Abnormalities of developing white matter in lysosomal storage diseases.

Inborn metabolic errors causing lysosomal storage have well-recognized effects on neuronal function and morphology. In some classically "neuronal" storage diseases, however, neuroradiologic observations of infants have suggested a delay in central nervous system myelination based on persistently "immature" signal intensities monitored over time. This review summarizes reported neuropathologic evaluations of central white matter in infantile and juvenile patients and in corresponding animal models with lysosomal storage disorders. The observed neuropathology is examined in light of published studies of the biochemistry and microscopic anatomy of normal myelinogenesis. Finally, arguments are advanced that at least part of the deficiency of white matter is attributable to direct effects of the metabolic state on oligodendrocyte maturation and function, in addition to secondary effects on neurons and their axons.

Mucolipidosis IV: morphology and histochemistry of an autopsy case.

Mucolipidosis Type IV is a rare, autosomal recessive disorder characterized by corneal opacification, mental retardation, and delayed motor milestones. Whereas lysosomal storage material has been demonstrated in biopsied tissues and leukocytes, the complete autopsy pathology, including neuropathology, is unknown. The metabolic defect remains speculative. We report the general and neuropathologic findings of the only known autopsy. In the central nervous system, neuronal loss in the cerebral cortex, basal ganglia, deep cerebellar nuclei, and brainstem nuclei was marked by astrocytosis; the cytoplasm of residual neurons had brown granules. These granules were positive with periodic acid-Schiff, Concanavalia ensiformis, and Sudan black, but not with Luxol-fast blue. Ultrastructurally, neurons contained lysosomes laden with osmiophilic, amorphous and granular material, and few lamellated membrane structures. Hepatocytes, epithelia, endothelia, chondrocytes, and tissue macrophages also stained positively with Datura stramonium and Ricinus communis-I agglutinins, with renal glomeruli also staining with peanut agglutinin; most non-neural cells contained osmiophilic granules on toluidine blue-stained, plastic embedded sections, corresponding to lamellated membrane structures. These findings complement the previously reported ocular morphology and brain and liver biochemistry performed in the same patient, and suggest that the storage material in neurons differs from that in non-neural cells. Furthermore, the underlying defect is not likely to be a deficiency of a single enzyme (i.e. a lysosomal hydrolase).

Survival and proliferation of nonneural tissues, with obstruction of cerebral ventricles, in a parkinsonian patient treated with fetal allografts.

BACKGROUND: Since 1985, treatment of idiopathic Parkinson's disease (PD) by surgical transfer of adult or fetal chromaffin tissue or of fetal central neural tissue to the brains of afflicted patients has been attempted, with variable clinical results. Neuropathologic studies of the status of these transplants are few and show wide variation in degree of graft survival. METHODS: We report the case of a 52-year-old man, who, 23 months earlier, received both intrastriatal implantation and intraventricular infusion of tissues derived from fetuses of 15 to 16 weeks and 5 to 6 weeks gestational age. Clinical improvement, as measured by increased amounts of "on" time with reduced levodopa requirements, seemed to occur over the subsequent months. He died suddenly at home after a several-hours interval of progressive lethargy and breathing difficulties. RESULTS: At autopsy, the diagnosis of PD was confirmed. Intrastriatal graft sites were identified, but contained no viable neurons; astrogliosis, focal microgliosis, and mixed inflammatory response, suggesting allograft rejection, were present. Surprisingly, the intraventricular tissues survived and showed ectodermal and mesenchymal, but no neural, differentiation, as well as cellular response; the left lateral and fourth ventricles were filled completely by this proliferated tissue. CONCLUSIONS: By intraventricular infusion, tissues from early-gestation sources can engraft successfully, grow, and survive for at least 23 months in the brain of a PD patient. However, contamination by, or differentiation into, nonneural tissues can occur, can lead to proliferation of tissues within ventricular spaces, and may result in ventricular obstruction. Grafts, whether intraventricular or intraparenchymal, are capable of inciting host responses, which in turn may limit their long-term survival. Finally, post-transplant clinical improvement in symptoms of PD may be unrelated to survival of engrafted neurons.

Xanthomatous hypophysitis.

Inflammatory lesions of the hypophysis include lymphocytic hypophysitis, pituitary abscess, and granulomatous inflammation, with or without specific infections (i.e., sarcoidosis, mycobacteria). These lesions are known to mimic pituitary neoplasms. We report the clinical and pathologic findings in three patients who underwent transsphenoidal resection for presumed pituitary adenoma. Two were women aged 30 years (one with a 5-month history of headache, the other with a 1-year history of menstrual irregularity) and one was a 12-year-old girl with headache, nausea, and diabetes insipidus. Preoperative endocrinologic studies showed increased prolactin in one patient and normal serum thyroid stimulating hormone and prolactin levels in another. By magnetic resonance imaging (MRI), the first case had a 1.2-cm mass with increased signal on T1 and isointensity on T2, ring enhancement after gadolinium, and lateral deviation of the pituitary stalk. The second patient had a 1.1-cm "cystic" mass seen during magnetic resonance imaging with adjacent bony changes seen during computed tomography. In the third, computed tomography showed a hypodense pituitary mass that enlarged during 1-month observation. At surgery, abnormal soft tissue surrounded liquefied material in the anterior pituitary in all cases. Histologic studies showed fragments of intact normal anterior pituitary with preserved vascular and reticulin network and regions of anterior pituitary infiltrated by foamy histiocytes. Other fragments resembled granulation tissue, and some consisted of acellular debris. Histiocytes were immunoreactive for the macrophage marker CD68 and negative for S-100 and CD1a. Ultrastructurally, the normal adenohypophysis was permeated by lipid-laden macrophages. There were no well-formed granulomas or giant cells, hemosiderin, acid-fast bacilli, or fungi. Serial sections and keratin immunostains failed to identify an epithelial cyst lining or keratin among the debris. We propose the term "xanthomatous hypophysitis" for this lesion.

Surgical reversal of a subacute complete unilateral visual loss from an ovarian metastasis to the pituitary gland.

A 56-year-old woman with ovarian papillary cystadenocarcinoma that metastasized to the pituitary gland sought treatment with a 7-day history of total loss of vision in one eye. Ten days after transsphenoidal tumor resection, the patient's vision suddenly returned to baseline. This unusual case indicates that surgical decompression of the optic nerve and chiasm can completely salvage vision, even after prolonged total visual loss.

Arthrogryposis multiplex congenita with posterior column degeneration and peripheral neuropathy: a case report.

Congenital sensory neuropathies associated with arthrogryposis multiplex congenita (AMC) are rare. We report a unique case of a nine-week-old, full-term infant with AMC, congenital sensory neuropathy, and posterior column degeneration. The family history was negative for neuromuscular disease. At birth, the infant was small for gestational age, indicative of intrauterine growth retardation. He was hypotonic and hyporeflexic, and failed to sustain respiration. He remained ventilator-dependent throughout his life. Electrodiagnostic studies indicated widespread peripheral neuropathy. At two weeks of age, biopsied sural nerve was almost completely devoid of myelinated axons; quadriceps skeletal muscle contained only mild and nonspecific abnormalities. Autopsy showed pulmonary hypoplasia. The major nervous system findings were severe, bilateral posterior column degeneration, mild posterior horn gliosis, atrophy of posterior roots, and axonal degeneration of the peripheral nerves. Sensory and autonomic (vagal) nerves were preferentially involved, with relative sparing of motor nerves. This case suggests that interruption of kinesthetic pathways early in gestation may result in fixed joints.

Use of perfusion fixation for improved neuropathologic examination.

OBJECTIVE: To assess the efficacy of 10% formalin perfusion fixation as a method of rapid fixation to examine the human brain immediately following autopsy. DESIGN: Compare the histology and immunohistochemistry from human brains in which one hemisphere undergoes perfusion fixation using 10% buffered formalin, and the contralateral nonperfused hemisphere undergoes standard 14-day immersion fixation in 8 L of 10% buffered formalin. SETTING: Autopsy material in a general medical-surgical university hospital. PARTICIPANTS: Pathologists, neuropathologists, resident pathologists, and pathology assistants. INTERVENTION: Immediately following brain removal, a single hemisphere was perfused with 1 L 10% buffered formalin over a 15- to 20-minute period. The contralateral nonperfused hemisphere served as a control, undergoing standard immersion fixation for 2 weeks in 10% formalin. The perfusion-fixation hemisphere was immediately available for neuropathologic examination, and histologic sections of the brain were processed immediately with the other necropsy tissue sections. This allows completion of a final autopsy neuropathology report within 3 to 5 days in concert with the systemic section of the report. MAIN OUTCOME MEASURE: Perfusion-fixation brain sections were compared with immersion-fixation brain sections from the same brain. The effects on hematoxylin-eosin, Bielschowsky's silver, and immunohistochemical staining were evaluated by an experienced neuropathologist and a general pathologist with no prior knowledge of the fixation technique. RESULTS: Perfusion fixation revealed equal and occasionally superior histologic sections compared with traditional immersion fixation in terms of (1) technical preparation of section, (2) quality and intensity of staining with both hematoxylin-eosin and silver, and (3) immunoreactivity localization with a variety of immunohistochemical reactions. CONCLUSIONS: Immediate perfusion of the brain is an easily performed fixation technique that yields comparable or superior fixation to prolonged immersion fixation and allows an immediate complete neuropathologic examination and report within 3 to 5 days of performance of the autopsy.

Smears and frozen sections in the intraoperative diagnosis of central nervous system lesions.

The rapid diagnostic techniques of smears and frozen sections are fundamental to the strategy of the neuropathologist in evaluating tissue received at the time of operating room consultation with the neurosurgeon. This strategy begins with the exclusion of nonneoplastic lesions and proceeds to determination of the neoplastic cell type, or, in the case of reoperation of a treated tumor, the distinction of viable from necrotic tumor. In the interest of conserving unfrozen tissue for permanent sections, a smear may be made and examined initially, with a frozen section prepared only if the smear is equivocal or technically inadequate. This approach has been shown to result in a degree of diagnostic accuracy comparable to that described in general surgical material subject to frozen section analysis.

NeuN expression correlates with reduced mitotic index of neoplastic cells in central neurocytomas.

In the developing brain, neuronal differentiation is associated with permanent exit from the mitotic cycle. This raises the possibility that neuronal differentiation may suppress proliferative activity, even in neoplastic cells. As a first step towards understanding the relation between neuronal differentiation and mitotic cycling in brain tumours, we studied the expression of NeuN (a neuronal marker) and Ki-67 (a mitotic marker) by double-labelling immuno-fluorescence in 16 brain tumours with neuronal differentiation. The tumours included a series of 11 central neurocytomas, and five single cases of other tumour types. In the central neurocytomas, NeuN(+) cells had a 15-fold lower Ki-67 labelling index, on average, than did NeuN(-) cells (P < 0.01). In the other tumours (one extraventricular neurocytoma, one desmoplastic medulloblastoma, one olfactory neuroblastoma, one ganglioglioma and one anaplastic ganglioglioma), the Ki-67 labelling index was always at least fourfold lower in NeuN(+) cells than in NeuN(-) cells. These results indicate that neuronal differentiation is associated with a substantial decrease of proliferative activity in neoplastic cells of central neurocytomas, and suggest that the same may be true across diverse types of brain tumours. However, tumours with extensive neuronal differentiation may nevertheless have a high overall Ki-67 labelling index, if the mitotic activity of NeuN(-) cells is high. The correlation between NeuN expression and reduced mitotic activity in neurocytoma cells is consistent with the hypothesis that neuronal differentiation suppresses proliferation, but further studies will be necessary to determine causality and investigate underlying mechanisms.

Descriptive analysis and quantification of angiogenesis in human brain tumors.

Quantitative determination of the degree of vascularity has been shown to be independently prognostically significant in many human tumor types. In particular, tumor vascularity has known importance in astrocytomas, in which endothelial proliferation is a criterion for anaplasia in many grading schemes. This review analyzes reports of microvessel quantification performed on histologic sections of human brain tumors, and in which correlations with clinical outcome, or other pathobiologic factors have been made. Among the conclusions are: (1) brain tumors have the unique feature of complex 'glomeruloid' vessels, as well as heterogeneity of microvascular distribution and caliber; (2) lower-grade astrocytomas may incorporate pre-existing vessels, while glioblastomas may develop new vessels; (3) quantification may have additional independent prognostic value over and above routine histologic grade in low-grade astrocytomas with low tumor cell proliferative indices. These findings have implications for the appropriateness of antiangiogenic therapies.

Organizing posterior fossa hematomas simulating developmental cysts on prenatal imaging: report of 3 cases.

OBJECTIVE: We encountered 3 organizing tentorial hematomas simulating posterior fossa lesions such as Dandy-Walker, dermoid, or arachnoid cysts. We sought to correlate the clinical and pathologic features that allow distinction of developmental cysts from hematomas in the posterior fossa on imaging. METHODS. Prenatal sonograms in all fetuses and fetal magnetic resonance scans in 2 of the 3 were reviewed. One case proceeding to term had serial imaging up to age 11 months. Two cases had complete neuropathologic evaluation after termination. Maternal records were reviewed. RESULTS: In each case, the ultrasonographic findings were reminiscent of a developmental cyst but with echogenic debris, a rim, or both. Magnetic resonance imaging suggested tentorial hemorrhage in 2, 1 also with falcine hemorrhage. Serial prenatal and postnatal imaging showed resolution in the surviving case. Pathologically, 2 fetuses had organizing tentorial hematomas causing brain displacement. Calcifications, white matter damage, germinal matrix hemorrhage, and brain stem necrosis were also present. One mother had von Willebrand disease. CONCLUSIONS: Tentorial hematomas, with or without maternal coagulopathy, should be considered in the prenatal ultrasonographic diagnosis of cystlike posterior fossa abnormalities containing echogenic material. Fetal magnetic resonance imaging can suggest blood products. Hypoxic-ischemic brain damage may be concurrent; however, resolution of the hematoma, with no apparent neurologic sequelae, can occur.

Microvessel density is a prognostic indicator for patients with astroglial brain tumors.

BACKGROUND: Microvessel density in tumors, a measure of angiogenesis, has been shown to be a prognostic indicator that correlates with an increased risk of metastasis in various epithelial cancers and with overall and relapse free survival in patients with breast cancer. Astrocytic brain tumors, particularly malignant astrocytomas, are recognized to be highly vascular tumors with potent angiogenic activity. However, the prognostic significance of microvessel density in these tumors is not known. METHODS: Sections from formalin fixed paraffin embedded tumor tissue from 93 unselected adult patients with supratentorial astrocytic brain tumors were immunostained for factor VIII-related antigen in order to highlight microvessel endothelial cells. Microvessels were counted at 200x and 400x magnification. Microvessel density was graded as 1+ to 4+ on 1 low power field, without knowledge of clinical outcome. Microvessel count and microvessel grade were correlated with postoperative survival using the Cox proportional hazards regression model. The prognostic significance of microvessel count and grade were also compared with established prognostic indicators, including patient age, Karnofsky performance status, and tumor histology using multivariate analyses. RESULTS: Both microvessel grade and microvessel count correlated significantly with postoperative survival by univariate analysis in both previously untreated and treated patients. Patients with tumors containing a microvessel Grade of 3+ or 4+ had significantly shorter survival time than patients with a microvessel Grade of 1+ or 2+ (P = 0.0022). Likewise, patients with microvessel counts of 70 or greater had significantly shorter survival than those with microvessel counts of fewer than 70 (P = 0.041). Patient age, Karnofsky performance status, tumor histology, and extent of resection were also correlated with survival by univariate analysis. Microvessel count was further shown to be an independent prognostic indicator by multivariate analyses. There were correlations between microvessel density and patient age and between microvessel density and astrocytic tumor grade. CONCLUSIONS: These findings support the importance of microvessel density as a prognostic indicator of postoperative survival of patients with astroglial brain tumors. Regional tumor heterogeneity may limit the use of these techniques for routine pathologic examination.

Relapse of acute myelogenous leukemia as a cerebellar myeloblastoma showing megakaryoblastic differentiation.

Myeloblastomas (granulocytic sarcomas) occurring within the central nervous system (CNS) are extremely rare lesions that may develop in patients with acute or chronic myeloproliferative disorders. The majority of such lesions involve brain or spinal cord by contiguous spread from meningeal or bony sites, rather than originating within the CNS parenchyma. We describe a patient with acute myelogenous leukemia in remission, who developed a purely intraparenchymal cerebellar myeloblastoma with megakaryocytic differentiation. The neoplastic cells expressed the megakaryocytic markers factor VIII-related antigen and platelet glycoprotein-IIIa (CD61), and showed ultrastructural features that were indicative of megakaryocytic differentiation. Clinically, myeloblastomas of the CNS invoke a broad differential diagnosis that includes abscess, hemorrhage, and metastatic neoplasms because of their intraparenchymal location and radiologic features. Although they are rare, myeloblastomas should be included in the histopathologic differential diagnosis of a poorly differentiated neoplasm occurring within the CNS, particularly in a patient with a history of myeloproliferative or myelodysplastic disease.

Infantile G(M1) gangliosidosis: complete morphology and histochemistry of two autopsy cases, with particular reference to delayed central nervous system myelination.

Inborn metabolic errors causing lysosomal storage, such as beta-galactosidase deficiency (G(M1) gangliosidosis [G(M1)]), have well-recognized effects on cellular function and morphology. In some classically "neuronal" storage diseases, including G(M1), neuroradiologic observations of infants have suggested a delay in myelination on the basis of persistently "immature" signal intensities monitored over time. We sought to evaluate in a semiquantitative fashion the pattern and degree of myelination in two infantile G(M1) patients, one boy and one girl, autopsied at 15 months of age. We assigned myelination degrees for defined sites on an ordinal scale of 0 to 4, and compared them to published population-based values for autopsied infants. In both patients, earlier-myelinating structures were comparable in development to that expected for postconceptional age, whereas later-myelinating structures were delayed. These data correlate well with the neuroradiologic diagnosis of myelination delay in these infants and suggest that the metabolic defect has a primary influence on myelin development, in addition to effects related to neuronal storage. Furthermore, our analysis by light and electron microscopy and lectin histochemistry of both CNS and systemic tissues, several of which had not been described, add to the understanding of the stored material in different cell types.

Aggressive oligodendroglioma predicted by chromosome 10 restriction fragment length polymorphism analysis. Case study.

Oligodendrogliomas are indolent brain tumors with mean postoperative survival of about 5 years. However, the range of postoperative survivals is wide, suggesting that these tumors are heterogeneous in their biologic behavior. Using restriction fragment length polymorphism (RFLP) analysis, we studied a case of an oligodendroglioma with loss of chromosome 10 sequences, a finding that has only been reported in glioblastoma multiforme and anaplastic astrocytomas. Four and a half months after the initial surgery the patient returned with a recurrent tumor having classic radiologic and pathologic features of glioblastoma multiforme. Loss of chromosome 10 alleles in oligodendroglioma may be predictive of aggressive biologic behavior, even in the absence of recognized histopathologic characteristics of anaplasia, and may enable us to select more appropriate treatments for this group of patients.

Evidence for clonal origin of neoplastic neuronal and glial cells in gangliogliomas.

Gangliogliomas are rare tumors of the central nervous system that account for approximately 1% of all brain tumors. Histologically, gangliogliomas are composed of intimately admixed glial and neuronal components, the pathological origins of which remain to be characterized. Clonal analysis through examination of the pattern of the X chromosome inactivation allows one to distinguish monoclonal differentiation of a genetically abnormal progenitor cell from parallel, but independent, clonal expansion of two different cell types during tumorigenesis in biphasic neoplasms, such as gangliogliomas. In the present study, we investigated the clonality of eight gangliogliomas from female patients using both methylation- and transcription-based clonality assays at the androgen receptor locus (HUMARA) on the X chromosome. Among tumors from seven patients who were heterozygous at the HUMARA locus, five were identified as monoclonal with the methylation-based clonality assay, and the results were confirmed by the transcription-based method, whereas two were shown to be polyclonal by the methylation-based clonality assay but monoclonal by transcription-based clonality analysis. We conclude that the predominant cell types in most gangliogliomas are monoclonal in origin and derive from a common precursor cell that subsequently differentiates to form neoplastic glial and neuronal elements.

Amyloid myopathy masquerading as polymyositis.

OBJECTIVE: It is not well appreciated that the clinical presentation of amyloid myopathy can mimic that of polymyositis. By retrospective clinicopathologic analysis we determined distinctive features of amyloid myopathy that differentiate the 2 diseases. METHODS: Two patients with clinical and histologic evidence of an inflammatory myopathy had fatal outcomes despite appropriate treatment for polymyositis. Their clinical course and original pathologic specimens were reviewed. In addition, original tissue samples were obtained and analyzed using Congo red staining and immunoperoxidase. RESULTS: The initial diagnosis of polymyositis was supported in both cases by muscle biopsies showing inflammatory infiltrates and elevations of creatine phosphokinase and by classic electromyography. Retrospective evaluation of the initial muscle biopsies disclosed subtle but incontrovertible evidence of vascular amyloid. Further analysis of the original specimens confirmed the presence of immunoglobin light chain (AL) amyloid. CONCLUSION: Amyloid myopathy can mimic polymyositis. Both can have similar clinical symptoms, as well as inflammatory infiltrates on muscle biopsy. Failure to recognize amyloid myopathy deprives patients of potentially life prolonging treatment. Congo red staining and immunohistochemical analysis of tissue could prevent misdiagnosis.

Parasagittal solitary fibrous tumor of the meninges. Case report and review of the literature.

The clinical, radiologic and pathologic features of a case of parasagittal solitary fibrous tumor of the meninges are reported. The patient was a 44 year-old male who presented with a complex partial seizure and a history of headaches and confusion. Radiological studies showed a large extra-axial dural-based mass in the right parietal region, predominantly isointense with gray matter and hypointense with respect to white matter on T1-weighted images, and hypointense with respect to gray matter on T2-weighted images. At surgery, the mass was very vascular, quite firm and very adherent to the convexity. Histologically the tumor was composed of spindle-shaped cells growing in fascicles within a collagenous matrix. Solitary fibrous tumor of the meninges is a newly described entity, which should be kept in mind in the clinical and radiological differential diagnosis of extra-axial brain tumors.