is obscure, they support the potential of glial derivatives to produce melanin and indicate that melanogenesis in such neoplasms may have no adverse prognostic import.

Synaptophysin: a sensitive and specific marker for ganglion cells in central nervous system neoplasms.

Synaptophysin, a 38-kilodalton glycoprotein found in synaptic vesicle membranes, has been shown to be a sensitive marker of neuroendocrine differentiation in non-central nervous system (CNS) tumors. We analyzed the patterns of synaptophysin immunoreactivity in CNS neoplasms in comparison with various normal CNS sites in biopsies. Normal gray matter structures all showed a diffuse punctate granular pattern of neuropil staining without staining of neuronal cell bodies. In contrast, neoplastic ganglion cells in 18 of 18 gangliogliomas/gangliocytomas showed intense immunoreactivity outlining the borders of the cell bodies. Focal staining was also seen in five of 16 primitive neuroectodermal tumors and in one of three central neurocytomas, but these tumors had a finely granular neuropil pattern of immunoreactivity more like that of normal gray matter than like that of the gangliogliomas. All 35 examples of pure gliomas of various types showed no immunoreactivity. Our data highlight synaptophysin as a sensitive and specific marker of both neuronal lineage and neoplastic character in gangliogliomas.

Synaptophysin: a sensitive and specific marker for ganglion cells in central nervous system neoplasms.

Synaptophysin, a 38-kilodalton glycoprotein found in synaptic vesicle membranes, has been shown to be a sensitive marker of neuroendocrine differentiation in non-central nervous system (CNS) tumors. We analyzed the patterns of synaptophysin immunoreactivity in CNS neoplasms in comparison with various normal CNS sites in biopsies. Normal gray matter structures all showed a diffuse punctate granular pattern of neuropil staining without staining of neuronal cell bodies. In contrast, neoplastic ganglion cells in 18 of 18 gangliogliomas/gangliocytomas showed intense immunoreactivity outlinging the borders of the cell bodies. Focal staining was also seen in five of 16 primitive neuroectodermal tumors and in one of three central neurocytomas, but these tumors had a finely granular neuropil pattern of immunoreactivity more like that of normal gray matter than like that of the gangliogliomas. All 35 examples of pure gliomas of various types showed no immunoreactivity. Our data highlight synaptophysin as a sensitive and specific marker of both neuronal lineage and neoplastic character in gangliogliomas.

Leukoencephalopathy in normal and pathologic aging: 1. CT of brain lucencies.

Central white matter lucencies are commonly seen in CT scans of elderly patients. Reports in the literature have implicated demyelination due to subcortical vascular disease (Binswanger disease) as the cause of these lucencies. Binswanger disease, however, is thought to be rare. Because of this apparent discrepancy we decided to determine the incidence and to attempt to define the clinical significance of the CT white-matter changes in a study population at New York University Medical Center. The studies of 275 normal and demented subjects, ages 23 to 85 years, were reviewed. All subjects received neurologic, psychiatric, and medical evaluation, formal psychometric evaluation of their cognitive status, and a CT scan. CT scans were evaluated for the presence and severity of white-matter changes (leukoencephalopathy). The incidence and severity of white-matter changes increased significantly with age (p less than 0.01). Leukoencephalopathy was consistently more common in demented patients than in normal subjects, but the difference was not statistically significant, and the severity of the leukoencephalopathy was not related to the severity of dementia (p less than 0.05). Five patients (ages 74 to 95 years) with a clinical diagnosis of Alzheimer disease who had CT evidence of lucencies were examined at autopsy. Neuropathology demonstrated extensive changes of Alzheimer disease in one brain and mild-to-moderate changes in the other four brains; areas of white-matter rarefaction were present in all brains, with microscopic evidence of arteriolar hyalinization. This study demonstrates that leukoencephalopathy is strongly related to the aging process and is seen in both "normal" and cognitively impaired individuals who have no other evidence of vascular disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Sarcoma arising in metastatic carcinoma in the brain. A second instance.

A second instance in which a carcinoma metastatic to the brain has induced the formation of a sarcoma in the associated cerebral blood vessels, is reported. This is analogous to the more common gliosarcoma, a tumor in which a primary glioma, most often anaplastic astrocytoma (glioblastoma multiforme), has induced the formation of a similar sarcoma, with both neoplastic tissues in the same tumor mass. The formation of the sarcoma is attributed to a neoplastic change in the markedly hyperplastic endothelial cells of the cerebral blood vessels that are very commonly found with anaplastic astrocytomas and are often found in relation to metastatic carcinoma. The progression of hyperplasia to neoplasia has long been considered of oncogenetic significance, and in this specific circumstance, appears to be due to some factor or substance which passes from the carcinoma cells to the cerebral vessels.

Giant intracranial aneurysm presenting as a posterior fossa mass.

A patient with signs of brainstem compression and hydrocephalus is reported. The clinical picture suggested a posterior fossa neoplasm. Computed tomography, however, proved highly accurate in making the diagnosis of a giant, partially thrombosed vertebrobasilar aneurysm. The radiographic appearance of this entity is summarized and pathologic correlation is offered.

Painful neuroma: changes produced in peripheral nerve after fascicle ligation.

Sixteen months after resection of a painful neuroma and fascicle ligation of the proximal nerve segments, the fascicle ligated neural tissue was examined by light and electron microscopy. No significant neuroma formation was found in the fascicle-ligated regions. The distal portion consisted mainly of connective tissue fibroblasts with an absence of neural elements. Maintaining the perineurium intact by fascicle ligation seems to alter significantly axonal regeneration in humans, as is indicated by minimal neuroma formation. Similar findings after fascicle ligation in animals have also been reported. This lack of neuroma formation after resection of a painful neuroma and fascicle ligation may play a significant role in relieving pain in patients with painful neuromas.

An axoplasmic component of the Schmidt-Lanterman deformation.

In three instances, peripheral nerves containing numerous Schmidt-Lanterman discontinuities of myelin revealed transverse, wedge-shaped, or arrowhead-shaped axoplasmic excrescences visible with axon stains. These were arranged with a frequency and length like that of the myelin clefts, but the axonal materials were located within the myelin masses bordering the clefts, not in the clefts themselves. These axoplasmic changes are not consistent with most assumptions concerning the physiologic functions of the clefts, and supports the concept that the clefts are artifactual, due possibly to mechanical factors acting an abnormal nerve fibers.

The influence of the ground substance on the extracellular water of normal and edematous human brain: focal edema and the demyelinating diseases, including multiple sclerosis.

The presence of a ground substance in brain provides a mechanism by which edema localized to one region of the white matter might occur without spreading diffusely into the adjacent tissues. The most common such localization is the sparing of the arcuate white matter when the deeper white matter is markedly edematous. This may be related to the higher concentration of mucopolysaccharides in the former. Petechial hemorrhages in the white matter may be surrounded by a zone free of edema, although the hemorrhagic zone itself is almost certainly edematous. This, and the presence of a central zone within some of the petechiae forming a ring hemorrhage may reflect the influence of the ground substance. Focal lesions of the dorsum of the corpus callosum and similar lesions of the basal surface of the pons, these probably due to traumatization by the contiguous falx or arteries, are characterized by myelin loss and axon preservation, a characteristic of edema; the surrounding tissues are not edematous. Severe hypertension is sometimes associated with the presence of clusters of focal perivenous demyelinating lesions in the white matter, the axons being preserved. These resemble the lesions of acute disseminated encephalomyelitis and may be due to edema; they are surrounded by nonedematous white matter. It is suggested that the same concept may apply to the focal demyelinating lesions of acute disseminated encephalomyelitis, multifocal leukoencephalopathy, central pontine myelinolysis and of multiple sclerosis, i.e. the "true" demyelinating diseases, just as has already been suggested for diffuse sclerosis.