Retroperitoneal fibrosis is a rare syndrome hallmarked by a fibrosclerotic tissue in the retroperitoneum, often leading to encasement of the ureters. About two-thirds of cases of retroperitoneal fibrosis are idiopathic, while the remaining cases are secondary to a variety of different causes, including drugs, tumors and infections. Idiopathic retroperitoneal fibrosis may be associated with abdominal aorta aneurysms, with vasculitis of the thoracic aorta and of epi-aortic vessels, or both. Most patients present with abdominal and/or low back pain. Serum markers of inflammation are usually, but not invariably, elevated. The diagnosis is secured by computed tomography or magnetic resonance imaging, which typically show an enhancing retroperitoneal mass medially dislodging the ureters. Positron emission tomography can be useful to document the extent and metabolic activity of the inflammatory process. Treatment rests on glucocorticoids with a tapering scheme variably combined with immunosuppressive agents. In cases of ureter obstruction, relief of obstruction by stenting or ureterolysis is required.
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Idiopathic retroperitoneal fibrosis is a fibro-inflammatory disorder characterised by a retroperitoneal mass often encasing the ureters.
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Computed tomography or magnetic resonance imaging is required to secure the diagnosis.
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Glucocorticoid therapy is usually effective, but relapses are high upon glucocorticoid tapering.
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Immunosuppressive agents should be used in patients with frequent relapses.
Introduction
Retroperitoneal fibrosis is a rare syndrome characterised by the development of fibrosclerotic tissue in the retroperitoneum, which often leads to encasement of the ureters and, less frequently, of blood and lymphatic vessels . About two-thirds of cases of retroperitoneal fibrosis are idiopathic, while the remaining cases are secondary to intake of a number of drugs, infections, malignancies, surgery or exposure to radiation . In this review, we will focus on the idiopathic form of retroperitoneal fibrosis, and discuss the latest developments in the understanding of its pathogenesis, imaging and treatment.
Classification of retroperitoneal fibrosis
There are no formal criteria to classify idiopathic retroperitoneal fibrosis (IRF). Currently, IRF is considered part of the spectrum of chronic periaortitis (CP), a large-vessel vasculitis . Specifically, IRF is characterised by a retroperitonal fibro-inflammatory tissue in the absence of a dilated aorta, while in inflammatory abdominal aorta aneurysms (IAAAs) the fibro-inflammatory tissue develops around a dilated aorta, and in perianeurysmal retroperitoneal fibrosis the fibro-inflammatory tissue spreads from a dilated aorta into the retroperitoneum . CP has been shown to be associated with large-vessel vasculitis in vessels other than the abdominal aorta, including the epiaortic and gastrointestinal vessels, as well as with various auto-immune disorders such as Hashimoto thyroiditis and primary Sjøgren’s syndrome, in agreement with its auto-immune nature .
There is evidence that, in a number of patients, CP may be part of the so-called immunoglobulin G4 (IgG4)-related disease (IgG4-RD), an auto-immune disorder characterised by elevated serum levels of IgG4 and abundant infiltration of IgG4-positive plasma cells in different organs . A study assessing 17 patients with retroperitoneal fibrosis demonstrated that 10 patients had elevated numbers of IgG4-positive plasma cells both in the serum and at tissue level . Likewise, approximately 50% of patients with IAAA have evidence of IgG4-RD .
Epidemiology
CP is a rare disease with prevalence of 1.4/100 000 and a yearly incidence of 0.1–1.3/100,000 . Mean age at onset is approximately 55–60 years . Men are affected two to three times more often than females . An even stronger male predominance has been observed in patients with IgG4-related CP, including those with aneurysmal forms of CP .
Aetiology and pathogenesis
CP is a fibro-inflammatory disorder . Although its pathogenesis is still obscure, its pathological appearance shows the co-existence of fibrous and inflammatory components . Earlier studies proposed that advanced aortic atherosclerosis be regarded as a sine qua non for the development of CP, and that CP arise as an exaggerated localised inflammatory reaction to atherosclerotic plaque components . Findings supporting such a view included circulating antibodies directed against modified lipids such as oxidised-low-density lipoprotein (LDL) and ceroid (found at higher levels in the serum of CP patients than in controls), tissue deposition of immunoglobulins close to extracellular ceroid in CP biopsies and the presence of ceroid-laden macrophages in the adventitia and nearby lymph nodes .
However, CP may also arise in patients who do not have evidence of advanced atherosclerosis or have suffered no major cardiovascular events. More importantly, in most patients CP has the features of a systemic disease. Patients often complain of systemic symptoms (e.g., fatigue, anorexia, fever and weight loss), have raised acute-phase reactant levels and in some cases have evidence of extra-retroperitoneal diseases, particularly systemic or organ-specific auto-immune diseases such as Hashimoto’s thyroiditis, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, psoriasis and Sjøgren’s syndrome .
Subsequent studies postulated that CP might originate as a primary aortitis which, in turn, would trigger a fibro-inflammatory reaction in the adjacent periaortic retroperitoneum. In keeping with this hypothesis, aortic inflammation in CP predominates in the media and adventitia, where vasculitis of vasa vasorum can often be observed; this would contrast with the concept that atherosclerotic plaque is the initial triggering event. Further, patients with CP often show fibro-inflammatory involvement of the thoracic aorta and of the origin of epi-aortic arteries, as well as of other large arteries such as the mesenteric and the coeliac arteries . Finally, post-mortem studies in CP have revealed adventitial inflammation in aortic sections lacking periaortic fibrosis, which probably indicates that aortitis is an early stage of CP .
Whatever the anatomic site of origin of the disease, the pathogenesis of CP is certainly contributed to by different factors. Genetic studies have demonstrated that CP is associated with human leucocyte antigen (HLA) DRB1*03, an allele linked to a number of auto-immune disorders such as type 1 diabetes, Hashimoto’s thyroiditis and myasthenia gravis . In a more recent study, CP was also found to be associated with the Δ32 single-nucleotide polymorphism (SNP) of the chemokine receptor CCR5 gene; this SNP was particularly enriched in patients with the perianeurysmal forms of CP, namely IAAA and perianeurysmal retroperitoneal fibrosis. Interestingly, this association was stronger in patients without established atherosclerotic disease, suggesting that genetic variants independent of atherosclerosis confer susceptibility to the development of CP .
Environmental factors also play a role. Occupational exposure to asbestos is a risk factor for CP, and in some cases CP may occur in patients with overt pulmonary asbestosis . Further, cigarette smoking proved to be a strong and independent risk factor for CP . Microbial agents such as Mycobacterium tuberculosis may also act as disease triggers , whereas the role of viruses is still elusive.
The molecular mechanisms underlying the development of CP are still unclear. Studies performed on aortic biopsies in CP patients revealed the expression of gene transcripts consistent with lymphocyte activation, such as interferon-γ (IFN-γ), interleukin-1α (IL-1α), IL-2 and IL-4, which lends support to the hypothesis that CP may originate as an active inflammatory disease of the aortic wall . Chemokines also appear to have a pathogenetic role. As CP tissue biopsies often show eosinophilic infiltration, and eosinophils are able to promote fibrosis, a recent study investigated bio-markers of eosinophilia and fibrosis in CP. Serum levels of eotaxin/chemokine (C-C motif) ligand 11 (CCL11) were found to be significantly higher in CP patients than in healthy controls; this chemokine was also highly expressed by mononuclear cells in the inflammatory infiltrate of retroperitoneal biopsies obtained from CP patients. Eotaxin/CCL11 induces tissue recruitment of eosinophils and mast cells; in addition to eosinophils, mast cells were also found to be abundant in CP biopsies. Notably, CCR3, the receptor for eotaxin/CCL11, was diffusely expressed in CP biopsies by different cell types including eosinophils, mast cells and fibroblasts, thus indicating that eotaxin/CCL11 may act by inducing tissue influx of eosinophils and mast cells, and also by directly stimulating collagen-producing cells. In a genetic association analysis, CP was found to be associated with a particular haplotype within the CCL11 gene. Altogether, these findings suggest that the CCL11–CCR3 axis may be pathogenetically relevant in CP (Mangieri D, Corradi D, Martorana D, Malerba G, Palmisano A, Libri I et al. Eotaxin/CCL11 in idiopathic retroperitoneal fibrosis. Nephrol Dial Transplant in press).
CCL18 is a marker of fibrotic activity in idiopathic pulmonary fibrosis, which is why it was also studied in patients with CP. CCL18 serum levels were markedly higher in CP patients than in healthy subjects and in patients with aortic sclerosis. CCL18 levels correlated with CP thickness in untreated patients, and their reduction also seemed to parallel CP shrinkage. Although the pathophysiological significance of this marker in CP is still unknown, its clinical correlations and the apparent specificity for CP are intriguing findings .
CP is considered to be part of the spectrum of IgG4-related disease, a condition also including sclerosing (auto-immune) pancreatitis and cholangitis, chronic sialoadenitis and other disorders histologically hallmarked by intense infiltration of IgG4-bearing plasma cells as well as storiform fibrosis, tissue eosinophilia and obliterative phlebitis, and also characterized by a frequent increase in serum IgG4 levels . An intense infiltration of IgG4 + plasma cells (generally considered as an IgG4/IgG ratio greater than 30%) has been demonstrated in both aneurysmal and non-aneurysmal forms of CP . A study showed that more than 50% of non-aneurysmal CP cases had a significant IgG4-positive plasma cell infiltration, but these data need to be confirmed by larger studies. Nevertheless, as IgG4-skewed immune responses are commonly driven by T-helper 2 (Th2) cytokines such as IL-4, IL-5 and the immunoregulatory IL-10, it is likely that such reactions also play a pathogenetic role in CP. In a study on auto-immune sclerosing pancreato-cholangitis, increased expression of IL-4, IL-13, IL-10 and transforming growth factor-β (TGF-β) was detected along with an enhanced infiltration of regulatory CD4 + CD25 + FoxP3 + T cells . Although not yet demonstrated in the setting of CP, the main pathogenic effects of these cytokines well recapitulate CP pathology: TGF-β promotes fibrosis, IL-5 induces eosinophil maturation and tissue infiltration, while IL-4, IL-10 and IL-13 boost B-cell responses and humoral immunity. B cells are indeed abundant in CP tissue, and constitute the core of the pseudo-nodular inflammatory aggregates interspersed within the fibrous tissue. Their pathogenetic role is still unclear, but the observed benefit of the B-cell-depleting agent rituximab in patients with CP suggests that they are key players in the development of the disease.
Clinical manifestations
The most common presenting symptoms of CP are abdominal, lower back or flank pain . The pain is usually dull in nature, although colicky pain may occur in the presence of ureter encasement . Renal failure due to obstruction of the ureters resulting in hydronephrosis develops in 42–95% patients, with higher rates being reported from renal compared with rheumatology centres . Involvement of retroperitoneal blood and lymphatic vessels is less common, occurring in one-quarter of cases or less . Venous or lymphatic involvement manifests typically as oedematous changes (rarely thrombophlebitis) of the lower limbs, while arterial encasement can cause claudication . Other clinical manifestations related to compression of vascular segments include varicocoele, hydrocoele and scrotal swelling . Constipation, nausea and vomiting are also reported by some patients . Up to one-half of patients complain of constitutional manifestations such as fever, weight loss, fatigue and night sweats which, however, quickly resolve after onset of glucocorticoid therapy . Finally, some patients may complain of symptoms related to vascular involvement at sites different from the abdominal aorta , particularly when CP arises in the context of an IgG4-related disease .
Investigations
Laboratory tests
Inflammatory markers, such as the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), are elevated in approximately one-half to two-thirds of patients with CP . However, both ESR and CRP lack sensitivity and specificity for the diagnosis of retroperitoneal fibrosis . It is also controversial to what extent ESR and CRP correlate with disease activity . In a longitudinal study, in untreated patients ESR and CRP correlated with pain intensity, while decreases in ESR and CRP serum levels correlated with the amount of shrinkage of the retroperitoneal mass in the long (4–8 months), but not in the short (6 weeks) term . Anaemia is not infrequent; it is usually normochromic and normocytic, consistent with anaemia of chronic inflammation, but can also be related to renal dysfunction . Leukocytosis, eosinophilia, hyperferritinaemia and hypergammaglobulinaemia may also be observed in some patients . Creatinine is variably raised in patients with ureter encasement, depending on the severity of ureter obstruction . Anti-nuclear antibodies (ANA) are positive in 5–60% of patients , but other autoantibodies can also test positive, including rheumatoid factor, anti-neutrophil cytoplasmic, anti-smooth muscle cells and anti-thyroid antibodies . However, positive autoantibodies do not necessarily portend the presence or the development of clinical manifestations of the diseases associated with such autoantibodies .
Serum IgG4 levels may be raised in patients with CP classifiable as part of the IgG4-RD . On the other hand, high serum levels of IgG4 are not entirely specific to the IgG4-RD, being also detectable in ca. 5% of healthy controls as well as in a number of disorders such as Churg–Strauss syndrome, eosinophilic pneumonia, and systemic Castleman’s disease . Therefore, IgG4 serum levels should always be interpreted in conjunction with clinical findings.
Imaging procedures
Imaging procedures are essential to secure the diagnosis of CP and to monitor the disease course. Ultrasonography may be used as first-line screening test, and is particularly useful to monitor patients with hydronephrosis and aortic aneurysms . However, ultrasonography needs to be complemented by computed tomography (CT) or magnetic resonance imaging (MRI) of the abdomen . Abdominal CT and MRI are currently considered the investigations of choice to diagnose CP. CT demonstrates a homogeneous periaortic mass isodense to muscle that compresses and displaces the uretes medially . Similarly, MRI is able to depict a periaortic tissue that appears hypointense on T1-weighted sequences and hyperintense on T2-weighted sequences . If renal function is not compromised, it is useful to perform CT or MRI with contrast media. In active CP, the periaortic mass enhances on CT and MRI . CT and MR, often combined with angiography, can reveal signs of aortitis (vessel wall thickening with mural enhancement) as well as aortic dilation. Both CT and MRI can be used to monitor the disease course of CP. Contrast enhancement on CT or MRI and MR signal hyperintensity on T2-weighted sequences in the retroperitoneal mass correlate with disease activity, and can be used to evaluate response to treatment . On a note of caution, signs of vasculitis seen on MRI and CT may persist for some time despite achievement of clinical remission . A further limitation of abdominal CT and MRI is that neither technique can detect vasculitis in vessels other than the abdominal aorta, which has been described in 43% of patients with CP .
Nuclear medicine procedures are useful complements to radiographic imaging. Compared with the latter, nuclear medicine studies have the advantage of easily visualising almost the entire body, thus providing information on the full extent and metabolic activity of CP . Two procedures have proved valuable for the diagnosis and monitoring of CP, 67 gallium (Ga) scintigraphy and 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET). Ga scan has prospectively been evaluated in a study on 34 patients with CP . All patients were assessed prior to therapy onset, and the scan was repeated 3 months after starting tamoxifen therapy in those with initial positive scans. Overall, 71% of patients had evidence of abnormal Ga uptake. At baseline, periaortic mass thickness was greater in patients with positive Ga scans compared with those with negative scans, while visual tracer uptake scores correlated with mass thickness, although not with ESR and CRP levels. Visual scores significantly decreased following tamoxifen treatment; such decreases were paralleled by reductions in serum levels of inflammatory markers and in periaortic mass sizes. Ga scintigraphy was able to detect extra-abdominal involvement in one patient and to demonstrate disease relapses in two symptomatic patients with normal inflammatory markers and stable residual mass. These findings suggest that Ga scan may be useful to assess disease activity and to gauge response to treatment in CP.
PET is another technique that has proved useful in diagnosing and monitoring CP ( Fig. 1 ). Studies performed in large-vessel vasculitis suggest that PET is more sensitive than inflammatory markers and MR in assessing disease activity. Virtually all data on PET in CP derive from case reports and small case series. We have previously shown that PET was able to reveal active vasculitis of the abdominal aorta, of the iliac arteries, or both, in seven patients with CP, but not in matched controls . In addition, PET revealed abnormal vascular FDG uptake by other vessel segments in nearly half of patients with CP, underscoring its role in determining the extent of the disease. A study from another research group has confirmed the value of PET in the diagnosis of CP, and also investigated its role in gauging response to therapy . Twenty-six patients with CP receiving tamoxifen monotherapy were assessed by PET at baseline; PET was repeated at 3 months in those with initial positive findings. Twenty patients had a positive PET, six of whom had also evidence of abnormal vascular FDG uptake at distant sites. Following treatment, PET visual scores decreased in parallel with a drop in ESR and CRP levels, whereas no correlation was found between PET score and mass regression. These findings suggest a role for PET both in diagnosis and in monitoring of CP.
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