Causes of Retroperitoneal Fibrosis
Primary Classification
Retroperitoneal fibrosis is idiopathic in approximately two-thirds to three-quarters of cases, with the remaining cases secondary to malignancies, infections, medications (particularly ergot derivatives), radiotherapy, or autoimmune/inflammatory conditions. 1, 2
Idiopathic Retroperitoneal Fibrosis
Idiopathic RPF accounts for 70-75% of all cases and represents an immune-mediated fibro-inflammatory disease originating around the abdominal aorta and iliac arteries. 1, 3
This form is part of the chronic periaortitis spectrum, which includes inflammatory abdominal aortic aneurysm and perianeurysmal retroperitoneal fibrosis, all sharing similar fibro-inflammatory pathology. 4, 5
IgG4-related disease represents a significant subset of idiopathic RPF, with many cases previously labeled as "idiopathic" now recognized as manifestations of IgG4-related systemic disease. 6, 2, 3
Risk factors for idiopathic RPF include occupational asbestos exposure and tobacco smoking, both of which should be assessed in the patient history. 3
Medication-Induced Causes
Ergot-derived medications, particularly methysergide, are well-established causes of RPF, with retroperitoneal and retropleural fibrosis reported after long-term, mostly uninterrupted administration. 6
The manufacturer recommends discontinuing methysergide for 3-4 weeks after each 6-month treatment course to reduce fibrosis risk. 6
Other medications implicated include cyclophosphamide and ketamine, though the evidence base is more limited. 6
Malignancy-Related Causes
Secondary malignant RPF occurs from direct tumor invasion, desmoplastic reaction to tumor, or metastatic disease affecting the retroperitoneum. 1, 4
Lymphoma, sarcoma, and metastatic carcinomas (particularly gastrointestinal, genitourinary, and breast primaries) are the most common malignant causes requiring exclusion. 1
Biopsy and histopathological evaluation are necessary to differentiate malignant from idiopathic RPF, as therapeutic approaches differ dramatically. 1, 4
Infectious Causes
- Tuberculosis, histoplasmosis, and actinomycosis are rare infectious causes of secondary RPF that must be considered, particularly in endemic regions or immunocompromised patients. 1, 4
Radiation-Induced Fibrosis
Prior abdominal or pelvic radiation therapy can cause retroperitoneal fibrosis months to years after exposure, typically following doses exceeding 45 Gy. 6
Radiation-induced RPF shares pathophysiology with radiation enteropathy, affecting gut permeability, secretion, motility, and blood supply. 6
Autoimmune and Inflammatory Associations
RPF may occur with systemic autoimmune diseases including systemic sclerosis, Sjögren's syndrome, rheumatoid arthritis, and sarcoidosis, though these associations are uncommon. 6
Primary sclerosing cholangitis has a recognized association with retroperitoneal fibrosis, and this connection may relate to IgG4-related disease misdiagnosed as PSC. 6
Takayasu's arteritis and other large-vessel vasculitides can produce external compression mimicking or coexisting with RPF. 6
Rare Histiocytic Disorders
- Erdheim-Chester disease and Rosai-Dorfman-Destombes disease are rare histiocytic disorders that can manifest with retroperitoneal fibrosis. 6, 1
Clinical Subtypes Requiring Different Approaches
Vascular Subtype
- Characterized by nondilated aorta or inflammatory abdominal aortic aneurysm with numerous atherosclerosis risk factors, this subtype requires vascular surgery evaluation. 4
Renoureteral Subtype
- Dominated by obstructive uropathy with hydronephrosis and acute kidney injury, this presentation requires urgent urological intervention with stenting or nephrostomy placement. 4
Key Diagnostic Pitfalls
The differential diagnosis between idiopathic and secondary RPF is crucial because therapeutic approaches differ dramatically—idiopathic RPF responds to immunosuppression while secondary forms require treatment of the underlying cause. 1
IgG4-related RPF may be misdiagnosed as purely idiopathic, so serum IgG4 levels and tissue IgG4+ plasma cell infiltration should be assessed. 6, 2, 3
Malignancy must be excluded through biopsy in atypical presentations, particularly in older patients, those with constitutional symptoms, or when imaging shows irregular or asymmetric soft tissue. 1, 4
Periaortitis detected on imaging should prompt early treatment to prevent progression to full RPF with ureteral obstruction and renal failure. 5