Evidence for clonal fibroblast proliferation and autoimmune process in idiopathic retroperitoneal fibrosis

Idiopathic retroperitoneal fibrosis is an uncommon disease characterized by encasement of retroperitoneal structures by fibrosis and chronic inflammation. Multiple etiologies have been proposed. First, we investigated if idiopathic retroperitoneal fibrosis is a clonal fibroblast proliferation by performing X-chromosome inactivation analyses. Second, we sought to determine if idiopathic retroperitoneal fibrosis is an autoimmune or immunoglobulin G4-driven process. Thirty cases of idiopathic retroperitoneal fibrosis, in whom known causes of retroperitoneal fibrosis were excluded and those for which paraffin blocks were available, were included in this study. We performed clonality analysis in 16 female patients. Genomic DNA samples were prepared from formalin-fixed, paraffin-embedded tissue sections using laser capture microdissection. Of the 16 cases, 15 were informative. Of 15 informative cases, 8 (53%) showed nonrandom X-chromosome inactivation or a clonal process. Of the 26 patients for which immunoglobulin G4 analysis was performed, 14 (54%) were positive for immunoglobulin G4-positive plasma cells, and all were negative for anaplastic lymphoma kinase. Of cases positive for immunoglobulin G4, the immunoglobulin G4:immunoglobulin G ratio ranged from 0.30 to 1.00 (mean, 0.80). Of the 12 patients for which both clonality analysis and immunoglobulin G4 analysis were performed, 4 (33%) were clonal and immunoglobulin G4 negative; 2 (17%), clonal and immunoglobulin G4 positive; 2 (17%), nonclonal and immunoglobulin G4 positive; and 4 (33%), nonclonal and immunoglobulin G4 negative. Our data indicate that a significant proportion (53%) of idiopathic retroperitoneal fibrosis cases in women is associated with a clonal expansion of fibroblasts. In addition, a subset of idiopathic retroperitoneal fibrosis cases could be classified in the immunoglobulin G4-related sclerosing disease spectrum.