Autopsy of malignant paraganglioma causing compressive myelopathy due to vertebral metastases.

Paraganglioma is a neuroendocrine tumor arising from extra-adrenal sites in the peripheral nervous system. Although malignant paraganglioma is known to metastasize to bones, including vertebral bodies, there is little literature on the compressive myelopathy accompanied by sphincter dysfunction; to our knowledge, only 12 cases have been reported. Moreover, neuropathological investigations of the spinal cord in this state have not been well-documented. This autopsy report describes a 55-year-old man with malignant paraganglioma and compression myelopathy caused by vertebral metastasis. The present case showed a gradual numbness and a sudden onset of irreversible paraplegia with sphincter dysfunction, which were not palliated these neurologic dysfunctions despite radiotherapy. Computed tomography (CT) revealed multiple metastases to the bones, lymph nodes, and lungs when he was diagnosed with malignant paraganglioma. At the same time, he had numbness, and magnetic resonance imaging (MRI) showed multiple diffuse metastatic lesions in the vertebral bodies. Following abrupt onset of paralysis, MRI showed fractured third and sixth thoracic vertebral bodies. An autopsy revealed residual vertebral metastases with fractures of the third and sixth thoracic vertebral bodies, resulting in compressive myelopathy at the fourth thoracic segment, which was characterized by complete spinal cord destruction. Destructive spinal cord lesion-induced secondary degeneration was observed in the gracile fasciculus at the rostral side and in the pyramidal tract at the caudal side, which showed Wallerian degeneration. Such pathology was consistent with the presenting neurological symptoms, including paraplegia and somatic sensory loss below the fourth thoracic spinal cord segment. Although it is difficult to identify the pathognomonic morphological changes responsible for the sphincter dysfunction, the present case suggests a supranuclear dysregulation of the somatosensory and central autonomic nervous systems involved in urination and defecation. Based on a review of the literature and the features of the present case, paraganglioma can metastasize aggressively even with a low pathological grading. This case of vertebral metastasis as a result of malignant paraganglioma may not be extraordinary but the autopsy report is rare. This autopsy revealed transverse myelopathy as a result of malignant vertebral metastasis of malignant paraganglioma.

Intensity-modulated radiation therapy for small cell carcinoma of the prostate: A case report.

Small cell carcinomas (SCC) make up only 1% of malignancies of the prostate. Reports of several case series have described outcomes of surgery and chemotherapy for SCC of the prostate, but few reports address radiotherapy. We treated a case of SCC of the prostate with intensity-modulated radiation therapy (IMRT) consisting of 70 Gy administered in 35 fractions followed by hormonal therapy using only luteinizing hormone-releasing hormone (LH-RH) agonist. The tumor volume decreased remarkably by 4 months after IMRT. The rapid decrease in tumor size of this SCC of the prostate seemed to suggest a similar high radiosensitivity to that of SCC of the lung, but the tumor increased rapidly thereafter within the radiation fields, and pelvic lymph node metastases had developed by 24 months after IMRT. By 28 months after IMRT, multiple lung metastases developed, and the patient died of SCC of the prostate 31 months after initial diagnosis.

Post-transcriptional regulation of fukutin in an astrocytoma cell line.

Fukutin is the gene responsible for Fukuyama-type congenital muscular dystrophy (FCMD), an autosomal recessive disease associated with central nervous system (CNS) and eye anomalies. Fukutin is involved in basement membrane formation via the glycosylation of α-dystroglycan (α-DG), and hypoglycosylation of α-DG provokes the muscular, CNS and eye lesions of FCMD. Astrocytes play an important role in the pathogenesis of the CNS lesions, but the post-transcriptional regulation of fukutin mRNA has not been elucidated. In this study, we investigated the characteristics of fukutin mRNA using an astrocytoma cell line that expresses fukutin and glycosylated α-DG. The glycosylation of α-DG was considered to be increased by over-expression of fukutin and decreased by knockdown of fukutin. Knockdown of Musashi-1, one of the RNA-binding proteins involved in the regulation of neuronal differentiation, induced a decrease in fukutin mRNA. Immunoprecipitation and ELISA-based RNA-binding assay demonstrated possible binding between fukutin mRNA and Musashi-1 protein. A relationship between fukutin mRNA and vimentin protein was also proposed. In situ hybridization for fukutin mRNA showed a positive cytoplasmic reaction including cytoplasmic processes. From these results, fukutin mRNA is suggested to be a localized mRNA up-regulated by Musashi-1 and to be a component of a mRNA-protein complex which includes Musashi-1 and (presumably) vimentin proteins.

4-Hydroxy-2-nonenal upregulates and phosphorylates cytosolic phospholipase A(2) in cultured Ra2 microglial cells via MAPK pathways.

Several studies have suggested the involvement of neuroinflammation in the pathomechanism of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). We recently demonstrated increased levels of protein-bound 4-hydroxy-2-nonenal (HNE) as a highly reactive lipid peroxidation product and cytosolic phospholipase A(2) (cPLA(2)) as a proinflammatory enzyme in glial cells as well as motor neurons in the spinal cord of sporadic ALS patients. However, a link between HNE and cPLA(2) in ALS remains to be determined. To address this issue, we investigated effects of HNE stimulation on the state of cPLA(2) expression in cultured microglial cell line (Ra2). Exposure of Ra2 cells to HNE significantly increased expression levels of cPLA(2) and its activated form phosphorylated at amino acid residue S(505) (p-cPLA(2)) on immunoblots. Pretreatment of Ra2 cells with the antioxidant N-acetylcysteine, the extracellular signal-regulated kinase (ERK) inhibitor PD98059 or the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 prevented the HNE-induced increased expression of cPLA(2) and p-cPLA(2). Immunocytochemical analysis revealed that staining for p-cPLA(2) in Ra2 cells was localized in the cytoplasm and more intense in the HNE-stimulated group than in the vehicle group. The present results provide in vitro evidence that HNE upregulates and phosphorylates cPLA(2) in microglia via the ERK and p38 MAPK pathways.

Roles of fukutin, the gene responsible for fukuyama-type congenital muscular dystrophy, in neurons: possible involvement in synaptic function and neuronal migration.

Fukutin is a gene responsible for Fukuyama-type congenital muscular dystrophy (FCMD), accompanying ocular and brain malformations represented by cobblestone lissencephaly. Fukutin is related to basement membrane formation via the glycosylation of α-dystoglycan (α-DG), and astrocytes play a crucial role in the pathogenesis of the brain lesion. On the other hand, its precise function in neurons is unknown. In this experiment, the roles of fukutin in mature and immature neurons were examined using brains from control subjects and FCMD patients and cultured neuronal cell lines. In quantitative PCR, the expression level of fukutin looked different depending on the region of the brain examined. A similar tendency in DG expression appears to indicate a relation between fukutin and α-DG in mature neurons. An increase of DG mRNA and core α-DG in the FCMD cerebrum also supports the relation. In immunohistochemistry, dot-like positive reactions for VIA4-1, one of the antibodies detecting the glycosylated α-DG, in Purkinje cells suggest that fukutin is related to at least a post-synaptic function via the glycosylation of α-DG. As for immature neurons, VIA4-1 was predominantly positive in cells before and during migration with expression of fukutin, which suggest a participation of fukutin in neuronal migration via the glycosylation of α-DG. Moreover, fukutin may prevent neuronal differentiation, because its expression was significantly lower in the adult cerebrum and in differentiated cultured cells. A knockdown of fukutin was considered to induce differentiation in cultured cells. Fukutin seems to be necessary to keep migrating neurons immature during migration, and also to support migration via α-DG.

Activation of STAT3 and inhibitory effects of pioglitazone on STAT3 activity in a mouse model of SOD1-mutated amyotrophic lateral sclerosis.

Signal transducer and activator of transcription-3 (STAT3) is a member of the proinflammatory transcription factor STAT family. Several studies have documented implications for neuroinflammation in amyotrophic lateral sclerosis (ALS). We recently demonstrated activation of STAT3 in spinal cords obtained at autopsy from sporadic ALS patients. To determine the involvement of STAT3 and effects of pioglitazone on STAT3 activity in familial ALS with superoxide dismutase-1 (SOD1) mutation, we performed immunoblot and immunohistochemical analyses of the active form of STAT3 (p-STAT3) in spinal cords from mice overexpressing mutant SOD1 (ALS mice) and nontransgenic littermates (control mice). Immunoblot analysis delineated significant increases in nuclear p-STAT3 levels in non-treated ALS mice as compared with pioglitazone-treated ALS mice and non-treated and pioglitazone-treated control mice. Immunohistochemical analysis revealed prominent p-STAT3 accumulations in the nucleus of motor neurons, reactive astrocytes and activated microglia in non-treated ALS mice but not pioglitazone-treated ALS mice and non-treated and pioglitazone-treated control mice. The present results provide in vivo evidence for increased phosphorylative activation and nuclear translocation of STAT3 in motor neurons and glia in mouse motor neuron disease, suggesting a common pathological process between sporadic and SOD1-mutated familial forms of ALS. Moreover, it is likely that pioglitazone may exert inhibitory effects on STAT3-mediated proinflammtory mechanisms in this disease.

Involvement of 4-hydroxy-2-nonenal accumulation in multiple system atrophy.

Recent studies have suggested implications for α-synuclein cytotoxicity in the pathomechanism of multiple system atrophy (MSA). Given in vitro evidence that α-synuclein generates oxidative stress, it is proposed that lipid peroxidation may be accelerated in MSA. To address this issue, we performed an immunohistochemical analysis of protein-bound 4-hydroxy-2-nonenal (P-HNE) in sections of archival, formalin-fixed, paraffin-embedded pontine materials of eight sporadic MSA patients and eight age-matched control subjects. In the MSA cases, P-HNE immunoreactivity was localized in all of the neuronal cytoplasmic inclusions and glial cytoplasmic inclusions, both of them identified with α-synuclein and ubiquitin. It was also detectable in reactive astrocytes and phagocytic microglia but undetectable in activated microglia. By contrast, P-HNE immunoreactivity in the control cases was only very weak or not at all in the parenchyma including neurons and glia. The present results provide in vivo evidence that HNE participates in α-synuclein-induced cytotoxicity and neuroinflammation in MSA.

Recurrent pericardial effusion with pericardial amyloid deposition: a case report and literature review.

Pericardial amyloidosis is a rare cause of pericardial effusion. Here, we report a case of recurrent pericardial effusion because of pericardial amyloid deposition. The patient was a man in his 40s admitted for pulmonary embolism. During hospitalization, arterial fibrillation and cardiac tamponade were observed, and an initial pericardial puncture was performed. Thereafter, pericardial puncture was repeated nine times over the next two years. Cytological examination of the pericardial effusion suggested malignant mesothelioma. Afterward, pericardial fenestration and partial resection were performed. Intraoperatively, a thickened pericardium and hemorrhagic pericardial effusion were noted. Histologically, the surface of the pericardium was covered by an eosinophilic amorphous material. Congo red and DYLON stains, electron microscopy, and immunohistochemical findings revealed localized amyloidosis composed of an immunoglobulin lambda light chain. Although the patient did not receive further treatment for 5 years postoperatively, his renal and cardiac functions remained within normal limits. Based on these findings, the patient was diagnosed with localized amyloidosis. So far, hemorrhagic pericardial effusion has been reported in few cases with systemic amyloidosis. Because localized immunoglobulin light-chain-derived (AL) amyloidosis may progress to systemic disease (although it is a very rare occurrence), long-term follow-up is necessary to detect recurrence or progression to a systemic form.

Well-differentiated adenocarcinoma associated with ulcerative colitis.

OBJECTIVES: Adenocarcinoma is known to be associated with ulcerative colitis, but the diagnosis is sometimes challenging, both clinically and pathologically. METHODS AND RESULTS: We present a case of extremely well-differentiated adenocarcinoma associated with ulcerative colitis, in which preoperative diagnosis was not possible. Glands in biopsy specimens showed a serrated appearance that looked like low-grade dysplasia or regenerative mucosa. After an operation due to severe symptoms of stenosis, carcinoma was diagnosed. Tumor cells, especially in invasive glands, tended to show stronger immunoreactivity against anti-CK7, TNF-α and Aurora B antibodies compared to cells of mucosal lesion. Interestingly, CD44v6, one of the adhesion molecules, was less expressed in invasive glands, while those glands exhibited stronger expression of a disintegrin and metalloproteinase 17 (ADAM 17), one of the sheddases that cleaves an extracellular domain of CD44. CONCLUSIONS: These observations appear interesting to consider the pathogenesis and to diagnose extremely well-differentiated adenocarcinoma in ulcerative colitis, although further investigation is needed.

Synchronous and bilateral oncocytic carcinoma of the breast: A case report and review of the literature.

Synchronous bilateral breast cancer is rare, and oncocytic carcinoma is an even rarer breast cancer histological subtype. In general, oncocytic tumors are defined as neoplasms with eosinophilic granular cytoplasm and have been reported in various organs. Oncocytic carcinoma of the breast was first documented by Gadaleanu and Craciun in 1987, and 48 cases have since been reported. The present study reports a case of synchronous bilateral breast oncocytic carcinoma. The patient was a 78-year-old woman. Although she exhibited no symptoms, chest computed tomography revealed three multinodular breast tumors: Two in the right breast and one in the left. Core needle biopsy was performed on the three tumors, and the patient was diagnosed with invasive ductal carcinoma with potential apocrine carcinoma. A bilateral modified radical mastectomy was performed. Surgical specimens of the three tumors revealed cord- or nest-forming tumor cells with eosinophilic granular cytoplasm. Immunohistochemically, the tumor cells were markedly positive for mitochondria. Electron microscopy of the tumor samples additionally revealed numerous mitochondria filling the cytoplasm. Based on these findings, the tumors were diagnosed as oncocytic carcinoma. The pathogenesis of oncocytic carcinoma remains to be fully elucidated; thus, additional clinicopathological studies are required.

The muscular dystrophies associated with central nervous system lesions: a brief review from a standpoint of the localization and function of causative genes.

The muscular dystrophies have been traditionally classified based mainly on clinical manifestation and mode of inheritance. Owing to the discoveries of causative genes, new terminologies derived from each gene, such as dystrophinopathy, α-dystroglycanopathy, sarcoglycanopathy and fukutinopathy, have also become common. Mutations of each gene may cause several clinical phenotypes. Some muscular dystrophies accompany central nervous system (CNS) lesions, especially in the congenital muscular dystrophies. Cobblestone lissencephaly (type II lissencephaly) is a well-known CNS malformation observed in severe forms of α-dystroglycanopathy. Moreover, CNS involvement has been reported in other muscular dystrophies, such as Duchenne muscular dystrophy. In this review, genes related to the muscular dystrophies associated with CNS lesions are briefly described along with the molecular characteristics of each gene and the pathomechanism of the CNS lesions. Understanding of both the clinicopathological characteristics of these CNS lesions and their molecular mechanisms is important for the diagnosis, care of patients, and development of new therapeutic strategies.

A case of adenoid cystic carcinoma presenting as Garcin's syndrome without mass formation.

Adenoid cystic carcinoma (ACC) is a malignant neoplasm that commonly arises in the major or minor salivary gland and usually forms mass lesions. Here, we report a case of ACC involving a 56-year-old man, who displayed right multiple cranial nerve palsies with ipsilateral severe facial pain but not any mass formation. Right submaxillary gland biopsy after repeated challenges at last revealed the primary focus of ACC with perineural invasion and without lymph node metastasis. The neurological manifestations were considered to be attributed to the perineural spread of ACC. It is extremely rare for ACC to show Garcin's syndrome without mass formation.

Intravascular large B-cell lymphoma of the uterus: a case with favorable clinical outcome.

Intravascular lymphoma (IVL) of the uterus, a rare manifestation of malignant lymphoma, was diagnosed in a 71-year-old woman, who had fever, edema, and genital bleeding. Only 4 cases of uterine IVL have been reported in detail in the literature in English, to the author's knowledge. The patient was treated with total hysterectomy with bilateral salpingo-oophorectomy, accompanied by subsequent chemotherapy in combination with rituximab. Preoperative endometrial cytology and biopsy showed atypical lymphocytes intermingled with nonneoplastic epithelial cells. Intravascular proliferation of atypical lymphocytes was detected by histological examination of the resected materials, in which almost the entire uterine structure, including a large endometrial polyp, ovaries, and uterine tubes were involved. Immunohistochemically, tumor cells were positive for CD20 and CD79a and negative for CD5 and CD10. In situ hybridization for Epstein-Barr virus was negative. IVL generally has a poor prognosis. However, in the present case, the patient has been disease free for at least 51 months, and a favorable outcome can be expected.