Metastases from primary malignancies anywhere in the body can spread to the retroperitoneum or the mediastinum; the sites of origin mentioned in the literature most frequently are the breast, stomach, colon, prostate, lung, and kidney [14, 21, 22, 28, 29].

Carcinoids are likely to induce RPF in the absence of metastases, or primary localizations in the retroperitoneum, 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 [30]. Mesenteric fibrosis and associated ischemia, caused by a characteristic desmoplastic reaction, is often present in association with small bowel carcinoids. These tumors are also frequently associated with buckling or tethering of the intestine caused by extensive mesenteric involvement [31, 32].

Desmoid tumors are uncommon, with an estimated incidence of 2.4–4.3 per million per year, accounting for less than 3 % of soft-tissue lesions. Although there is some variability, there is a 2–3.5-fold increased incidence in women. Most cases occur between the ages of 15 and 60 years with an average age of 36.7 years. The majority of cases are sporadic with no known predisposing factors, except the genetic syndrome familial adenomatous polyposis or in association with pregnancy or trauma. Desmoid tumors are benign tumors of soft tissue, locally invasive and highly recurrent, equivalent to low-grade fibrosarcoma but without metastatic potential [33]. They represent less than 3 % of soft tissue tumors. In principle, desmoid tumors can affect all parts of the body: extra-abdominal injury (neck, shoulders, upper extremities, gluteal region), abdominal (from the fascia to the abdominal/chest wall, and rarely in the mesenteric or retroperitoneal space. Smooth and firm masses are usually detected by palpation. Desmoid tumors result from the proliferation of well-differentiated myofibroblasts, and their pathogenesis is driven by the Wnt/beta-catenin pathway. The diagnosis is confirmed by biopsy of the tumor showing an abundant collagen surrounding elongated fusiform cells with small nuclei and regular and clear cytoplasm. The immunohistochemical examination reveals the expression of beta-catenin and the absence of CD34, c-kit, desmin, and S-100. In addition, the diagnosis can be confirmed by screening for mutations of CTNNB1, the beta-catenin gene. Indeed, approximately 85–90 % of sporadic desmoid tumors are associated with somatic mutations in CTNNB1. Differential diagnosis is wide, ranging from fibrosarcoma, gastrointestinal stromal tumor, solitary fibrous tumor, inflammatory myofibroblastic tumor, sclerosing mesenteritis, benign RPF to hypertrophic keloid scars [34].

Finally, RPF may also arise as a sclerotic response to radiotherapy, trauma, or surgical injury. Less common causes include rare infiltrative diseases, such as the non-Langerhans histiocytosis form named Erdheim–Chester disease (Chap. 12).

The secondary forms of RPF caused by malignancies are characterized by the presence of neoplastic cells scattered into an abundant fibrous tissue; disruption or infiltration of neighboring muscle and bone structures is commonly found. However, microscopic (rather than macroscopic) characteristics drive the diagnosis toward a malignant form of RPF. For example, clonality of the inflammatory infiltrate or the presence of Reed-Sternberg cells suggest the presence of an underlying lymphoma [35]. The presence of lipoblasts may suggest the diagnosis of well-differentiated liposarcomas with sclerosing and inflammatory features [18]. For comparison, benign RPF manifests on gross examination, as a pale, grayish, rubbery plaque-like mass with poorly defined margins enveloping adjacent viscera, including the ureters and the inferior vena cava; benign RPF usually extends from the origin of the renal arteries to the caudal portion of the common iliac vessels [2].

All the forms of (retroperitoneal and/or mediastinal) fibrosing disorders have similar clinical manifestations, thus their clinical presentation is often of no help in the differential diagnosis. Malignancies of the retroperitoneum cannot be identified by any specific laboratory test. However, it is recommended to perform an age-appropriate cancer screening, when exploring a patient with a RPF, especially because constitutional symptoms, such as low-grade fever, weight loss, anorexia, and fatigue classically related to malignancy, often herald the onset of idiopathic RPF in addition to pain [36]. In cases with advanced bilateral obstructive uropathy, manifestations related to uremia may predominate: hypertension, fluid and electrolyte disturbances, anemia, nausea, and vomiting [37]. Involvement of the biliary tree by the fibrotic tissue may cause obstructive jaundice [38].

Patients with benign RPF have a median age of 50 to 55 years [39–41] whereas malignant retroperitoneal RPF may affect older people: in a study by Rosenkrantz et al., retroperitoneal lymphomas affected patients aged 72.4 ± 13.3 years [39]; in a study of ours, malignant RPF patients had a median age of 63.6 years [8].

There is a 3:1 male-to-female preponderance in benign RPF, whereas sex ratio may be more balanced in case of malignancy [8, 39, 42].

Age-appropriate cancer screening, when exploring a patient with a RPF, may include laboratory tests, and elevated prostatic specific antigen, beta2-microglobulin, or lactate dehydrogenase, for example, would turn toward a prostatic carcinoma or a lymphoma. Autoantibodies are often detected in patients who have benign and not in malignant RPF [37, 43]. The degree of renal failure generally depends on the extent of ureteral involvement. Renal dysfunction and the systemic inflammatory response contribute to the development of a normochromic, normocytic anemia [13].

As detailed above, a wide spectrum of neoplastic and nonneoplastic proliferative conditions may involve the mediastinal, retroperitoneal, or perirenal space either in isolation or as part of a systemic disease. Although some tumors and pseudotumors of these spaces (e.g., angiomyolipoma, hemangioma, and lymphangioma) have characteristic imaging findings that permit their diagnosis, biopsy and histopathologic evaluation are required in most cases to establish a definitive diagnosis. Nevertheless, familiarity with the spectrum of imaging features may facilitate accurate diagnosis [44].