A. Characteristics

1. Idiopathic fibrotic-inflammatory disorder affecting retroperitoneum
2. Thickened retroperitoneal fibrotic mass compressing abdominal aorta and/or iliac vessels
3. Incidence ~1:1 million annually, prevalance ~13.8 / million persons
4. Typically in persons 50-60 years old
5. Males to female ratio is ~2.5:1
6. Disease Entities
   1. Primary (idiopathic) ~70% of cases
   2. Primary form often coexists with mediastinal fibrosis, Riedel thyroiditis, sclerosing cholangitis
   3. Secondary form associated with variety of causes
7. Likely immunologically related, often with T and B cells present in lesions

B. Secondary Retroperitoneal Fibrosis

1. Drugs ( risk / odds ratio ~9X) [1,2]
   1. Serotonergic: methysergide, ergot alkyloids
   2. Dopaminergic: bromocriptine, pergolide, methyldopa
   3. Hydralazine - likely autoimmune
   4. ß-adrenergic blockers
   5. Analgesic
2. Asbestos exposure - odds ratio ~5.5X [2]
3. Periarteritis [3]
   1. Usually with aortic aneurysm
   2. Likely underlying autoimmune disease
   3. Pathology similar to giant cell and Takayatsu arteritis
4. Malignant tumors
   1. Carcinoids - likely mediated by serotonin and other neuroendocrine factors
   2. Lymphomas - Hodgkin's and non-Hodgkin's
   3. Sarcomas
   4. Adenocarcinomas: colon, prostate, breast, stomach
5. Radiation fibrosis
6. Infection - intrabdominal, gonorrhea, abscess, tuberculosis
7. Lymphangitis
8. Retroperitoneal Hemorrhage (often after invasive proceedure)
9. Connective Tissue / Autoimmune Disease - systemic sclerosis, systemic lupus
10. Granulomatous Disease - tuberculosis, sarcoidosis, Wegener's granulomatosis [4]
11. Biliary Tract Disease - including primary biliary cirrhosis, sclerosing cholangitis

C. Symptoms / Signs

1. Abdominal Pain, chronic - flank, lower abdomen, lumbosacral region
2. Systemic Symptoms: fatigue, fever, weight loss
3. Renal Dysfunction (including hypertension) - ureteral obstruction
4. Abdominal Mass - only rarely palpated (usually found on CT or MRI)
5. Leg pain / edema

D. Pathology

1. Located around abdominal aorta and iliac arteries
   1. Inferior vena cava and ureters are usually involved
   2. Usually begins at origin of renal arteries and pelvic brim
   3. Atypical localizations can occur including periduodenal, peripancreatic, pelvic, renal hilum
2. White, hard retroperitoneal plaque of varying thickness
3. Sclerotic (fibrotic) tissue infiltrated by mix of mononuclear cells
   1. Inflammatory cells include more B lymphocytes (CD20+) than T lymphocytes
   2. Macrophages, plasma cells and eosinophils are present without neutrophils
   3. Fibrotic tissue has perivascular and/or perineural disposition
   4. Granulomas uncommon
   5. Spindle-shaped, fibroblast-like cells are present

E. Evaluation and Differential Diagnosis

1. Usually seen as mass on CT or MRI evaluation
2. Primary Tumors of Retroperitoneum
   1. Sarcomas
   2. Neuroendocrine tumors - neurofibroma, ganglioneuroma, pheochromocytoma
   3. Lymphomas
   4. Diffuse retroperitoneal carcinomas (undifferentiated and metastatic)
   5. Chordomas
3. Laboratory
   1. Highly elevated ESR and/or C-reactive protein in most cases
   2. Positive anti-nuclear antibodies in ~60%
   3. Other autoantibodies such as rheumatoid factor are occasionally found
   4. In methysergide associated disease, elevated serum procollagen III was found [5]
   5. Anti-cardiolipin (ß2-glycoprotein I) may be found [5]
4. Associated Inflammatory Diseases
   1. Most commonly occurs with autoimmune thyroiditis (usually Hashnimoto's)
   2. Small and medium vessel vasculitis
   3. Ankylosing spondylitis
   4. Systemic lupus erhythematosus
   5. Rheumatoid arthritis
   6. Glomerulonephritis
   7. Primary biliary cirrhosis and sclerosing cholangitis
   8. Uveitis

F. Treatment

1. Stop offending agent and/or treat underlying condition
2. Glucocorticoids with Immunosuppressive Agents [6]
   1. Oral prednisone 1.5mg/kg/d po x 3 weeks then tapered with discontinuation at 6 months
   2. Add azathioprine 2.2mg/kg/d po x 6 months then down to 1.5mg/kg/d x 6 months OR
   3. Cyclophosphamide 2mg/kg/d po x 3 months or IV pulse 1000mg/m2 monthly x 6
   4. Mycophenolate or methotrexate have been used anecdotaly with success
   5. Early immunosuppressive therapy with periodic ureteral stenting can produce remissions
3. Tamoxifen (Nolvadex®) [7]
   1. Selective estrogen receptor modifying (SERM) agent
   2. Tamoxifen monotherapy 20mg bid po for non-malignant retroperitoneal fibrosis
   3. 15 of 19 patients with symptom resolution within 2.5 weeks
   4. Reduction in ESR and CRP
   5. CT scans and gallium-67 scans improved in nearly all responding patients
   6. Tamoxifen may be active in this disease
4. Aspirin 300mg/day has been used as well [6]
5. Uereteral stenting for obstruction

References

1. Vaglio A, Salvarani C, Buzio C. 2006. Lancet. 367(9506):
2. Uibu T, Oksa P, Auvinen A, et al. 2004. Lancet. 363(9419):1422
3. Vaglio A, Corradi D, Manenti L, et al. 2003. Am J Med. 114(6):454
4. Izzedine H, Servais A, Launay-Vacher V, Deray G. 2002. Am J Med. 113(2):165
5. Bucci JA and Manoharan A. 1997. Mayo Clin Proc. 72(12):1148 (Case Report)
6. Marcolongo R, Tavolini IM, Laveder F, et al. 2004. Am J Med. 116(3):194
7. Van Bommel E, Hendriksz TR, Huiskes AW, Zeegers AG. 2006. Ann Intern Med. 144(2):101