The clinical entities included in the spectrum of CP are idiopathic. About one third of RPF, particularly if nonaneurysmal, are instead secondary to different etiologies, including drugs, malignancies, infections, and external-beam radiation [1, 7].

The drugs most frequently associated with RPF are derivatives of ergot alkaloids (e.g., methysergide, ergotamine) and dopamine agonists (e.g., pergolide, methyldopa). Methysergide and other ergotamine-derived agents increase the levels of endogenous serotonin that can lead to fibrous reactions through stimulation of myofibroblast proliferation and increase in collagen matrix deposition. This fibrogenic effect is often not limited to the retroperitoneum, but may involve pericardium, pleura, and lungs [8, 9]. Other medications reported as associated with RPF include beta-blockers, hydralazine, and phenacetin, but the pathogenesis of this process is still unclear [10]. Recently, some case reports described the relation between RPF and the previous or concomitant use of biological agents. In particular, the drugs involved are infliximab, a monoclonal antibody directed against tumor necrosis factor-alpha (TNF-alpha) and etanercept, a soluble receptor that acts as a TNF-alpha blocker, both widely employed in the treatment of rheumatic diseases. It was already reported that they may trigger a number of autoimmune conditions, but the mechanisms through which they may stimulate fibrotic reactions are still unknown [11].

Malignancies are a frequent cause of secondary forms of RPF. In most of these cases, RPF is the consequence of an exuberant desmoplastic response to retroperitoneal metastases (e.g., carcinoma of the prostate, breast, colon) or is due to primary retroperitoneal neoplasms (e.g., Hodgkin and non-Hodgkin lymphomas, various types of sarcomas, and well-differentiated liposarcoma sclerosing variant) [12]. The only exception are carcinoids, where RPF can arise in absence of metastasis or primitive retroperitoneal lesions, probably through a mechanism mediated by serotonin or by the release of fibrogenic growth factors such as platelet-derived growth factor, insulin-like growth factor, epidermal growth factor, and the family of transforming growth factors alpha and beta [13].

Infection-related RPF is usually secondary to the local spread of a contiguous infectious focus (e.g., spinal or paraspinal abscesses), or to an immune response triggered by a remote infection. The primary infections more often reported are tuberculosis, actinomycosis, or histoplasmosis [14].

Finally, other potential causes of RPF include radiotherapy, trauma, major abdominal surgery, proliferative disorders such as Erdheim–Chester disease, and other histiocytoses [15].

The association with autoimmune disorders is an interesting aspect of idiopathic RPF and highlights the relevance of autoimmune mechanisms in the pathogenesis of the disease. Autoimmune thyroiditis is the most frequently associated autoimmune condition: in a recent case–control study, idiopathic RPF patients had a prevalence of antithyroperoxidase antibodies of 24.7 % (versus 10.6 % in healthy controls) and a significantly higher frequency of ultrasound signs of chronic thyroiditis; after a median follow-up of 45 months, 25 % of RPF patients developed hypothyroidism requiring L-thyroxine. Where available, histology most often showed typical Hashimoto thyroiditis or its fibrous variant [16]. Cases of Riedel’s thyroiditis were also described [17].

Idiopathic RPF can also arise in the context of a systemic fibroinflammatory condition recently reclassified as IgG4-related disease (IgG4-RD), a heterogeneous disorder whose spectrum of manifestations include sclerosing (autoimmune) pancreatitis and cholangitis, chronic sialoadenitis, fibrosing mediastinitis, orbital pseudotumor, and tubulointerstitial nephritis. These organ manifestations can be variably associated and can develop simultaneously or metachronously. Histologically, the affected organs reveal similar aspects to those seen in idiopathic RPF (abundant fibrosis and a chronic inflammatory infiltrate), but more specific manifestations include an intense infiltration by IgG4-bearing plasma cells, fibrosis with a storiform pattern, tissue eosinophilia, and – rarely – obliterative phlebitis [18]. An increase in serum IgG4 levels is also often detected in these patients [19]. Recent studies have demonstrated that, based on histologic findings (e.g., IgG4+ plasma cell infiltration), approximately 50 % of idiopathic RPF can be histologically classified as “IgG4-related” even when the disease is not associated with other IgG4-RD lesions. However, these data have not yet been confirmed. IgG4-related and IgG4-unrelated RPF do not appear to differ clinically, except for a higher frequency of extraretroperitoneal manifestations in the former group; in particular, they have similar demographic and laboratory characteristics, comparable mass location and thickness, and comparable rates of ureteral involvement. Therefore, it is likely that they represent different ends of the same disease spectrum [5].

Idiopathic RPF has also been found in association with different types of glomerulonephritis (GN), particularly membranous nephropathy (MN) [20, 21]. Idiopathic MN is also mediated by glomerular deposition of IgG4. Notably, target antigens in MN associated with RPF or IgG4-RD differ from those (e.g., phospholipase A2 receptor) detected in idiopathic MN [22, 23].

Finally, other associations reported in the literature include rheumatoid arthritis, ankylosing spondylitis, ANCA-associated vasculitis, systemic lupus erythematosus, and psoriasis [24–27].

CP is a rare disease and data about its epidemiology are not well known and limited to idiopathic RPF and IAAA. The incidence of idiopathic RPF is estimated to be 0.1–1.3 per 100,000 person-years and its prevalence 1.4 per 100,000 inhabitants [7, 28]. Data available about IAAAs show that they represent 4–10 % of all abdominal aortic aneurysms. No data are available about the incidence of secondary RPF. Idiopathic RPF most commonly occurs in individuals aged 50–60 years and has a male predominance (male/female ratio of 2:1 to 3:1) [29, 30]. Pediatric cases are rare, with up to 30 patients described in the literature [31].

The first studies on the pathogenesis of the disease, carried out during the 1980s and 1990s by Parums and Mitchinson, defined CP as an exaggerated localized reaction to antigens contained in the atherosclerotic plaques of the abdominal aorta. These authors postulated that plaque macrophages process oxidized low-density lipoproteins (LDLs) and, migrating from the intima-media to the adventitia (especially when there is medial thinning as it occurs in atherosclerosis), they present such lipids to lymphocytes and plasma cells, triggering adventitial and periadventitial inflammation and fibrosis [4, 32].

However, the observation of idiopathic RPF in patients who do not suffer from atherosclerosis and, at the same time, the high frequency in these patients of constitutional symptoms, high concentrations of acute-phase reactants, autoantibodies, and the association with other autoimmune diseases, have led to the hypothesis that CP is a manifestation of a systemic autoimmune disease [33]. This systemic immune-mediate theory is also in line with the evidence that idiopathic RPF usually shows a good response to immunosuppressive therapy [34]. Idiopathic RPF could arise as a primary aortitis that subsequently elicits a periaortic fibroinflammatory response. In keeping with this hypothesis is the observation that inflammation predominates in the adventitia and is often associated with vasa vasorum vasculitis together with adventitial lymphoid follicles with germinal centers [35]. The pathogenesis of the disease is multifactorial. Genetic studies have demonstrated that CP is associated with human leucocyte antigen (HLA) DRB1*03, an allele linked to other autoimmune diseases such as type 1 diabetes, myasthenia gravis, and Hashimoto’s thyroiditis [36]. A more recent study also described an increased susceptibility to develop CP, especially its aneurysmal form, in patients carrying the delta 32 (∆32) polymorphism of the CC-chemokine receptor 5 (CCR5) gene. CCR5 is expressed on many immune cells, especially Th1 cells, and this SNP may produce a nonfunctional receptor that could shift T-cell response towards a Th2 pattern [37].

Environmental factors also play a definite role. A recent case–control study confirmed the predisposing role of asbestos exposure and also identified smoking as a risk factor. Smoking and asbestos had a multiplicative effect on disease risk, with an odds ratio of 12.04 (95 % confidence interval, 4.32–38.28) in those subjects exposed to both risk factors [38]. Microbial agents such as Mycobacterium tuberculosis may also act as disease triggers [14], while the role of viruses is still uncertain.

The molecular mechanisms underlying the development of CP are still unclear. Studies performed on aortic biopsies in these patients revealed the expression of gene transcripts of interferon-γ (IFN-γ), interleukin-1α (IL-1α), IL-2, and IL-4, suggesting lymphocytic activation [39]. A number of chemokines have certainly a pathogenetic role. A recent study showed that serum levels of eotaxin/chemokine (C-C motif) ligand 11 (CCL11) are significantly higher in CP patients than in healthy controls and this chemokine is also highly expressed by mononuclear cells in the inflammatory infiltrates of retroperitoneal biopsies obtained from CP patients. Eotaxin/CCL11 induces tissue recruitment of eosinophils and mast cells which have been found in periaortic biopsies. In addition, the receptor for eotaxin/CCL11, CCR3, has been demonstrated to be diffusely expressed by eosinophils, mast cells, and fibroblasts, suggesting that this chemokine may have a peculiar pathogenetic role not only by inducing tissue influx of eosinophils and mast cells, but also by directly stimulating collagen-producing cells [40]. Fibroblast proliferation and collagen production are also stimulated by eosinophil and mast cell products (e.g., eosinophil granule proteins, tryptase) [41]. Fibroblasts activation is also induced by CCL18, a marker of fibrotic activity in pulmonary idiopathic fibrosis, whose serum levels were found to be increased also in CP and correlated with tissue shrinkage after therapy [42].

The recent considerations about the association of idiopathic RPF or IAAAs with IgG4-RD, together with the frequent observation of intense infiltration by IgG4+ plasma cells in both aneurysmal and nonaneurysmal forms of CP, led to new pathogenetic hypotheses [43]. In fact, because IgG4-skewed immune responses are commonly driven by T-helper 2 (Th2) cytokines such as IL-4, IL-5, IL-10, and by TGF-β, it is likely that such reactions play a pathogenetic role both in IgG4-RD and in CP, with TGF-β that promotes fibrosis and IL-5 inducing eosinophil maturation and tissue infiltration [44]. IL-4, IL-10, and IL-13 instead can boost B-cell responses and humoral immunity. B cells are abundant in CP tissue [45]. Their pathogenetic role is still unclear, but it is known that these cells are critical for antigen presentation to Th2 effector cells or CD4+ effector memory cells and have an important role in the persistence of the disease, modulating immunity independently of antibody production, both as effective antigen-presenting cells and as source of cytokines. In addition, in CP, it has been shown that T cells locally produce IL-6, which can activate B cells and fibroblasts [46].

The pathogenic importance of the IL6-mediated axis and of B cells was confirmed in vivo by the efficacy of therapies targeting the IL-6 receptor (tocilizumab) and the B-cell marker CD20 (rituximab), but these data are limited to small case series and need to be confirmed by larger studies [46, 47].

CP is a rare and severe disease that may progress until kidney failure due to the complete obstruction of the ureters and/or of the blood vessels of the kidney peduncle involved by the process. A prompt diagnosis and an appropriate treatment may prevent the development of irreversible complications. Unfortunately, the clinical presentation of CP is often vague and insidious and an early diagnosis is usually difficult. The most common presenting symptoms of CP are abdominal, lower back, or flank pain. The pain is usually dull and constant. A colicky pain due to ureteral encasement may occur but is not mandatory. Renal failure due to bilateral ureteral obstruction resulting in hydronephrosis is seen in about 42–95 % of the cases [28, 30]. Ureteral encasement can frequently be unilateral and, for this reason, renal function may remain normal for a long time. In these cases, the correct diagnosis is made tardily and the chronic entrapment of the ureter can lead to a severe and sometimes irreversible damage to the corresponding kidney.

Retroperitoneal blood and lymphatic vessel involvement is less frequent (one-quarter of the cases) and manifests typically as edema (rarely thrombophlebitis) of the lower limbs, while arterial encasement may cause – although not frequently – claudication. Other complications include scrotal swelling, varicocele or hydrocele, due to the compression of the gonadal vessels, and constipation, nausea, and vomiting. Constitutional manifestations such as fever, weight loss, fatigue, and night sweats often occur [1, 7]. If the thoracic aorta or the periaortic arteries are involved, patients may suffer from hoarseness, secondary to recurrent laryngeal nerve paralysis, dry cough, or upper limb claudication [3].

Acute-phase reactants, such as the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), are elevated in more than half of the patients but they lack sensitivity and specificity for the diagnosis of RPF and are not able to distinguish idiopathic from secondary forms. However, ESR and CRP correlate with the symptoms and the amount of mass shrinkage after therapy, thus they are useful to monitor the clinical course of the disease [48].

Renal function is variably impaired in patients with ureteral encasement, depending on the severity of obstruction. Urinary sediment and proteinuria should be checked to exclude an underlying glomerulonephritis. Even in absence of any parenchymal renal disease, macroscopic and microscopic hematuria may be found, probably as a result of ureteral involvement. Anemia is quite frequent, due to chronic inflammation and/or renal dysfunction [49].

Antinuclear antibodies (ANAs) and anti–smooth muscle antibodies are the most frequently positive autoantibodies. They can be positive even in patients without any associated autoimmune disorder and their presence may support the autoimmune origin of the disease [34].

Serum IgG4 levels may be raised in patients with both nonaneurysmal and aneurysmal forms of CP [19]. However, these findings do not always allow to classify the disease as part of IgG4-RD; high serum IgG4 levels are also found in approximately 5 % of healthy controls and in patients with other diseases such as eosinophilic granulomatosis with polyangiitis (EGPA), Castelman’s disease, and eosinophilic pneumonia [50, 51]. Thus, the finding of high serum IgG4 needs to be interpreted within the clinical context.

The macroscopic findings of the idiopathic and the secondary forms of RPF are often similar [1]. The lesion appears as a hard and white mass of varying thickness without a capsule, which infiltrates the retroperitoneal adipose tissue surrounding the abdominal aorta and iliac vessels, as well as the inferior vena cava and the ureters.

The microscopic observation of idiopathic RPF samples reveals the presence of two components: a fibrous tissue and a chronic inflammatory infiltrate. The fibrous component consists of an extracellular matrix composed of type I collagen fibers organized in thick irregular bundles and a population of spindle-shaped cells characterized immunohistochemically as fibroblasts and myofibroblasts (positive for vimentin and α-smooth muscle actin, respectively). The fibroblast population rarely shows mitoses, although these cells have been shown to undergo clonal proliferation. The collagenous stroma contains varying quantities of nerves and small blood vessels that often show a prominent perivascular hyalinization. The inflammatory component infiltrates the fibrous tissue and consists of B and T lymphocytes, macrophages, plasma cells, and rare eosinophils. It can be diffuse or organized into a perivascular pattern. In the former case, inflammatory cells are interspersed within the collagen bundles; in the latter, aggregated lymphocytes surround the small retroperitoneal vessels and tend to have a central core of B cells and a periphery of CD4+ and CD8+ T cells [45]. In the late stages of the disease, histology shows especially pronounced sclerosis with scattered calcifications and a reduction of the inflammatory component [1].

In IgG4-related RPF, the microscopic findings are very similar to those of the idiopathic form, with associated obliterative phlebitis, a mild-to-moderate eosinophilic infiltrate, and fibrosis with a storiform pattern. As in idiopathic RPF, the inflammatory infiltrate is composed of T and B lymphocytes, whereas B cells are typically organized in germinal centers and T cells are distributed diffusely. Although IgG4-bearing plasma cells may be also found in the inflammatory infiltrate of idiopathic RPF, a ratio of IgG4-bearing plasma cells to total IgG-bearing plasma cells higher than 30–50 % is essential for the diagnosis of IgG4-related RPF [18].

Imaging procedures are essential for the diagnosis and follow-up of CP [52]. Ultrasonography is usually the first-line study performed at the disease onset to assess the presence of hydronephrosis and aortic dilatation/aneurysm; sometimes a hypoechoic periaortic tissue may be observed [53].

Abdominal CT and MRI are currently considered the investigations of choice to reach a correct diagnosis [53]. CP appears at CT as a homogeneous periaortic and peri-iliac mass isodense to muscle that can compress neighboring structures and displace the ureters medially. Unlike secondary forms of RPF due to neoplasms or lymphomas that appear as lobulated or nodular masses infiltrating or destroying psoas muscles or bones, idiopathic RPF is usually characterized by a mass of soft-tissue density and a plaque-like appearance, located distal to the kidney hilum, anteriorly and laterally to the aorta. In aneurysmal CP (IAAAs or PRF), the aorta has aneurysmal dilatation and the tissue usually encircles its entire circumference. Some localized lymphadenopathies adjacent to the mass can occur in idiopathic forms but they are never confluent (Fig. 8.2).

On MRI, CP appears hypointense in T1-weighted images; in T2-weighted images, its intensity is low in the quiescent phases of the disease and high in the active stages, when there is abundant tissue edema and hypercellularity [54]. If renal function is not compromised, it is useful to perform CT or MRI with contrast medium. The contrast-enhancement on CT or MRI of the retroperitoneal mass correlates with disease activity, and can be used to evaluate the response to treatment [53].

Nuclear medicine is a suitable complement to radiographic imaging because it provides an easy visualization of almost the entire body. Specifically, fluorodeoxyglucose-positron emission tomography (FDG-PET) is a nuclear medicine technique able to identify accurately in vivo areas characterized by elevated glucose metabolism, such as inflammatory, infectious, and neoplastic lesions. In patients with CP, FDG-PET is able to show a vasculitic process in the large branches of the aorta, both abdominal and thoracic [55]. The presence of atherosclerotic plaques or of other large-vessel vasculitides such as giant cell arteritis or Takayasu’s arteritis can also produce a positive vascular FDG uptake, reducing the specificity of this technique for the diagnosis of CP. Recent studies showed the abnormal FDG uptake by the retroperitoneal mass in active disease phases tends to reduce parallel to ESR and CRP through remission [56, 57]. In clinical practice, FDG-PET is used to assess disease activity. In addition, it can also reveal active vasculitis in other vascular territories and may disclose other affected areas, such as those observed in IgG4-RD, or occult neoplastic or infectious processes, thus turning very useful in differential diagnosis with secondary forms of RPF [55]. If imaging studies are not completely diagnostic for CP, tissue biopsy becomes mandatory. Biopsy may be recommended in cases with atypical localization (e.g., periureteral, perirenal) [58, 59], or with clinical or imaging findings consistent with neoplastic RPF [60] and in patients refractory to conventional steroid therapy. Multiple biopsy techniques have been used in sampling CP, including open, laparoscopic, or transcaval retroperitoneal biopsy, and fine-needle aspiration.

The first aim of treatment of CP is reversing ureteral obstruction and preserving kidney function [1]. In all cases of renal failure and severe bilateral hydronephrosis, ureteral decompression should be promptly performed in order to avoid permanent kidney damage. Surgical ureterolysis with intraperitonealization and omental wrapping of the ureters is no longer the first-line approach, while conservative procedures (e.g., double-J stent or nephrostomy placement) followed by medical therapy are preferred [61, 62]. Surgical approach is often mandatory also in the perianeurysmal forms of RPF when the aortic diameter exceeds 5–5.5 cm; in these cases, open repair is the traditional method, although the less invasive endovascular prosthesis placement is now widely used with good efficacy. No clear differences between inflammatory and noninflammatory abdominal aortic aneurysms are reported in terms of risk of rupture, postoperative complications, and long-term outcome [1]. Some case reports describe the possibility of a complete regression of the perianeurysmal mantle [63]. However, several studies indicate that it frequently persists or even progresses after surgery or endovascular treatment. For this reason, medical treatment might be the treatment of choice when there are no surgical indications for aneurysm repair, to improve the symptoms and to reduce the risks of obstructive complications. In the other cases, the need for starting medical therapy will be considered depending on patient condition and, however, a strict follow up is mandatory [1].