Retroperitoneal Fibrosis 

Updated: Sep 02, 2021
Author: Chandra Shekhar Biyani, MS, MBBS, DUrol, FRCS(Urol), FEBU; Chief Editor: Bradley Fields Schwartz, DO, FACS 

Overview

Practice Essentials

Retroperitoneal fibrosis (RPF) is characterized by the development of extensive fibrosis throughout the retroperitoneum, typically centered over the anterior surface of the fourth and fifth lumbar vertebrae and resulting in entrapment and obstruction of retroperitoneal structures, notably the ureters. See the image below.

Intravenous urogram shows medial deviation of the Intravenous urogram shows medial deviation of the middle part of both ureters.

Signs and symptoms

The symptoms and signs associated with RPF are nonspecific, including the following:

  • Dull, poorly localized, noncolicky pain in the flank, back, scrotum, or lower abdomen [1] : Present in 92% of cases; in children, pain may be referred to the ipsilateral hip or gluteal region, resulting in resistance to hip extension [2]
  • Fever
  • Lower-extremity edema
  • Phlebitis
  • Deep venous thrombosis
  • Weight loss, nausea, vomiting, anorexia, and malaise: Uncommon presentations
  • Raynaud phenomenon, ureteric colic, hematuria, claudication, and urinary frequency: Rare manifestations

RPF can also be associated with Crohn disease, ulcerative colitis, and sclerosing cholangitis.

See Presentation for more detail.

Diagnosis

The diagnosis of RPF requires a high degree of suspicion, and the evaluation of patients with presumed idiopathic RPF includes ruling out secondary RPF due to malignancy, infection, retroperitoneal injury, or drugs.

Examination in patients with retroperitoneal fibrosis includes the following findings:

  • Hypertension: Present in approximately 50% of affected individuals with RPF
  • Presence of an abdominal mass (occasionally)
  • Obstruction of the ureters, with varying degree of abnormal kidney function: Earliest and most common organ involvement

Uncommon physical findings due to late complications include the following:

  • Ascites
  • Peripheral edema or thrombosis
  • Hydrocele
  • Jaundice
  • Small- or large-bowel obstruction
  • Spinal cord compression

Testing

Laboratory studies and potential results for patients with suspected RPF include the following:

  • Erythrocyte sedimentation rate level: Elevated
  • C-reactive protein level: Elevated
  • Urea and creatinine levels: Elevated
  • Complete blood count: Normocytic normochromic anemia
  • Alkaline phosphatase levels (also reported as a marker [3] )
  • Antinuclear antibody levels (present in 60% of cases) [4]
  • Urinalysis: Usually normal; rarely, microscopic hematuria or pyuria is seen
  • Plasma electrophoresis: Polyclonal hypergammaglobulinemia

Imaging tests

The following imaging studies may be used to evaluate RPF:

  • Plain chest and abdominal radiography
  • Intravenous urography
  • Retrograde pyelography
  • Lymphangiography
  • Kidney ultrasonography
  • Abdominal CT scanning: Most frequently used imaging method for diagnosis and follow-up of RPF
  • Abdominal MRI
  • Positron emission tomography

Procedures

Biopsy and histologic/immunohistochemical examination of the affected tissue can aid in the diagnosis and determination of the extent of the disease, which in turn affect treatment management strategies. Open biopsy can ensure a definite histologic diagnosis, but it is associated with significant morbidity. Laparoscopic biopsy is safe, minimally invasive, cost-effective, and useful in making therapeutic decisions for retroperitoneal masses.

See Workup for more detail.

Management

There is currently no consensus on the appropriate management of patients with RPF, because no controlled therapeutic trials have been performed, and conservative therapy has occasionally yielded successful outcomes.[5, 6]

Optimal care in patients with RPF requires an integrated approach of surgical and nonsurgical therapies, and depends on the stage of the disease at diagnosis. The aims of management include the following:

  • Preserve kidney function
  • Prevent other organ involvement
  • Exclude malignancy
  • Relieve symptoms

Surgical option

Surgical ureterolysis has been the preferred primary mode of treatment for RPF, because it allows biopsy specimens to be obtained while ureteral obstruction is relieved. Thus, primary management of RPF consists of open biopsy, ureterolysis, and lateral/intraperitoneal transposition or omental wrapping of the involved ureter.

Other surgical interventions that may be involved in RPF include the following:

  • Temporizing maneuvers in the form of percutaneous nephrostomy or ureteral stenting: Recommended in the presence of obstructive uropathy

  • Laparoscopic surgery: Includes complex ablative and reconstructive procedures

  • Endourologic treatment via percutaneous balloon dilatation or endoscopic incision, dilatation, and permanent wall stent[7]

  • Long-term ureteral stenting: Reasonable approach in high-risk and elderly patients to bypass ureteral obstruction

  • Short-term ureteral stenting: Adjunct to open surgical procedures

  • Relatively newer innovative surgical techniques: Ureterolysis and wrapping with Gore-Tex, excision of the ureter and reanastomosis, posterior preperitoneal flap, and kidney autotransplantation[8]

Pharmacotherapy

Medications used in the management of RPF include the following:

  • Glucocorticoids (eg, prednisolone, prednisone)
  • Immunosuppressive agents (eg, mycophenolate, azathioprine)
  • Estrogen receptor antagonists (eg, tamoxifen)
  • Rituximab

Empirical therapy includes corticosteroids, tamoxifen, and azathioprine. The possibility of autoallergic etiology prompted the use of corticosteroids and cytotoxic drugs in managing RPF. Glucocorticoids and azathioprine are most useful in patients with signs of inflammation.

See Treatment and Medication for more detail.

Background

Retroperitoneal fibrosis (RPF) is characterized by the development of extensive fibrosis throughout the retroperitoneum, typically centered over the anterior surface of the fourth and fifth lumbar vertebrae. This fibrosis leads to entrapment and obstruction of retroperitoneal structures, notably the ureters. In most cases, the etiology is unknown. However, its occasional association with autoimmune diseases and its response to corticosteroids and immunosuppressive therapy suggest it is probably immunologically mediated.[9, 10] Approximately 8% of cases are associated with metastatic malignancy.[11]

The symptoms and signs associated with retroperitoneal fibrosis are nonspecific, and diagnosis requires a high degree of suspicion. Although a definitive diagnosis can only be made based on biopsy findings, intravenous urography may provide further support for the diagnosis of retroperitoneal fibrosis, particularly if the classic features are present. CT scanning or MRI is essential for evaluating the extent of the disease process.

The aims in management of retroperitoneal fibrosis include preserving kidney function, reducing the morbidity, and suppressing inflammatory processes. Although most cases are idiopathic, precipitating causes should be excluded, particularly malignancy. Surgical ureterolysis has been the preferred primary mode of treatment because it allows biopsy specimens to be obtained while ureteral obstruction is relieved. The knowledge of a possible autoallergic etiology has prompted the use of corticosteroids and cytotoxic drugs.

Pathophysiology

Anatomy of the retroperitoneum

The retroperitoneal space is bordered anteriorly by the posterior parietal peritoneum, posteriorly by the transversalis fascia, and superiorly by the diaphragm. Inferiorly, it extends to the level of pelvic brim. The anterior and posterior layers of renal fascia (Gerota fascia) subdivide the retroperitoneal space on either side of the spine into 3 compartments. The posterior space contains the pararenal fat. The intermediate space contains the kidney, the adrenal gland, and the perirenal fat. The anterior space is more extensive.

The anterior pararenal space is bordered anteriorly by the posterior parietal peritoneum, posteriorly by the anterior layer of renal fascia, and laterally by the lateral conal fascia. The anterior pararenal space contains the extraperitoneal portions of the ascending and descending colon, the duodenum, and the pancreas. The anterior pararenal space is continuous across the midline; however, collections of fluid tend to remain ipsilateral to the site of origin. Medially, the anterior layer of renal fascia blends with the connective tissue around the aorta and the inferior vena cava. The posterior layer fuses with the psoas fascia. Laterally, both layers merge to form lateral conal fascia.

Pathogenesis

Although the exact pathogenesis of retroperitoneal fibrosis has not been definitively described, good evidence supports the suggestion that it develops as an immunologic response to antigens within atherosclerotic plaques. Autopsy and CT studies have shown that fibrosis often begins around a severely atherosclerotic aorta. Thinning or breaching of the media may allow insoluble lipids, such as ceroid, an oxidized low-density lipoprotein, to leak into periaortic tissue, stimulating an immunologic reaction. This theory is supported by the presence of circulating anticeroid antibodies and the finding of ceroid-containing macrophages in nearby lymph nodes.

For this reason, Mitchinson suggested in a 1984 report that the condition should be termed chronic periaortitis.[12] The frequent association of retroperitoneal fibrosis with aortic aneurysm and the regression of fibrosis reported following aneurysm repair further supports this theory.[13] However, the occurrence of retroperitoneal fibrosis in children and those without an aneurysm suggests that other factors must be involved.

In some cases, an immune reaction to an external agent may initiate fibrosis. Drugs such as beta-blockers, methysergide, and methyldopa have been implicated, possibly by acting as haptens, leading to a hypersensitivity or autoimmune reaction.[14] The fibrous reaction associated with carcinoid tumor is believed to be the result of circulating serotonin or its metabolites. Methysergide is a strong serotonin antagonist, and the rebound release of serotonin following prolonged intake may be an alternate mechanism in this case.

The association of retroperitoneal fibrosis with other connective-tissue diseases and reported familial occurrences suggest that genetic factors may also play a role.[15] The human leukocyte antigen (HLA)–B27 cell marker has been demonstrated in several patients with retroperitoneal fibrosis.[16]

Retroperitoneal fibrosis can be a presentation of immunoglobulin G4 (IgG4)–related disease, an insidiously progressive immune-mediated fibro-inflammatory condition typified by formation of tumor-like masses in any of several organs, including the salivary glands, lacrimal glands/orbit, lymph nodes, and pancreas.[17, 18] The etiology is unknown but increasing evidence supports an autoimmune basis, with IgG4 generated in response to autoantigens; the IgG4 antibody itself is not thought to be pathogenic. IgG4-related disease has a 2:1 male preponderance, and the median age of affected patients at diagnosis is in the sixth to seventh decade of life.[18]

A study in a large Chinese cohort found that, compared with idiopathic retroperitoneal fibrosis, the features significantly more likeliy to be found in IgG4-related retroperitoneal fibrosis include the following[19] :

  • Involvement of other organs (eg, lymph nodes, salivary glands) in most patients
  • Elevated C-reactive protein (CRP) level
  • High serum IgG4 concentration
  • High serum IgE concentration
  • Eosinophilia
  • Reduced serum C4 concentration

A 2004 case-control study concluded that occupational exposure to asbestos increases the risk of retroperitoneal fibrosis. Other environmental risk factors identified were use of ergot derivates and smoking for more than 20 pack-years.[20]

Ureteral obstruction in retroperitoneal fibrosis often appears minimal despite severe kidney failure. This suggests that the obstruction relates to impairment of normal ureteric peristalsis by fibrotic tissue rather than to mechanical obstruction.

Frequency

International

Retroperitoneal fibrosis is a relatively uncommon disease. The estimated annual incidence varies from 1 per 200,000-500,000 population.[21, 22]

Mortality/Morbidity

Because of the nonspecific nature of the symptoms, the diagnosis of retroperitoneal fibrosis is often delayed. This may lead to progressive loss of renal function.

Envelopment of the inferior vena cava and lymphatics may result in compression or thrombosis and leads to lower-limb edema. In addition, involvement of gonadal vessels may cause scrotal edema. Occasionally, the duodenum, biliary tract, pancreas, large bowel, and mesentery are involved.[23, 24]

Malignant retroperitoneal fibrosis is associated with poor prognosis, and most patients have an average survival of approximately 3-6 months.[25] Idiopathic retroperitoneal fibrosis carries a good prognosis, with little effect on long-term morbidity or mortality.

Race-, Sex-, and Age-related Demographics

Retroperitoneal fibrosis has no reported racial predilection. The condition occurs twice as commonly in males as in females. The peak incidence of retroperitoneal fibrosis is in adults aged 40-60 years.[11, 26] Childhood presentation is extremely rare. To date, approximately 33 cases in children younger than 18 years have been reported.[27]

 

Presentation

History and Physical Examination

The symptoms and signs associated with retroperitoneal fibrosis are nonspecific. Pain, often accompanied by significant weight loss, constipation, and constitutional symptoms, is a common presenting symptom.[28] Pain is present in 92% of cases; it is typically in the flank, back, scrotum, or lower abdomen and is dull, poorly localized, and noncolicky.[1] in children, pain may be referred to the ipsilateral hip or gluteal region, resulting in resistance to hip extension.[2]

Other manifestations may include the following:

  • Fever
  • Lower-extremity edema
  • Phlebitis
  • Deep venous thrombosis
  • Nausea, vomiting, anorexia, and malaise are uncommon
  • Raynaud phenomenon, ureteric colic, hematuria, claudication, and urinary frequency occur rarely

Retroperitoneal fibrosis can also be associated with Crohn disease, ulcerative colitis, and sclerosing cholangitis.

 

DDx

Diagnostic Considerations

In the evaluation of patients with presumed idiopathic retroperitoneal fibrosis (RPF), exclude secondary retroperitoneal fibrosis due to malignancy, infection, retroperitoneal injury, or drugs.

Retroperitoneal fibrosis can be a feature of Erdheim-Chester disease, a rare form of histiocytosis that is often characterized by symmetric osteosclerosis but may also manifest as diabetes insipidus, exophthalmos, xanthelasmas, cardiovascular involvement, bilateral adrenal enlargement, renal impairment, testis infiltration, or interstitial lung disease. Affected tissues demonstrate xanthomatous infiltration by foamy histiocytes, surrounded by fibrosis.[29]

 

Workup

Laboratory Studies

Blood study results in patients with retroperitoneal fibrosis may include the following:

  • Elevated erythrocyte sedimentation rate (ESR)
  • Raised C-reactive protein (CRP) level
  • Raised urea and creatinine levels (50%-75%)
  • Normocytic normochromic anemia
  • Polyclonal hypergammaglobulinemia
  • Raised alkaline phosphatase level (has also been reported as a marker [3] )
  • Antinuclear antibodies (ANA; present in 60% of cases) [4]

Urinalysis results are usually normal. Rarely, microscopic hematuria or pyuria is observed.

Imaging Studies

Computed tomography (CT) scanning is the most frequently used imaging method for diagnosis and follow-up of retroperitoneal fibrosis. However, a number of other imaging methods can provide useful information. For example, positron emission tomography/magnetic resonance imaging (PET/MRI) has potential advantage for imaging small lesions, while offering reduced radiation exposure.[30] For complete discussion, see Retroperitoneal Fibrosis Imaging.

Plain radiography

Findings are nonspecific and usually due to the late complications. Abdominal films may show obliteration of the psoas shadow and an enlarged renal outline due to hydronephrosis. Features of ankylosing spondylitis or metastasis may also be visible.

Chest radiography may demonstrate pulmonary edema or fibrosis. Mediastinal widening may result from a soft-tissue mass associated with mediastinal fibrosis.

Intravenous urography

The classic triad consists of the following[1, 31] :

  • Delay of contrast material with unilateral (20%) or bilateral (68%) hydronephrosis

  • Medial deviation of the middle third of the ureters (see the image below)

  • Tapering of the ureter at the level of L4/L5 vertebrae

Up to 18%-20% of control subjects may show this triad.[32]

Intravenous urogram shows medial deviation of the Intravenous urogram shows medial deviation of the middle part of both ureters.

Medial deviation of the ureter may result from retroperitoneal neoplasm, aneurysm, and bladder diverticulum.

Retrograde pyelography

Retrograde pyelography may show features similar to those described above. In addition, it may demonstrate poor distensibility of the ureters, as depicted in the images below.

Retrograde ureterogram reveals smooth narrowing an Retrograde ureterogram reveals smooth narrowing and medial shift of the ureter.
Retrograde pyelogram demonstrates hydronephrosis. Retrograde pyelogram demonstrates hydronephrosis.

Retrograde pyelography delineates the pelvic calyceal anatomy and is usually performed prior to insertion of the stent to decompress the kidneys.

Interestingly, very little resistance is encountered during ureteric catheterization despite the extensive extrinsic fibrosis.

Lymphangiography

The retroperitoneal lymphatics are delicate and fine structures; therefore, they are more easily compressed by retroperitoneal fibrosis than by the adjacent blood vessels and ureters. Thus, lymphatic obstruction should precede ureteric compression.

Lymphangiography may show obstruction of lymphatic flow at L3/L4 level, opacification of collateral channels, nonvisualization of lymphatics above the L4 vertebra, and delay in passage of contrast through the iliac and para-aortic lymphatics.[33]

Ultrasonography

Ultrasonography is a simple noninvasive modality used to assess response to therapy. Findings may include the following:

  • On a sonogram, retroperitoneal fibrosis appears as a retroperitoneal, extensive, well-defined, hypoechoic mass centered over the sacral promontory.

  • The degree of hydronephrosis and hydroureter may vary.

  • Doppler ultrasonography has no role in differentiating benign from malignant retroperitoneal fibrosis.[34]

CT scanning

On unenhanced CT scans, retroperitoneal fibrosis appears as a plaque that is isodense with muscle and that envelops the aorta and inferior vena cava between the renal hila and sacral promontory and usually extends laterally to incorporate the ureters. Obliteration of the fat plane between the mass and the psoas muscle may be observed, as depicted in the images below.

Contrast-enhanced CT scan demonstrates a periaorti Contrast-enhanced CT scan demonstrates a periaortic soft tissue attenuating mass.
Noncontrast CT scan shows periaortic fibrotic reac Noncontrast CT scan shows periaortic fibrotic reaction associated with an inflammatory aortic aneurysm. Note bilateral ureteric stents.

Retroperitoneal hemorrhage, primary retroperitoneal sarcoma, metastatic deposits to the retroperitoneum, and retroperitoneal amyloidosis may show similar findings on CT scans. CT scan features that suggest malignant pathology include lateral displacement of the ureter, anterior displacement of the aorta, local bone destruction, and a large bulky lesion.

Elevation of the aorta from the spine is uncommon in benign retroperitoneal fibrosis. If present, it may be a sign of malignancy.[35]

After contrast injection, the plaque may show a variable degree of enhancement, depending on the stage of the disease. Enhancement is usually significant in the early active vascular stage. On the other hand, enhancement is poor in the late vascular stage.

Magnetic resonance imaging

Both benign and malignant retroperitoneal fibrosis have low-to-intermediate signal density on T1-weighted images and density on T2-weighted images that varies based on the disease stage. During the early stage, signal density is high because of high fluid content and hypercellularity. In contrast, late-stage disease has low T2 signal intensity as a result of avascular acellular fibrosis and decreased fluid content.[36] Steroid therapy may lead to similar changes because of decreased tissue edema.

Inhomogeneity of signal intensity on T2-weighted images may suggest malignancy; however, differentiation between benign and malignant retroperitoneal fibrosis on MRI is difficult, and biopsy is usually required to confirm the diagnosis.[25]

One study assessed delayed gadolinium enhancement ratios by comparing retroperitoneal fibrosis enhancement with that of psoas muscle. The dynamic enhancement ratio in acute retroperitoneal fibrosis significantly differed from the ratio in chronic retroperitoneal fibrosis. Dynamic gadolinium enhancement may be useful in differentiating newly diagnosed retroperitoneal fibrosis from treated chronic disease and may have a role in assessing disease activity, monitoring response to treatment, and detecting relapse.[37]

MRI has some advantages over CT scanning, including multiplanar capability, independence of renal function, and absence of radiation.

Positron emission tomography

Positron emission tomography (PET) scanning with 18F-fluorodeoxyglucose (18F-FDG) is a functional imaging modality that has proved useful in the evaluation of retroperitoneal fibrosis. 18F-FDG identifies areas of high glucose metabolic activity. Because inflammatory cells have an increased glucose uptake, high levels of glucose metabolism are seen in a retroperitoneal mass associated with retroperitoneal fibrosis if inflammation is present.

However, uptake of 18F-FDG by retroperitoneal fibrosis tends be lower than that by malignancy. A study of 18F-FDG PET/CT by Wang et al found that lesions of idiopathic retroperitoneal fibrosis displayed a lower frequency of high 18F-FDG uptake than retroperitoneal malignancies (P = 0.017) and a lower mean maximum standardized uptake value (SUVmax).[38]

No noninvasive method can reliably assess disease activity. However, 18F-FDG may be more reliable than acute phase reactants (ie, ESR, CRP) for monitoring the course of retroperitoneal fibrosis and response to therapy.[39, 40]  In addition, it can reveal other sites of disease (eg, thyroid, thorax) and may help to identify the most appropriate sites for retroperitoneal biopsy.

Histologic Findings

In 1948, Ormond described two histologic features in retroperitoneal fibrosis: an inflammatory early stage and a chronic stage.[41] In the early stage, an inflammatory infiltrate contains macrophages, lymphocytes, plasma cells, and occasional eosinophils; neutrophils are generally absent. The macrophages are often lipid-laden and contain areas of perivascular lymphocytic infiltrate composed of T cells and B cells. Generally, tissue is highly vascular with numerous small blood vessels throughout. In the chronic stage, the tissue becomes avascular and acellular with scattered calcification and progresses to fibrous scarring.[42] Occasionally, surrounding structures are invaded by retroperitoneal fibrosis. Invasion of the large veins may cause fibrous thickening of the intima, resulting in complete occlusion. Periaortic lymphatics may be blocked within the mass. Submucosal edema and lymphocytic infiltration may be observed in the ureter.

Corradi et al (2007) recently reported the presence of CD20 and CD3 cells, IgG4 plasma cells, and subtle vasculitic activity in idiopathic retroperitoneal fibrosis.[43]

Malignant retroperitoneal fibrosis demonstrates the presence of scattered nests of malignant cells within the inflammatory infiltrate. Hodgkin disease and sclerosing retroperitoneal lymphomas are the most challenging differential diagnoses for the pathologist to exclude. In 2002, Wu et al recommended the use of immunostains such as c-Kit, Leu-M1, Ki-1, LCA, and kappa and lambda light chain.[44]

Table. Differential Diagnoses of Retroperitoneal Fibrosis [43] (Open Table in a new window)

 

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

Biopsy

A wide spectrum of fibroinflammatory disorders can mimic retroperitoneal fibrosis on imaging. Management strategies are diverse and depend strongly on the histological diagnosis and extent of the disease. Histology and immunohistochemistry are required to confirm the diagnosis.

The amount of tissue harvested via core needle biopsy may not be sufficient for the histological diagnosis. Therefore, open biopsy can ensure a definite histological diagnosis and is traditionally performed. However, it is associated with significant morbidity. Laparoscopic biopsy is safe, minimally invasive, cost-effective, and useful in making therapeutic decisions for retroperitoneal masses.

Tissue for histologic diagnosis can be obtained under CT or ultrasonographic guidance. In a 1999 publication, Dash et al described fine-needle aspiration for the diagnosis of retroperitoneal fibrosis, but most clinicians prefer a Tru-Cut needle biopsy.[45] In 1998, Pfammatter et al performed transcaval retroperitoneal core biopsies and suggested that the technique may have a role in patients at high operative risk, especially if the results from standard biopsies are inconclusive.[46]

 

Treatment

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:

  • Preserve renal function
  • Prevent involvement of other organs
  • Exclude malignancy
  • 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.[5, 6, 13] The treatment of retroperitoneal fibrosis depends on the stage of the disease at diagnosis, as depicted in the image below.

Management algorithm of retroperitoneal fibrosis. Management algorithm of retroperitoneal fibrosis.

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 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.[47] 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 results, positive PET findings).[48]

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%.[49] However, response may vary, and an unacceptably high dose of steroid may be required to control retroperitoneal fibrosis.

Long-term corticosteroid treatment can cause an array of adverse effects, including the following:

Tamoxifen

In 1991, Clarke et al were the first to use tamoxifen, a nonsteroidal antiestrogen, in the treatment of retroperitoneal fibrosis.[50] 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).[51]

Its mechanism of action 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.[52] 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.[53, 54]

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.[28]

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).[28]

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.[55]

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.[56]

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.[57]

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.[58]

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.[59] McDougal and MacDonell reported successful outcome in combination with prednisolone in a 14-year-old girl.[26]

Rituximab

Rituximab, a humanized anti-CD20 monoclonal antibody, has proved useful in both idiopathic and IgG4-related retroperitoneal fibrosis.[60, 61]  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.[60]  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.[61]

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.[62, 63]

Surgical Care

See the list below:

  • 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,[64] and lateral/intraperitoneal transposition or omental wrapping of the involved ureter,[65] as depicted in the image below.

    Postureterolysis intravenous urogram demonstrates Postureterolysis intravenous urogram 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.[66, 67]

  • 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.[68] 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.[68, 69, 70]

  • 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=.004).[71] 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.[7]

  • 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 renal autotransplantation.[8]

Consultations

Patients with kidney failure should be referred to a nephrologist early in the course of their disease and have continued nephrologic follow-up.

 

Medication

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. Empirical therapy includes corticosteroids, immunosuppressives, and tamoxifen.

Glucocorticoids

Class Summary

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli. Doses of up to 10 mg/d of prednisone or prednisolone are typically used, but some patients may require higher doses. Adverse events associated with long-term steroid use make dose reductions and cessation important in due course.

Prednisolone (Pediapred, Delta-Cortef, Articulose-50, AK-Pred)

Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and suppresses lymphocytes and antibody production.

Prednisone (Deltasone, Meticorten, Orasone)

Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and suppresses lymphocytes and antibody production.

Immunosuppressives

Class Summary

Some agents function as antimetabolites to decrease DNA and RNA synthesis and are used to treat a number of autoimmune conditions. These agents can also be used in patients with inadequate response or excessive toxicity to corticosteroids.

Mycophenolate (CellCept, Myfortic)

Inhibits purine synthesis and proliferation of human lymphocytes. Promising published case report of 3 patients with resistant disease treated with mycophenolate mofetil. Reduced toxicity makes this regimen an attractive alternative.

Azathioprine (Imuran)

Imidazolyl derivative of 6-mercaptopurine. Many of biological effects are similar to those of parent compound. Both compounds are eliminated rapidly from blood and are oxidized or methylated in erythrocytes and liver. No azathioprine or mercaptopurine is detectable in urine 8 h after administration.

Antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. Mechanism whereby azathioprine affects autoimmune diseases unknown. Works primarily on T cells. Suppresses hypersensitivities of cell-mediated type and causes variable alterations in antibody production.

Immunosuppressive, delayed hypersensitivity, and cellular cytotoxicity tests are suppressed to a greater degree than antibody responses. Works very slowly; may require 6-12 mo of trial prior to effect. Up to 10% of patients may have an idiosyncratic reaction that disallows use. Do not allow WBC count to drop to less than 3000/mL or lymphocyte count to drop to less than 1000/mL.

Available in tab form for oral administration or in 100-mg vials for IV injection.

Estrogen receptor antagonists

Class Summary

These agents bind to estrogen receptors, preventing stimulating effects of estrogen on nucleic acid synthesis.

Tamoxifen (Nolvadex, Tamofen-10, Tamofen-20)

Nonsteroidal antiestrogen agent. Competitively binds to estrogen receptor, producing nuclear complex that decreases DNA synthesis and inhibits estrogen effects.

 

Follow-up

Further Outpatient Care

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 renal 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 renal function until much later.

Further Inpatient Care

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.

Complications

See the list below:

  • Renal failure

  • Hypertension

  • Scrotal edema

  • Inferior vena cava thrombosis

Prognosis

The natural history of retroperitoneal fibrosis (RPF) has not been clearly established. However, the outcome of nonmalignant retroperitoneal fibrosis is generally good.[72, 73, 74, 75, 76, 77, 78, 79] Renal recovery is usually observed within the first 2 weeks. Checking these patients periodically is always better because some patients may regain renal function much later. The prognosis of malignant retroperitoneal fibrosis is poor.

Patient Education

Patients with renal failure should be educated about the following:

  • The importance of compliance with secondary preventative measures

  • Natural disease progression

  • Prescribed medications (highlighting their potential benefits and adverse effects)

  • Diet

 

Questions & Answers

Overview

What is the clinical presentation of retroperitoneal fibrosis (RPF)?

What are the signs and symptoms of retroperitoneal fibrosis (RPF)?

What is required to diagnosis retroperitoneal fibrosis (RPF)?

Which physical exam findings suggest retroperitoneal fibrosis (RPF)?

Which physical findings may be due to late complications of retroperitoneal fibrosis (RPF)?

What is the role of lab testing in the workup of retroperitoneal fibrosis (RPF)?

Which imaging studies are performed in the workup of retroperitoneal fibrosis (RPF)?

What is the role of biopsy in the workup of retroperitoneal fibrosis (RPF)?

What is included in optimal care of retroperitoneal fibrosis (RPF)?

Which surgical interventions are used in the treatment of retroperitoneal fibrosis (RPF)?

Which medications are used in the treatment of retroperitoneal fibrosis (RPF)?

What is retroperitoneal fibrosis (RPF)?

What is the anatomy of the retroperitoneum relevant to retroperitoneal fibrosis (RPF)?

What is the pathogenesis of retroperitoneal fibrosis (RPF)?

What are the pathogenic features of idiopathic retroperitoneal fibrosis (RPF)?

What is the prevalence of retroperitoneal fibrosis (RPF)?

What is the mortality and morbidity associated with retroperitoneal fibrosis (RPF)?

Which patient groups have the highest prevalence of retroperitoneal fibrosis (RPF)?

Presentation

Which clinical history findings are characteristic of retroperitoneal fibrosis (RPF)?

DDX

Which conditions should be included in the differential diagnoses of retroperitoneal fibrosis (RPF)?

Workup

Which lab tests are performed in the workup of retroperitoneal fibrosis (RPF)?

What is the role of imaging studies in the workup of retroperitoneal fibrosis (RPF)?

What is the role of plain radiography in the workup of retroperitoneal fibrosis (RPF)?

What is the role of IV urography in the workup of retroperitoneal fibrosis (RPF)?

What is the role of retrograde pyelography in the workup of retroperitoneal fibrosis (RPF)?

What is the role of lymphangiography in the workup of retroperitoneal fibrosis (RPF)?

What is the role of ultrasonography in the workup of retroperitoneal fibrosis (RPF)?

What is the role of CT scanning in the workup of retroperitoneal fibrosis (RPF)?

What is the role of MRI in the workup of retroperitoneal fibrosis (RPF)?

What is the role of PET scanning in the workup of retroperitoneal fibrosis (RPF)?

Which histologic findings are characteristic of retroperitoneal fibrosis (RPF)?

How is a diagnosis of retroperitoneal fibrosis (RPF) confirmed?

Treatment

How is retroperitoneal fibrosis (RPF) treated?

What is the role of corticosteroids in the treatment of retroperitoneal fibrosis (RPF)?

What are the adverse effects of long-term corticosteroid treatment for retroperitoneal fibrosis (RPF)?

What is the role of tamoxifen in the treatment of retroperitoneal fibrosis (RPF)?

What is the role of mycophenolate mofetil in the treatment of retroperitoneal fibrosis (RPF)?

What is the role of azathioprine in the treatment of retroperitoneal fibrosis (RPF)?

What is the role of rituximab in the treatment of retroperitoneal fibrosis (RPF)?

What is the role of medroxyprogesterone acetate in the treatment of retroperitoneal fibrosis (RPF)?

What is the role of surgery in the treatment of retroperitoneal fibrosis (RPF)?

Which specialist consultations are beneficial to patients with retroperitoneal fibrosis (RPF)?

Medications

What is the goal of medical treatment of retroperitoneal fibrosis (RPF)?

Which medications in the drug class Estrogen receptor antagonists are used in the treatment of Retroperitoneal Fibrosis?

Which medications in the drug class Immunosuppressives are used in the treatment of Retroperitoneal Fibrosis?

Which medications in the drug class Glucocorticoids are used in the treatment of Retroperitoneal Fibrosis?

Follow-up

What is included in the long-term monitoring of patients with retroperitoneal fibrosis (RPF)?

What is included in inpatient care for retroperitoneal fibrosis (RPF)?

What are the possible complications of retroperitoneal fibrosis (RPF)?

What is the prognosis of retroperitoneal fibrosis (RPF)?

What is included in patient education about retroperitoneal fibrosis (RPF)?