Rethinking Ormond’s Disease

Idiopathic retroperitoneal fibrosis (RPF) is a periaortic sclerotic disease that encases adjacent retroperitoneal structures, particularly the ureters. A subset of idiopathic RPF cases can be associated with IgG4related disease, but the frequency of this association is not clear. We selected 23 cases of idiopathic RPF and identified IgG4-related RPF cases based on the presence of IgG4+ plasma cells in the tissue, using an IgG4/ IgG ratio cutoff of 940%. We then compared the IgG4-related RPF patients and the non-IgG4-related RPF patients in terms of both the presence of histopathologic features typical of IgG4-related disease and the simultaneous occurrence (or history) of other organ manifestations typical of IgG4-related disease. The IgG4-related RPF and non-IgG4-related RPF groups were also analyzed in terms of clinical, laboratory, and radiologic features and treatment review. We identified 13 cases of IgG4-related RPF (57% of the total cohort). The distinguishing features of IgG4-related RPF were histopathologic and extra-organ manifestations of IgG4-related disease. The IgG4-related RPF patients were statistically more likely than non-IgG4-related RPF patients to have retroperitoneal biopsies showing lymphoplasmacytic infiltrate (p = 0.006), storiform fibrosis (p = 0.006), or tissue eosinophilia (p = 0.0002). Demographics of the 2 groups, including a middle-aged, male predominance (mean age, 58 yr; 73% male), were similar. IgG4-related disease accounts for a substantial percentage of patients with ‘‘idiopathic’’ RPF. Histopathologic features such as storiform fibrosis, obliterative phlebitis, and tissue eosinophilia are critical to identifying this disease association. Extraretroperitoneal manifestations of IgG4-related disease are also often present among patients with IgG4-related RPF. Elevated IgG4/total IgG ratios in tissue biopsies are more useful than the number of IgG4+ plasma cells per high-power field in cases of RPF that are highly fibrotic. (Medicine 2013;92: 82Y91) Abbreviations: ANA = antinuclear antibody, CRP = C-reactive protein, CT = computed tomography, ESR = erythrocyte sedimentation rate, HPF = high-power field, IgG4-RD = IgG4-related disease, RPF = retroperitoneal fibrosis. INTRODUCTION R etroperitoneal fibrosis (RPF), sometimes termed ‘‘Ormond’s disease,’’ is an enigmatic disorder characterized by sclerotic tissue in the periaortic or periiliac retroperitoneum that encases adjacent structures. A urologist, Dr. John Ormond, described RPF in 1948 upon observing intraoperatively the fibrous tissue encasement of both ureters in a patient with renal failure. The most common symptoms of RPF include abdominal or flank pain, weight loss, fatigue, and urinary frequency. Specific serologic markers for RPF do not exist, but acute-phase reactants such as the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are frequently elevated. Imaging studies show a soft tissue density that envelops the abdominal aorta or iliac vessels, often leading to hydronephrosis of 1 or both kidneys. RPF can be divided into idiopathic and secondary subsets. Idiopathic RPF is essentially a diagnosis of exclusion after secondary causes of RPF, for example, drug exposure, infection, and malignancy, have been eliminated. Definitive diagnosis generally requires histopathologic confirmation by biopsy. IgG4-related disease (IgG4-RD) is an immune-mediated disease characterized by unique histopathologic features in affected organs. These features are a lymphoplasmacytic infiltrate, storiform fibrosis, and obliterative phlebitis. Mild to moderate tissue eosinophilia is also present in many patients, consistent with the strong history of allergic disease or atopy that frequently accompanies (or is an integral part of ) IgG4-RD. Immunostaining of tissue lesions in IgG4-RD demonstrates an enrichment with IgG4+ plasma cells, indicated by either an increase in their overall concentration in tissue (number per high-power field [HPF]), an elevated IgG4/total IgG ratio, or both. Characteristic organs affected in IgG4-RD include the pancreas, salivary glands, orbits, lung, kidney, and aorta, but the disease has also been described in the thyroid gland (Riedel thyroiditis), the prostate gland, the pachymeninges, skin, and nearly every other organ system. An association between RPF and ‘‘multifocal fibrosclerosis’’ has been acknowledged for decades. Multifocal fibrosclerosis is now known to be synonymous with IgG4-RD. However, there have been few studies of the retroperitoneum during the era in which IgG4-RD has been recognized. These studies are contradictory with regard to any potential relationship of IgG4-RD to ‘‘idiopathic’’ RPF. Zen et al observed the typical histopathologic features and immunostaining characteristics of IgG4-RD in 10 of 17 RPF patients from Japan, suggesting that a proportion of idiopathic RPF cases are part of the IgG4-RD spectrum. In contrast, 82 www.md-journal.com Medicine & Volume 92, Number 2, March 2013 From Rheumatology Unit (AK, MNC, JHS), Division of Rheumatology, Allergy, and Immunology, Department of Medicine; Department of Pathology (SS, RPH, VD); and Department of Radiology (NS), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. Drs. Khosroshahi and Carruthers contributed equally to this manuscript. Dr. Khosroshahi’s current address/affiliaton is Rheumatology Division, Department of Medicine, Emory University, Atlanta, Georgia. Figures 2 and 4 can be viewed in color online at http://www.md-journal.com. Financial support and conflicts of interest: Dr. Stone reports financial support for work outside this study fromGenentech (visiting lectureship and grant support to his institution for open label trial of rituximab in IgG4-related disease) and Roche (consultancy and grant support to his institution for multicenter clinical trial). Dr. Hasserjian reports financial support for work outside this study from Genzyme (consultancy) and Amgen (consultancy), as well as support from the Colorado Society of Pathologists, Elsevier, American Society for Clinical Pathology, United States and Canadian Academy of Pathology, and Harvard Medical School (for lectures, royalties, and/or travel expenses). The other authors have no funding or conflicts of interest to disclose. Reprints: John Stone, MD, MPH, Rheumatology Unit, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114 (e-mail: [email protected]). Copyright * 2013 by Lippincott Williams & Wilkins ISSN: 0025-7974 DOI: 10.1097/MD.0b013e318289610f Copyright © 2013 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. other investigators writing on idiopathic RPF did not comment on the potential contribution of IgG4-RD to their cases. We conducted the current study to address the possible role of IgG4-RD in the clinical entity known as idiopathic RPF. We identified 23 cases of idiopathic RPF and evaluated them for the possibility of IgG4-related RPF on the basis of their IgG4/ total IgG ratios within tissue. We then compared the presence of histopathologic features typical of IgG4-RD, the simultaneous occurrence or previous history of other organ manifestations typical of IgG4-RD, and other clinical and radiologic findings in the 2 categories of idiopathic RPF.