Intravascular malignant lymphomatosis

Intravascular malignant lymphomatosis (IML) is a rare form of extranodal non-Hodgkin lymphoma characterized by proliferation of malignant lymphoid cells within the lumen of small blood vessels. We describe a case of IML presenting with non-specific pulmonary symptoms, weight loss, intermittent fever and a confusing collection of laboratory findings. Later on the patient developed cardiac symptoms, and finally diffuse cerebral symptoms and skin lesions. His condition deteriorated and he died within six months. The diagnosis of IML was made at autopsy. Complete remission and long-term disease-free survival may be obtained with standard chemotherapy directed at high-grade lymphomas. It is important to remember IML in the differential diagnosis of patients with confusing and changing ischaemic symptoms and signs from several organs.     

Increased contact time improves adenovirus-mediated CFTR gene transfer to nasal epithelium of CF mice

By combining retrograde and anterograde tracing, evidence for a bineuronal connection from the suprachiasmatic nucleus (SCN) to the intermediolateral cell column in the spinal cord (IML) was obtained. The retrograde tracer cholera toxin subunit B (ChB) was pressure-injected into the spinal cord and the anterograde tracer Phaseolus vulgaris-leucoagglutinin (PHA-L) was iontophoretically injected into the SCN. The two tracers were visualized simultaneously by a double immunohistochemical procedure. In the hypothalamus, ChB injections gave rise to retrogradely labeled cell bodies in the paraventricular nucleus, retrochiasmatic area, perifornical region, lateral hypothalamic area, and the posterior hypothalamic area. The SCN were found to project to all of these areas. Furthermore, spinal-projecting neurons were found in the brain stem, but no efferents from the SCN were observed to innervate these areas. In the most sparsely innervated areas, the lateral hypothalamic area and the perifornical region, only occasionally a PHA-L fiber in close apposition to a ChB-ir cell body was observed. This was also the case in the retrochiasmatic area and posterior hypothalamic area, although these areas received a moderate number-immunoreactive (ir) PHA-L-ir fibers. The highest number of closely apposed PHA-L-ir fibers and ChB-ir cell bodies was observed in the dorsal parvicellular and in the ventral division of the medial parvicellular paraventricular nucleus, which were also the areas receiving the densest input from the SCN. By anterograde tracing from the paraventricular nucleus of the hypothalamus, the exact topography of the terminal field formed by descending paraventricular neurons was established. Thus, it was confirmed that the paraventricular nucleus of the hypothalamus predominantly innervates the IML. The present study suggests the existence of a bineuronal link between the SCN and the IML, possibly involved in transmission of circadian signals from the endogenous clock to the pineal gland and other organs receiving sympathetic afferents.     

Three-dimensional gray scale ultrasonographic imaging of the celiac axis: preliminary report

BACKGROUND AND OBJECTIVES: We have previously reported the isolation of a G protein-coupled receptor, CXCR-4, that is overexpressed in glioblastoma multiforme tumor tissue (GMTT), as compared to normal brain tissue (NBT). METHODS: Gene-specific RT-PCR, Northern blotting, and in situ hybridization techniques were used to study its expression in a variety of normal tissues, tumor tissues, and cell lines, as well as during development. Antisense CXCR-4 was overexpressed in glioblastoma cells to study its effect on cell proliferation. RESULTS: Gene-specific RT-PCR analysis indicated that the CXCR-4 gene is overexpressed in several malignant glioma tissues, breast tumor tissues and cell lines. Northern blot analysis indicated that CXCR-4 is expressed at high levels in certain leukemias, uterine cancer, and Burkitt's lymphoma cell line. The occipital and temporal lobe showed high levels of CXCR4 in normal human brain. The CXCR-4 gene was expressed in all organs in the early stages of development (days 8-10). In adult mouse, CXCR-4 is expressed only in brain, spinal cord, bone marrow, and pituitary gland. Antisense CXCR-4 overexpression in glioblastoma cells caused inhibition of cell proliferation and induction of cellular differentiation in vitro. This suggests that CXCR-4 expression may play an important role during embryonic development and also in the genesis of human gliomas. CONCLUSIONS: On the basis of CXCR4 expression data and antisense overexpression data, we conclude that CXCR-4 plays an important role in the tumorigenic properties of brain, breast, and other tumor types. On the basis of its unique expression during mouse development, we conclude that it may play an important role in the normal functioning of brain, spinal cord, and bone marrow during development.     

Meningeal carcinomatosis

An anatomopathologic study of 18 cases of pure meningeal carcinomatosis is presented. In five of these cases, the brain, spinal cord, choroid plexuses, cerebral vessels, and prevertebral soft tissues, including the lumbosacral nerve plexuses and ganglia, were examined microscopically in an attmept to determine the routes of tumor spread. Our results suggest that the malignant cells reach the cerebrospinal leptomeninges via perineural, endoneural, and perivascular lymphatics and sheaths through the intervertebral and possibly cranial foramina. Involvement of the choroid plexuses appears to be secondary to, rather than the avenue for, leptomeningeal carcinomatosis, with the tumor cells reaching the choroid plexuses via the perivascular sheaths of choroidal vessels. Leptomeningeal carcinomatosis was the only manifestation of metastatic spread beyond regional lymph nodes in about 40% of all reported cases in which this information is available. This implies that radiation or other forms of local therapy to the cerebrospinal leptomeninges may provide an effective means of palliation in many of these cases.     

Successful treatment with CPT-11 and adriamycin for hemophagocytic syndrome associated with intravascular lymphomatosis

A 75-year-old man was admitted because of non-Hodgkin's lymphoma (histology undetermined) of the rib. A complete remission was achieved after CHOP therapy and irradiation. One year later, high fever, thrombocytopenia and liver dysfunction developed. Bone marrow aspirate revealed a hypoplastic marrow with hemophagocytic histiocytes, and a diagnosis of hemophagocytic syndrome (HPS) was made. Although no lymphomatous lesions were detected, HPS due to relapsed lymphoma was strongly suspected. The patient received MEVP therapy including etoposide and prednisolone, but without any improvement. Soon after the initiation of CPT-11 and adriamycin (ADM) therapy, all symptoms of HPS disappeared. This combination chemotherapy was repeated over a three-week span, and the patient remained in partial remission for the next 10 months. In November 1997, a tumor developed in the paranasal sinus, and the patient died three months later. The autopsy disclosed many B lymphoma cells filling the small vessels of almost all organs, and a final diagnosis of intravascular lymphomatosis (IVL) was made. These findings indicate that combination CPT-11 and ADM therapy is effective for cases of IVL accompanied by HPS that are refractory to conventional chemotherapies.     

Imaging and pathological features of primary malignant rhabdoid tumours of the brain and spine

In this article two cases of primary malignant extrarenal rhabdoid tumour are described. In the affected children the brain and the spinal cord were the primary sites of origin of the tumour. The imaging findings are presented and the pathology discussed. Although the imaging features are non-specific, rhabdoid tumour should be included in the differential diagnosis of childhood intracranial and spinal neoplasms.     

Intravascular malignant lymphomatosis with neurologic presentation: factors facilitating antemortem diagnosis

Intravascular malignant lymphomatosis (IML) is a rare disorder of small and medium size vessels that frequently goes undiagnosed until the time of autopsy. The clinical courses of two such patients were examined to determine factors that would facilitate antemortem diagnosis. Both patients had mental status changes, pyramidal tract signs, and peripheral neuropathy. Despite postmortem evidence of widespread lymphocytic invasion of vessels throughout the body including peripheral and central nervous systems, neuroimaging studies, cerebrospinal fluid analysis, peripheral blood studies, and bone marrow biopsy failed to reveal diagnostic evidence of the underlying neoplastic process. Although markedly abnormal, nerve conduction studies were nonspecific. Familiarity with IML and its consideration in the differential diagnosis when central and peripheral nervous system dysfunction occur concurrently may guide the physician to tissue biopsy facilitating antemortem diagnosis and institution of appropriate therapy.     

Mortality among workers in the pulp-paper industry. A successive follow up of the cohort

Neuropathologic findings are described, for the first time, in a neonatal dog model of circulatory arrest in normothermic conditions, and the findings are compared to those reported in neonatal dogs with hypothermic circulatory arrest. Total circulatory arrest was produced in 3- to 6-day-old anesthetized, paralyzed and ventilated, normothermic dogs either by asphyxiation or cardioplegia. Duration of circulatory arrest was 8-20 min and 10-40 min in asphyxiated and cardioplegic animals, respectively. The animals were resuscitated and maintained under controlled systemic physiologic conditions until neuropathologic examination after 8 or 24 h of recovery. The results suggest that the minimal durations of circulatory arrest for brain damage to occur following asphyxia or cardioplegia are 10 and 15 min, respectively. Ischemic lesions in both groups consisted of neuronal necrosis and involved mainly the brain stem structures, particularly the reticular nuclei and the spinal cord gray matter. The medulla was more severely involved than midbrain and pons. There was a direct correlation between the length of circulatory arrest and the severity of damage in the medulla (P = 0.001) and overall brain stem damage (P = 0.004) in animals with cardioplegia, but not in animals with asphyxia. These findings are compared to the neuropathologic changes previously described in newborn dogs subjected to hypothermic circulatory arrest, in which ischemic lesions are focused on the cerebral cortex and basal ganglia. It is concluded that hypothermia in this model not only prolongs the period of circulatory arrest that is required to produce brain damage, but also shifts the pattern of regional ischemic vulnerability from caudal to more rostral structures.     

Effects of ultrafine and fine particles in urban air on peak expiratory flow among children with asthmatic symptoms

Post-mortem morphological, neuropathological and neurochemical findings are described in a girl, aged 14 months, with the early-infantile form of galactosialidosis. An elevation in non-lipid sialic acid was noted in both the grey and white matter of the brain, whereas the white matter displayed a clear reduction in all the major lipids. Multiple cortical-subcortical infarctions were found in the brain, most probably caused by compromised circulation due to endothelial luminal encroachment. Electron microscopy of cerebral blood vessels revealed major swelling of the endothelium due to prominent cytoplasmic vacuolisation. Multiple cytoplasmic vacuoles containing sparse granular or membranous matter were also seen in neurons and glial cells of the brain and spinal cord. Zebra bodies were found in the Purkinje cells, as well as in the spinal anterior horn cells. Prominent endothelial vacuolisation was noted in the liver and kidneys. The renal vascular encroachment was probably the cause of the arterial hypertension with elevated plasma renin activity in the present case. There were innumerable fine vacuoles in the renal epithelium and in the Kupffer cell of the liver, whereas coarser vacuoles were observed in the hepatocytes. The neuronal ultrastructural findings in the present case bear some resemblance to the few reported cases of late-infantile and adult cases of galactosialidosis. The prominent endothelial vacuolisation and focal cerebrovascular lesions, that have not previously been described in galactosialidosis, may be features specific to the rapidly progressive early-infantile form.     

Intraoperative monitoring for spinal cord tumor by spinal cord evoked potential following unilateral spinal cord stimulation

We described our experiences with intraoperative spinal cord monitoring in 6 cases of spinal cord tumor. During the operation, spinal cord evoked potential following unilateral spinal cord stimulation was recorded from subdural monitoring electrodes. This series included two cases of intradural extramedullary tumor (one case each of neurinoma and of meningioma) and four cases of intramedullary tumor (2 cases of cavernous angioma, one case each of ependymoma, and of glioblastoma multiforme). Before the removal of the tumor, the spinal cord evoked potential showed lower amplitude or no response on the more affected side in all 6 cases. During the operation, the different intraoperative changes were shown on each side. The authors think that the detection of unilateral damage to the spinal cord is possible in spinal cord evoked potential using unilateral spinal cord stimulation.     

FGF-2 is sufficient to isolate progenitors found in the adult mammalian spinal cord

The adult rat brain contains progenitor cells that can be induced to proliferate in vitro in response to FGF-2. In the present study we explored whether similar progenitor cells can be cultured from different levels (cervical, thoracic, lumbar, and sacral) of adult rat spinal cord and whether they give rise to neurons and glia as well as spinal cord-specific neurons (e.g., motoneurons). Cervical, thoracic, lumbar, and sacral areas of adult rat spinal cord (>3 months old) were microdissected and neural progenitors were isolated and cultured in serum-free medium containing FGF-2 (20 ng/ml) through multiple passages. Although all areas generated rapidly proliferating cells, the cultures were heterogeneous in nature and cell morphology varied within a given area as well as between areas. A percentage of cells from all areas of the spinal cord differentiate into cells displaying antigenic properties of neuronal, astroglial, and oligodendroglial lineages; however, the majority of cells from all regions expressed the immature proliferating progenitor marker vimentin. In established multipassage cultures, a few large, neuron-like cells expressed immunoreactivity for p75NGFr and did not express GFAP. These cells may be motoneurons. These results demonstrate that FGF-2 is mitogenic for progenitor cells from adult rat spinal cord that have the potential to give rise to glia and neurons including motoneurons.     

Frequent deletion and 5' CpG island methylation of the p16 gene in primary malignant lymphoma of the brain

A total of 10 primary malignant lymphomas of the brain were examined for deletion, mutation, and 5' CpG island methylation of the p16 gene, which is a candidate tumor suppressor gene with CDK-inhibitory function. In Southern blot analysis, p16 gene deletion was suggested in nine cases, homozygously (five cases) or hemizygously (four cases). In the remaining one case, p16 gene deletion was not suggested. Although single-strand conformation polymorphism and nucleotide analyses suggested no mutations of the p16 gene in these cases, methylation analyses revealed 5' CpG island methylation in three cases, of which two were those with presumed hemizygous deletion and one was that without deletion in Southern blot analysis. Thus, p16 gene abnormality was detected in all 10 of the brain lymphomas examined, and in 8 of them, actual p16 gene inactivation was suggested by their homozygous deletion (5 cases) or 5' CpG island methylation (3 cases). These findings suggest that p16 gene abnormality and inactivation are closely related to carcinogenesis in primary malignant lymphoma of the brain. The p15 gene, another candidate tumor suppressor gene located in the vicinity of the p16 gene, to which it shows structural and functional similarity, was also presumed to be deleted similarly in most cases. Its methylation was seen in one case, the case without the methylated p16 gene.     

An autopsy case of an extensive epidural spinal abscess demonstrating necrotizing poliomyelopathy

A 59-year-old man with a history of diabetes mellitus (NIDDM) presented with fever, back pain and weakness in the left lower limb. Three weeks later he suddenly developed flaccid paraklegia, a sensory deficit below the abdomen and sphincter dysfunction. MR images of the spinal cord showed an extensive anterior spinal epidural abscess extending from the seventh cervical to the twelfth thoracic spine and osteomyelitis in the lower thoracic spines. He died of pulmonary infection one year after the disease onset. Postmortem examination revealed a large empyema in the lung. On neuropathological examination, small multiple hemorrhagic or ischemic lesions were found in the basal ganglia and the pons. The spinal cord was markedly atrophic in the lumbar cord. However, there was neither compression deformity in the cord nor occlusion in the anterior spinal artery. Throughout the thoracic cord, rarefaction and focal cavity formation was selectively present in the gray matter, particularly the posterior horns. In the white matter, vacuolar changes were seen peripherally as well as Wallerian degeneration in the lateral and anterior corticospiral tracts and in the fascicles gracilis bilaterally. The mechanisms inducing the cord damage in cases of epidural spinal abscess have been speculated to be either direct compression by the abscess or the secondary circulatory disturbance in the cord due to compression. In our case, the cord showed necrotizing poliomyelopathy, which was similar to that of ischemic myelopathy found in the cases of cardiac arrest or dissecting aneurysm of the aorta. Autopsy study of spinal cord lesion associated with epidural abscess has been limited in number and our case should contribute to the understanding of the pathomechanism of such myelopathy.     

Percutaneous occlusion of arterial vessels using permanent embolization for the treatment of an air sac hemorrhage in horses. A case report

We report a case of intravascular malignant lymphomatosis observed in a 71 year-old male and characterised by the presence of a proteinuria in relation to the specific intraglomerular localisation. This malignant lymphoma, usually of the B phenotype, is rare and affects predominantly the central nervous system and the skin. Neoplastic cells home selectively to endothelium. Histological renal infiltration is frequent but a glomerular localisation, with proteinuria, is rare. The mechanism whereby lymphocytes home to endothelium cells is unclear but it could be related to the expression of lymphocyte-endothelium adhesion molecules. When present the nephrotic syndrome is associated with minimal change disease.     

Intramedullary localization of a primary cerebral lymphoma in AIDS

A 36 years-old male with AIDS, presented with left hemiparesis revealing a right parietal tumour. Stereotactic biopsy demonstrated a malignant non-Hodgkin's lymphoma. His condition partially improved following radiotherapy and chemotherapy. Three months later he was re-admitted with progressive bilateral root pain and urinary incontinence resulting in paraplegia with sensory loss below T10. He died one month later from generalized sepsis. Neuropathology confirmed an immunoblastic B-cell malignant non-Hodgkin's lymphoma in the white matter of the right parietal lobe and revealed a centrospinal localisation of the lymphoma in the thoracic cord at T10. There was no visceral localisation of the tumour. Secondary spread to the spinal cord of malignant non Hodgkin's lymphomas, usually causes meningo-myelo-radiculitis. Intraspinal deposits of primary cerebral lymphomas are uncommon and have never been previously described in AIDS, to our knowledge. Their pathogenesis is unclear. In our case, neuropathological findings are consistent with diffusion of the primary tumour to leptomeninges and secondary infiltration of the spinal cord along the perivascular spaces.     

Development and malignant progression of astrocytomas in GFAP-v-src transgenic mice

We have generated a transgenic mouse model for astrocytoma by expressing the v-src kinase under control of the glial fibrillary acidic protein (GFAP) gene regulatory elements in astrocytes. Abnormal astrogliosis was observed in all transgenic animals already at 2 weeks postnatally, frequently followed by the development of dysplastic changes. Later, small proliferative foci arose, and overt astrocytoma developed in the brain and spinal cord in 14.4% of mice after a follow up time of 65 weeks. While early lesions were histologically consistent with low-grade astrocytoma, at later stages most tumors were highly mitotic and frankly malignant. Vascular endothelial growth factor (VEGF) was expressed by tumor cells already at early stages, suggesting induction by v-src, and it was most pronounced in pseudopalisading cells surrounding necrotic areas, implying additional upregulation by hypoxia. In larger lesions, mitotic activity and expression of flk-1, the cognate receptor of VEGF were induced in endothelial cells. Therefore, end-stage tumors mimicked the morphological and molecular characteristics of human glioblastoma multiforme. Time course and stochastic nature of the process indicate that v-src did not suffice for malignant transformation, and that astrocytomas were the result of a multistep process necessitating co-operation of additional genetic events.     

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.     

Lymphoma of the spinal extradural space

Ninety-four patients with lymphoma involving the extradural space with spinal cord compression proven at the time of laminectomy were reviewed. There were about three times as many patients with non-Hodgkin's lymphoma than with Hodgkin's disease. The majority of those with Hodgkin's disease had a proven histologic diagnosis before the onset of the spinal cord compression syndrome, whereas only 15% of those with non-Hodgkin's lymphoma had previously been so diagnosed. Plain roentgenograms of the spine were suggestive of tumor involvement in less than one-third of the patients, whereas myelograms were invariably abnormal. As noted by others, the outlook for functional recovery and extended life expectancy is relatively good for patients with this type of cancer, in contrast to reports in the literature regarding prognosis for patients who have metastatic carcinoma with extradural spinal cord compression.     

Surgical treatment for primary cardiac malignant lymphoma

A 60-year-old woman who complained of palpitation was diagnosed as ventricular tachycardia on electrocardiography and admitted to our hospital. The ultrasonic cardiography showed cardiac tumor in right ventricle and right atrium. Due to the obstruction of the right ventricle inflow by the tumor, we immediately performed resection of cardiac tumor and repair of right ventricle wall under cardiopulmonary bypass. The tumor was diagnosed as malignant lymphoma by pathological examination for surgical specimen of tumor. After operation her general condition was good, but residual cardiac lymphoma developed large size. We performed radiation therapy for cardiac lymphoma. Therefore the lymphoma was reduced to minimum size. Six months after operation metastatic malignant lymphoma appeared at whole body. So we performed chemotherapy for reduction of systemic malignant lymphoma. At first the chemotherapy was very effective. But metastasis spread rapidly and effectiveness of chemotherapy reduced. Thirteen months after operation she died for respiratory distress, probably due to metastatic brain tumor.     

Characterization of benzodiazepine receptors in primary cultures of fetal mouse brain and spinal cord neurons

Primary cultures of fetal mouse brain and spinal cord were examined for the presence of binding sites for [3H]diazepam. Both brain and spinal cord cultures contain high affinity binding sites which resemble benzodiazepine receptors found in mammalian CNS with respect to both pharmacologic profile and response to exogenously applied GABA. These observations, coupled with the electrophysiologic properties of these cells suggest that primary cultures of fetal mouse brain and spinal cord may be valid models for studying the role and regulation of the benzodiazepine receptor.