Anaplastic astrocytoma with eosinophilic granular cells

A 68‐year‐old man, who had no remarkable past medical history, was referred to a hospital because of disorientation and right‐sided hemiparesis. On magnetic resonance imaging, a contrast‐enhanced tumor in the left frontal lobe with perifocal edema was noted. He underwent left frontal lobectomy. Microscopic examination revealed infiltrative atypical astrocytes showing increased cellularity, distinct nuclear atypia, and many mitotic figures, while microvascular proliferation and necrosis were absent. Thus, the tumor was histologically diagnosed as anaplastic astrocytoma. It was of note that cytoplasmic eosinophilic granules were observed in approximately 25% of neoplastic cells. The granules were positively immunostained with anti‐αB‐crystallin antibody, and the other histochemical and immunohistochemical results also corresponded to Rosenthal fibers. The MIB‐1 labeling index of the highest area of the tumor was 22%, while that of granular cells was 2.1%. An ultrastructural study revealed amorphous electron‐dense structures attached to intermediate filament bundles, compatible with Rosenthal fibers. Such structures are relatively common in oligodendroglial tumors; however, they are extremely rare in astrocytic tumors. Fluorescence in situ hybridization targeted against chromosome 1 failed to demonstrate allelic loss of the short arm. The present case should also be discriminated from granular cell astrocytoma. We review related literature and discuss the significance of granules in gliomas.     

Chronic eosinophilic perimyositis with persistent myalgias

A 43-year-old man with an 8-year history of hypereosinophilia was evaluated for persistent muscle pain. Methotrexate and corticosteroids were ineffective. Examination, limited by pain even with passive motion, showed only mild weakness. Electromyography and muscle enzymes were normal. A needle muscle biopsy specimen revealed eosinophilic perimyositis. This case illustrates that the diagnosis of eosinophilic perimyositis requires histopathological evaluation, which should be pursued in patients with eosinophilia and persistent myalgia despite normal electromyography and muscle enzymes.     

Meningioma with eosinophilic granular inclusions

Rare meningiomas have been described that contain eosinophilic inclusions that have a granular or granulofilamentous ultrastructure. We describe a 66-year-old woman who developed a planum sphenoidale meningioma. Histologically, the tumor was composed of meningothelial cells arranged in fascicles and whorls, typical of a well-differentiated meningioma. Many tumor cells contained round intracytoplasmic eosinophilic inclusions that were periodic acid Schiff-negative and red on Masson trichrome. The inclusions were immunopositive for vimentin, and were immunonegative for epithelial membrane antigen, smooth muscle actin, desmin and type IV collagen. Ultrastructural examination showed the inclusions were composed of round to oval, well-demarcated, non-membrane-bound, osmiophilic granular material. The inclusions within this tumor had histochemical, immunohistochemical and ultrastructural properties not described in other reported meningiomas with eosinophilic granular or granulofilamentous inclusions.     

Myositis in a patient with large granular leukocyte leukemia

We describe the case of a 58-year-old patient with subacute progressive weakness in both legs accompanied by recurrent opportunistic infections. White cell count was normal, but immunophenotyping revealed an increased number of CD8(+) T cells and deficiency of natural killer cells, B cells, and CD4(+) T cells in the peripheral blood. Large granular leukocyte (LGL) leukemia was diagnosed based on a clonal T-cell receptor rearrangement. Muscle biopsy demonstrated severe myositis with extensive CD8(+) T-cell infiltrates. Since no evidence of microbial muscle infection was found, autoimmune myositis was diagnosed. Immunosuppressive treatment resulted in clinical improvement and normalization of creatine kinase (CK) serum levels. The immunological phenotype of the patient and the positive response to treatment adds further to the concept that CD8(+) T cells mediate disease in autoimmune myositis.     

Characterization of refractile eosinophilic granular cells in oligodendroglial tumors

Refractile eosinophilic granular cells (rEGCs), which are distinct from the previously reported eosinophilic granular cells in oligodendroglial tumors, were characterized. The granules of rEGCs showed intense eosinophilia and prominent refractility, and were arranged in clusters or piled up in the perikaryon. The rEGCs tended to distribute in the vicinity of fibrovascular stroma and collagenous areas. They appeared in oligodendroglial tumors with numerous minigemistocytes and gliofibrillary oligodendrocytes. More rEGCs were present in WHO grade III oligodendroglial tumors. Histochemically, the granules stained blue with Kluver-Barrera and vividly red with Masson's trichrome stain, but negative with periodic acid-Schiff reagent. Almost all of the rEGCs were immunopositive for glial fibrillary acidic protein (GFAP) and heat shock protein 27 (HSP27), and some of them showed immunopositivity with alphaB-crystallin. No MIB-1 immunopositivity of rEGCs was found. Ultrastructurally, the rEGCs had many ellipsoidal structures associated with bundles of glial fibers in the cytoplasm. The morphological features of granules of rEGCs were similar to those of Rosenthal fibers except for the size and shape of the structure. We considered that the rEGCs originated from overexpression and accumulation of alphaB-crystallin and HSP27 in GFAP-positive oligodendroglial cells due to various pathological conditions. The presence of the rEGCs in the oligodendrogliomas may suggest more aggressive clinical behavior of tumors.     

Immunocytochemical and ultrastructural studies of eosinophilic granular bodies in astrocytic tumors

Summary Eosinophilic granular bodies (EGBs) are studied immunocytochemically and ultrastructurally in a case of low-grade and a case of high-grade astrocytoma. EGBs are recognized as brightly eosinophilic round bodies of variable size in hematoxylin and eosin-stained sections. Immunocytochemically some EGBs are positive for antibodies raised against B-crystallin, ubiquitin and glial fibrillary acidic protein with the staining patterns for each being different from one another. Ultrastructurally EGBs consist of membrane-bound round body of various diameter ranging from 50 nm to 20 m. Small EGBs contain electron-dense homogeneous material with occasional myelin figures, while large EGBs contain small EGB-like structures within electron-dense homogeneous material or loose granular profiles. Our studies demonstrate (1) ultrastructural variety of EGB; (2) and B-crystallin epitope in EGB; and (3) the presence of EGB in high-grade as well as low-grade astrocytoma.Supported in part by UPHS NS24453, HD03110, and ES01104     

Cerebral granular cell tumor

Intracerebral granular cell tumors (GCTs) are a rare finding. We report here on a case of cerebral GCT in a 47‐year‐old man who suffered with severe headache. The tumor appeared as a relatively well‐defined, enhancing mass at the periventricular white matter of the left occipital lobe of the brain. Histologically, the tumor was entirely composed of granular cells. Some of the tumor cells showed peripherally accentuated cytoplasmic granules with central clearing, which produced a unique “targetoid” appearance. The granular cells of the current case were positive for neuron‐specific enolase (NSE), S‐100 protein, GFAP, vimentin, CD 68, lysozyme, and α‐1‐antitrypsin. These wide immunoexpressions were not observed for the previously reported cerebral GCTs. Interestingly, this case showed “targetoid” or “reversed targetoid” immunoreactive patterns in NSE, CD68, GFAP, and vimentin. Despite these wide immunoexpressions and the lack of any association with astrocytoma, the histogenesis of cerebral GCTs is still suggested to be of a glial origin, based on the tumor location, the GFAP positivity and the ultrastructural findings, of which the latter showed intermediate filaments, and these are reminiscent of neoplastic astrocytes.     

Pigmented ependymoma with signet‐ring cells and Rosenthal fibers: A rare variant of ependymoma

We report a rare case of ependymoma with vacuolar features, signet cells, pigmentation and numerous Rosenthal fibers arising in the fourth ventricle of a 35‐year‐old woman. The tumor was composed of cells with cytoplasmic vacuoles, signet cells and clear cells. The clear cells were compactly arranged resembling oligodendroglioma. Pseudovascular and ependymal rosettes were observed only in focal areas. Additionally, some tumor cells contained brown cytoplasmic pigment, which was histochemically compatible with lipofuscin and neuromelanin. On immunohistochemical examination, the tumor cells were positive for S100, glial fibrillary acidic protein and vimentin, and negative for synaptophysin, cytokeratin, neurofilament and HMB45. Epithelial membrane antigen staining showed dot‐like and small vesicular reactivity. The case is presented to increase familiarity with these extraordinary variants of ependymoma.     

TDP-43 immunoreactivity in anoxic,ischemic and neoplastic lesions of the central nervous system

TDP-43 proteinopathies are a newly categorized group of neurodegenerative diseases characterized by progressive cognitive and motor impairments associated with the abnormal accumulation and mislocalization of the nuclear TAR–DNA-binding protein-43 (TDP-43) in neurons and glia. Little is known about the expression and distribution of TDP-43 in normal and pathologic states. To determine whether TDP-43 inclusions arise in response to metabolic insults such as anoxia or ischemia, a panel of anoxic, ischemic and neoplastic lesions was examined for TDP-43 expression by immunohistochemistry. These lesions did not exhibit TDP-43 inclusions like those seen in neurodegenerative frontotemporal dementia and motor neuron disease. However, TDP-43 was found in Rosenthal fibers and eosinophilic granular bodies associated with low-grade tumors and reactive brain tissue. Furthermore, cytoplasmic TDP-43 was seen in M-phase tumor cells, but not in mitotic spindles. These findings expand our knowledge of the distribution and localization of TDP-43, and indicate that the TDP-43 inclusions seen in frontotemporal dementias and motor neuron diseases are specific to a neurodegenerative process.     

Rosenthal fibers,eosinophilic inclusions,and anchorage densities with desmosome-like structures in astrocytes in Alzheimer's disease

Ultrastructural study of the cerebral cortex of nine brains of individuals with Alzheimer's disease (AD) revealed four types of pathological changes of astrocytes. Rosenthal fibers were found in three cases, eosinophilic inclusions in one, anchoraged densities with desmosome-like structures in two, and corpora amylacea in four. In two biopsies, Rosenthal fibers were seen in less than 5% of astrocytes, but in a third biopsy with numerous plaques, tangles, and severe neuronal loss, they were present in about 40% of astrocytes. In one case with severe AD pathology and numerous Rosenthal fibers, the cytoplasm of some astrocytes was occupied by inclusions composed of electron-dense granules 3–6 m in diameter or aggregates of inclusions greater than 12 m in diameter. Ultrastructurally, they were similar to eosinophilic inclusions observed in Aicardi syndrome and brain malformations. The presence of eosinophilic inclusions in the brain of elderly persons with Alzheimer's disease does not confirm the previous suggestion that this form of astrocyte pathology is typical for protoplasmic astrocytes and developmental brain malformations. Development anchorage densities associated with hemidesmosome-like structures, which reinforce astrocyte cell membranes facing the perivascular space, may reflect adaptation of astrocytes to the complex of changes that occurs in atrophic brain. Morphological changes in astrocytes in areas with numerous plaques and massive infiltration of intercellular space with -amyloid fibrils and remnants of neurons and ghost tangles suggest that astrocyte pathology is a late unspecific reaction to the cascade of changes induced by -amyloid deposition that causes neuronal degeneration and brain atrophy.Supported in part by funds from the New York State Office of Mental Retardation and Developmental Disabilities and a grant from the National Institutes of Health, National Institute of Aging No. P01-AGO-4220     

Alexander's disease in infancy and childhood: a report of two cases

Summary Two cases of Alexander's disease are described. One case of infantile onset died at the age of 6 months and the second case was of the juvenile type with onset at 2 years and death at 10 years. A clinical diagnosis of this disease is difficult since signs can vary according to the age of the patient. The severity of the pathological changes can also depend upon the age of onset of this disease, but they are restricted to the central nervous system. The Rosenthal fibre is the characteristic feature of Alexander's disease and we have examined for the first time its ultrastructure and immunocytochemical characteristics at the electron microscopical level and demonstrated coexpression of anti-glial fibrillary acidic protein and anti-ubiquitin antisera.     

Rapidly increasing incidence of eosinophilic esophagitis in a large cohort

Background Recent literature has shown increasing incidence and prevalence rates of eosinophilic esophagitis (EoE). However, data are mainly based on small studies and come from centers dedicated to EoE. Aim of this study was to estimate the incidence rates of EoE by using a large database. Methods We performed a cross‐sectional study of the pathology reports describing esophageal eosinophilia from 1996 through 2010, using the nationwide network and registry of histo‐ and cytopathology in The Netherlands (PALGA). All histopathology reports nationwide enter this database. We classified cases according to the diagnosis made by the pathologist. Annual incidence rates of EoE were estimated. Key Results Our search criteria yielded 8838 positive pathology reports. Eosinophilic esophagitis was diagnosed in 674 patients, of which 74% were men. In another 174 patients, no distinction was made between eosinophilia caused by gastro‐esophageal reflux disease or EoE. The incidence of EoE increased considerably over the years, being 0.01 in 1996, 0.01 in 2000, 0.14 in 2005, and 1.31 per 100 000 persons in 2010. Eosinophilic esophagitis was diagnosed in all age groups, but in 2010 the highest incidence was seen in 20–29 years old males, in whom it was estimated to be 3.23 per 100 000 persons. The incidence in children was 0.73 per 100 000 in 2010. No seasonal variation in diagnosis of EoE was observed. Conclusions & Inferences In this large study, we found robust data on increasing incidence rates of pediatric and adult EoE in the past 15 years. This rapidly increasing incidence has not reached a plateau yet.     

Rosenthal fibers producing a granular cell appearance in a glioblastoma

Summary In this report we describe a glioblastoma multiforme with focal granular cell change. In most astroglial tumors with granular cells, the granular appearance is due to the presence of periodic acid-Schiff-positive, membrane-bound cellular debris. In the present case the granular appearance was due to the presence of many small Rosenthal fibers, which were immunoreactive for glial fibrillary acidic protein, vimentin, ubiquitin, and heat-shock protein 27, but not for -B crystallin. The ultrastructural characteristics are described. These findings demonstrate that granulofilamentous inclusions with the appearance of Rosenthal fibers in glial tumors are a structurally heterogeneous feature.     

Anaplastic astrocytomas with abundant Rosenthal fibers in elderly patients: A diagnostic pitfall of high‐grade gliomas

To investigate the clinicopathological features of anaplastic astrocytoma (AA) with abundant Rosenthal fibers (RFs), this study assessed four cases of AA (elderly patients; age ≥70 years). Histologically, these tumors were composed of diffusely infiltrating astrocytomas with brightly eosinophilic cytoplasmic granules or cork‐screw or beaded bundles. Tumor cells showed pleomorphism, bizarre giant cells, and mitotic activity, but no necrosis. The cytoplasmic granules showed negativity on PAS staining. Immunohistochemically, the tumor cells with cytoplasmic granular cells showed a positive reaction for GFAP. The cytoplasmic eosinophilic granules or bundles were positive for αB‐crystallin, ubiquitin and HSP27. In addition, tumor cells showed strong cytoplasmic positivity for isocitrate dehydrogenase 1 (IDH1)‐R132H protein in all cases. The MIB‐l labeling index of these cases ranged from 7% to 10%. In cases 1 and 2, ultrastructurally, the tumor cells had electron‐dense, amorphous structures in the cytoplasm and in the processes. These structures were bound to glial intermediate filaments. Based on these microscopic, immunohistochemical and ultrastructural findings, case 1 was diagnosed as AA with abundant, mixed, common type of RFs and miniature (m) RFs, and cases 2,3, and 4 were diagnosed as AA with abundant mRFs. These results indicate that the presence of RFs in astrocytic tumors does not necessarily exclude a diagnosis of high‐grade astrocytoma. In addition, AAs with abundant mRFs in elderly patients should be classified as a peculiar variant of AA.     

Cerebellar granular layer aplasia in congenital hydrocephalus

An unusual case of cerebellar granular layer aplasia is reported. A 5‐year‐old boy was born with hydrocephalus and a peritoneal drainage shunt was placed after the delivery. Symptoms of cerebral paralysis, impaired mental function and cerebellar ataxia had developed gradually. Patient's karyotype was 46,XY. Laboratory tests for cytomegalovirus, Herpes simplex virus, Toxoplasma gondii, human immunodeficiency virus, rubella and hepatitis B virus were negative. Further laboratory investigation showed no signs of Tay‐Sachs disease, Niemann‐Pick disease, Gaucher disease, phenylketonuria, galactosemia or glycogen storage disease. No congenital malformations were traced in other family members for three generations. Radiation exposure and infections during the pregnancy were refuted.     

Nickel induction of Rosenthal fibers in rat brain

Nickel wire implants into the central nervous system of Lewis rats induces the formation of structures morphologically similar to Rosenthal fibers. The nickel-induced lesions are similar to those seen in Alexander's disease and other human conditions in which Rosenthal fibers are found. This is the first report on the induction of Rosenthal fibers in animals. It might be used to design animal models to study Rosenthal fiber formation and possibly Alexander's disease.     

Manometric features of eosinophilic esophagitis in esophageal pressure topography

Background Although most of the patients with eosinophilic esophagitis (EoE) have mucosal and structural changes that could potentially explain their symptoms, it is unclear whether EoE is associated with abnormal esophageal motor function. The aims of this study were to evaluate the esophageal pressure topography (EPT) findings in EoE and to compare them with controls and patients with gastro‐esophageal disease (GERD). Methods Esophageal pressure topography studies in 48 EoE patients, 48 GERD patients, and 50 controls were compared. The esophageal contractile pattern was described for ten 5‐mL swallows for each subject and each swallow was secondarily characterized based on the bolus pressurization pattern: absent, pan‐esophageal pressurization, or compartmentalized distal pressurization. Key Results Thirty‐seven percent of EoE patients were classified as having abnormal esophageal motility. The most frequent diagnoses were of weak peristalsis and frequent failed peristalsis. Although motility disorders were more frequent in EoE patients than in controls, the prevalence and type were similar to those observed in GERD patients (P = 0.61, chi‐square test). Pan‐esophageal pressurization was present in 17% of EoE and 2% of GERD patients while compartmentalized pressurization was present in 19% of EoE and 10% of GERD patients. These patterns were not seen in control subjects. Conclusions & Inferences The prevalence of abnormal esophageal motility in EoE was approximately 37% and was similar in frequency and type to motor patterns observed in GERD. Eosinophilic esophagitis patients were more likely to have abnormal bolus pressurization patterns during swallowing and we hypothesize that this may be a manifestation of reduced esophageal compliance.