Medical Care
Optimal care in patients with retroperitoneal fibrosis (RPF) requires an integrated approach of surgical and nonsurgical therapies. The aims of management are as follows:
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Preserve kidney function
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Prevent involvement of other organs
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Exclude malignancy
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Relieve symptoms
The literature reports no consensus on the appropriate management of patients with retroperitoneal fibrosis because no controlled therapeutic trials have been performed. Furthermore, successful outcome has occasionally been reported with conservative therapy. [7, 8, 12] The treatment of retroperitoneal fibrosis depends on the stage of the disease at diagnosis, as depicted in the image below.
Empirical therapy includes corticosteroids, tamoxifen, and azathioprine; experimental therapy includes rituximab, cyclophosphamide, mycophenolate mofetil, cyclosporine, medroxyprogesterone acetate, and progesterone. Glucocorticoids and azathioprine are most useful in patients with signs of inflammation (eg, raised erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP] level, increased white blood cell count, and positive antinuclear antibody [ANA] results).
Corticosteroids
In 1958, Ross and Tinckler first reported the use of corticosteroids in the treatment of retroperitoneal fibrosis. The beneficial effect is thought to be due to anti-inflammatory action and the ability to inhibit fibrotic tissue maturation.
A pooled analysis of nonmalignant retroperitoneal fibrosis treated with steroids revealed a satisfactory outcome. In 2002, van Bommel analyzed 147 patients and noted good results in 122 patients (83%) and recurrence in 55 patients (16%). Most recurrences were noted within 12 months, and some responded to reintroduction of steroid. [55] Despite their proven success, using steroids as a first-line therapy in retroperitoneal fibrosis remains controversial because many clinicians believe that multiple deep biopsies are still essential to exclude malignancy.
A standard protocol is prednisolone at 40-60 mg/d tapered to 10 mg/d within 2-3 months and discontinued after 12-24 months. Timely dose reductions and cessation are important because of the adverse effects associated with long-term steroid use.
In 1994, Harreby et al used methylprednisolone pulse therapy (MPPT) at 1 g/d IV for 3 days along with azathioprine or penicillamine. This therapy was used in 11 cases of retroperitoneal fibrosis with ureteric obstruction following initial insertion of ureteral stents. The treatment was successful in 7 patients but only moderately effective in 4 patients. The combination of glucocorticoid and azathioprine is most useful in patients with signs of inflammation (raised ESR, positive ANA, positive PET findings). [56]
Steroids can be used in combination with surgery. In one study, concomitant use of steroids with surgery reduced the rate of ureteric restenosis from 48% to 10%. [57] However, response may vary, and an unacceptably high steroid dose may be required to control retroperitoneal fibrosis.
Long-term corticosteroid treatment can cause an array of adverse effects, including the following:
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Obesity
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Cushing syndrome
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Increased susceptibility to infections
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Hypertension
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Cataracts
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Diabetes mellitus
Tamoxifen
In 1991, Clarke et al were the first to use tamoxifen, a nonsteroidal antiestrogen, in the treatment of retroperitoneal fibrosis. [58] Clinicians have subsequently reported successful treatment with tamoxifen. Various authors have used tamoxifen with a variable protocol (10-40 mg for 6 mo to 3 y). [59]
Tamoxifen's mechanism of action in this disease is not entirely clear, and different hypotheses have been proposed. Tamoxifen increases the synthesis and secretion of transforming growth factor–beta (TGF-β), an inhibitory growth factor, by human fetal fibroblast in vitro. In retroperitoneal fibrosis, fibroblast and immune cells in the inflammatory mass may increase their secretion of TGF-β, which may then decrease the size of the fibrous plaque. [60] Other possible mechanisms of action include inhibition of protein kinase C, reduction of epidermal growth factor production, inhibition of calmodulin, and blockage of growth-promoting histaminelike receptor. [61, 62]
A retrospective study by van der Bilt et al of initial treatment in 118 patients with idiopathic retroperitoneal fibrosis concluded that corticosteroids are superior to tamoxifen as monotherapy. In patients who respond to initial therapy with either medication, however, those treated with tamoxifen were less likely to experience relapse. [36]
Amelioration of symptoms after treatment initiation occurred in 2 weeks with steroids versus 4 weeks with tamoxifen (P < 0.01), and mass regression at first follow-up CT scan was observed in 84.0% of steroid-treated patients versus 68.3% of those receiving tamoxifen (P = 0.05). Recurrence rate after successful initial treatment was 62.5% with steroids versus 21.4% with tamoxifen (P < 0.01). [36]
Corticosteroids also proved superior to tamoxifen for maintaining remission of idiopathic retroperitoneal fibrosis, in a randomized, open-label, controlled trial in 40 patients (18-85 y) who had achieved remission with prednisone. Vaglio et al compared tapered prednisone (initial dose 0.5 mg/kg daily) with fixed-dose tamoxifen (0.5 mg/kg daily), both given for 8 months, and found that after 18 months, the estimated cumulative relapse probability was 17% with prednisone and 50% with tamoxifen (P=0.0372). However, cushingoid changes and grade 2 hypercholesterolemia were more common with prednisone. [63]
Compared with steroids, the adverse effect profile of tamoxifen is low; thus, clinicians consider tamoxifen a reasonable treatment option. However, the adverse effects of tamoxifen, especially an increased risk of thromboembolism and ovarian cancer, should be carefully considered for each patient.
Mycophenolate mofetil
To block the proliferation of T cells and B cells, a combination of mycophenolate mofetil (MMF) and steroid appears to be a promising option.
Swartz et al (2008) reported their experience with high-dose corticosteroid and MMF in 21 patients. They used prednisone 60 mg or 120 mg qid for 3-6 months and tapered the dose upon clinical improvement. In addition, steroid-sparing therapy with MMF (1000 mg bid) was recommended, with discontinuation after 6-12 months of therapy. [64]
Adler et al (2008) observed radiologic regression following therapy with MMF 2 g/d and prednisolone 1 mg/kg in 9 patients. Therapy led to removal of the ureteral catheter in 5 of 7 patients. Complications of MMF therapy included recurrent urinary infections and upper gastrointestinal disturbance. [65]
Scheel et al (2011) reported benefit in a prospective case series of 28 patients treated with MMF (1000 mg bid) and prednisone, 40 mg/d, tapered over 6 months, for a mean of 24.3 months. In all patients, systemic symptoms resolved, and elevated ESR and serum creatinine level and decreased hemoglobin level normalized. Periaortic mass decreased by 25% or more in 89% of patients. Disease recurred in two patients. [66]
Azathioprine
Azathioprine has been used when steroid therapy has failed and as a steroid-sparing drug. Cogan and Fastrez used a 6-week course of azathioprine (150 mg/d) in a patient whose condition recurred soon after prednisone treatment was discontinued. They observed a significant response with azathioprine. [67] McDougal and MacDonell reported successful outcome in combination with prednisolone in a 14-year-old girl. [23]
Rituximab
Rituximab, a humanized anti-CD20 monoclonal antibody, has proved useful in both idiopathic and IgG4-related retroperitoneal fibrosis. [68, 69] A retrospective study by Wallwork et al in 19 patients with IgG4-related and 7 with idiopathic retroperitoneal fibrosis reported that treatment with rituximab—as monotherapy or in combination with steroids—led to symptom resolution in all patients and radiographic improvement in the majority. Although rituximab was generally well tolerated, 3 (12%) patients experienced severe infections. [68] A review by Almeqdadi et al concluded that rituximab monotherapy can be used to induce and maintain remission in patients with IgG4-related retroperitoneal fibrosis. [69]
Medroxyprogesterone acetate
In vitro, medroxyprogesterone acetate inhibits fibroblastic proliferation. Use of progesterone and medroxyprogesterone acetate as an alternative treatment has been reported with successful outcome. [70, 71]
Treatment of diuresis
After relief of long-standing obstruction, a physiologic diuresis is expected. This is usually a self-limiting process and can be managed conservatively with fluid and electrolyte replacement.
Urea diuresis is the most common. It is self-limiting, lasting 24-48 hours. Monitoring of fluid balance and electrolytes is required. Unless otherwise contraindicated, increased oral fluid intake should suffice.
Sodium diuresis is the second most common postobstructive diuresis. It usually is self-limiting but may have a longer duration (> 72 h). Monitor fluid balance and electrolytes more aggressively (ie, intake and output [I/O], central venous pressure [CVP], urine and serum electrolytes).
Ultrasonography may be used to assess hydronephrosis.
Surgical Care
Temporizing maneuvers in the form of percutaneous nephrostomy or ureteral stenting are recommended in the presence of obstructive uropathy.
Primary management of retroperitoneal fibrosis consists of open biopsy, ureterolysis, [72] and lateral/intraperitoneal transposition or omental wrapping of the involved ureter, [73] as depicted in the image below.
Postureterolysis intravenous urogram in a patient with retroperitoneal fibrosis demonstrates lateral displacement of both ureters and a double J stent on the right side.
Open ureterolysis, although effective in 90% of patients, is associated with significant morbidity (60%) and mortality (9%) rates. [74, 75]
In recent decades, the use of laparoscopic surgery has expanded to include complex ablative and reconstructive procedures. Kavoussi first described laparoscopic ureterolysis for retroperitoneal fibrosis in 1992. [76] Since then, a few authors have reported successful laparoscopic ureterolysis with a more rapid recovery and a shorter hospital stay. Although the success rate is no better than that of open ureterolysis, the laparoscopic technique has the advantage of reducing mean hospital stay, use of analgesia, convalescence period, and morbidity. [76, 77, 78]
Styn et al compared open ureterolysis (12 patients) with laparoscopic ureterolysis (13 patients) and reported a significantly shorter hospital stay (open 5.9 d vs laparoscopic 2.1 d; P = 0.004). [79] The complication rates did not differ between the groups. The success rate was 87.5% after open ureterolysis and 93.8% after laparoscopic ureterolysis (P = 1).
More recently, with the advancement of technology, cases of endourologic treatment of retroperitoneal fibrosis via percutaneous balloon dilatation or endoscopic incision, dilatation, and permanent wall stent have been reported, with varying results. [9]
Long-term ureteral stenting is a reasonable approach in high-risk and elderly patients. Ureteral stenting may be placed on a long-term basis (months to years) in order to bypass ureteral obstruction. Short-term stenting (weeks to months) may be used as an adjunct to open surgical procedures.
Other newer innovative surgical techniques have been described, such as ureterolysis and wrapping with Gore-Tex (GSM, WL Gore & Associates, Flagstaff, Ariz), excision of the ureter and reanastomosis, posterior preperitoneal flap, and kidney autotransplantation. [10]
Consultations
Patients with kidney failure should be referred to a nephrologist early in the course of their disease and have continued nephrologic follow-up.
Complications
Possible complications include:
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Kidney failure
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Hypertension
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Scrotal edema
Long-Term Monitoring
Biochemical markers (eg, C-reactive protein, erythrocyte sedimentation rate, renal function) should be monitored every 4-8 weeks to assess the response.
Radiologic assessment (eg, CT scanning, MRI) is performed every 3 months. Once disease is stabilized, scanning can be repeated at 6 months.
Recurrence of stenosis has been reported as late as 10 years; thus, long-term follow-up is necessary.
Patients with kidney failure should be referred to a nephrologist early in the course of their disease and have continued nephrologic follow-up. Renal recovery is usually observed within the first 2 weeks, but some patients may not regain kidney function until much later.
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Intravenous urogram in a patient with retroperitoneal fibrosis shows medial deviation of the middle part of both ureters.
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Retrograde ureterogram in a patient with retroperitoneal fibrosis reveals smooth narrowing and medial shift of the ureter.
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Retroperitoneal fibrosis. Retrograde pyelogram demonstrates hydronephrosis.
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Retroperitoneal fibrosis. Contrast-enhanced CT scan demonstrates a periaortic soft tissue attenuating mass.
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Retroperitoneal fibrosis. Noncontrast CT scan shows periaortic fibrotic reaction associated with an inflammatory aortic aneurysm. Note bilateral ureteric stents.
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Management algorithm of retroperitoneal fibrosis.
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Postureterolysis intravenous urogram in a patient with retroperitoneal fibrosis demonstrates lateral displacement of both ureters and a double J stent on the right side.
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Retroperitoneal fibrosis. Retrograde pyelogram shows satisfactory positioning of a wall stent in a patient with postureterolysis obstruction.
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Retroperitoneal fibrosis. Abdominal radiograph demonstrates a wall stent on the right side.
Tables
|
Retroperitoneal Fibrosis |
Retroperitoneal Lymphoma |
Sclerosing Mesenteritis |
Desmoid-Type Fibromatosis |
Inflammatory Myofibroblastic Tumor |
Well-Differentiated Liposarcoma Sclerosing Variant |
Ureteral displacement |
Medial |
Lateral |
|
|
|
|
Ureteral obstruction |
~80% |
~50% |
Rare |
Rare |
Rare |
Unknown |
Aortic displacement |
Rare |
Anterior |
|
|
|
|
Reactive perivascular lymphoid aggregates |
100% |
Absent |
Variable |
Rare |
Variable |
Present in the inflammatory type |
Necrosis |
Absent |
Variable |
Fat necrosis |
Rare |
Focal |
Fat necrosis |
Vasculitis |
~50% |
Absent |
Absent |
Absent |
Absent |
Absent |
Clonality |
Absent |
Variable |
Absent |
Absent |
Absent |
Present |
Β-catenin |
Negative |
Unknown |
Negative |
Positive in 90% of cases |
Negative |
Variable positivity |
ALK-1 |
Negative |
Usually negative |
Negative |
Negative |
Positive in 50% of cases |
Negative |
CD-117 |
Negative in spindle cell component |
Rare |
Variable |
Negative |
Rare |
Negative |
Desmin |
Negative |
Negative |
Variable |
Rare |
Usually positive |
Rare |
S100 |
Negative |
Negative |
Negative |
Rare |
Negative |
Usually positive in the adipocytic component |
