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Idiopathic Retroperitoneal Fibrosis

Prospective Evaluation of Incidence and Clinicoradiologic Presentation

van Bommel, E. F. H. MD, PhD; Jansen, I. MD; Hendriksz, T. R. MD; Aarnoudse, A. L. H. J. MD, PhD

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doi: 10.1097/MD.0b013e3181afc420
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Abstract

INTRODUCTION

Retroperitoneal fibrosis (RPF) is an uncommon disorder that encompasses several different pathophysiologic entities, all of which lead to fibrosis in the retroperitoneum.8,30 If unrecognized or left untreated, progressive disease leads to compression of retroperitoneal structures, notably the ureters.8,31 Before a condition can be labeled idiopathic RPF, all identifiable causes, particularly malignancy, certain drugs, and chronic infection, should be excluded.8,31

Few earlier studies of sizable patient numbers focused on symptoms and diagnosis of RPF; these include 1 retrospective single-center study,34 1 retrospective multicenter study,2 and 2 overlapping studies12,14 analyzing cumulative data from reported cases in the literature. Many comprehensive reviews8,11,27,31 of the disease have been published over the years; however, attention has been increasingly focused on the primary medical treatment of idiopathic RPF, and on whether idiopathic RPF represents a localized disease process or if it is but the most prominent manifestation of a systemic disease.

To our knowledge, no data exist to date on the true incidence of RPF.27,31 It is also unclear if age, male-female ratio, and/or clinical picture has changed over the years, and if the routine application of sophisticated imaging techniques has led to earlier recognition of the disease. We sought to address these issues by analyzing 53 consecutive patients with idiopathic RPF seen at our tertiary care referral center. The prospective design of the study and the size of the series permit more firm conclusions to be made as to the incidence and presentation of idiopathic RPF in adults.

PATIENTS AND METHODS

Patients

From April 1998 through January 2008, all patients who had an initial diagnosis of recurrence of RPF defined according to the diagnostic protocol in our tertiary care referral center were included in the current prospective study. This included patients from our catchment area and referred patients from elsewhere with suspected idiopathic RPF. Since 1998 all patients with suspected RPF in the Albert Schweitzer Hospital have been referred to our department. If RPF was radiologically suspected in an as-yet undiagnosed and unreferred patient in our hospital, our RPF-expert radiologists were routinely informed, and they then reviewed radiologic findings. If the findings were confirmed, the treating physician was contacted by the first author and asked for permission to include the patient in our diagnostic and therapeutic follow-up study. No physician or patient refused referral. A search for RPF cases in our pathology database (biopsy and autopsy results) revealed no other cases during the study period. Referred patients from outside our catchment area with an established diagnosis of idiopathic RPF in whom treatment was already initiated and patients with synchronic malignancy were excluded from the study.

The diagnosis of idiopathic RPF was based on the typical clinical picture and the presence of characteristic computed tomography (CT) findings, in the absence of any sign of malignancy. Contrast-enhanced CT typically shows a well-defined retroperitoneal soft-tissue attenuation mass, enveloping but not displacing the lower abdominal aorta with caudad extension following the bifurcation of the iliac vessels.8,11,27,31 Malignancy was ruled out on the basis of a detailed patient history, review of all patient records, physical examination, laboratory investigation including prostate-specific antigen in men and thyroid status, chest radiography, abdominal CT scanning including the basal lung regions, and whole-body nuclear imaging. In several cases, additional mammography, colonoscopy, chest CT scanning, or histologic examination of biopsy material was performed. Dynamic nuclear imaging with 67gallium single photon emission CT (67Ga SPECT) and/or 18F-fluorodeoxyglucose positron emission tomography (18FDG-PET) was routinely performed. Detailed evaluation of the value of 67Ga SPECT in the diagnostic and therapeutic workup of patients with RPF has been reported previously by our group,32 whereas the specific value of 18FDG-PET is the subject of an ongoing study. Hence, we report herein only results of nuclear imaging at presentation. The study complied with the Declaration of Helsinki. All patients provided informed consent at presentation.

Radiologic Imaging

All CT scans were independently reviewed by 2 experienced radiologists who were unaware of the patient's status. Differences between radiologists were resolved by consensus. The maximal thickness (mm) of the retroperitoneal mass was measured in 3 different CT-view directions (anterior-posterior, left lateral, and transversal direction). The craniocaudal length (mm) of the mass was also documented. Mass localization and extension were recorded for each patient. Densitometric values (Hounsfield units, HU) of the RPF mass after contrast infusion were documented and compared to that of psoas muscle. For this, we determined the ratio between attenuation values of the RPF mass and psoas muscle. We noted infrarenal aortic diameter (mm); presence or absence (= 0) of unilateral (= 1) or bilateral (= 2) hydro-ureteronephrosis; the number of atrophic kidneys (defined as kidney diameter ≤8.5 cm); and any other observed intraabdominal abnormalities. As the basal lung regions were routinely scanned, pleural and diaphragm abnormalities including asbestos-related pathology (pleural thickening, plaques, calcification) were also recorded. Nuclear imaging showing enhanced (that is, pathologic) 67Ga or 18FDG uptake in the paravertebral midline at the same position as the CT-documented retroperitoneal mass was considered a "positive" gallium/PET scan result. A "negative" gallium/PET scan result implicated no pathologic uptake.19,32 Foci of pathologic uptake at other sites were also documented.

Measurements

Measurements included age, sex, clinical signs and symptoms, duration of symptoms, blood pressure, and body mass index (BMI). A detailed history was taken to assess the presence of cardiovascular risk factors and/or cardiovascular disease (CVD)-that is, established coronary, cerebrovascular, or peripheral vascular disease-in each patient. Smoking history was assessed as never smoked (= 0); past smoker (= 1); and current smoker (= 2). Patients were specifically asked if they had had possible environmental or occupational asbestos exposure. Apart from documentation of subjective complaints, we used the 100 mm horizontal visual analogue scale (VAS) to objectify severity of primary symptoms in each individual, using pain and discomfort as variables.36 Laboratory measurements included erythrocyte sedimentation rate (ESR); C-reactive protein; serum creatinine; hemoglobin (Hb); hematocrit; mean corpuscular volume; white blood cell count (WBC); and serum albumin. Serum samples were assayed for the presence of antinuclear antibodies (ANA) with indirect immunofluorescence at 1:40 dilution using Hep-2000 epithelial cells as substrate. Antibodies to extractable nuclear antigens (ENA) and antineutrophil cytoplasmic antibodies (ANCA) were assayed by enzyme-linked immunosorbent assay (ELISA). Thyroid status and presence of anti-thyroperoxidase (anti-TPO) antibodies (ELISA) were assessed in study patients. Findings of nuclear imaging and CT scanning were documented as described.

Statistical Analysis

Continuous variables were reported as mean ± standard deviation (SD) or, in case of skewed distribution, as median and interquartile range (IQR, 25th-75th percentile). Differences between continuous variables were analyzed using (paired) t-test or, in case of skewed distribution, using the Mann-Whitney test or Wilcoxon signed rank-sum test. Categorical variables were expressed as proportions and compared with the Fisher exact test.

We performed age- and sex-adjusted regression analyses, testing magnitude and direction of effect for different variables on mass size on CT and on the VAS scores for pain and discomfort. Consecutively, we tested statistically significant determinants of these outcomes in multivariate models, including clinically significant factors as potential confounders. First, potential confounders were added 1 at a time to the model containing the determinant of interest, age and sex. Confounders that had a p value of <0.1 in this model were stepwise entered in a model, thus keeping in the most relevant confounders of the determinant. Likewise, we tested smoking as a determinant for abdominal aortic diameter, adjusting for relevant confounders in a step-wise multivariate model. All reported p values are 2-sided. A p value of < 0.05 was considered significant. All statistical analyses were performed with SPSS software (version 11.0.1; SPSS inc., Chicago, IL).

RESULTS

During the study period, 53 patients (that is, cases) were diagnosed as having idiopathic RPF in our center. No patient used drugs or suffered from chronic infection that could have been associated with RPF. The diagnosis was confirmed histologically in 8 patients. Follow-up revealed no other pathology that could have accounted for the findings at presentation. The catchment area of our hospital constitutes 290,000 inhabitants (Practice analysis, Stichting Prismant, June 2006, Utrecht, The Netherlands). Excluding patients who presented with recurrent disease but who were diagnosed with RPF before the study period, and/or patients who were referred to our center from outside our catchment area (n = 16), we encountered 37 new cases over a 9.7-year period, or 3.8 cases per year, for an incidence of 1.3 cases per 100,000 inhabitants per year.

There were 41 male patients, and a male-female ratio of 3.3:1.0 (Table 1). Patients usually presented in the fifth through seventh decades of life (mean age, 64 yr). Median duration of symptoms was 6 months, but there was large inter-individual variation (Figure 1). Age and duration of symptoms at presentation did not differ between men and women (see Figure 1). Cardiovascular risk factors and/or established CVD were present in most patients (see Table 1). Previous (psoriasis, n = 1; uveitis posterior, n = 1; polymyalgia rheumatica, n = 2; autoimmune hypo- or hyperthyroidism, n = 3; primary hyperparathyroidism, n = 1) or concurrent (acute interstitial nephritis, n = 1; polyarteritis nodosa, n = 1; Crohn disease, n = 1) manifestation of chronic inflammatory and/or autoimmune diseases was recorded in 8 patients (15%). Eight patients, all male (20%), were occupationally exposed to asbestos. A history of (1 or more episodes of) deep vein thrombosis was noted in 3 patients (6%).

F1-1
FIGURE 1:
Distribution of age and time from onset of symptoms to RPF diagnosis according to sex in 53 patients with idiopathic RPF.
T1-1
TABLE 1:
Demographic and Clinical Characteristics of Study Patients

Pain was the most common symptom with 92% of patients complaining of lower back, abdominal, and/or flank pain, often radiating to the groin (24%) and/or the lateral upper leg and hip region (30%) (Table 2). Pain was often most severe at night. Other frequent symptoms were urinary frequency, weight loss, constipation, and in men, testicular pain with or without scrotal swelling (see Table 2). Physical examination was unremarkable except for the presence of increased BMI and hypertension, and in men, scrotal swelling (see Tables 1 and 2). Lower extremity edema was found in 8% of patients.

T2-1
TABLE 2:
Major Symptoms and Signs at Presentation

Laboratory investigation usually but not invariably revealed increased acute-phase reactants, often accompanied by normocytic anemia (64%), leukocytosis (36%), and hypoalbuminemia (32%) (Table 3). Female patients had higher ESR (79 mm/h [IQR 38-115] vs. 36 mm/h [IQR 20-66]; p = 0.01), higher WBC (10.3 × 109/L [IQR 8.6-11.9] vs. 8.3 × 109/L [IQR 6.7-10.0]; p = 0.02), and lower Hb content (6.6 mmol/L [IQR 6.3-7.5] vs. 8.0 mmol/L [IQR 7.2-8.9]; p < 0.01) than male patients at presentation.

T3-1
TABLE 3:
Laboratory and Nuclear Imaging Findings at Presentation

Thirty-five (66%) patients presented with impaired renal function, 29 of whom had unilateral or bilateral hydro-ureteronephrosis (Tables 3 and 4). Patients with hydronephrosis presented earlier than those without hydronephrosis (duration of symptoms: 4 mo [IQR 4-7] vs. 8 mo [IQR 4-17]; p = 0.03), with higher creatinine values (1.6 mg/dL [IQR 1.3-2.3] vs. 1.1 mg/dL [IQR 0.9-1.4]; p < 0.0001) but similar pain severity (VAS pain, 42.5 mm [IQR 17.0-64.5] vs. 38.5 mm [IQR 15.5-73.0]; p = 0.85).

T4-1
TABLE 4:
CT Findings in Study Patients at Presentation

Nuclear imaging showed pathologic 68Ga or 18FDG uptake at the level of the retroperitoneal mass in more than 70% of cases. Extraabdominal pathologic uptake, usually pulmonary, was noted in 11% of patients (see Table 3). CT scans typically showed a well-defined fibrotic mantle enveloping but not displacing the lower abdominal aorta with caudad extension into the iliac arteries (Figure 2). One patient had infrarenal caval vein and common iliac vein obstruction. Craniocaudal extension of the RPF mass up to or above the level of the renal vessels was noted in 3 patients (6%) with involvement of the left and, to a lesser extent, the right proximal renal arteries but without visible narrowing. Left renal vein involvement was noted in 2 of these patients. Five patients (9%) presented with a bulky mass extending into the pelvis (Figure 2). In 44 patients (83%), maximal mass thickness was measured in transversal view direction (Figure 3). Patients with hydronephrosis had greater RPF mass thickness at presentation compared to those without hydronephrosis (Figure 4). Densitometric values of the RPF mass after contrast infusion were equivalent to or somewhat higher than psoas muscle (see Table 4). Localized lymphadenopathy adjacent to the RPF mass was frequently noted and was characterized by multiple lymph nodes, sometimes encapsulated and matted, usually with diameter <1 cm (Figure 5). Using aortic diameter interval 19-22 mm as the reference for our age-group,13,21 32 patients (60%) had an increased aortic diameter. Aneurysmal dilation (infrarenal aortic diameter ≥30 mm) was frequently present (see Table 4). RPF mass distribution was similar in patients with or without aneurysmal dilation. Current smoking was more prevalent among patients with aneurysmal dilation (72% vs. 30%; p = 0.01). C-reactive protein level was also higher in patients with aneurysmal dilation (35 mg/L [IQR 14-90] vs. 23 mg/L [IQR 6-37]; p = 0.04). Otherwise there were no differences in studied variables between patients with or without aneurysmal dilation (data not shown). Unilateral atrophic kidneys were found in 11 patients with hydro-ureteronephrosis.

F2-1
FIGURE 2:
Abdominal contrast-enhanced CT scan in an 80-year-old man with recurrent active RPF, 14 years after first presentation. Coronal (A) and axial (B) views show a well-defined periaortic soft-tissue mass, isodense to psoas muscle, and surrounding but not displacing the atherosclerotic abdominal aorta with caudad extension to the iliac arteries. Note the incorporation of the inferior caval vein into the RPF mass on the right side of the aorta (not readily discernible from RPF mass) and the hydronephrotic left kidney. Nonfunctioning hydronephrotic right kidney was removed at first presentation. Additional axial view of the same patient (C) shows an oval presacral mass (40 × 28 mm), histologically confirmed to represent an additional RPF location, noncontiguous with the aforementioned periaortic/iliac mass (arrow).
F3-1
FIGURE 3:
Maximal thickness of the retroperitoneal mass on CT scan as measured in 3 different view directions: anterior-posterior (AP), left lateral, and transverse direction. In 44 patients (83%), maximal thickness was measured in transverse view direction.
F4-1
FIGURE 4:
Maximal mass thickness as measured on CT scan in study patients with and without hydronephrosis.
F5-1
FIGURE 5:
Contrast-enhanced abdominal CT scan (axial view) in a 72-year-old man with extensive RPF shows localized lymphadenopathy adjacent to the RPF mass (A): multiple small lymph nodes (maximal diameter, 12 mm) surrounding at that level minimal periaortic soft-tissue mass (arrows). Axial view of the basal lung territories in the same patient (B) shows extensive right-sided pleural plaques with partial calcification (arrows). There is also minimal calcification of the left basodorsal pleura (dotted arrow). C = inferior caval vein.

CT scans in 7 male patients (17% of the 41 male patients) showed unilateral or bilateral pleural plaques or pleural thickening. Two of these patients showed extensive bilateral calcified pleural plaques (See Figure 5). Six of these 7 patients were occupationally exposed to asbestos. In 1 of these patients, nuclear imaging showed pathologic uptake of the involved pulmonary region. Further analysis revealed no evidence of mesothelioma in these patients.

ANA testing proved positive in 17 patients (32%). ENA testing proved negative in all cases. Anti-TPO antibodies were present in 4 patients (8%), 1 of whom had subclinical hypothyroidism (thyroid-stimulating hormone, 12 U/L). Three of these patients were ANA negative. One patient showed p-ANCA titer but was negative for anti-PR3 and anti-MPO. One patient who presented with concurrent polyarteritis nodosa was strongly positive for p-ANCA (anti-MPO >160 U/mL).29

None of the studied variables differed between patients at first presentation and patients at recurrent presentation (data not shown). Age- and sex-adjusted regression coefficients (β) of studied variables showed a significant association of baseline ESR values with VAS score for pain (β 0.33; 95% confidence intervals [CI], 0.08-0.57; p = 0.01) and discomfort (β 0.30; 95% CI, 0.08-0.52; p = 0.01). We tested duration of symptoms, RPF mass thickness, presence of hydronephrosis, and abdominal aortic diameter as potential confounders of this association. None of these was a significant confounder at p < 0.1. Furthermore, we forced duration of symptoms into the model because it changed the regression coefficient of the determinants with >10%. This did not diminish the association of ESR with the VAS score for pain (β 0.27; 95% CI 0.02-0.52; p = 0.04) or discomfort (β 0.26; 95% CI 0.03-0.48; p = 0.03).

RPF mass thickness was negatively associated with duration of symptoms (β −0.62; 95% CI, −19.1 to −0.05; p = 0.03) and positively associated with the presence of hydronephrosis (β 11.0; 95% CI, 4.8-17.3; p = 0.001). There was no association of RPF mass thickness with other study variables (data not shown). Age- and sex-adjusted regression coefficients were significant for the association between infrarenal aortic diameter and the presence of established CVD (β 6.2; 95% CI, 1.8-10.6; p = 0.007), BMI (β 0.9; 95% CI, 0.3-1.5; p = 0.003), body surface area (BSA) (β 19.8; 95% CI, 9.2-30.4; p < 0.001) and current smoking (β 10.2; 95% CI, 4.7-15.7; p < 0.001). BMI, BSA, and the presence of CVD were significant confounders of the association between current smoking and infrarenal aortic diameter at p < 0.1, whereas the number of antihypertensive drugs was not. The presence of CVD was not considered a confounder but rather the same disease. In the stepwise model, only BSA was left as a confounder, but current smoking remained significant (β 7.3; 95% CI, 1.5-13.1; p = 0.02).

DISCUSSION

This unique single-center prospective study in a large cohort of patients extends our knowledge about the clinicoradiologic presentation of idiopathic RPF. [Editor's note: See also the new study by Scheel and Feeley22a and the commentary by Vaglio26a in this same issue.] To our knowledge, only rough estimates of the incidence of RPF were available previously, which-not surprisingly-differed markedly (1: 200,000 to 1: 500,000).27,31 In a retrospective case-control study, age-standardized incidence was estimated as 0.10 (95% CI, 0.07-0.14) per 100,000 person-years.26 Our prospective data indicate a higher than previously assumed annual incidence of 1.3 cases per 100,0000 inhabitants. Mean age at diagnosis was higher in the current study than in earlier studies (Table 5). In addition, age distribution of RPF patients in the current study differed significantly from that in previous studies,2,14,34 with more cases diagnosed in patients aged in their 70s and even 80s now. It is noteworthy that the male-female ratio also seems to have altered over the years (see Table 5). Considering the suggested pathogenetic role of advanced atherosclerosis in RPF,11,27,31 this increasing incidence may be the result of the increasing incidence of atherosclerotic disease in men.

T5-1
TABLE 5:
Main Characteristics of RPF, Present and Previous Major Reports

Despite the difference between the earlier unavailability or limited use of CT scanning and the now regular use of CT scanning and magnetic resonance imaging, no clear difference in the time interval from onset of symptoms to establishment of diagnosis can be observed between previous studies and the present report (see Table 5). The insidious and nonspecific nature of symptoms in RPF is probably responsible for this persistent delay in diagnosis.

As in previous studies, pain in the lower back, abdomen, and/or flank was the most common symptom. It often radiated to the upper lateral leg and hip region and/or to the groin, and was frequently most severe at night. Severity of pain correlated strongly with ESR values but not with other study variables. This may suggest that pain severity is mainly determined by degree of inflammation and not by duration of symptoms, presence of hydro-ureteronephrosis, or RPF mass thickness. Other frequent symptoms were urinary frequency, weight loss, and constipation. Testicular pain, scrotal swelling, and/or anejaculation were frequently present in men, probably through involvement of gonadal vessels and lymphatics. Of note, patients with hydronephrosis presented earlier than those without hydronephrosis, but with similar severity of pain and discomfort, suggesting that other factors are involved. It may be that finding impaired renal function and/or hydro-ureteronephrosis leads to earlier aggressive investigation and/or consideration of the diagnosis. Comparison of male and female patients showed no difference in age and duration of symptoms. However, laboratory investigation suggested more severe inflammation in women than in men, which warrants further investigation.

RPF mass thickness differed significantly between patients in all CT view directions. However, in most patients maximal mass thickness was measured in transversal view direction. Therapeutic follow-up studies frequently lack documentation of a defined CT measure of mass regression.9,10,16,35 For research purposes, we therefore propose that CT-documented mass thickness as measured in transversal view direction should be 1 of the variables reported in therapeutic follow-up studies. Although infrequent, atypical localization and/or presentation as a bulky mass may occur in idiopathic RPF. In such cases, histologic confirmation of the diagnosis through biopsy may be indicated.5 This indication and the choice of biopsy technique (that is, open surgical vs. CT-guided percutaneous biopsy) not only depend on the radiologic appearance of the mass but also on the overall estimated risk of malignancy and the clinician's and radiologist's experience with the disease. While a provisional diagnosis of RPF can thus not always be made with near-certainty, the observation of clinical and radiologic improvement following initiation of medical treatment will be reassuring as to the diagnosis. If no such positive treatment response is observed during initial follow-up, the possibility of malignancy or other causes should be reconsidered.8,10,27,30,34

Our data indicate that symptomatic obstruction of the iliocaval tree by RPF is rare. A feature not previously recognized is the frequent occurrence of localized lymphadenopathy adjacent to the RPF mass. This probably relates to the sometimes severe retroperitoneal inflammatory reaction, and should not confuse the diagnosis. The typically observed enhanced uptake and increase in density following radionuclide and contrast infusion, respectively, demonstrate that the RPF mass is metabolically active and vascularized.

The current study confirms that the mass in RPF is typically closely associated with the infrarenal aorta and the common iliac arteries.4,33 It lies anterior and lateral to the aorta, sparing the posterior aspect. We noted aortic displacement by posterior location of the mass in only 3 patients (5.6%). In the current study, RPF typically occurred in patients at high cardiovascular risk. Previous studies also noted the frequent occurrence of hypertension (see Table 5). When compared to published reference values,13,21 an increased aortic diameter was usually observed in our study. This is important because infrarenal aortic diameter, not just in the aneurysmal range, is an independent marker of subsequent death.14 Moreover, the frequency of aneurysmal aortic dilation (defined as infrarenal aortic diameter ≥30 mm) was high and compared highly unfavorably to the observed frequency in similarly aged healthy patients (23% vs. 4.6%).21 Similar mass distribution was seen in patients with or without aneurysmal dilation. These combined findings strongly support the concept that at least in a subset of patients with idiopathic RPF, as in perianeurysmal fibrosis ("inflammatory aneurysm"), the disease is secondary to advanced aortic wall atherosclerosis, possibly through an autoallergic reaction to components of atherosclerotic plaque.3,18,22 It is for this reason that some proposed the term chronic periaortitis to encompass idiopathic RPF, perianeurysmal fibrosis, and mediastinal fibrosis.3,18,22 Smoking, a major risk factor for atherosclerotic aortic aneurysm, was shown to be an even stronger risk factor for the inflammatory variant.20 We found an independent influence of smoking on aortic diameter in all study patients. Cessation of smoking should therefore be strongly encouraged in all patients with RPF, regardless of the presence of aneurysmal aortic dilation.

Previous studies have noted an increased incidence of autoimmune phenomena and/or disease in idiopathic RPF and in inflammatory aneurysm.7,28 Frequency of HLA-DRB1*03 allele, found in association with several autoimmune diseases, was also found to be increased in patients with idiopathic RPF.17 Signs of vasculitis may be observed upon histologic investigation of biopsy specimen.27,31 However, as in the large retrospective study of Baker et al,2 previous or concurrent manifestation of other chronic inflammatory or autoimmune disease was uncommon in the current series. ANA testing proved positive, albeit at low titer, in 32% of cases. As in other studies,28 ENA testing proved negative in all cases. Interpreting ANA positivity is difficult. ANA positivity, particularly at screening dilution, is seen in a wide range of diseases other than connective tissue disease, where it has no diagnostic or prognostic value.23,24 It is also seen in increasing frequency with aging.23,24 The reported prevalence of ANA is high in the general population, ranging from 22.6% to 38%.23,24 As in other chronic inflammatory disorders, it may be that ANA expression is not causally related but secondary to chronic inflammation.23,24 Frequency of anti-TPO antibodies and ANCA was low in the current series and does not seem to differ from those reported in the literature.15,25 Taken together, the results of our study do not support the concept of idiopathic RPF being a systemic autoimmune disorder. However, we observed 1 patient who presented with concurrent p-ANCA-positive polyarteritis nodosa,30 and 1 patient with a history of Hashimoto thyroiditis, uveitis posterior, and polymyalgia rheumatica who presented with concurrent acute interstitial nephritis. Although this may be coincidental, in some patients RPF may be an expression of a systemic autoimmune disorder and/or deranged self-tolerance. Autoimmune/inflammatory disease was noted to develop late in the course of RPF.29 The active search for autoimmune/inflammatory conditions is therefore strongly encouraged during follow-up of RPF.

In a retrospective case-control study, occupational asbestos exposure significantly increased the risk of developing RPF (odds ratio 8.8 for ≥ 10 fiber-years).26 We frequently observed prolonged asbestos exposure and asbestos-induced changes in the lung and pleura in male patients, providing further evidence for the association of RPF with occupational asbestos exposure.6,26 The mechanism by which this occurs is unknown, but in necropsies of asbestos-exposed patients, numerous asbestos bodies are found throughout the body, including retroperitoneal organs.1

In summary, the current prospective study reveals a higher annual RPF incidence than previously assumed. Age at diagnosis and male-female ratio seem to have changed over time. Idiopathic RPF typically affects patients at high cardiovascular risk, including an increased-often aneurysmal-infrarenal aortic diameter. Clinical presentation is influenced by sex, severity of inflammation, and presence or absence of hydro-ureteronephrosis. Localized lymphadenopathy adjacent to the RPF mass was observed frequently and should not confuse the diagnosis. Although rare, RPF may present as an inflammatory pseudotumor. Our study provides further evidence for the association of RPF with occupational asbestos exposure. Smoking was independently associated with increased infrarenal aortic diameter. Hence, cessation of smoking should be strongly encouraged in all patients with RPF, regardless of the presence of aneurysmal dilation.

ACKNOWLEDGMENTS

We thank the referring physicians for trusting their patients to our care and thank Pieter Westenend, pathologist, for searching the pathology database for RPF cases. We gratefully acknowledge the patients without whom this study would not have been possible.

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