Pseudoxanthomatous salpingitis as an ex vivo model of fallopian tube serous carcinogenesis: a clinicopathologic study of 49 cases.

Iron is a well-documented carcinogen based on both animal models and observational studies in humans. There are limited published data on pseudoxanthomatous salpingitis, an uncommon condition characterized by the accumulation of histiocytes containing iron and iron-related compounds-lipofuscin and hemosiderin-in the lamina propria of the fallopian tube. The clinical and pathologic features of 49 consecutive cases were evaluated. The mean patient age was 53. A history of endometriosis was found in 20%, infertility in 17%, and tubal ligation in 7%. Thirteen (27%) had endometrial cancer and 2 patients had prior radiation therapy for cervical carcinoma. Histologic evidence of endometriosis other than tubal pigment deposition was identified in 65%, and in the fallopian tubes in 35%. Pigment deposition was unilateral in 65% and multifocal or diffuse in 80%. Plasma cells, eosinophils, and neutrophils were present in the tubal lamina propria in 57%, 18%, and 24%, respectively. Hydrosalpinx was present in 51%. An iron stain was positive in pseudoxanthoma cells lacking hemosiderin in 14 of 18 cases (78%). By immunohistochemistry, 2 of 22 cases displayed p53 signatures. The Ki67 proliferation index was elevated (>10%) in 11 of 22 cases, with a mean index of 32% in those cases. An elevated proliferation index did not correlate with inflammation. In summary, these findings characterize the clinical and pathologic features of pseudoxanthomatous salpingitis and confirm its close association with endometriosis, occasional association with radiation therapy, and the presence of iron in the histiocytes. In view of the evolving paradigm shift implicating the fallopian tubal epithelium as the site of origin of high-grade extrauterine serous carcinoma, the presence of iron and iron-related compounds in the fallopian tube provides an opportunity to study the early events in high-grade serous carcinogenesis in a setting characterized by a well-documented carcinogen in close anatomic proximity to the putative epithelium of origin.

Peroxynitrite mediates TNF-alpha-induced endothelial barrier dysfunction and nitration of actin.

We tested the hypothesis that tumor necrosis factor (TNF)-alpha induces a peroxynitrite (ONOO(-))-dependent increase in permeability of pulmonary microvessel endothelial monolayers (PMEM) that is associated with generation of nitrated beta-actin (NO(2)-beta-actin). The permeability of PMEM was assessed by the clearance rate of Evans blue-labeled albumin. beta-Actin was extracted from PMEM lysate with a DNase-Sepharose column. The extracted beta-actin was quantified in terms of its nitrotyrosine/beta-actin ratio with anti-nitrotyrosine and anti-beta-actin antibodies, sequentially, by dot-blot assays. The cellular compartmentalization of NO(2)-beta-actin was displayed by showing confocal localization of nitrotyrosine-immunofluorescence with beta-actin-immunofluorescence but not with F-actin fluorescence. Incubation of PMEM with TNF (100 ng/ml) for 0.5 and 4.0 h resulted in increases in permeability to albumin. There was an increase in the nitrotyrosine/beta-actin ratio at 0.5 h with minimal association of the NO(2)-beta-actin with F-actin polymers. The TNF-induced increase in the nitrotyrosine/beta-actin ratio and permeability were prevented by the anti-ONOO(-) agent Urate. The data indicate that TNF induces an ONOO(-)-dependent barrier dysfunction, which is associated with the generation of NO(2)-beta-actin.