Chapter 298 – MULTIFOCAL FIBROSCLEROSIS

Idiopathic multifocal fibrosclerosis (IMF) is an inflammatory disease characterized by the development of inflammatory pseudotumors; it results in some combination of retroperitoneal fibrosis, mediastinal fibrosis, orbital pseudotumor, Dupuytren's contracture, lymphoid hyperplasia, Peyronie's disease, vasculitis, thyroiditis, primary biliary cirrhosis, testicular fibrosis, and pachymeningitis. Retroperitoneal fibrosis (Ormond's disease) is a subset of IMF and is characterized by fibrosis of the retroperitoneum that entraps and distorts retroperitoneal structures, including the great vessels, ureters, nerves, kidneys, and biliary tree.

Epidemiology

IMF is a rare condition with a prevalence estimated at less than 20 per 100,000 and an incidence of less than 3 per 100,000 per year. However, in relevant populations with predisposing conditions, these figures are considerably higher. For example, methysergide is associated with an incidence of IMF at the rate of 1 case in 5000 users per year. The mean age at diagnosis is 56 years, and the male-to-female ratio is 3:1. The cumulative actuarial survival rate is 86% at 1 year and 78% at 2 years.

Pathobiology

The histopathology of IMF is characterized by multifocal fibrosis, granulation tissue, B cells, helper T cells, large numbers of spindle-shaped cells expressing macrophage markers, and activated fibroblasts. T-cell receptor gene rearrangements have been reported as having a 40% association with HLA-B27, but these associations have not been proved. Degenerative and inflammatory diseases of the aorta (atherosclerosis, aortitis, inherited diseases of collagen, trauma, infection, aortic aneurysm) shed inflammatory lipids and oxidized lipoproteins through the aortic adventitia into the retroperitoneum, thereby resulting in an intense inflammatory process in which cytokines, including platelet-derived growth factor and connective tissue growth factor, have been implicated. Thus, the presence of IMF should trigger an evaluation for aortic disease. Confounding syndromes, including lymphoma, crystal-storing histiocytosis, immunocytoma, neuroblastoma, diffuse retroperitoneal carcinoma (pancreatic, scirrhous gastric, prostate, ovarian, renal, uterine cervix, carcinoid), Wegener's granulomatosis, xanthogranulomatous pyelonephritis, chronic pyelonephritis, tuberculosis, guinea worm infestation, sarcoidosis, and aortic graft infection, should be excluded by appropriate imaging, biopsy, aspiration, or serologic tests, or any combination. Secondary retroperitoneal fibrosis can be caused by drugs and toxins (methysergide, methyldopa, levodopa, ergot, bromocriptine, pergolide, asbestos, fluoropyrimidine), aortic aneurysm, malignant tumors (metastatic carcinomas, carcinoid, lymphoma), retroperitoneal injury (hemorrhage, infection, radiation, surgery, stenting, angioplasty), autoimmune disease, Erdheim-Chester disease, tuberculosis, sarcoidosis, biliary tract disease, gonorrhea, and ascending lymphangitis.

Clinical Manifestations

IMF is commonly manifested as (1) isolated retroperitoneal fibrosis; (2) retroperitoneal, mesenteric, pulmonary, and periarticular fibrosis accompanied by subcutaneous panniculitis; (3) a triad of sclerosing cholangitis, retroperitoneal fibrosis, and Riedel's thyroiditis; and (4) other less common combinations. The retroperitoneal form of IMF is typically manifested as (1) ill-defined pain in the lower part of the abdomen, lumbosacral region, or flank; (2) visceral obstruction resulting in vomiting, diarrhea, or dehydration; (3) hydronephrosis and renal insufficiency; (4) severe peripheral edema and venous varicosities; or (5) claudication, pain, dysesthesias, weakness, or spasticity resulting from nerve entrapment and epidural cord compression. Pulmonary emboli, deep venous thrombosis, and obstruction of the bowel, bladder, or bronchi can occur. Mediastinal fibrosis may result in a lymphoma-like mass and superior vena cava syndrome with edema and venous dilation of the arms, neck, and head. Extrahepatic portal vein obstruction, portal hypertension, esophageal varices, and uveitis may occur. A definitive diagnosis should be undertaken rapidly and therapy seriously considered.

Diagnosis

Computed tomography (CT), magnetic resonance imaging (MRI), and urography with appropriate contrast demonstrate a retroperitoneal inflammatory reaction; obstruction of the ureters, great vessels, biliary tree, or pancreatic ducts; or the presence of diffuse or discrete unifocal or multifocal retroperitoneal masses. Fibrosis may extend into the root of the mesentery, the bladder, and peribronchial areas and result in traction, distortion, and obstruction of the gut, urethra, and bronchi. Indium 111–labeled leukocyte and gallium radionuclide scans and 18F-fluorodeoxyglucose positron emission tomography are useful to exclude abscesses, demonstrate inflammatory processes, and monitor disease activity. The presence of autoimmune diseases, drug use, and toxin exposure should be excluded by appropriate history and serologic testing. After suspicious masses are identified, biopsy is usually essential to confirm the diagnosis and to exclude confounding conditions, especially neoplasia and infection. Biopsy may be guided by CT, ultrasound, mediastinoscopy, laparoscopy, or retroperitoneal exploration and can often be accomplished by percutaneous needle biopsy.

Treatment

All recommendations for prevention and treatment of IMF are based on relatively small series and case reports. The most important therapy or prevention of IMF is removal of the cause, most commonly an offending drug. Otherwise, treatment of IMF is largely empirical but may be necessary because the disease is often progressive and fatal. Nonsurgical therapies include high-dose oral corticosteroids, pulse methylprednisolone, penicillamine, azathioprine, cyclophosphamide, and cyclosporine, all of which have had some success. Tamoxifen has been used as primary therapy on a limited basis with some success and very little toxicity. Lifelong anticoagulation is required for patients with large vein involvement and associated deep venous thrombosis. Surgical interventions include lysis of fibrotic masses and stenting of ureteral, biliary, venous, and arterial obstructions. Surgical repair or stenting of an abdominal aortic aneurysm may be either an exacerbating or ameliorating factor for IMF; thus, therapy for aneurysm must be individualized.

Future Directions

The inflammatory and cytokine networks that are triggered by drugs, crystals, or anatomic changes associated with IMF are poorly understood and parallel those of other fibrotic diseases. Animal models of IMF need to be developed and validated. National registries and interinstitutional cooperative studies are also necessary to support basic and clinical research in this rare disease. New treatments to prevent cellular inflammation and biologic-derived therapies directed at individual cytokines may be applicable in therapy for IMF. Antilipid agents, especially the statins, may have some effect in halting the local dissemination of cholesterol crystals from atherosclerotic aortas, thus preventing IMF. New interventional modalities, including transcutaneous biopsy, retroperitoneoscopy, intravascular and intraureteral stenting, and angioplasty and arterioplasty performed together, may also be helpful in treating IMF.