Interobserver reproducibility among neuropathologists and surgical pathologists in fibrillary astrocytoma grading.

UNLABELLED: Many of the problems associated with the current grading approaches for fibrillary astrocytomas center around the lack of consistency in grading. This study compares the diagnoses of five neuropathologists with five experienced surgical pathologists with regard to assigning astrocytoma grade. Thirty neoplastic and non-neoplastic lesions were sent to each of five neuropathologists and five surgical pathologists for placement into one of three grades as outlined by modified Ringertz schema. Grading criteria (Burger et al., 1985. Cancer 56:1106-1111) were distributed to all participants, who have been practicing for at least 5 years. An additional category for non-neoplastic or normal tissue was also provided. The diagnoses, based on the majority opinion of the neuropathologist group, included six low grade astrocytomas, 11 anaplastic astrocytomas, seven glioblastoma multiforme, and six normal/reactive lesions. Agreement by all neuropathologists was reached in 12 cases (40%). A discrepant diagnosis was obtained in one of five neuropathologists in 14 additional cases (46.7%). In the remaining four cases, two neuropathologists deviated from the majority opinion; in each of these cases, the diagnostic problem involved differentiating tumor from reactive gliosis. All five surgical pathologists agreed in six cases (20%). One discrepant diagnosis among the surgical pathologist group was seen in seven cases (23.3%). In the remaining 17 cases, two or more discrepant diagnoses were obtained (56.7%); discrepancies in these cases included differences in assignment of tumor grade and in distinguishing low grade astrocytoma from gliosis. IN CONCLUSION: (1) it is likely that experience with grading accounts for the better level of agreement among the neuropathologist group (kappa statistic 0.63) versus the surgical pathologist group (kappa statistic 0.36); (2) in most cases, the neuropathologists all agreed or had one discrepant diagnosis (86.7%) versus the surgical pathologist group (43.3%); (3) the discrepancies in diagnosis among both groups is likely related, in good part, to the limitations of the grading schema in fully enumerating the spectrum of such grading parameters as cytologic atypia and vascular proliferation.

Rippling muscles and myasthenia gravis with rippling muscles.

OBJECTIVE: To describe a patient with rippling muscles and myasthenia gravis. DESIGN: Clinical, laboratory, electrophysiologic, and muscle biopsy data are reported. SETTING: Medical office and hospital. PATIENT: We describe a patient with rippling muscles (as seen in rippling muscle disease) and myasthenia gravis (MG) with thymoma. There was no family history of rippling muscle disease in our patient. Diplopia and other symptoms of MG were initially overshadowed by the striking rippling phenomenon. The rippling resolved when the MG became florrid. INTERVENTIONS: The patient was treated with pyridostigmine, prednisone, and plasmaphereses before removal of a thymoma. MAIN OUTCOME AND RESULTS: His MG improved with treatment and the rippling has not recurred 4 months after thymectomy. CONCLUSIONS: Rippling muscle disease is rare and usually inherited. Our patient with rippling muscles (but no family history of rippling muscle disease) and MG suggests that rippling muscles may also be triggered by an autoimmune phenomenon.

Calbindin-D28k in subsets of medulloblastomas and in the human medulloblastoma cell line D283 Med.

OBJECTIVE: To evaluate the antigenic expression of calbindin-D28k in surgically resected cerebellar medulloblastomas and the human medulloblastoma cell line D283 Med in relation to glial neoplasms, the human glioblastoma (U-251 MG) and rat glioma (C-6) cell lines, and other primary and metastatic brain tumors. DESIGN: Immunohistochemical staining was performed using an antiserum and a monoclonal antibody against calbindin-D28k on (1) formalin-fixed, paraffin-embedded human, predominantly posterior fossa, brain tumor specimens (49 medulloblastomas, 59 glial and mesenchymal primary central nervous system tumors, 1 posterior fossa rhabdoid tumor, and 34 metastatic tumors); (2) formalin-70% alcohol-, or Bouin's-fixed tumor cell lines (D283 Med, U-251 MG, and C-6) maintained in a three-dimensional gelatin foam (Gelfoam matrix) system, with or without treatment with dibutyryl cyclic adenosine monophosphate; and (3) formalin-fixed, paraffin-embedded C-6 glioma cells transplanted intracerebrally to rats. RESULTS: Calbindin-D28k immunohistochemical staining was detected in 20 of 49 cerebellar medulloblastomas and in cells of the human medulloblastoma cell line D283 Med grown in gelatin Gelfoam matrices, with or without treatment with dibutyryl cyclic adenosine monophosphate. In surgical resection specimens, calbindin-D28k reactivity was evident in populations of poorly differentiated cells of classic (non-nodular) medulloblastomas (16/20) and in mature Purkinje neuronlike phenotypes in medulloblastomas with ganglion cells (4/6) but was absent in desmoplastic medulloblastomas, including in areas of neoplastic neuritogenesis ("pale islands") (0/23). Calbindin-D28k staining was also present in D283 Med explants for up to 29 days in vitro. Reactivity was more widespread in dibutyryl cyclic adenosine monophosphate-treated cultures, coinciding with neuronal morphologic alterations of cultured cells. Focal calbindin-D28k stainig was present in neural-like cells of an embryonal cerebellar tumor with divergent mesenchymal, epithelial, and neuroectodermal/neuroendocrine differentiation suggestive of a malignant rhabdoid tumor. No calbindin-D28k staining was obtained in primary glial and mesenchymal (intra- and extra-axial) brain tumors (0/59), in explants of human glioblastoma cell line U-251 MG, or in the rat glioma line C-6 maintained in Gelfoam matrices or transplanted intracerebrally. Among 34 epithelial and mesenchymal tumors metastatic to the posterior fossa, only subpopulations of cells in two small-cell (neuroendocrine) carcinomas originating in the lung were calbindin positive. CONCLUSION: Calbindin-D28k expression in classic medulloblastomas, medulloblastomas with ganglion cells, and in the human medulloblastoma cell line D283 Med (which was derived from a metastatic classic medulloblastoma) suggests a phenotypic kinship between subsets of this tumor and neuronal progeny of the ventricular neuroepithelium, thus conferring additional support for its neuroblastic nature.

Chromosomal abnormalities in 47 pediatric brain tumors.

The karyotypes of 47 pediatric brain tumors (14 cerebellar pilocytic astrocytomas, six cerebral pilocytic astrocytomas, seven anaplastic astrocytomas and glioblastomas, nine medulloblastomas [PNETs], one cerebral neuroblastoma, four ependymomas, and seven miscellaneous other neoplasms) are presented. Most of the pilocytic astrocytomas and ependymomas had normal karyotypes. In contrast, the majority of the anaplastic astrocytomas-glioblastomas were abnormal. The abnormalities included losses and structural abnormalities of chromosomes 9, 13, and 17, and double minutes. There were no losses of chromosomes 10 and 19q or gains of chromosome 7, which are among the most common abnormalities of adult glioblastomas. The chromosomal abnormalities in the medulloblastomas were similar to those reported in the literature but less frequent. Four tumors (choroid plexus papilloma, meningioma, cerebral malignant rhabdoid tumor, and immature teratoma) had losses of chromosome 22.

Rhizomelic chondrodysplasia punctata: report of a case with review of the literature and correlation with other peroxisomal disorders.

A 3-year-old girl with rhizomelic chondrodysplasia punctata (RCDP) had severe microcephaly but a normal gyral pattern, neuronal density, and cortical cytoarchitecture. The white matter was diffusely decreased in mass but normally myelinated. There was optic atrophy and cerebellar degeneration. Leukodystrophy in peroxisomal disorders is caused by elevated very long chain fatty acids. The absence of a fatty acid abnormality in RCDP explains the normal myelination. Cerebellar and retinal degeneration and possible stunted dendritogenesis may be due to plasmalogen deficiency, which is the most severe biochemical abnormality in RCDP.

Localization of the neuronal class III beta-tubulin isotype in foci of early neuritogenesis supports divergent neuroblastic differentiation potential in Wilms' tumors.

Wilms' tumors are embryonic neoplasms that have been proposed to originate from the metanephric blastema and are capable of divergent epithelial and mesenchymal differentiation. Neuroepithelial differentiation in these tumors remains controversial. The aim of this study was to examine the phenotypic profile of certain neuronal and glial antigenic determinants in a series of 21 Wilms' tumors. Immunohistochemical studies were performed by using monoclonal antibodies against the neuronal class III beta-tubulin isotype (beta III), the phosphorylated and phosphorylation-independent epitopes of neurofilament protein, and synaptophysin; antisera to gamma-enolase (neuron-specific enolase) glial fibrillary acidic protein, and S100 protein were also used. Foci of neoplastic cells with neurite-like processes that exhibited intense beta III staining were demonstrated in blastemalike areas of three of 21 tumors. In one case, Homer Wright rosettes (stained for beta III) were identified. Areas of abortive neuritic development were also labeled with antibodies to gamma-enolase. No reactivity was obtained in these foci for phosphorylated and phosphorylation-independent epitopes of neurofilament protein, synaptophysin, glial fibrillary acidic protein, and S100 protein. The remainder of the tumors (18 of 21) were negative with the panel of neural markers. Our results indicate that divergent neuroblastic differentiation, evidenced as early neoplastic neuritogenesis, may be present in the blastematous component of Wilms' tumor subsets.

Neonatal glycine encephalopathy: biochemical and neuropathologic findings.

A patient with neonatal glycine encephalopathy who had severe neurologic retardation, spasticity, and seizures died at 17 years of age. Glycine concentration was markedly elevated in brain tissue, especially in the cerebellum. Neuropathologic study revealed spongy myelinopathy throughout the central nervous system and calcium oxalate crystals in the cerebellum, which are probably derived from degradation of glycine. Myelinopathy appeared to be static compared to neonatal patients. The neurologic manifestations of neonatal glycine encephalopathy are probably due to neurotransmitter abnormalities, not to myelin damage.

Fusarium meningoencephalitis in a child with acute leukemia.

A 15-year-old boy with acute lymphoblastic leukemia (ALL) developed disseminated fusarium infection with meningoencephalitis following a contaminated skin wound. With antifungal therapy, the cutaneous lesions cleared but central nervous system (CNS) infection persisted causing a fibrosing meningitis and a brain granuloma. Fusaria are soil saprophytes that are more commonly associated with superficial eye and skin lesions, but may also cause severe systemic infections with CNS involvement in immuno-compromised patients. The organism may be confused with Aspergillus in tissue sections, and can only be diagnosed by culture.

Tumors of skeletal muscle.

The most common tumors arising in muscle are soft tissue sarcomas, fibromatoses, and hemangiomas. Rhabdomyosarcoma is primarily a tumor of childhood and adolescence and arises most commonly in extramuscular sites. Most intramuscular rhabdomyosarcomas are alveolar. Increased diagnostic accuracy and the recognition of malignant fibrous histiocytoma have changed understanding of adult, intramuscular, pleomorphic rhabdomyosarcoma. Immunohistochemistry is playing an increasingly important role in the diagnosis of rhabdomyosarcoma, and the correlation between the histologic features and clinical behavior of rhabdomyosarcoma is under investigation. Because of their diversity and overlapping histologic features, muscle tumors are a challenge for the pathologist and require intensive study by current techniques.

Lipoprotein disorder, cirrhosis, and olivopontocerebellar degeneration in two siblings.

Two siblings had olivopontocerebellar degeneration, failure to thrive, hepatic fatty change and cirrhosis, and a dyslipoproteinemia characterized by low cholesterol and elevated triglycerides. This condition was distinct from other cerebellar atrophies and ataxias and was not due to malabsorption or malnutrition. Cerebellar degeneration progressed rapidly during the first year of life, and both children died from intercurrent infections and surgical complications at 11 and 17 months. Stereotyped clinical and pathologic findings in the two patients suggest a previously unreported genetic metabolic disorder affecting the liver and the CNS.

Arnold-Chiari malformation. Report of four cases with contamination of the central nervous system by amniotic contents.

Four patients with the Arnold-Chiari malformation had massive prenatal contamination of the spinal cord and brainstem (and also of the cerebral ventricles in one case) by amniotic squamous cells and lanugo hair, which had entered through open meningomyeloceles. Amniotic contents were present in the subarachnoid space, central canal, fourth ventricle, and aqueduct and were also embedded in neural tissue, causing severe gliosis, fibrosis, and blockage. The mechanism of the complication and its implications in the prognosis of patients with the Arnold-Chiari malformation are discussed.

Sacrococcygeal myxopapillary ependymomas and ependymal rests in infants and children.

The occurrence of sacrococcygeal myxopapillary ependymal tissue appears to be exceedingly rare. We report on five cases of this lesion in infants, four of which occurred in the first year of life. These cases, the youngest on record, should be added to the thirteen cases previously reported. The lesions were completely removed, and the patients have been followed without recurrence for five months to six years. These lesions arise from the coccygeal medullary vestige, which corresponds to the original site of the final closure of the posterior neuropore. The unique embryology of this region can account for the presence of sacrococcygeal teratomas, lipomas, chordomas, as well as the above described lesion. The presence of ependymal rests, as described by Bale, in most patients with postanal dimples, suggests that the incidence of this lesion should be greater. This lesion has a potential for lymph node and pulmonary metastasis and when clinically palpable, should be completely excised.

Slipped capital femoral epiphysis: a pathological study. I. A light microscopic and histochemical study of 21 cases.

Core biopsy specimens of slipped proximal femoral epiphyseal growth plates and of normal controls were examined by light microscopy and histochemistry. Slipped growth plates showed diminished cellularity with an overall excess of matrix as well as severe disorientation and misalignment of chondrocytes. Decrease in number of argyrophilic fibers in the longitudinal septa suggested deficiency in collagen. Histochemical staining of slipped plates did not deviate from normal except in severely deformed areas. Anatomic and histochemical observations did not conclusively support or exclude biochemical or biomechanical factors in the etiology of epiphyseal slipping.

Slipped capital femoral epiphysis: a pathological study. II. An ultrastructural study of 23 cases.

Twenty-three core biopsy specimens from patients with slipped capital femoral epiphysis and 11 control growth plates were studied by electron microscopy. Block staining with toluidine blue for demonstration of proteoglycans at the ultrastructural level was also used. The proliferative and hypertrophic zones of slipped growth plates showed diminished cellularity and marked distortion of the architecture with disarray of the cartilage columns. There was a deficiency and abnormality in the supporting collagenous framework of slipped plates. Chondrocyte degeneration and death were seen at all levels of the proliferative and hypertrophic zones, suggesting a disturbance in the life cycle of chondrocytes. The significance of these findings and their relationship to mechanistic, endocrine, and other proposed etiologies of epiphyseal slipping is discussed.

Arnold-Chiari malformation: report of a case with contamination of ventricular and subarachnoid spaces by amniotic sac contents.

An infant with the Arnold-Chiari malformation had a lumbosacral amniotic-central nervous system fistula that allowed massive amounts of squamous cells and lanugo hair to enter the ventricular and subarachnoid spaces causing blockage, gliosis, and fibrosis. This rare complication can be diagnosed by cytologic examination of cerebrospinal fluid and should be considered in the prognosis of Arnold-Chiari malformation and selection of cases for treatment.

Occult hepatic sinusoid tumor of infancy simulating neuroblastoma.

Two infants with hepatosplenomegaly and an occult tumor of hepatic sinusoids are reported. Although secretion of biogenic amines of neuroblastoma was not elevated, infrequent neurosecretory granules were observed by electron microscopy in the cytoplasmic processes of the tumor cells. The infants responded to vincristine and prednisone therapy and are tumor free 8 and 2 years later, respectively. The clinical, radiographic, biochemical, and microscopic findings of these cases are presented. The distinction from other infantile hepatic sinusoid small round cell tumors is based on the light and electron microscopic findings. This neuroepithelial tumor is either an unusual form of neuroblastoma or a neoplasm of APUD cell origin. If chemotherapy is utilized, it should be selective and limited.

Congenital dysautonomia. A case with a posterior interhemispheric cyst and microcephaly.

A non-Jewish child had a congenital sensory and autonomic neuropathy, cerebral hypoplasia, and a posterior interhemispheric cyst. The clinical findings, neuropathologic changes in the spinal cord, the peripheral nerves, the sensory and autonomic ganglia, as well as sural nerve morphometry, showed similarities, but also differences from familial dysautonomia and hereditary sensory neuropathy, type IV. The relationship of this case to hereditary sensory neuropathies and dysautonomias is discussed, and it is suggested that this is an atypical form of familial dysautonomia with coincidental developmental abnormalities.

The neuropathology of glycine encephalopathy: a report of five cases with immunohistochemical and ultrastructural observations.

We studied the spongy myelinopathy of glycine encephalopathy in five patients by using specific antisera. The walls of the vacuoles were stained with the myelin basic protein but not with the myelin associated glycoprotein or the glial fibrillary acidic protein immunostains. The pattern suggested that the vacuoles originated in compact myelin and not from the adaxonal portion of the sheath or from glial processes. Ultrastructural study revealed myelin vacuoles resulting from intraperiod splitting, and there were unusual intranuclear and cytoplasmic inclusions in skeletal muscle in two cases. In addition to the action of glycine as an inhibitory neurotransmitter, structural alterations of myelin may be important in the pathogenesis of the neurologic disorder of glycine encephalopathy.

Muscle phosphofructokinase deficiency: two cases with unusual polysaccharide accumulation and immunologically active enzyme protein.

Two patients with phosphofructokinase (PFK) deficiency had exercise intolerance and increased serum activity of creatine kinase; one presented with hemolytic anemia, hyperuricemia, and gouty arthritis. The glycogen concentration in the muscle of these patients was about twice normal. PFK activity was virtually absent in muscle, but antibodies against the M subunits of the normal human PFK showed cross-reacting material in muscle from both patients. The PFK level in red blood cells, studied in one case, was lower than normal in the patient and both parents. Morphologically, there was extensive deposition of normal glycogen underneath the sarcolemma and in the intermyofibrillar space. In addition, 2% to 3% of the myofibers contained hyaline, PAS-positive, diastase-resistant inclusions that had a filamentous fine structure; histochemical reactions suggested an insoluble form of glycogen. Similar inclusions have not been described previously in PFK deficiency. Accumulation of an abnormal polysaccharide in muscle may be due to a second undiscovered enzymatic defect or may be a metabolic consequence of PFK deficiency.