Chromophobe renal cell carcinoma with prominent lymph node metastasis and polysomy of chromosome 21: poorly differentiated form or "presarcomatoid" form?

Lymph node metastasis of chromophobe renal cell carcinoma (RCC) is extremely rare. It has been recently reported that sarcomatoid chromophobe RCC frequently show polysomy of chromosomes 1, 2, 6, 10, and 17. In this article, we report an unusual case of chromophobe RCC. A 42-year-old Japanese woman presented with hematuria and complained of inguinal pain 2 months after the initial symptoms. Radical nephrectomy and renal hilar lymphadenectomy were performed. The tumor was 8 cm in greatest diameter; its cut surface was beige in color. Large metastasis to the renal hilar lymph node was identified. Histological examination of the right renal tumor met the criteria of chromophobe RCC. In addition to histological findings of typical chromophobe RCC, small cell foci, comedo-like necrosis, trabecular growth pattern, and sclerosing stroma were observed. However, no sarcomatoid foci were identified anywhere, despite extensive tumor sampling including lymph node lesions. Immunohistochemically, neoplastic cells were positive for E-cadherin and CD117 (c-kit). Ultrastructurally, tumorous cells contained abundant mitochondria and cytoplasmic microvesicles. Fluorescence in situ hybridization showed monosomy of chromosomes 2 and 10 and polysomy of chromosome 21. Finally, we suggest that this tumor may show the poorly differentiated or presarcomatoid form of chromophobe RCC.     

Histological alterations following fine-needle aspiration for parathyroid adenoma: Incidence and diagnostic problems

This study aimed to clarify the histological alterations following fine-needle aspiration for parathyroid adenoma and discuss the occurrence of diagnostic problems. Among the 392 patients with parathyroid adenoma who underwent resection, fine-needle aspiration was performed for 21 (5.1%) parathyroid adenoma nodules. Histological findings that were significantly more frequent in cases that underwent fine-needle aspiration were considered histological alterations following fine-needle aspiration for parathyroid adenoma, including the following six findings: thick fibrous capsule (71.4%), multilayered fibrous capsules (14.3%), capsular pseudo-invasion (42.9%), fibrous bands (57.1%), hemosiderin deposition (14.3%), and tumor implantation (14.3%). Eighteen parathyroid adenoma nodules (85.7%) exhibited one or more of the six findings. Tumor cells and adipocytes entrapped within the thick fibrous capsule were occasionally observed. The fibrous bands were frequently connected to the thick fibrous capsule. The number of passes, duration between fine-needle aspiration and resection, tumor size, and purpose of fine-needle aspiration were not related to the incidence of histological findings. Because of the histological alterations following fine-needle aspiration for parathyroid adenoma that can be easily mistaken for signs of atypical adenoma or parathyroid carcinoma, we recommend that the six findings be excluded from pathological findings indicating atypical adenoma or parathyroid carcinoma in patients with preoperative fine-needle aspiration.     

Matrix metalloproteinases and tissue inhibitors of metalloproteinases in bronchial squamous preinvasive lesions

Metalloproteinases and their inhibitors are known to play an important role in the extracellular matrix remodeling associated with preinvasive lesions and invasive carcinomas; however, little is known about their role in early lung carcinoma. Immunohistochemical studies were made of the reactivity of bronchial squamous preneoplastic lesions from cigarette smokers, including basal cell hyperplasia, squamous metaplasia, dysplasia, carcinoma in situ, and invasive squamous cell carcinoma for matrix metalloproteinases (MMPs), their tissue inhibitors (TIMPs), and type IV collagen in 13 patients. Staining for type IV collagen disclosed discontinuities in basement membranes from basal cell hyperplasia to dysplasia, progressing to destruction in carcinoma in situ and invasive carcinoma. Reactivity for MMP-9 was mild in basal cell hyperplasia and squamous metaplasia, increasing in carcinoma in situ and invasive carcinoma. In contrast, reactivity for MMP-1 was strong in basal cell hyperplasia and squamous metaplasia, decreasing in carcinoma in situ and invasive carcinoma. Some neoplastic cells in carcinoma in situ and invasive carcinoma were MMP-3 positive. Staining for MMP-2 and TIMP-1 was moderate to strong in all squamous preinvasive lesions. Confocal microscopy showed MMP-9-positive cells passing through fragmented basement membranes in which type IV collagen and MMP-9 were colocalized. Type IV collagen colocalized with MMP-2 in all lesions and with TIMP-1 in basal cell hyperplasia and squamous metaplasia. The inverse relationships between the reactivity for MMP-1 and MMP-9 with progression of bronchial squamous preinvasive lesions suggest important roles for these MMPs in basement membrane remodeling in these lesions.     

Myopathy phenotype of transgenic mice expressing active site-mutated inactive p94 skeletal muscle-specific calpain, the gene product responsible for limb girdle muscular dystrophy type 2A

A defect of the gene for p94 (calpain 3), a skeletal muscle-specific calpain, is responsible for limb girdle muscular dystrophy type 2A (LGMD2A), or 'calpainopathy', which is an autosomal recessive and progressive neuromuscular disorder. To study the relationships between the physiological functions of p94 and the etiology of LGMD2A, we created transgenic mice that express an inactive mutant of p94, in which the active site Cys129 is replaced by Ser (p94:C129S). Three lines of transgenic mice expressing p94:C129S mRNA at various levels showed significantly decreased grip strength. Sections of soleus and extensor digitorum longus (EDL) muscles of the aged transgenic mice showed increased numbers of lobulated and split fibers, respectively, which are often observed in limb girdle muscular dystrophy muscles. Centrally placed nuclei were also frequently found in the EDL muscle of the transgenic mice, whereas wild-type mice of the same age had almost none. There was more p94 protein produced in aged transgenic mice muscles and it showed significantly less autolytic degradation activity than that of wild-type mice. Although no necrotic-regenerative fibers were observed, the age and p94:C129S expression dependence of the phenotypes strongly suggest that accumulation of p94:C129S protein causes these myopathy phenotypes. The p94:C129S transgenic mice could provide us with crucial information on the molecular mech-anism of LGMD2A.     

Dedifferentiated liposarcoma with chondroblastic osteosarcomatous dedifferentiation

We describe a rare case of dedifferentiated liposarcoma with features resembling chondroblastic osteosarcoma in the dedifferentiated component. The tumor was removed from the left thigh in a 78-year-old male. It consisted of a well-differentiated liposarcoma and an anaplastic component that contained numerous osteoid and cartilaginous tissues surrounded by high-grade spindle cell sarcoma. To our knowledge, only two cases similar to the divergent chondroblastic osteosarcomatous dedifferentiation of this disease have been reported in the literature.     

Reduction of voltage-dependent magnesium block of N-methyl-D-aspartate receptor-mediated current by in vivo axonal injury

The post-traumatic change of the voltage-dependent Mg(2+) block of N-methyl-D-aspartate response was investigated using nystatin perforated patch recording mode under the voltage-clamp condition. Motor neurons of the dorsal motor nucleus of vagus nerve were freshly dissociated from rat brain at 2h to 10 days after receiving axonal crush injuries in vivo at the neck. The reduction of voltage-dependent Mg(2+) block of N-methyl-D-aspartate response became evident at more than 12h after the injury, sustained for at least five days and recovered within 10 days. Other characteristics examined such as reversal potentials, the Hill coefficient and EC(50) of N-methyl-D-aspartate-induced current were not affected by axonal injury. The Mg(2+) block of N-methyl-D-aspartate response was not affected at all by local application of colchicine onto the vagal axon in in vivo condition, suggesting that axonal injury, but not the blockade of the axonal flow, is responsible for the change of the sensitivity of N-methyl-D-aspartate response to extracellular Mg(2+). In addition, the reduction of Mg(2+) block by the nerve injury persisted regardless of the presence of protein kinase C modulators, such as 10(-6)M chelerythrine and 10(-7)M calphostin C. Therefore alteration of protein kinase C activity after axonal injury is not responsible for the maintenance of the reduced Mg(2+) block.These findings suggest that injured neurons acquire immature characteristics of plasticity with respect to the sensitivity of N-methyl-D-aspartate receptors to extracellular Mg(2+) or a long-term increase in the susceptibility to Ca(2+) excitotoxicity.     

Mechanisms of neonatal tolerance induced in an animal model for primary Sjögren's syndrome by intravenous administration of autoantigen

Neonatal exposure to autoantigen is believed to induce effective antigen‐specific T‐cell tolerance in experimental models of autoimmunity. We have identified 120 kDa α‐fodrin autoantigen in an animal model for primary Sjögren's syndrome (SS), that has been determined as a candidate autoantigen in both an animal model and the patients with primary SS. We demonstrate here that neonatal injection of autoantigen induce relevant tolerance when treated with intravenous (i.v.) administration within 24 h after birth, but not with i.v. injection after the thymectomy or with intraperitoneal injection. Autoantigen‐specific T‐cell response was significantly reduced in mice induced neonatal tolerance, and the activation markers of splenic CD4⁺ T cells were down‐regulated in mice treated with neonatal administration. Because we detected that neonatal i.v. injection of autoantigen prevented Th1 response, it is possible that the autoantigen administration within 24 h after birth induce regulatory T cells that had a protective effect against Th1‐mediated autoimmune diseases. These results indicate that the prevention of the spontaneous anti‐120 kDa α‐fodrin response in vivo, by tolerization of the autoantigen‐reactive T cells, blocked the development of autoimmune lesions in an animal model for primary SS.     

Characterization of epstein-barr virus-infected mantle cell lymphoma lines

It has been reported that Epstein-Barr virus (EBV) resides in resting B cells in vivo. However, an ideal in vitro system for studying EBV latent infection in vivo has not yet been established. In this study, a mantle cell lymphoma line, SP53, was successfully infected with a recombinant EBV containing a neomycin-resistant gene. The EBV-carrying SP53 cells were obtained by selection using G418. They expressed EBER-1, EBNAs, and LMP1; this expression pattern of the EBV genes was similar to that in a lymphoblastoid cell line (LCL). However, proliferation assay showed that the EBV-carrying SP53 cells have a doubling time of 73 h, compared with 57 h of SP53 cells. Transplantation of 10(8) SP53 cells to nude mice formed tumors in 4 of 10 mice inoculated, but the EBV-carrying SP53 cells did not. Unexpectedly, EBV infection reduced the proliferation and tumorigenicity of SP53 cells. However, the EBV-carrying SP53 cells showed higher resistance to apoptosis induced by serum starvation than did the SP53 cells. The inhibition of proliferation and the resistance to apoptosis induced in SP53 cells by EBV infection indicate that this cell line might to some extent provide a model of in vivo EBV reservoir cells.