Immature teratoma of the tectum mesencephali with histopathological detection of rudimentary eye anlage in a 3-year-old boy: Report of a rare case.

Intracranial teratoma is a rare neoplasm derived from omnipotent germinal cells that can contain mesoderm, endoderm and/or ectoderm layer tissue. Histologically teratomas are characterized by abnormal structures like teeth or bone that can be further subdivided into mature and immature according to the presence of incompletely differentiated tissue. Characteristic intracranial teratomas are space-occupying lesions in the pineal region and often present with hydrocephalic symptoms due to aqueduct stenosis. A 3-year-old boy presented with a peracute hemiparesis, fatigue and speech deficit. MRI diagnostics showed a cystic, partially solid, inhomogeneous contrast-enhancing formation at the top of the tectum mesencephali with consecutive aqueduct compression. The patient underwent a sub-occipital craniotomy via a supracerebellar approach and complete resection was achieved. The histopathological examination mainly showed mature tissue of ectodermal, mesodermal and endodermal origin. However, small areas of undifferentiated neuroectodermal tissue within an optic vesicle formation were detected, leading to the diagnosis of an immature teratoma. In due course, the patient was discharged in good health without neurological deficits. To our knowledge, optic vesicle-containing intracranial germ cell tumors are extremely rare. Here we report a unique case with immature neuroectodermal tissue within an optic vesicle formation in an otherwise mature teratoma.

ATP synthase deficiency due to TMEM70 mutation leads to ultrastructural mitochondrial degeneration and is amenable to treatment.

TMEM70 is involved in the biogenesis of mitochondrial ATP synthase and mutations in the TMEM70 gene impair oxidative phosphorylation. Herein, we report on pathology and treatment of ATP synthase deficiency in four siblings. A consanguineous family of Roma (Gipsy) ethnic origin gave birth to 6 children of which 4 were affected presenting with dysmorphic features, failure to thrive, cardiomyopathy, metabolic crises, and 3-methylglutaconic aciduria as clinical symptoms. Genetic testing revealed a homozygous mutation (c.317-2A>G) in the TMEM70 gene. While light microscopy was unremarkable, ultrastructural investigation of muscle tissue revealed accumulation of swollen degenerated mitochondria with lipid crystalloid inclusions, cristae aggregation, and exocytosis of mitochondrial material. Biochemical analysis of mitochondrial complexes showed an almost complete ATP synthase deficiency. Despite harbouring the same mutation, the clinical outcome in the four siblings was different. Two children died within 60 h after birth; the other two had recurrent life-threatening metabolic crises but were successfully managed with supplementation of anaplerotic amino acids, lipids, and symptomatic treatment during metabolic crisis. In summary, TMEM70 mutations can cause distinct ultrastructural mitochondrial degeneration and almost complete deficiency of ATP synthase but are still amenable to treatment.

Gliosarcoma with bone infiltration and extracranial growth: case report and review of literature.

Gliosarcoma is a relatively rare and highly malignant brain tumor consisting of both a glioblastoma and a mesenchymal component. Because of the natural barrier of the dura mater, that prevents intra or extradural neoplasm dissemination, cases of penetration of the dura and cranium by gliosarcomas without previous surgery or radiation are very rarely reported. We report an unusual case of gliosarcoma that involved the temporal skull base and the dura without antecedent radiation or surgery, although the lesion traversed the dura without radiologic or gross interruption of the dura. Remarkable in our case is the initial integrity of cerebral parenchyma. Follow-up revealed a tumorous infiltration of the temporal lobe almost one year after initial diagnosis. Thus the origin of the gliosarcoma in our case seemed to be extradural in the temporal skull base. Furthermore, this report demonstrates that extensive multi-modality treatment might be effective in patients with gliosarcomas and poor prognostic factors, for example unmethylated MGMT status.

Multiple endocrine neoplasia type 1-associated thyrotropin-producing pituitary carcinoma: report of a probable de novo example.

Pituitary carcinomas are exceedingly rare. At present, the sole diagnostic criterion is metastatic spread, either craniospinal or systemic. There is no agreement on a histologic, immunohistochemical, and/or ultrastructural definition. We report a clinically and morphologically well-documented example of pituitary thyrotropin cell carcinoma in a man with multiple endocrine neoplasia type 1 syndrome. The tumor produced thyrotropin, alpha-subunit, and prolactin and, through electron microscopy, was found to consist solely of Thyrotroph cells. Over a protracted course, craniospinal and systemic metastases were noted. The primary and metastatic deposits of this aggressive tumor were studied. To our knowledge, this tumor is the first reported case of thyrotropin cell carcinoma occurring in association with the multiple endocrine neoplasia type 1 syndrome. The literature regarding thyrotropin carcinomas is reviewed. Based on the study of several biopsies during disease progression, we believe that the carcinoma originated de novo without an intermediary adenoma phase.

Stereotactic biopsy in gliomas guided by 3-tesla 1H-chemical-shift imaging of choline.

OBJECTIVE: To investigate chemical-shift imaging (CSI) to guide stereotactic biopsy of the choline 'hot spot' in cerebral lesions suggestive of low-grade glioma. METHODS: Nine patients with hyperintense lesions on T(2)-weighted images of standard magnetic resonance imaging without contrast enhancement underwent advanced magnetic resonance studies. These studies included 3-dimensional T(1)-weighted sequences with contrast enhancement and 2-dimensional (1)H-CSI spectroscopy at 3 T. Signal intensity maps with relative signal intensities for choline were generated. The region with the highest choline signal intensity (the hot spot) was chosen as the target for stereotactic biopsy. The histopathological results were correlated with the increase in choline. RESULTS: All spectroscopic data were of sufficient quality. In 5 instances the neuropathological diagnosis was grade II glioma, according to the WHO classification, and in 4 instances it was grade III glioma. According to the CSI criteria, all grade III gliomas and 4 of the 5 grade II gliomas were classified correctly. One grade II glioma was overestimated by CSI as a high-grade glioma. CONCLUSION: (1)H-CSI-guided stereotactic biopsy may offer advantages as compared to conventional stereotactic biopsy. The biopsy of the choline hot spot in suggestive low-grade gliomas may help to identify focal points of higher tumor malignancy independent of contrast enhancement.

SMAC-expression in denervated human skeletal muscle as a potential inhibitor of coexpressed inhibitor-of-apoptosis proteins.

In multinucleated skeletal muscle fibers, apoptotic muscle fiber loss is mediated by a consecutive disassembly of single fiber segments. During this period of time, proapoptotic and antiapoptotic factors compete for promotion or inhibition of apoptotic fiber degradation. In 16 patients with a neurogenic muscular atrophy, we studied the immunohistochemical expression of the inhibitor-of-apoptosis proteins (IAP) survivin, cIAP1, and XIAP and also of second mitochondria-derived activator of caspase (SMAC), which is released during apoptosis and binds to IAPs to prevent them from inhibiting caspases. Although normal control muscle fibers show no expression of SMAC and IAPs, there was a distinct sarcoplasmic expression of SMAC (12.0%+/-3.5%), survivin (10.2%+/-4.0%), cIAP1 (9.0%+/-3.1%), and XIAP (11.0%+/-4.6%) in varying numbers of muscle fibers in neurogenic muscular atrophy. Coexpression of SMAC and IAPs varied. Some denervated muscle fibers displayed up-regulation of either SMAC or IAPs. Other groups of atrophic muscle fibers showed coexpression of SMAC and IAPs. All factors were exclusively up-regulated in atrophic muscle fibers. These findings indicate that IAPs may inhibit apoptotic degradation of denervated muscle fibers. However, IAPs are finally insufficient to counterbalance and prevent muscle fiber apoptosis, as up-regulated expression of SMAC can antagonize this antiapoptotic potential and promote apoptotic muscle fiber disassembly and loss. The interplay between IAPs and SMAC may represent a threshold for muscle fiber-degrading caspase activities. If this bears a therapeutic potential in the prevention of loss of denervated muscle fibers, it remains highly speculative.

Expression of extracellular matrix-degrading proteins in classic, atypical, and anaplastic meningiomas.

Although the majority of meningiomas, commonly benign tumors (WHO I), are amenable to surgical resection, a percentage of up to 3% will recur as higher-grade meningiomas with potential brain invasion. Our study aims at the in situ identification of proteolytic, extracellular matrix-degrading enzymes in a broad spectrum of meningiomas. We examined 80 meningiomas (50 classic meningiomas WHO I, 19 meningiomas WHO II, including atypical, chordoid, and clear cell types, as well as 11 anaplastic meningiomas WHO III) for the immunohistochemical expression patterns of cathepsin D and metalloproteinases MMP-2 and MMP-9. Meningiomas of all types and grades revealed a distinct expression of MMP-9 and cathepsin D, while MMP-2 was found predominantly in WHO II and III meningiomas. There was a significant increase in positive tumor cells from WHO grade I to II and III for MMP-2 (p<0.001), but not for cathepsin D (p=0.099). MMP-9 displayed an increased number of positive tumor cells from WHO grade I to II, but a decrease in WHO III meningiomas (p<0.002). Routine screening for the expression of metalloproteinases and cathepsin D will not reveal any new diagnostically or prognostically relevant information. However, these factors may represent a potential target for pharmacological blocking as an anti-invasive therapy.

Characterization of initiator and effector caspase expressions in dystrophinopathies.

There is evidence that apoptotic cell death mechanisms contribute to muscle fiber loss in dystrophin-deficient muscle but there is little knowledge about the final degrading events of muscle fiber apoptosis. In muscle biopsy specimens from 14 patients with a dystrophinopathy (10 patients with DMD, two with Becker MD, two DMD carriers), expression of APAF-1 and caspase-9, upstream members of the apoptotic protease cascade, as well as of the downstream executioners caspase-2, -6 and -7, were studied by immunohistochemistry and Western blots. Besides predominant immunoreactivity in regenerating muscle fibers, which may contribute to apoptotic events during new muscle fiber formation, caspase-9, -6 and -7 displayed upregulation in non-regenerating, light microscopically intact but atrophic muscle fibers. Western blot analyses confirmed the upregulations. These findings indicate that, once activated, caspase-9 initiates a proteolytic, muscle fiber degrading cascade involving the downstream executioners caspase-6 and -7. However, lacking coexpression of APAF-1 suggests the existence of other pathways of caspase-9 activation than through the "apoptosome" in dystrophinopathies.

Delayed or late-onset type II glycogenosis with globular inclusions.

Three unrelated patients, one girl, one boy, and an adult female, aged 14, 11 and 41 years, respectively, at the time of biopsy, revealed lysosomal glycogen storage, autophagic vacuoles and peculiar globular inclusions of distinct ultrastructure, which were reducing but did not appear like true "reducing bodies" as described in the congenital myopathy "reducing body myopathy". All three patients had residual activity of acid alpha-glucosidase in their muscle biopsy samples. Leukocytes in the girl showed normal acid alpha-glucosidase activity, but in the boy activity was reduced. Molecular genetic analysis of the GAA gene revealed disease-causing mutations in each patient: H568L/R672W, IVS1-13T>G/G615F, and IVS1-13T>G/IVS1-13T>G. Although only one patient with such globular inclusions has been reported up to now, the three patients described here indicate that in the late-onset type of GSD II such inclusions may not be rare.

Muscle-fiber apoptosis in neuromuscular diseases.

Muscle-fiber loss is a characteristic of many progressive neuromuscular disorders. Over the past decade, identification of a growing number of apoptosis-associated factors and events in pathological skeletal muscle provided increasing evidence that apoptotic cell-death mechanisms account significantly for muscle-fiber atrophy and loss in a wide spectrum of neuromuscular disorders. It became obvious that there is not one specific pathway for muscle fibers to undergo apoptotic degradation. In contrast, certain neuromuscular diseases seem to involve characteristic expression patterns of apoptosis-related factors and pathways. Furthermore, there are some characteristics of muscle-fiber apoptosis that rely on the muscle fiber itself as an extremely specified cell type. Multinucleated muscle fibers with successive muscle-fiber segments controlled by individual nuclei display some specifics different from apoptosis of mononucleated cells. This review focuses on the expression patterns of apoptosis-associated factors in different primary and secondary neuromuscular disorders and gives a synopsis of current knowledge.

Tumour necrosis factor-mediated cell death pathways do not contribute to muscle fibre death in dystrophinopathies.

There is evidence that apoptotic cell death mechanisms contribute to muscle fibre loss in dystrophinopathies, but little knowledge about the activators of the final degrading caspase cascade in muscle fibre apoptosis. As mitochondria-related activation of this caspase cascade, through e.g. APAF-1, could not be proven in dystrophin-deficient muscle, this study searches for other prospective candidates that may directly trigger apoptotic cell degradation by mitochondria-independent pathways involving the interaction of tumour necrosis factor-alpha (TNF-alpha) and TRAIL with death receptors and subsequent activation of caspase-8. The expression of TNF-alpha, TNF-R1, TRAIL, NF-(kappa)B and caspase-8 were studied in muscle biopsy specimens from 14 patients with a dystrophinopathy [10 Duchenne muscular dystrophies (DMD), 2 Becker MD, and 2 DMD carriers] by immunohistochemistry and Western blotting. In all types of dystrophinopathies, necrotic muscle fibres undergoing myophagocytosis displayed strong expression of TNF-alpha, TNF-R1, and TRAIL, which, however, was attributed to phagocytosing cells and not to the muscle fibres themselves. There was no up-regulation in normal-shaped or atrophic non-necrotic muscle fibres, or in intact muscle fibre segments adjacent to segmental necrosis and myophagocytosis. The expression profiles of caspase-8 and NF-(kappa)B resembled that of normal control muscle. There were likewise no significant differences in the Western blot analyses between normal control and dystrophin-deficient muscle. Based on these findings, a contribution of TNF-alpha or TRAIL-mediated cell death pathways to muscle fibre apoptosis or necrosis in dystrophinopathies could not be confirmed.

Expression patterns of initiator and effector caspases in denervated human skeletal muscle.

There is evidence that apoptotic cell death contributes to the loss of denervated muscle fibers. In 17 patients with neurogenic muscular atrophy, we studied the expression of the apoptosis mediators APAF-1/caspase-9 and degrading caspases-2, -3, and -7 by immunohistochemical and western blot analyses. Muscle with neurogenic atrophy showed distinct upregulation of caspase-9 and -7 and no expression for APAF-1 (apoptosis protease-activating factor-1) and caspase-2 and -3. Expression of caspase-7 was restricted to atrophic fibers, but caspase-9 was also found in normal-sized muscle fibers where its expression was often confined to single fiber segments. These findings indicate that upregulated expression of caspase-9 can initiate the proteolytic cascade involving the downstream executioner caspase-7, which mediates degradation of denervated muscle fibers. However, apoptotic events may be restricted to single muscle-fiber segments, where apoptotic cell degradation contributes to the long-term process of atrophy. Pharmacological inhibition of caspases may be a therapeutic strategy in diminishing muscle atrophy.