Clinical manifestations and diagnosis of retroperitoneal fibrosis

INTRODUCTION — Retroperitoneal fibrosis (RPF) is a rare condition characterized by the presence of inflammatory and fibrous tissue in the retroperitoneum. The tissue is generally localized around the infrarenal portion of the abdominal aorta and the iliac arteries, often encasing the ureters or other abdominal organs [1]. This disorder was initially called Ormond's disease [2] and has also been referred to as periureteritis fibrosa, periureteritis plastica, chronic periureteritis, and fibrous retroperitonitis.

RPF may be primary (idiopathic) or secondary. Idiopathic disease accounts for 70 percent of cases and can be immunoglobulin G4 (IgG4)- or nonIgG4-related. It may develop alone or in association with other autoimmune entities, and it may involve other vascular districts (mainly the thoracic aorta and epiaortic vessels). Secondary RPF can result from infections, malignancy, drugs, retroperitoneal hemorrhage, or various other disorders.

Idiopathic RPF, inflammatory abdominal aortic aneurysm, and perianeurysmal RPF are all forms of chronic periaortitis and are marked histologically by a mixture of fibrous tissue and chronic inflammation [3].

The epidemiology, pathogenesis, clinical features, and diagnostic evaluation of nonIgG4-related idiopathic RPF and secondary RPF will be reviewed here. The treatment of RPF is presented separately. (See "Treatment of retroperitoneal fibrosis".)

Related diseases are presented elsewhere:

●IgG4-related disease including IgG4-related idiopathic RPF (see "Clinical manifestations and diagnosis of IgG4-related disease" and "Treatment and prognosis of IgG4-related disease")

●Castleman disease (see "Unicentric Castleman disease" and "HHV-8/KSHV-associated multicentric Castleman disease" and "HHV-8-negative/idiopathic multicentric Castleman disease")

●Erdheim-Chester disease (see "Erdheim-Chester disease")

EPIDEMIOLOGY — RPF is a rare disease, and few epidemiologic studies are available. In various studies, the incidence of idiopathic (primary) disease ranged from 0.1 to 1.3 cases per 100,000 persons per year [4-6]. Inflammatory abdominal aortic aneurysm, a manifestation of RPF, accounts for 4 to 10 percent of all abdominal aortic aneurysms [7].

Idiopathic disease is most prevalent in individuals 40 to 60 years of age [5,8-10]. Some [5,8-10] but not all [11,12] studies suggest a 2:1 to 3:1 male-to-female predominance. Exposure to either asbestos or tobacco smoke may result in a three- to fourfold increase in the risk of RPF [13,14]. The combination of smoking and asbestos exposure is associated with an 8- to 12-fold increased risk [14].

The incidence of secondary RPF is not known.

ETIOLOGY AND PATHOGENESIS — RPF may be idiopathic or secondary to other causes. Idiopathic RPF is an immune-mediated disease accounting for over 70 percent of cases. It can either present in isolation or in association with other autoimmune diseases and/or inflammatory disorders, such as the fibroinflammatory immunoglobulin G4 (IgG4)-related disease [15]. IgG4-related RPF accounts for 35 to 60 percent of idiopathic RPF [16,17]. The pathogenesis of the IgG4-related disease is discussed at length elsewhere.

Although there are no standardized criteria for classification, idiopathic RPF is part of the disease spectrum of chronic periaortitis (CP), a condition characterized by inflammation and fibrosis surrounding the aorta and iliac arteries [1,11,18]. CP includes periaortic RPF (in which the aortic caliber is normal) and inflammatory abdominal aortic aneurysm (in which the aorta is dilated); these two entities are grouped together because of similar clinical and histologic characteristics [10,19]. Most cases of idiopathic RPF are classifiable as CP because they have the typical peri-aortoiliac localization. Idiopathic RPF cases that cannot be classified as CP are those atypically localized (eg, pelvic, peri-pancreatic, isolated peri-ureteral).

Idiopathic RPF (in its typical periaortic presentation) probably arises as an aortitis and elicits a periaortic fibroinflammatory response. This phenomenon can be a manifestation of a systemic autoimmune disease, a hypothesis that is supported by frequent presence of constitutional symptoms, elevated levels of acute phase reactants, presence of autoantibodies, a prompt response to glucocorticoids or other immunosuppressive drugs, and coexistence of autoimmune diseases involving other organs [20]. In addition, the disease often involves other vascular segments such as the thoracic aorta and mesenteric arteries, suggesting a multifocal origin [21]. This multifocal presentation is seen in idiopathic RPF (whether IgG4-related or not), but is usually not associated with secondary RPF due to malignancy, radiotherapy, or surgery.

A multifactorial pathogenesis is likely, and environmental and genetic factors contribute to disease susceptibility. Among environmental factors, smoking and exposure to asbestos are major risk factors for idiopathic RPF. The main genetic associations are with HLA-DRB1*03, a genetic marker of autoimmunity [22]. This genetic association suggests that the disease may be antigen driven. Antigen-presenting cells probably present antigens to cluster of differentiation 4 positive (CD4+) cells within the aortic wall and retroperitoneum. CD4+ T cells then expand and secrete interleukin (IL)-6, which is able to activate B cells and fibroblasts. CD4+ T cells also secrete Th2 cytokines, such as IL-4, IL-10, IL-13, and transforming growth factor beta (TGF-beta), which drive the proliferation and maturation of B cells into plasma cells, and thereby, may result in preferential expansion of IgG4-producing plasma cells [23,24]. Local and systemic production of IL-6 and Th2 cytokines has been demonstrated in idiopathic RPF. A complex network of chemokines (eg, CXCL12 and CCL11) and cytokines (eg, IL-6, IL-12, and IL-13) likely mediates the inflammatory response and simultaneously promotes fibrosis [25]. These findings are observed both in IgG4-related and unrelated forms of idiopathic RPF [26,27].  

Secondary RPF can be caused by a number of conditions [1,4,8,13,18,28-31]:

●Drugs – Ergot alkaloids (eg, methysergide, ergotamine) and dopamine agonists (eg, pergolide, methyldopa). The increased serotonin levels may lead to fibrotic reactions through proliferation of myofibroblasts and an increase in collagen matrix deposition.

●Biological agents such as etanercept, a soluble receptor that acts as a tumor necrosis factor (TNF)-alpha blocker, and infliximab, an anti-TNF-alpha monoclonal antibody. These agents may trigger a fibrotic reaction but the mechanism is unknown.

●Malignancy – Carcinoid, Hodgkin and non-Hodgkin lymphoma, sarcomas, colorectal, breast, prostate, and bladder carcinoma may cause secondary RPF. In most cases, RPF is due to an exuberant desmoplastic response associated with retroperitoneal metastases or a primary tumor. However, with carcinoid tumors, fibrosis is mediated by the release of serotonin and other fibrogenic growth factors (image 1 and image 2).

●Infections –Spinal or paraspinal abscess, tuberculosis, histoplasmosis, and actinomycosis may lead to RPF; in these cases, the retroperitoneum may be the site of the primary infection or may be involved as a result of local spread.

●Radiation therapy for testicular seminoma, colon, or pancreatic cancer (image 3).

●Retroperitoneal hemorrhage.

●Surgery – Lymphadenectomy, colectomy, aortic aneurysmectomy.

In addition, there are case reports of RPF associated with secondary (AA) amyloidosis, mesenteric panniculitis, and different forms of histiocytosis, particularly Erdheim-Chester disease [32-35]. (See "Sclerosing mesenteritis" and "Erdheim-Chester disease".)

CLINICAL FEATURES — RPF frequently presents with a nonspecific clinical pattern, and therefore diagnosis may be delayed. Most patients with RPF present with pain; estimated glomerular filtration rate (eGFR) is often decreased at the time of presentation.

Pain in the lower back, abdomen, or flank is the most common presenting symptom among patients with RPF [18]. In two of the largest retrospective series, pain was noted on presentation in over 90 percent of patients [5,11]. Pain tends to be dull and poorly localized, is not affected by activity or posture, and can be characterized by nocturnal exacerbation. Some patients may describe unilateral or bilateral flank pain that radiates to the inguinal region [11]. Testicular pain was noted in more than 50 percent of male patients in one study [10]. Pain may be acute in onset and can be mistaken for renal colic. Pain may be more responsive to nonsteroidal antiinflammatory agents compared with opiates, probably due to the inflammatory nature of the lesion.

Other common symptoms, which may occur with pain or in isolation, include malaise, anorexia, weight loss, fever, nausea, vomiting, and lower extremity edema [5,11,36,37]. Edema may be due to inferior vena cava or lymphatic compression.

Patients may complain of urinary frequency, urgency, and dysuria [10]. Urine output may be reduced, normal, or even increased (due to a secondary concentrating defect) in patients with obstructive uropathy. Gross hematuria is uncommon.

Less commonly, patients may present with claudication due to compromise of the arterial circulation of the lower extremities [1,5] or abdominal pain due to mesenteric ischemia from compression of the mesenteric arteries [1,9,18,38-40]. Compression of the thoracic aorta and/or the epi-aortic arteries can lead to hoarseness and dry cough secondary to recurrent laryngeal nerve paralysis, or upper-limb claudication [1,5,12].

On physical examination, new-onset hypertension (likely due to encasement of renal arteries producing renovascular hypertension) is noted in approximately 30 to 60 percent of patients [5,9,11,18,38-40]. Patients may have lower extremity edema, thrombophlebitis, or deep vein thrombosis resulting from obstruction of the inferior vena cava and/or iliac veins. In most cases, compression of the venous axis is a gradual process that leads to the formation of collateral venous circulation [41]. Hydrocele or varicocele, likely from compression of retroperitoneal testicular vessels, are common among men with RPF, seen in approximately 30 to 60 percent of patients [5,10,11].

Kidney function impairment with elevated blood urea nitrogen and creatinine, most commonly due to obstruction, is present in more than 50 percent of patients at presentation [5,10]. Patients may also have normocytic anemia, even among those with preserved kidney function. (See 'Laboratory studies' below.)

Prior to the diagnosis of RPF, patients may undergo a kidney ultrasound as part of their evaluation for kidney function impairment or acute flank pain. Kidney ultrasound may reveal hydronephrosis with or without bilateral encasement of renal vessels by peri-iliac fibrotic tissue [1,5,12]. At diagnosis, 8 to 30 percent of patients may have unilateral or bilateral kidney parenchymal atrophy either from slowly progressive or intermittent ureteral obstruction, or from chronically diminished blood supply due to renal artery compression.

DIAGNOSTIC APPROACH

When to suspect the disease — RPF should be suspected among patients who have characteristic clinical features, such as flank or abdominal pain, in association with newly detected kidney function impairment. However, it is more commonly identified incidentally when radiologic studies are performed to evaluate for urinary tract obstruction or lower limb venous or arterial insufficiency.

Patients with a suspected diagnosis of RPF should undergo further testing to confirm the diagnosis. (See 'Diagnosis (contrast CT or MRI preferred)' below and 'Indications for a biopsy and diagnostic histopathology' below.)

Diagnosis (contrast CT or MRI preferred) — The diagnosis of RPF is often made either by contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI). However, findings on imaging are characteristic but not pathognomonic. Thus, the diagnosis integrates imaging and clinical presentation [42]. A definitive diagnosis may require a biopsy in some patients. (See 'Indications for a biopsy and diagnostic histopathology' below.)

In addition to revealing the presence of RPF, cross-sectional imaging of the chest, abdomen, and pelvis can sometimes suggest a secondary cause of RPF (eg, malignancy, prior surgery, prior radiotherapy). By contrast, other causes of secondary RPF may be radiographically indistinguishable from idiopathic RPF (eg, drug-induced RPF).

A contrast-enhanced CT enables visualization of the extent of RPF (image 4) and the presence of lymphadenopathy or tumors [43,44]. Typical findings of idiopathic RPF include presence of a confluent retroperitoneal mass, with homogeneous attenuation similar to muscle, that encases (but not displaces) the anterior and lateral sides of the aorta, encircles and compresses the inferior vena cava, and often causes a medial deviation of the ureters (image 5) [45]. Localized reactive lymphadenopathy, generally with subcentimeter lymph nodes adjacent to the mass, is observed in approximately 25 percent of the cases [5]. No infiltration of the muscle or the bone is seen. The fibroproliferative tissue of RPF can have varying degrees of contrast enhancement depending upon the extent of active inflammation [46]. Assessment of renal vascular involvement (in the contrast-enhanced phase) is an important aspect of the evaluation [11]. In addition to its diagnostic advantages, a CT also allows a CT-guided vascular interventional procedure or biopsy of the tissue, when indicated [47].

MRI is equivalent to CT in the diagnosis of RPF [48], but may be the preferred imaging modality among patients with an iodinated contrast allergy or significantly reduced estimated glomerular filtration rate at presentation. Compared with CT, MRI has better definition and a higher contrast resolution relative to surrounding tissues. The use of gadolinium is recommended in order to define the exact extension of the tissue and to study the vasculature; however, if gadolinium cannot be used, unenhanced MRI can still differentiate RPF from the surrounding tissues. On MRI, idiopathic RPF appears hypointense in T1-weighted images; in T2-weighted images, its intensity is low (with a characteristic delayed-phase enhancement) in the quiescent phases of the disease and high in the active stages, when there is abundant tissue edema and hypercellularity [49]. MRI is also useful for the differential diagnosis since malignant lesions are more likely to have a bulky appearance, to be inhomogeneous, to originate above renal arteries, to cause anterior aorta displacement, and to produce lateral ureteral deviation (image 6) [48-50]. In our experience, when patients present with suspected RPF that has characteristic MRI features, the diagnosis can be made without biopsy. A detailed discussion regarding risks and benefits of gadolinium use with MRI is presented elsewhere. (See "Patient evaluation before gadolinium contrast administration for magnetic resonance imaging".)

Positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG) is a useful and reliable technique to assess the metabolic or inflammatory activity of the disease [51], but cannot be used to make a diagnosis of RPF.

We do not use intravenous urography (also known as intravenous pyelography) or retrograde pyelography for diagnosis, but these procedures may be used for further evaluation and management of hydronephrosis at the discretion of urologists. (See "Clinical manifestations and diagnosis of urinary tract obstruction (UTO) and hydronephrosis" and "Placement and management of indwelling ureteral stents".)

Indications and details of additional imaging in patients suspected of having IgG4-related RPF is discussed at length elsewhere. (See "Clinical manifestations and diagnosis of IgG4-related disease", section on 'Laboratory evaluation'.) [52,53]

Indications for a biopsy and diagnostic histopathology — It is controversial whether or not patients who have diagnostic features of idiopathic RPF by CT or MRI require a biopsy to confirm the diagnosis. The risk of complications resulting from biopsy (primarily bleeding) must be weighed against the benefits of having a histopathologic diagnosis.

Many clinicians do not perform a biopsy in patients who have an imaging diagnosis of idiopathic RPF, unless the patient is about to undergo surgery for repair of abdominal aortic aneurysm (in the case of inflammatory aneurysms or perianeurysmal fibrosis) or for surgical ureterolysis to treat urinary tract obstruction [1,18].

We suggest a biopsy in the following settings:

●If the location of the mass is atypical (eg, not peri-aortoiliac but instead in a pelvic, isolated peri-ureteral, or peri-bladder location).

●If clinical and laboratory findings suggest the presence of an underlying malignancy or infection.

●If there is bulky appearance of the retroperitoneal tissue, extension above the origin of the renal arteries, anterior displacement of the aorta, or infiltration of muscles, bone, or other structures and confluent lymphadenopathy. This appearance suggests the possibility of an underlying malignancy (eg, lymphoma, sarcoma, or other solid neoplasms).

●If there is a perirenal fibrotic tissue. This appearance suggests the possibility of underlying Erdheim-Chester disease.

●If there are other involved sites such as the pancreas or mesentery. In these cases, pancreatic cancer, IgG4-related or unrelated chronic pancreatitis, or sclerosing mesenteritis should be suspected.

●If local expertise with radiologic diagnosis of RPF is limited.

A biopsy may be performed either with CT-guidance or as an open (surgical) procedure [18,44,47]. Sometimes, an open biopsy is needed if the tissue obtained by CT-guidance yields inconclusive results. An open biopsy may also be performed as part of a surgical procedure planned for relief of urinary obstruction or correction of an abdominal aortic aneurysm. For the lowest risk of complications and the optimal diagnostic yield, the biopsy specimen should be obtained where the tissue is thickest and in areas that were demonstrated to be hypermetabolic on PET (if a PET scan was performed).

The pathologic findings of idiopathic and secondary disease may sometimes be indistinguishable [1]. Macroscopically, RPF appears as a hard white plaque of varying thickness surrounding the abdominal aorta, iliac vessels, inferior vena cava, and the ureters. Microscopically, the tissue comprises an extracellular matrix composed of type I collagen fibers organized in thick irregular bundles that surround small retroperitoneal vessels. The fibrous tissue is also rich in fibroblasts or myofibroblasts [54].

Inflammatory infiltrate consisting of B and T lymphocytes, macrophages, plasma cells, and, rarely, neutrophils may be present in a diffuse, pseudo-nodular, or perivascular aggregate configuration. The aggregates usually have a core rich in cluster of differentiation 20 (CD20) positive B cells and a periphery rich in CD3 positive T cells, with a CD4-to-CD8 ratio of 3:1. A varying percentage of immunoglobulin G4 (IgG4) positive plasma cells can be observed. If the proportion of CD138-positive plasma cells that are IgG4 positive is greater than 30 to 40 percent, then the RPF is likely IgG4-related. IgG4-related disease accounts for up to 50 percent of RPF cases [55,56]. However, the absence of IgG4-positive plasma cells does not necessarily rule out IgG4-related disease, as other extra-retroperitoneal IgG4-positive lesions may appear. Storiform fibrosis and obliterative phlebitis are also consistent with IgG4-related RPF.

Additional histologic features of idiopathic RPF include vasculitis of small retroperitoneal vessels (noted in approximately one-half of the cases) and hyaline rinds surrounding small retroperitoneal vessels and nerves.  

Secondary forms of RPF due to malignancies are characterized by the presence of neoplastic cells scattered among an abundant fibrous tissue; the inflammatory infiltrate can be monoclonal in cases of lymphoma. In Erdheim-Chester disease, the presence of "foamy" histiocytes (CD68KP1 positive, CD1a negative) is a hallmark of the histologic pattern. Granulomatous formations are unusual in idiopathic RPF and should raise suspicion for tuberculosis or other granulomatous conditions.

Distinguishing between primary and secondary disease — Once a diagnosis of RPF is made, it is important to distinguish whether the patient has idiopathic or secondary disease. This is primarily to guide next steps in the evaluation, monitoring, and treatment of RPF. (See "Treatment of retroperitoneal fibrosis".)

Features suggestive of idiopathic (primary) disease — The main features suggestive of idiopathic RPF are its appearance on CT or MRI and the absence of clinical and laboratory signs of infection (eg, persistent high-grade fever, leukocytosis) or malignancy (eg, marked weight loss, gastrointestinal bleeding, or metastatic lesions on CT, MRI, or PET).

However, as noted above, some forms of secondary RPF may be radiographically and histologically indistinguishable from idiopathic RPF. (See 'Diagnosis (contrast CT or MRI preferred)' above and 'Indications for a biopsy and diagnostic histopathology' above.)

In such cases, the history, examination, and laboratory evaluation may suggest the presence of a secondary cause. (See 'Features suggestive of secondary disease' below.)

Features suggestive of secondary disease — Among patients who have a radiologic diagnosis of RPF, causes of secondary RPF should be sought. (See 'Etiology and pathogenesis' above.)

The patient should be asked about a history of the following to identify any potential cause of secondary disease:

●Drugs – Prolonged use of ergot-derivatives, methysergide, bromocriptine, beta blockers, methyldopa, hydralazine, and analgesics. Some drugs (ie, ergot-derivatives and dopamine agonists) have clearly causal associations with RPF; in such cases, further evaluation for other secondary causes is generally not performed [57].

●Biological agents such as etanercept, a soluble receptor that acts as a tumor necrosis factor (TNF)-alpha blocker, and infliximab, an anti-TNF-alpha monoclonal antibody.

●Malignancy – Carcinoid, Hodgkin and non-Hodgkin lymphoma, sarcomas, colorectal, breast, prostate, and bladder carcinoma (image 1 and image 2).

●Infections – Tuberculosis, histoplasmosis, actinomycosis. Actinomycosis should be ruled out in women with a history of intrauterine device use. (See "Intrauterine contraception: Management of side effects and complications", section on 'Actinomyces and related organisms'.)

●Radiation therapy for testicular seminoma, colon, pancreatic cancer (image 3).

●Retroperitoneal hemorrhage.

●Surgery – Lymphadenectomy, colectomy, aortic aneurysmectomy.

In addition to the history, a CT or MRI may reveal secondary causes, such as malignancies (lymphoma, carcinoid, or retroperitoneal sarcomas), or infection (tuberculosis, histoplasmosis, or actinomycosis). PET has a low specificity for distinguishing between idiopathic and secondary disease [58-60]. Further evaluation of patients with radiographic features suggestive of such secondary conditions is discussed elsewhere. (See "Pretreatment evaluation and staging of non-Hodgkin lymphomas", section on 'Imaging' and "Clinical presentation and diagnosis of classic Hodgkin lymphoma in adults", section on 'Imaging' and "Diagnosis of carcinoid syndrome and tumor localization", section on 'Tumor localization and staging' and "Diagnosis of pulmonary tuberculosis in adults", section on 'Radiographic imaging' and "Abdominal actinomycosis", section on 'Radiologic findings' and "Diagnosis and treatment of disseminated histoplasmosis in patients without HIV" and "Clinical presentation and diagnosis of retroperitoneal soft tissue sarcoma".)

Laboratory studies — Most patients have already had routine laboratory testing by the time they are diagnosed with RPF (ie, complete blood count, electrolytes, creatinine, liver function tests). There are no hematologic or biochemical abnormalities that are specific to RPF.

We order the following additional tests, which may help determine the underlying etiology of RPF:

●Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), which are typically elevated at the time of diagnosis and may be helpful in monitoring the response to therapy.  

●Serum immunoglobulin levels including IgG4.

●Thyroid function tests.

●Autoantibodies such as antinuclear antibody, anti-thyroid microsome, anti-thyroglobulin, anti-neutrophil cytoplasmic antibody, or anti-smooth muscle antibodies. Antibody tests may be omitted among patients with an unequivocal diagnosis of secondary RPF.

●Serum protein electrophoresis and serum free light chain assay.

Patients often have normocytic anemia possibly related to chronic kidney disease or chronic inflammation [1,5,11,61,62]. Other less common abnormalities include leukocytosis and eosinophilia.

ESR and CRP are elevated in a majority of patients at presentation, reflecting the inflammatory nature of the disease [5,63]. As an example, in one study of 53 patients with RPF, 74 and 62 percent had an elevated ESR and CRP, respectively [5]. High baseline levels of acute phase reactants are associated with more symptomatic disease, but levels generally do not correlate with the risk of subsequent disease flares.

Antinuclear antibody (ANA) may be present in up to 60 percent of cases of idiopathic RPF and may also predict relapse after therapy [64-66]. Other autoantibodies usually suggest the presence of concomitant autoimmune disease. As an example, about 25 percent of patients with idiopathic RPF have autoimmune thyroiditis, and such patients will have antibodies against thyroid microsome and thyroglobulin [57]. A positive antineutrophil cytoplasmic antibody (ANCA) may be present in patients who have granulomatosis with polyangiitis and microscopic polyangiitis in conjunction with RPF.

Patients with RPF may have a nonspecific elevation of serum IgG4 [55]. Compared with patients without elevated IgG4, patients with elevated IgG4 levels have more frequent fibroinflammatory lesions outside the retroperitoneum, but otherwise do not differ in their demographic, laboratory, or clinical presentation. However, IgG4 levels may also be elevated in other inflammatory or proliferative diseases that can mimic RPF, such as Castleman disease and Erdheim-Chester disease. (See "Unicentric Castleman disease" and "HHV-8-negative/idiopathic multicentric Castleman disease" and "HHV-8/KSHV-associated multicentric Castleman disease" and "Erdheim-Chester disease".)

Monoclonal or polyclonal dysproteinemias associated with RPF have also been reported. In one such report, all five affected patients had immunoglobulin heavy chain gene rearrangement [67].

DIFFERENTIAL DIAGNOSIS — Most patients present with abdominal or flank pain and kidney function impairment. Among such patients, the major differential diagnosis prior to imaging is nephrolithiasis, which is excluded by computed tomography (CT) scan. Among patients who have findings of hydronephrosis associated with presence of abnormal findings in the retroperitoneum, the differential diagnosis includes other conditions, including [68,69]:

●Lymphoma, germ cell tumors, or sarcomas of retroperitoneal origin (see "Clinical presentation and initial evaluation of non-Hodgkin lymphoma" and "Clinical presentation and diagnosis of retroperitoneal soft tissue sarcoma" and "Extragonadal germ cell tumors involving the mediastinum and retroperitoneum")

●Retroperitoneal metastases from various types of carcinomas (eg, carcinoma of the prostate, breast, colon) with an exuberant desmoplastic response (see "Overview of systemic treatment for recurrent or metastatic castration-sensitive prostate cancer" and "Overview of the treatment of castration-resistant prostate cancer (CRPC)" and "Endocrine therapy resistant, hormone receptor-positive, HER2-negative advanced breast cancer" and "Overview of the approach to metastatic breast cancer" and "Systemic therapy for nonoperable metastatic colorectal cancer: Selecting the initial therapeutic approach" and "Systemic therapy for metastatic colorectal cancer: General principles")

●Retroperitoneal fibromatosis (see "Desmoid tumors: Epidemiology, molecular pathogenesis, clinical presentation, diagnosis, and local therapy")

●Inflammatory pseudotumor (see "Inflammatory myofibroblastic tumor (plasma cell granuloma) of the lung")

●Infections such as tuberculosis and actinomycosis; actinomycosis should be ruled out in women with a history of intrauterine device use (see "Pulmonary tuberculosis: Clinical manifestations and complications", section on 'Clinical manifestations' and "Intrauterine contraception: Management of side effects and complications", section on 'Actinomyces and related organisms')

●Erdheim-Chester disease (see "Erdheim-Chester disease", section on 'Clinical manifestations')

As described above, certain characteristics on CT or magnetic resonance imaging scan may distinguish RPF from other retroperitoneal lesions. The presence of a confluent lymphadenopathy that tends to surround the large vessels is likely to be malignant, as is a fibrous mass dislocating the psoas muscles or destroying bone [70]. (See 'Diagnosis (contrast CT or MRI preferred)' above.)

Erdheim-Chester disease should be suspected in cases of symmetrical and bilateral perirenal fibrosis [71].

When the thoracic aorta and/or the epiaortic arteries are involved, giant-cell arteritis and Takayasu arteritis should be excluded.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease in adults" and "Society guideline links: IgG4-related disease".)

SUMMARY AND RECOMMENDATIONS

●Retroperitoneal fibrosis (RPF) is a rare condition characterized by the presence of inflammatory and fibrous tissue in the retroperitoneum. The tissue is generally localized around the infrarenal portion of the abdominal aorta and the iliac arteries, often encasing the ureters or other abdominal organs. (See 'Introduction' above.)

●RPF may be idiopathic or secondary to other causes. Idiopathic RPF is an immune-mediated disease that can either present in isolation or in association with other autoimmune diseases, such as the fibroinflammatory immunoglobulin G4 (IgG4)-related disease. Idiopathic RPF (in its typical periaortic presentation) probably arises as an aortitis and elicits a periaortic fibroinflammatory response. Secondary RPF can be caused by a number of factors, including drugs, malignancy, infections, radiation therapy, retroperitoneal hemorrhage, and surgery. (See 'Etiology and pathogenesis' above.)

●Typically, patients with RPF present with pain in the lower back, abdomen, or flank. Estimated glomerular filtration rate (eGFR) is often decreased at the time of presentation, usually as a result of urinary tract obstruction. Other common symptoms, which may occur with pain or in isolation, include malaise, anorexia, weight loss, fever, nausea, vomiting, and lower extremity edema. Edema may be due to inferior vena cava or lymphatic compression. Other findings can include new-onset hypertension and, in men, hydrocele or varicocele. (See 'Clinical features' above.)

●The diagnosis of RPF is often made either by contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) of the chest, abdomen, and pelvis without and with contrast. MRI is equivalent to CT in the diagnosis of RPF. The use of gadolinium is recommended in order to define the exact extension of the tissue and to study the vasculature; however, if gadolinium cannot be used, unenhanced MRI can still differentiate RPF from the surrounding tissues. (See 'Diagnosis (contrast CT or MRI preferred)' above.)

●Typical findings of idiopathic RPF include presence of a confluent retroperitoneal mass, with homogeneous attenuation similar to muscle, that encases (but not displaces) the anterior and lateral sides of the aorta, encircles and compresses the inferior vena cava, and often causes a medial deviation of the ureters (image 5). In addition to revealing the presence of RPF, cross-sectional imaging can sometimes suggest a secondary cause of RPF (eg, malignancy, prior surgery, prior radiotherapy). By contrast, other causes of secondary RPF may be radiographically indistinguishable from idiopathic RPF (eg, drug-induced RPF). (See 'Diagnosis (contrast CT or MRI preferred)' above.)

●Many clinicians do not perform a biopsy in patients who have an imaging diagnosis of idiopathic RPF, unless the patient is about to undergo surgery for repair of abdominal aortic aneurysm (in the case of inflammatory aneurysms or perianeurysmal fibrosis) or for surgical ureterolysis to treat urinary tract obstruction. We suggest a biopsy in the following settings (see 'Indications for a biopsy and diagnostic histopathology' above):

•If the location of the mass is atypical (eg, not periaortoiliac but instead in a pelvic, isolated periureteral, or peribladder location).

•If clinical and laboratory findings suggest the presence of an underlying malignancy or infection.

•If there is bulky appearance of the retroperitoneal tissue, extension above the origin of the renal arteries, anterior displacement of the aorta, or infiltration of muscles, bone, or other structures and confluent lymphadenopathy. This appearance suggests the possibility of an underlying malignancy (eg, lymphoma, sarcoma, or other solid neoplasms).

•If there is a perirenal fibrotic tissue. This appearance suggests the possibility of underlying Erdheim-Chester disease.

•If there are other involved sites such as the pancreas or mesentery. In these cases, pancreatic cancer, IgG4-related or unrelated chronic pancreatitis, or sclerosing mesenteritis should be suspected.

•If local expertise with radiologic diagnosis of RPF is limited.

●The main features suggestive of idiopathic RPF are its appearance on CT or MRI and the absence of clinical and laboratory signs of infection (eg, persistent high-grade fever, leukocytosis) or malignancy (eg, marked weight loss, gastrointestinal bleeding, or metastatic lesions on CT, MRI, or positron emission tomography). However, some forms of secondary RPF may be radiographically and histologically indistinguishable from idiopathic RPF. In such cases, the history, examination, and laboratory evaluation may suggest the presence of a secondary cause. (See 'Features suggestive of idiopathic (primary) disease' above and 'Features suggestive of secondary disease' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Carlo Buzio, MD, who contributed to earlier versions of this topic review.