Retroperitoneal Fibrosis

Etiology

Approximately 70% of cases of retroperitoneal fibrosis are idiopathic. Idiopathic retroperitoneal fibrosis is considered part of the spectrum of chronic periaortitis, a large vessel vasculitis. Ceroid, a complex polymer of oxidized proteins and lipids often found in atherosclerotic plaques, has been hypothesized as an antigen that initiates the inflammatory response.[1][2]

Thirty percent of retroperitoneal fibrosis cases are a result of an identifiable cause. Numerous drugs have been implicated in the development of RPF. Drugs such as methysergide (Sansert) and other ergot alkaloids are most commonly associated with this condition. Other medications that have been implicated include beta-blockers, methyldopa, hydralazine, and analgesics. The biological agents etanercept and infliximab have also been identified as secondary causes. Malignancy (carcinoid, Hodgkin and non-Hodgkin lymphoma, sarcomas), infections (TB, histoplasmosis, actinomycosis), radiation therapy for testicular seminoma, colon, and pancreatic cancer, retroperitoneal hemorrhage, and surgery have also been identified as secondary causes of retroperitoneal fibrosis. Studies have demonstrated exposure to asbestos and tobacco smoke may result in an increased risk of RPF.[3]

Epidemiology

RPF most commonly affects patients between the ages of 40 and 60. There is a male predominance, with a male-to-female ratio estimated to be approximately 2:1 or 3:1. The true incidence is unknown but is estimated to be 1 per 200,000 to 500,000 per year.

Pathophysiology

Idiopathic retroperitoneal fibrosis is currently hypothesized to be a manifestation of a systemic autoimmune disease, which may arise as a primary aortitis that elicits a periaortic fibro-inflammatory response. The condition is frequently associated with increased acute phase reactants, autoantibodies, and known autoimmune diseases. The disease also affects other vascular segments, such as the thoracic aorta and mesenteric arteries, which supports the concept that it is a primary systemic inflammatory disease of large arteries. Ceroid, a complex polymer of oxidized lipids and protein found in atherosclerotic plaques, is hypothesized as being the antigen that initiates the inflammatory response. Histologically, there is the presence of macrophages, plasma cells, and B and T lymphocytes. Most plasma cells are positive for immunoglobulin 4 (IgG4). The presence of IgG4-producing plasma cells suggests that RPF could also manifest IgG4-related disease (IgG4-RD). This multisystem disease is characterized by tumor-like swelling of involved organs, lymphoplasmacytic infiltrate enriched in IgG4-positive plasma cells, and variable degrees of fibrosis. The exact pathophysiology of drug-induced RPF remains unclear.[3][4][5][6]

Histopathology

Pathologically, the gross appearance of RPF is that of a smooth, flat, tan-colored dense mass that encases the retroperitoneal structures, usually centered at the fourth and fifth lumbar vertebrae. It has been shown to invade the ureter or psoas muscle. Histologically, the appearance of RPF is that of a nonspecific inflammatory process. There is fibroblastic proliferation with densely hyalinized collagen and variable chronic infiltrates of IgG4-positive plasma cells and lymphocytes.[3]

History and Physical

The retroperitoneal fibrosis mass centers around the distal aorta between L4 and L5 and encases the ureters. This can lead to hydronephrosis via extrinsic compression on the ureters leading to interference with ureteral peristalsis. Presenting symptoms usually include lower back and/or flank pain. This pain is often described as dull, non-colicky, unchanged with position, and with radiation into the groin or lower abdomen. The pain is relieved with aspirin rather than narcotics. In 2 of the largest retrospective series looking at RPF, pain was present upon presentation in over 90 percent of patients.[2] Testicular pain was noted in more than 50% of male patients in 1 randomized trial of 40 patients.[7] Other possible associated symptoms include nausea, generalized malaise, anorexia, weight loss, oliguria, and anuria. In retrospective studies, fatigue and substantial weight loss were present in 60% and 54% of presenting patients, respectively. The inferior vena cava can also be obstructed due to extrinsic compression from the mass, leading to deep venous thrombosis and lower extremity edema. Patients may also describe upper-leg claudication related to arterial compromise of the lower extremities or symptoms of mesenteric ischemia due to compression of mesenteric arteries.[3][2][8][2][8]

On physical exam, CVA tenderness to percussion is often present. Patients may have hypertension due to renal artery impingement. One study found hypertension present in 57% of patients on presentation. Lower extremity edema or evidence of thrombophlebitis or DVT may be present. A hydrocele may be evident on the genitourinary exam, as well as testicular tenderness.

Evaluation

Retroperitoneal fibrosis is often discovered incidentally in the workup of urinary tract obstruction or venous/arterial insufficiency. Imaging studies, including CT and MRIs, often make the diagnosis. A definitive diagnosis requires a tissue biopsy, though it is controversial whether a biopsy is necessary for patients with imaging studies demonstrating findings characteristic of RPF.

Typically, initial evaluation of the patient a laboratory workup is obtained, as well as an initial renal ultrasound, if the patient is presenting with complaints of flank pain. Laboratory findings can be varied, and no hematologic or biochemical abnormality is specific to RPF. Often an elevation in creatinine concentration and blood urea nitrogen is found, depending on the presence and extent of ureteral obstruction. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are elevated in one-half to two-thirds of RPF patients. Anemia can also be observed, likely related to renal insufficiency and chronic inflammation. Renal ultrasound often reveals a poorly marginated, periaortic mass that is typically hypoechoic and may be associated with hydronephrosis.[3]

A contrast-enhanced CT scan is the exam of choice to visualize the extent of RPF and the presence of lymphadenopathy and tumor. On non-enhanced CT, RPF exhibits the same attenuation numbers as the psoas muscle (1-25 Hounsfield units). After intravenous contrast administration, enhancement depends on the stage of the disease. Avid enhancement is often seen in the early stages of the disease, whereas in the late and inactive stages, there may be little or no enhancement. The mass is typically confluent, encasing the anterior and lateral sides of the aorta, often encircling and compressing the IVC. Typical findings also include hydronephrosis and medial deviation of the proximal ureter and mid-ureter and a smoothly tapered ureter at the level of the obstruction. One benefit of CT is it enables CT-guided biopsy to obtain tissue for pathologic diagnosis.[8][9][10]

MRI is considered equivalent to CT in diagnosing and monitoring RPF but has a higher contrast resolution. It is helpful as the mass has characteristic T1- and T2-weighted images. RPF is characterized by diffusely low signal intensity on T1-weighted imaging, although the T2 signal may vary considerably, with high signal intensity consistent with the active disease. With treatment, the T2 signal often diminishes and provides a measure of therapeutic efficacy. Gadolinium enhancement may also be valuable in assessing response to treatment. Associated decreases in gadolinium contrast enhancement should be expected after appropriate therapy.[9][2]

The role of biopsy is controversial. If surgical intervention is planned for the treatment of compression of ureters and/or IVC, an open biopsy of the mass is recommended. A CT-guided biopsy can be obtained during the initial workup prior to any treatment as well. Expert consensus suggests a biopsy of the mass in certain scenarios. These cases include:

• When the location of the mass is atypical 
• When clinical and laboratory findings suggest the presence of an underlying infection or malignancy 
• Bulky appearance on imaging studies; extension above the origin of the renal arteries or anterior displacement of the aorta 
• Local experience with RPF is limited
• Lack of response to initial therapy

The pathological findings in idiopathic and secondary RPF are often indistinguishable. Microscopically, the fibrous tissue is comprised of an extracellular matrix composed of type-1 collagen fibers organized in thick irregular bundles, often encircling small vessels. The infiltrate comprises macrophages, plasma cells, and B and T lymphocytes. The aggregates usually have a core rich in CD20+ B cells and a periphery rich in CD3+ T cells. Most plasma cells are positive for immunoglobulin G4 (IgG4).[11]

Treatment / Management

Initial Management

Initial management of RPF depends on the patient’s clinical status. Patients with signs of ureteral compression with hydronephrosis and uremia require emergent decompression by either a percutaneous nephrostomy tube or indwelling ureteral stents. Ureteral stent placement is usually not difficult in the setting of ureteral obstruction caused by RPF. The advantage of ureteral stent placement is the opportunity for retrograde pyelograms at the time of the procedure to evaluate the anatomy. In critically ill patients with electrolyte abnormalities and little or no urine output, nephrostomy tube placement is favored.

After renal decompression, the patient must be monitored closely for post-obstructive diuresis, renal function status, and appropriate replacement of fluids and electrolytes. Post-obstructive diuresis is a prominent polyuria that occurs after relieving complete obstruction of the urinary system (exceeding more than 200 mL per hour). Patients are at risk for severe dehydration, electrolyte imbalances, and hypovolemic shock. The condition usually lasts less than 48 hours. Treatment includes close monitoring of serum BUN, creatinine and electrolytes, and fluid replacement. Oral replacement is preferred, but if the patient cannot tolerate oral liquids or keep up with the loss, one-half of normal saline replaces half of the fluid loss (500 mL for every 1 L lost). After initial management, it is necessary to identify the potential cause of RPF. Any potential inciting drug should be discontinued immediately.

Medical Treatment

Once a diagnosis of RPF is made, whether by radiologic findings or biopsy-proven, the common primary medical management has been steroid therapy. The medical literature describes an 80% response rate when treating RPF with steroids alone. This includes resolution of pain and constitutional symptoms within days after initiation of treatment, rapid decline in ESR, and diuresis. Dosages and duration of steroid therapy vary considerably, but most regimens start with an initial dose of 60 mg daily tapered to 5 mg daily. One expert consensus recommends treating with prednisone 1 mg/kg per day for approximately 4 weeks. If improvement is observed, the dose is tapered over months to 10 mg/day and maintained for 6 to 18 months. Chronic steroid therapy for up to 2 years has been shown to provide a significant improvement in clinical symptoms and regression of retroperitoneal mass. Failure to detect clinical or radiologic improvement within 4 to 6 weeks of initiation of therapy should prompt reevaluation with a CT scan and a biopsy to determine if the diagnosis of RPF is correct. If it is confirmed that the disease is RPF, other agents can be used concurrently with steroids. These agents include azathioprine, methotrexate, mycophenolate mofetil, cyclophosphamide, and cyclosporine. Medroxyprogesterone acetate, progesterone, and tamoxifen have also been beneficial in treating RPF.[12][13][14] The use of immunosuppressive agents is reserved for when steroid therapy fails, as relapse rates have been documented as high as 50% during steroid tapering.[15][16][17][18](A1)

Monitoring a patient’s response to therapy requires close follow-up. The patient should be evaluated clinically within 1 month of initiating treatment for resolution of pain and resolution of urinary obstruction. After that, the patient should be monitored clinically every 2 to 3 months. Clinicians should obtain ESR, CRP, serum creatinine, and BUN monthly for the first 3 months, then every 2 to 3 months. A CT scan should be obtained 1 month after initiating therapy, then approximately every 3 months to follow the size of the fibrotic mass. Following discontinuation of medical therapy, it is recommended to monitor for disease relapse by obtaining a renal ultrasound, ESR, CRP, serum creatinine concentration every 3 to 6 months, and CT every 6 months for the first year, then laboratory testing every 6 to 12 months and CT every 1 to 2 years. Surveillance should be continued indefinitely.

Surgical Treatment

Surgical management is reserved for the following scenarios: 

• Technical difficulties or complications with other cystoscopic or endoscopic obstruction-relieving maneuvers
• Lack of regression of mass after medical therapy, with persistent encasement of ureters and other structures
• Findings to suggest underlying malignancy to obtain a definitive diagnosis

Surgical management can be approached with an open, laparoscopic, or robotic exploration and entails ureterolysis and manipulation of the ureters to prevent recurrent obstruction. Methods employed to prevent recurrent ureteral obstruction include wrapping the ureters with omental fat to serve as a barrier to prevent encasement by fibrous tissue and promote revascularization, transplantation of ureters to an intraperitoneal position, or transposition of the ureters laterally, with interposition of retroperitoneal fat between ureters and fibrous tissue.[19][20][21][22](B2)

Differential Diagnosis

The differential diagnoses for retroperitoneal fibrosis include the following:

• Retroperitoneal lymphoma: Retroperitoneal fibrosis is centered at the L4 to L5 level. If imaging studies show mass centered more cephalad to L4 to L5, consider possible lymphoma diagnosis.
• Retroperitoneal Erdheim-Chester disease: This is a rare non-Langerhans cell, non-familial multisystemic granulomatosis with widespread manifestations and variable severity that can sometimes present with involvement of retroperitoneum and hydronephrosis. Most commonly affects the bones and presents with bone pain.

Prognosis

Often, within a few days of initiating treatment, the patient's symptoms begin to improve. After several weeks CT imaging may demonstrate resolution of the mass. Full resolution of all associated manifestations depends on the degree of severity of the disease and the degree of entrapment of retroperitoneal structures. If medical management is not effective in treating the mass, surgical therapy can effectively remove the fibrotic tissue and protect the ureters.