Reconstructive Urology Urologic Manifestations of Erdheim-Chester Disease Daniel A. Yelfimov, Deborah J. Lightner, and Matthew K. Tollefson OBJECTIVE
METHODS
RESULTS
CONCLUSION
To describe the urologic manifestations of Erdheim-Chester disease (ECD). ECD is a rare multisystem disorder of non-Langerhans cell histiocytosis. In addition to classic long bone involvement, the retroperitoneum is a well-established site of disease infiltration. Herein, we present the urologic manifestations and outcomes of ECD in a large series of patients. We identified 47 patients diagnosed with ECD between 1996 and 2012 at our institution. The medical records and imaging for these patients were reviewed for urologic involvement, including perirenal soft tissue encasement, renal atrophy, hydronephrosis, chronic renal insufficiency, diabetes insipidus, and lower urinary tract symptoms. At diagnosis, the median patient age was 57 years (interquartile range 49, 68), and median followup after diagnosis was 3 years (interquartile range 1.8, 7.3). There were 31 male patients (66%) and 16 female patients (34%). The majority of these patients (37, 79%) demonstrated evidence of urologic involvement from ECD, requiring urologic surgery in 13 (28%). This urologic involvement included retroperitoneal infiltration (28, 60%), worsening lower tract urinary symptoms from diabetes insipidus (21, 45%), hydronephrosis (10, 21%), and chronic kidney disease (18, 38%). The incidence of urologic involvement with ECD is higher than previously reported in the published data. Urologists should be aware of this disorder, as it might mimic other retroperitoneal diseases and might contribute to lower urinary tract symptoms, hydronephrosis, renal atrophy, and chronic kidney disease. UROLOGY -: -e-, 2014. 2014 Elsevier Inc.
E
rdheim-Chester disease (ECD) is a rare inflammatory disorder of non-Langerhans cell histiocytosis, also known as lipogranulomatosis, as first described by Jakob Erdheim and William Chester in 1930.1,2 It is characterized by the xanthomatous infiltration of involved tissues by foamy histiocytes. ECD is notable because of the non-Langerhans cell histiocytic infiltrate identified on biopsy. ECD histiocytes express the histocyte marker CD68, but not CD1a or S100 proteins as seen in Langerhans cell histiocytosis.3 Nearly all patients with ECD are middle-aged and have symmetric infiltration and sclerosis of long bones, presenting with juxta-articular pain in most patients. However, the disorder might also involve visceral organs but infrequently involves the skin as is seen in Langerhans histiocytosis.3 Approximately 50% of patients with ECD suffer from extraskeletal involvement, including the central nervous system (CNS), such as diabetes insipidus and cerebellar symptoms, cardiopulmonary system (including pericardial effusions and conduction abnormalities), and the urinary Financial Disclosures: The authors declare that they have no relevant financial interests. From the Department of Urology, Mayo Medical School and Mayo Clinic, Rochester, MN Reprint requests: Matthew K. Tollefson, M.D., Department of Urology, Mayo Medical School and Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905. E-mail: [email protected] Submitted: September 19, 2013, accepted (with revisions): October 18, 2013
ª 2014 Elsevier Inc. All Rights Reserved
tract.4-8 From a urologic perspective, some patients might be largely asymptomatic or experience limited urinary complications; however, others might experience a more aggressive form of the disease, particularly when the infiltrate involves the CNS or causes ureteral obstruction and chronic renal insufficiency.9 The urinary manifestations of ECD are multifactorial and might be because of direct invasion of sheets of histiocytic infiltrate into the retroperitoneum, causing upper ureteral obstruction, encasement of the kidneys, adrenal insufficiency, and chronic renal failure. However, involvement of the urinary tract might be more insidious, particularly when CNS involvement results in central diabetes insipidus.3,10,11 A recent comprehensive review of the published reports noted approximately 30% overall incidence of retroperitoneal or urologic involvement in patients with ECD.2,3,12,13 Although the primary treatment of ECD is medical using interferon alfa, surgical intervention for urologic involvement is frequently required to manage its complications.9,14 Indeed, in patients so afflicted, urinary manifestations, and the needed interventions, might represent the primary source of morbidity of the disease. Owing to the protean nature of the ECD, the diagnosis is often overlooked, particularly from a urologic perspective. Furthermore, despite the frequency of involvement, the natural history of the urologic involvement of ECD 0090-4295/13/$36.00 http://dx.doi.org/10.1016/j.urology.2013.10.023
1
remains unclear. Therefore, the aim of the present study was to describe our contemporary institutional experience with the urologic manifestations, management, and outcomes of this rare disorder.
METHODS After institutional review board approval was obtained, we retrospectively identified 67 patients with a diagnosis of ECD from clinical, surgical, and pathologic reports at our institution from 1996 to 2012. This period was chosen in attempt to capture patients treated in a contemporary fashion with readily available cross-sectional abdominal and pelvic imaging as required. The medical records of these patients were then reviewed for accurate diagnosis and whether tissue histologic diagnosis was obtained through biopsy. ECD diagnosis was based on the criteria established by Veyssier-Belot et al12 and included the following: 1. Typical histologic findings such as infiltration by foamy histiocytes nested among polymorphic granuloma and/or immunohistochemical staining positively for CD-68 and negatively for CD1a. 2. Typical skeletal findings including symmetric cortical osteosclerosis of the diaphyseal and metaphyseal regions in the long bones on radiography or 99mTc bone scintigraphy. Patients with inadequate information in the medical record (n ¼ 12) and those who were found to have alternate diagnoses that explained their symptoms (n ¼ 8), such as other histiocytic disorders, idiopathic retroperitoneal fibrosis, and lymphoma, were excluded. These exclusions left 47 patients with confirmed ECD that constitute this report. Information extracted from the medical record included patient demographics, presenting symptoms, cross-sectional abdominopelvic imaging by computed tomography or magnetic resonance imaging, retroperitoneal involvement, hydronephrosis, renal atrophy, hypertension, chronic kidney disease (CKD), irritative or obstructive lower urinary tract symptoms (LUTS), and need for urologic surgery. CKD was defined as an estimated glomerular filtration rate 1.3 mg/dL. Descriptive statistics were used to characterize the patient cohort. A log-rank test was used to assess differences in survival based on urologic involvement. All tests were 2-sided with P .05 considered statistically significant.
RESULTS Patient Characteristics The demographic and clinical characteristics of the patient population analyzed are summarized in Table 1. Most patients presented with neurologic or orthopedic complaints such as bone pain, with only 4 patients having initial presentation of flank pain or incidentally identified retroperitoneal involvement. Of the 47 patients with ECD, most (38, 81%) had a tissue biopsy with pathology confirming the diagnosis. These biopsies demonstrated a dense histiocytic infiltration. No patients underwent biopsy of the renal parenchyma to assess for intrarenal pathology. The remaining patients (9, 19%) without a biopsy were diagnosed by classic radiologic and clinical features. There were 31 male patients (66%) and 16 female patients (34%). The median age of all patients was 2
Table 1. Patient demographic and clinical characteristics (n ¼ 47)
Feature Median age, y (IQR) Median follow-up, y (IQR) Sex, n (%) Male Female Presenting symptom, n (%) Urologic Nonurologic Pathologic diagnosis by biopsy, n (%) Cross-sectional imaging (CT/MRI), n (%) Urologic involvement, n (%) Retroperitoneal involvement, n (%) Any Perinephric soft tissue inflammation Hydronephrosis, unilateral or bilateral Renal atrophy, unilateral or bilateral Other CKD, n (%) Hypertension, n (%) LUTS, n (%) Any Storage symptoms Voiding symptoms Stent irritation Urologic surgery, n (%) Any Ureteral stent placement Open retroperitoneal, renal biopsy Other
57 (49, 68) 3.0 (1.8, 7.3) 31 (66%) 16 (34%) 4 43 38 35 37
(9%) (9%) (81%) (74%) (79%)
28 24 10 15 6 18 18
(60%) (51%) (21%) (32%) (13%) (38%) (38%)
21 11 8 4
(45%) (53%) (38%) (19%)
13 5 3 5
(28%) (11%) (6%) (11%)
CKD, chronic kidney disease; CT, computed tomography; IQR, interquartile range; LUTS, lower urinary tract symptoms; MRI, magnetic resonance imaging.
57 years (interquartile range 49, 68), and median followup was 3.0 years (interquartile range 1.8, 7.3). Crosssectional imaging of the abdomen, with abdominopelvic magnetic resonance imaging or computed tomographic scan was available in 35 patients (74%). Urologic Manifestations Urologic involvement of ECD was noted in 37 of 47 (79%) patients. In patients with available cross-sectional imaging, the vast majority had evidence of urologic involvement (30 of 35, 86%). The most common manifestation in the retroperitoneum included perinephric soft tissue inflammation (51%). Figure 1 illustrates the typical radiographic appearance of the perinephric encasement of dense inflammatory tissue. Furthermore, unilateral or bilateral hydronephrosis (21%) and renal atrophy (32%) were commonly identified features. CKD was identified at presentation in 38% of patients. Hypertension was noted in 18 (38%) patients; only 3 of these patients had medically refractory hypertension secondary to renal artery stenosis. A common finding in this cohort of patients was bothersome LUTS, which was seen in 21 patients (43%). Of these patients, most (11, 52%) had storage symptoms referable to their central diabetes insipidus and these included polydipsia, polyuria, and urinary frequency. None of these patients had evidence of nephrogenic UROLOGY
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Figure 1. Contrast-enhanced computerized tomography of a patient with the typical peri-renal encasement of inflammatory tissue. Biopsy of the perirenal infiltrate was performed and confirmed the diagnosis of Erdheim-Chester disease.
diabetes insipidus. Eight patients (38%) had voiding symptoms reporting with poor bladder emptying and weak stream. Finally, 4 patients (19%) had symptoms that were attributed to irritation from ureteral stents. Most patients underwent medical management of their urologic complications of ECD; 5 patients (11%) required retrograde ureteral stent placement for ureteral obstruction. Natural History and Survival Radiologic follow-up was performed in 24 patients, who underwent multiple cross-sectional imaging studies of the abdomen separated by at least 4 months. In these patients, the retroperitoneal infiltrate was progressive in 6 of 24 patients (25%). Eighteen patients (75%) had stable retroperitoneal disease. Despite medical management, no patient had any resolution or even significant regression of the retroperitoneal infiltrate on follow-up studies. Overall, there did not appear to be a hereditary component, as none of the 47 patients described a family history of ECD or similar disease process. Six patients (13%) died from cardiac or pulmonary complications during the median 3-year follow-up period of the study, confirming the aggressive behavior of the disease. Comparison of the survival between patients with and without urologic involvement yielded no significant difference between the 2 groups (P ¼ .32).
COMMENT ECD represents a rare systemic non-Langerhans cell histiocytosis with roughly 400 cases reported worldwide. The rarity of this disorder and its predilection to involve UROLOGY
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(-), 2014
multiple organ systems make this a multidisciplinary disorder. Urologists should be aware of the disease, as it frequently involves the retroperitoneum and renal collecting systems. As such, it frequently might masquerade as retroperitoneal hemorrhage, idiopathic retroperitoneal fibrosis, malignancy, and/or infection. Furthermore, these patients might endorse primarily urologic chief complaints, specifically diabetes insipidus, LUTS, and CKD. Although case reports exist in the urologic published data, to date, few series have focused on the urologic diagnosis and management of patients with ECD. The goal of this study was to describe the urologic manifestations of our contemporary institutional series of ECD. To this end, we are able to offer some unique insights. First, the incidence of urologic and/or retroperitoneal involvement might be significantly greater than previously recognized, at least 60% in our cohort and possibly as high as 85% if only patients with cross-sectional imaging are considered. This is in comparison with approximately 30% involvement of the retroperitoneum in most previous literature reviews and case series.2,3,12 The reason for this discrepancy is not entirely clear but might be because of the increased frequency of crosssectional imaging in the contemporary era, which might detect an otherwise clinically silent process in the majority of our cohort.15 Furthermore, when considering only patients with cross-sectional imaging, the incidence of retroperitoneal involvement increased from 60% to 77%. A recent review by Cavalli et al3 noted that the initial retroperitoneal involvement at presentation was approximately 14% but increased to 30% in the overall course of disease. They concluded that asymptomatic retroperitoneal processes are likely unrecognized initially by clinical evaluation only. It is also important to note that a study by Haroche et al of 53 patients (all of whom received some form of abdominopelvic cross-sectional imaging) identified a “hairy kidney” appearance in 68% of their patients.10 Thus, it appears that the majority (w70%) of patients with ECD do indeed have some form of retroperitoneal involvement. Second, there was an alarming incidence of retroperitoneal involvement leading to renal atrophy (32%) and CKD (38%) in our cohort. Case reports in the published data have described bilateral ureteral obstruction leading to renal failure, yet many of the patients in our cohort did not have concomitant hydronephrosis, as this was present in only 10 of 47 patients (21%).16,17 One possible explanation is that perinephric soft tissue encasement (Fig. 1) might preclude the formation of hydronephrosis through a mechanism of decreased renal collecting system compliance. This process appears to be independent of hypertension as comorbidity from renal compression by the perinephric infiltration, such as a “Page” kidney. Ultimately, the hypothesis is that this could lead to an insidious process of chronic renal failure even in the absence of hydronephrosis, consistent with a previous case report, which describes a patient with progressive renal failure on dialysis with significant bilateral 3
perinephric soft tissue encasement without hydronephrosis. Resection was performed of the fatty perinephric tissue resulting in remarkable improvement in renal failure.14 Putting together the high incidence of retroperitoneal involvement and the possibility of clinically silent obstruction of the kidneys leading to progressive renal deterioration, clinicians treating ECD might consider routine cross-sectional abdominopelvic imaging in all patients to help identify those at risk. In addition, one might consider surgical intervention in the patient with ECD who presents with perinephric tissue encasement and renal failure. None of the patients in our institutional series underwent this sort of decompression, but as already described previously, there is at least 1 case report in the published data that demonstrates a significant benefit with such an approach. In regard to ureteral stenting, patients managed in this fashion in our series usually had stable hydronephrosis and CKD. This is appears to be a reasonable management option in patients too ill to undergo more aggressive surgery or as a temporizing measure in conjunction with systemic treatment. Third, we note that almost half (45%) of the patients described LUTS. Storage symptoms of urinary frequency and polyuria predominated, noting that many of these patients were also diagnosed with central diabetes insipidus, a common CNS manifestation of ECD.18,19 It is important to note that patients with diabetes insipidus developed this process by CNS infiltrative destruction of the pituitary-hypothalamic axis and not as a manifestation of hydronephrosis or other nephrogenic causes. Most of the other irritative LUTS were attributed to stent irritation. In addition, LUTS secondary to benign prostatic hyperplasia might be a confounding factor in this predominantly male population with an age range of 4060 years. On the basis of our review of cross-sectional imaging, there was essentially no pelvic involvement in any of the patients in our cohort. We agree with previous observations that this disease appears to spare the pelvic ureters, lower urinary tract, and caudal retroperitoneum.2 The limitations of this study include its retrospective and nonrandomized design. We also recognize that not all patients (only 81%) had a histologic diagnosis from biopsy of ECD, but we are confident in the diagnosis for patients with classical clinical and radiographic findings. Furthermore, the findings of this study, specifically that these patients have high rates of retroperitoneal infiltration, CKD, and LUTS remain true in both patients with and without a confirmatory biopsy.
CONCLUSION In summary, although ECD is a rare disorder, it frequently involves the urinary tract. Our study suggests that such urologic involvement is much more common than previously recognized. Urologists should be aware of the disorder to effectively manage and treat these patients. Specifically, the retroperitoneal infiltrate in ECD might
4
be confused with other disorders of the retroperitoneum. Furthermore, the incidence of CKD and renal atrophy is significantly higher than previously recognized. Finally, these patients might be subject to worsening LUTS, and consideration should be given to central diabetes insipidus as a contributor to LUTS. References 1. W C, J E. Über lipoïdgranulomatose. Virchows Arch Pathol Anat. 1930;279:561-602. 2. Haroche J, Arnaud L, Amoura Z. Erdheim-Chester disease. Curr Opin Rheumatol. 2012;24:53-59. 3. Cavalli G, Guglielmi B, Berti A, et al. The multifaceted clinical presentations and manifestations of Erdheim-Chester disease: comprehensive review of the literature and of 10 new cases. Ann Rheum Dis. 2013;72:1691-1695. 4. Haroche J, Amoura Z, Dion E, et al. Cardiovascular involvement, an overlooked feature of Erdheim-Chester disease: report of 6 new cases and a literature review. Medicine (Baltimore). 2004;83: 371-392. 5. Allen TC, Chevez-Barrios P, Shetlar DJ, et al. Pulmonary and ophthalmic involvement with Erdheim-Chester disease: a case report and review of the literature. Arch Pathol Lab Med. 2004;128: 1428-1431. 6. Sedrak P, Ketonen L, Hou P, et al. Erdheim-Chester disease of the central nervous system: new manifestations of a rare disease. AJNR Am J Neuroradiol. 2011;32:2126-2131. 7. Bassou D, El Kharras A, Taoufik AT, et al. Cardiac erdheim-chester. Intern Med. 2009;48:83-84. 8. Chung JH, Park MS, Shin DH, et al. Pulmonary involvement in Erdheim-Chester disease. Respirology. 2005;10:389-392. 9. Yun EJ, Yeh BM, Yabes AP, et al. Erdheim-Chester disease: case report and review of associated urological, radiological and histological features. J Urol. 2003;169:1470-1471. 10. Arnaud L, Hervier B, Neel A, et al. CNS involvement and treatment with interferon-alpha are independent prognostic factors in Erdheim-Chester disease: a multicenter survival analysis of 53 patients. Blood. 2011;117:2778-2782. 11. Colin P, Ballereau C, Lambert M, et al. Retroperitoneal infiltration as the first sign of Erdheim-Chester disease. Int J Urol. 2008;15: 455-456. 12. Veyssier-Belot C, Cacoub P, Caparros-Lefebvre D, et al. ErdheimChester disease. Clinical and radiologic characteristics of 59 cases. Medicine (Baltimore). 1996;75:157-169. 13. Lee HJ, Lee KY, Shin DY, et al. A case of erdheim-chester disease with asymptomatic renal involvement. Cancer Res Treat. 2012;44: 146-150. 14. Wimpissinger TF, Schernthaner G, Feichtinger H, et al. Compression of kidneys in Erdheim-Chester disease of retroperitoneum: Open surgical approach. Urology. 2005;65:798.e29798.e31. 15. Surabhi VR, Menias C, Prasad SR, et al. Neoplastic and nonneoplastic proliferative disorders of the perirenal space: crosssectional imaging findings. Radiographics. 2008;28:1005-1017. 16. Castle EP, Humphreys MR, Andrews PE. Laparoscopic biopsy and ureterolysis in Erdheim-Chester disease. Mayo Clin Proc. 2005;80: 546-548. 17. Droupy S, Attias D, Eschwege P, et al. Bilateral hydronephrosis in a patient with Erdheim-Chester disease. J Urol. 1999;162:2084-2085. 18. Bohlega S, Alwatban J, Tulbah A, et al. Cerebral manifestation of Erdheim-Chester disease: clinical and radiologic findings. Neurology. 1997;49:1702-1705. 19. Weidauer S, von Stuckrad-Barre S, Dettmann E, et al. Cerebral Erdheim-Chester disease: case report and review of the literature. Neuroradiology. 2003;45:241-245.
UROLOGY
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(-), 2014
METHODS
RESULTS
CONCLUSION
To describe the urologic manifestations of Erdheim-Chester disease (ECD). ECD is a rare multisystem disorder of non-Langerhans cell histiocytosis. In addition to classic long bone involvement, the retroperitoneum is a well-established site of disease infiltration. Herein, we present the urologic manifestations and outcomes of ECD in a large series of patients. We identified 47 patients diagnosed with ECD between 1996 and 2012 at our institution. The medical records and imaging for these patients were reviewed for urologic involvement, including perirenal soft tissue encasement, renal atrophy, hydronephrosis, chronic renal insufficiency, diabetes insipidus, and lower urinary tract symptoms. At diagnosis, the median patient age was 57 years (interquartile range 49, 68), and median followup after diagnosis was 3 years (interquartile range 1.8, 7.3). There were 31 male patients (66%) and 16 female patients (34%). The majority of these patients (37, 79%) demonstrated evidence of urologic involvement from ECD, requiring urologic surgery in 13 (28%). This urologic involvement included retroperitoneal infiltration (28, 60%), worsening lower tract urinary symptoms from diabetes insipidus (21, 45%), hydronephrosis (10, 21%), and chronic kidney disease (18, 38%). The incidence of urologic involvement with ECD is higher than previously reported in the published data. Urologists should be aware of this disorder, as it might mimic other retroperitoneal diseases and might contribute to lower urinary tract symptoms, hydronephrosis, renal atrophy, and chronic kidney disease. UROLOGY -: -e-, 2014. 2014 Elsevier Inc.
E
rdheim-Chester disease (ECD) is a rare inflammatory disorder of non-Langerhans cell histiocytosis, also known as lipogranulomatosis, as first described by Jakob Erdheim and William Chester in 1930.1,2 It is characterized by the xanthomatous infiltration of involved tissues by foamy histiocytes. ECD is notable because of the non-Langerhans cell histiocytic infiltrate identified on biopsy. ECD histiocytes express the histocyte marker CD68, but not CD1a or S100 proteins as seen in Langerhans cell histiocytosis.3 Nearly all patients with ECD are middle-aged and have symmetric infiltration and sclerosis of long bones, presenting with juxta-articular pain in most patients. However, the disorder might also involve visceral organs but infrequently involves the skin as is seen in Langerhans histiocytosis.3 Approximately 50% of patients with ECD suffer from extraskeletal involvement, including the central nervous system (CNS), such as diabetes insipidus and cerebellar symptoms, cardiopulmonary system (including pericardial effusions and conduction abnormalities), and the urinary Financial Disclosures: The authors declare that they have no relevant financial interests. From the Department of Urology, Mayo Medical School and Mayo Clinic, Rochester, MN Reprint requests: Matthew K. Tollefson, M.D., Department of Urology, Mayo Medical School and Mayo Clinic, 200 First Street Southwest, Rochester, MN 55905. E-mail: [email protected] Submitted: September 19, 2013, accepted (with revisions): October 18, 2013
ª 2014 Elsevier Inc. All Rights Reserved
tract.4-8 From a urologic perspective, some patients might be largely asymptomatic or experience limited urinary complications; however, others might experience a more aggressive form of the disease, particularly when the infiltrate involves the CNS or causes ureteral obstruction and chronic renal insufficiency.9 The urinary manifestations of ECD are multifactorial and might be because of direct invasion of sheets of histiocytic infiltrate into the retroperitoneum, causing upper ureteral obstruction, encasement of the kidneys, adrenal insufficiency, and chronic renal failure. However, involvement of the urinary tract might be more insidious, particularly when CNS involvement results in central diabetes insipidus.3,10,11 A recent comprehensive review of the published reports noted approximately 30% overall incidence of retroperitoneal or urologic involvement in patients with ECD.2,3,12,13 Although the primary treatment of ECD is medical using interferon alfa, surgical intervention for urologic involvement is frequently required to manage its complications.9,14 Indeed, in patients so afflicted, urinary manifestations, and the needed interventions, might represent the primary source of morbidity of the disease. Owing to the protean nature of the ECD, the diagnosis is often overlooked, particularly from a urologic perspective. Furthermore, despite the frequency of involvement, the natural history of the urologic involvement of ECD 0090-4295/13/$36.00 http://dx.doi.org/10.1016/j.urology.2013.10.023
1
remains unclear. Therefore, the aim of the present study was to describe our contemporary institutional experience with the urologic manifestations, management, and outcomes of this rare disorder.
METHODS After institutional review board approval was obtained, we retrospectively identified 67 patients with a diagnosis of ECD from clinical, surgical, and pathologic reports at our institution from 1996 to 2012. This period was chosen in attempt to capture patients treated in a contemporary fashion with readily available cross-sectional abdominal and pelvic imaging as required. The medical records of these patients were then reviewed for accurate diagnosis and whether tissue histologic diagnosis was obtained through biopsy. ECD diagnosis was based on the criteria established by Veyssier-Belot et al12 and included the following: 1. Typical histologic findings such as infiltration by foamy histiocytes nested among polymorphic granuloma and/or immunohistochemical staining positively for CD-68 and negatively for CD1a. 2. Typical skeletal findings including symmetric cortical osteosclerosis of the diaphyseal and metaphyseal regions in the long bones on radiography or 99mTc bone scintigraphy. Patients with inadequate information in the medical record (n ¼ 12) and those who were found to have alternate diagnoses that explained their symptoms (n ¼ 8), such as other histiocytic disorders, idiopathic retroperitoneal fibrosis, and lymphoma, were excluded. These exclusions left 47 patients with confirmed ECD that constitute this report. Information extracted from the medical record included patient demographics, presenting symptoms, cross-sectional abdominopelvic imaging by computed tomography or magnetic resonance imaging, retroperitoneal involvement, hydronephrosis, renal atrophy, hypertension, chronic kidney disease (CKD), irritative or obstructive lower urinary tract symptoms (LUTS), and need for urologic surgery. CKD was defined as an estimated glomerular filtration rate 1.3 mg/dL. Descriptive statistics were used to characterize the patient cohort. A log-rank test was used to assess differences in survival based on urologic involvement. All tests were 2-sided with P .05 considered statistically significant.
RESULTS Patient Characteristics The demographic and clinical characteristics of the patient population analyzed are summarized in Table 1. Most patients presented with neurologic or orthopedic complaints such as bone pain, with only 4 patients having initial presentation of flank pain or incidentally identified retroperitoneal involvement. Of the 47 patients with ECD, most (38, 81%) had a tissue biopsy with pathology confirming the diagnosis. These biopsies demonstrated a dense histiocytic infiltration. No patients underwent biopsy of the renal parenchyma to assess for intrarenal pathology. The remaining patients (9, 19%) without a biopsy were diagnosed by classic radiologic and clinical features. There were 31 male patients (66%) and 16 female patients (34%). The median age of all patients was 2
Table 1. Patient demographic and clinical characteristics (n ¼ 47)
Feature Median age, y (IQR) Median follow-up, y (IQR) Sex, n (%) Male Female Presenting symptom, n (%) Urologic Nonurologic Pathologic diagnosis by biopsy, n (%) Cross-sectional imaging (CT/MRI), n (%) Urologic involvement, n (%) Retroperitoneal involvement, n (%) Any Perinephric soft tissue inflammation Hydronephrosis, unilateral or bilateral Renal atrophy, unilateral or bilateral Other CKD, n (%) Hypertension, n (%) LUTS, n (%) Any Storage symptoms Voiding symptoms Stent irritation Urologic surgery, n (%) Any Ureteral stent placement Open retroperitoneal, renal biopsy Other
57 (49, 68) 3.0 (1.8, 7.3) 31 (66%) 16 (34%) 4 43 38 35 37
(9%) (9%) (81%) (74%) (79%)
28 24 10 15 6 18 18
(60%) (51%) (21%) (32%) (13%) (38%) (38%)
21 11 8 4
(45%) (53%) (38%) (19%)
13 5 3 5
(28%) (11%) (6%) (11%)
CKD, chronic kidney disease; CT, computed tomography; IQR, interquartile range; LUTS, lower urinary tract symptoms; MRI, magnetic resonance imaging.
57 years (interquartile range 49, 68), and median followup was 3.0 years (interquartile range 1.8, 7.3). Crosssectional imaging of the abdomen, with abdominopelvic magnetic resonance imaging or computed tomographic scan was available in 35 patients (74%). Urologic Manifestations Urologic involvement of ECD was noted in 37 of 47 (79%) patients. In patients with available cross-sectional imaging, the vast majority had evidence of urologic involvement (30 of 35, 86%). The most common manifestation in the retroperitoneum included perinephric soft tissue inflammation (51%). Figure 1 illustrates the typical radiographic appearance of the perinephric encasement of dense inflammatory tissue. Furthermore, unilateral or bilateral hydronephrosis (21%) and renal atrophy (32%) were commonly identified features. CKD was identified at presentation in 38% of patients. Hypertension was noted in 18 (38%) patients; only 3 of these patients had medically refractory hypertension secondary to renal artery stenosis. A common finding in this cohort of patients was bothersome LUTS, which was seen in 21 patients (43%). Of these patients, most (11, 52%) had storage symptoms referable to their central diabetes insipidus and these included polydipsia, polyuria, and urinary frequency. None of these patients had evidence of nephrogenic UROLOGY
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Figure 1. Contrast-enhanced computerized tomography of a patient with the typical peri-renal encasement of inflammatory tissue. Biopsy of the perirenal infiltrate was performed and confirmed the diagnosis of Erdheim-Chester disease.
diabetes insipidus. Eight patients (38%) had voiding symptoms reporting with poor bladder emptying and weak stream. Finally, 4 patients (19%) had symptoms that were attributed to irritation from ureteral stents. Most patients underwent medical management of their urologic complications of ECD; 5 patients (11%) required retrograde ureteral stent placement for ureteral obstruction. Natural History and Survival Radiologic follow-up was performed in 24 patients, who underwent multiple cross-sectional imaging studies of the abdomen separated by at least 4 months. In these patients, the retroperitoneal infiltrate was progressive in 6 of 24 patients (25%). Eighteen patients (75%) had stable retroperitoneal disease. Despite medical management, no patient had any resolution or even significant regression of the retroperitoneal infiltrate on follow-up studies. Overall, there did not appear to be a hereditary component, as none of the 47 patients described a family history of ECD or similar disease process. Six patients (13%) died from cardiac or pulmonary complications during the median 3-year follow-up period of the study, confirming the aggressive behavior of the disease. Comparison of the survival between patients with and without urologic involvement yielded no significant difference between the 2 groups (P ¼ .32).
COMMENT ECD represents a rare systemic non-Langerhans cell histiocytosis with roughly 400 cases reported worldwide. The rarity of this disorder and its predilection to involve UROLOGY
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multiple organ systems make this a multidisciplinary disorder. Urologists should be aware of the disease, as it frequently involves the retroperitoneum and renal collecting systems. As such, it frequently might masquerade as retroperitoneal hemorrhage, idiopathic retroperitoneal fibrosis, malignancy, and/or infection. Furthermore, these patients might endorse primarily urologic chief complaints, specifically diabetes insipidus, LUTS, and CKD. Although case reports exist in the urologic published data, to date, few series have focused on the urologic diagnosis and management of patients with ECD. The goal of this study was to describe the urologic manifestations of our contemporary institutional series of ECD. To this end, we are able to offer some unique insights. First, the incidence of urologic and/or retroperitoneal involvement might be significantly greater than previously recognized, at least 60% in our cohort and possibly as high as 85% if only patients with cross-sectional imaging are considered. This is in comparison with approximately 30% involvement of the retroperitoneum in most previous literature reviews and case series.2,3,12 The reason for this discrepancy is not entirely clear but might be because of the increased frequency of crosssectional imaging in the contemporary era, which might detect an otherwise clinically silent process in the majority of our cohort.15 Furthermore, when considering only patients with cross-sectional imaging, the incidence of retroperitoneal involvement increased from 60% to 77%. A recent review by Cavalli et al3 noted that the initial retroperitoneal involvement at presentation was approximately 14% but increased to 30% in the overall course of disease. They concluded that asymptomatic retroperitoneal processes are likely unrecognized initially by clinical evaluation only. It is also important to note that a study by Haroche et al of 53 patients (all of whom received some form of abdominopelvic cross-sectional imaging) identified a “hairy kidney” appearance in 68% of their patients.10 Thus, it appears that the majority (w70%) of patients with ECD do indeed have some form of retroperitoneal involvement. Second, there was an alarming incidence of retroperitoneal involvement leading to renal atrophy (32%) and CKD (38%) in our cohort. Case reports in the published data have described bilateral ureteral obstruction leading to renal failure, yet many of the patients in our cohort did not have concomitant hydronephrosis, as this was present in only 10 of 47 patients (21%).16,17 One possible explanation is that perinephric soft tissue encasement (Fig. 1) might preclude the formation of hydronephrosis through a mechanism of decreased renal collecting system compliance. This process appears to be independent of hypertension as comorbidity from renal compression by the perinephric infiltration, such as a “Page” kidney. Ultimately, the hypothesis is that this could lead to an insidious process of chronic renal failure even in the absence of hydronephrosis, consistent with a previous case report, which describes a patient with progressive renal failure on dialysis with significant bilateral 3
perinephric soft tissue encasement without hydronephrosis. Resection was performed of the fatty perinephric tissue resulting in remarkable improvement in renal failure.14 Putting together the high incidence of retroperitoneal involvement and the possibility of clinically silent obstruction of the kidneys leading to progressive renal deterioration, clinicians treating ECD might consider routine cross-sectional abdominopelvic imaging in all patients to help identify those at risk. In addition, one might consider surgical intervention in the patient with ECD who presents with perinephric tissue encasement and renal failure. None of the patients in our institutional series underwent this sort of decompression, but as already described previously, there is at least 1 case report in the published data that demonstrates a significant benefit with such an approach. In regard to ureteral stenting, patients managed in this fashion in our series usually had stable hydronephrosis and CKD. This is appears to be a reasonable management option in patients too ill to undergo more aggressive surgery or as a temporizing measure in conjunction with systemic treatment. Third, we note that almost half (45%) of the patients described LUTS. Storage symptoms of urinary frequency and polyuria predominated, noting that many of these patients were also diagnosed with central diabetes insipidus, a common CNS manifestation of ECD.18,19 It is important to note that patients with diabetes insipidus developed this process by CNS infiltrative destruction of the pituitary-hypothalamic axis and not as a manifestation of hydronephrosis or other nephrogenic causes. Most of the other irritative LUTS were attributed to stent irritation. In addition, LUTS secondary to benign prostatic hyperplasia might be a confounding factor in this predominantly male population with an age range of 4060 years. On the basis of our review of cross-sectional imaging, there was essentially no pelvic involvement in any of the patients in our cohort. We agree with previous observations that this disease appears to spare the pelvic ureters, lower urinary tract, and caudal retroperitoneum.2 The limitations of this study include its retrospective and nonrandomized design. We also recognize that not all patients (only 81%) had a histologic diagnosis from biopsy of ECD, but we are confident in the diagnosis for patients with classical clinical and radiographic findings. Furthermore, the findings of this study, specifically that these patients have high rates of retroperitoneal infiltration, CKD, and LUTS remain true in both patients with and without a confirmatory biopsy.
CONCLUSION In summary, although ECD is a rare disorder, it frequently involves the urinary tract. Our study suggests that such urologic involvement is much more common than previously recognized. Urologists should be aware of the disorder to effectively manage and treat these patients. Specifically, the retroperitoneal infiltrate in ECD might
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be confused with other disorders of the retroperitoneum. Furthermore, the incidence of CKD and renal atrophy is significantly higher than previously recognized. Finally, these patients might be subject to worsening LUTS, and consideration should be given to central diabetes insipidus as a contributor to LUTS. References 1. W C, J E. Über lipoïdgranulomatose. Virchows Arch Pathol Anat. 1930;279:561-602. 2. Haroche J, Arnaud L, Amoura Z. Erdheim-Chester disease. Curr Opin Rheumatol. 2012;24:53-59. 3. Cavalli G, Guglielmi B, Berti A, et al. The multifaceted clinical presentations and manifestations of Erdheim-Chester disease: comprehensive review of the literature and of 10 new cases. Ann Rheum Dis. 2013;72:1691-1695. 4. Haroche J, Amoura Z, Dion E, et al. Cardiovascular involvement, an overlooked feature of Erdheim-Chester disease: report of 6 new cases and a literature review. Medicine (Baltimore). 2004;83: 371-392. 5. Allen TC, Chevez-Barrios P, Shetlar DJ, et al. Pulmonary and ophthalmic involvement with Erdheim-Chester disease: a case report and review of the literature. Arch Pathol Lab Med. 2004;128: 1428-1431. 6. Sedrak P, Ketonen L, Hou P, et al. Erdheim-Chester disease of the central nervous system: new manifestations of a rare disease. AJNR Am J Neuroradiol. 2011;32:2126-2131. 7. Bassou D, El Kharras A, Taoufik AT, et al. Cardiac erdheim-chester. Intern Med. 2009;48:83-84. 8. Chung JH, Park MS, Shin DH, et al. Pulmonary involvement in Erdheim-Chester disease. Respirology. 2005;10:389-392. 9. Yun EJ, Yeh BM, Yabes AP, et al. Erdheim-Chester disease: case report and review of associated urological, radiological and histological features. J Urol. 2003;169:1470-1471. 10. Arnaud L, Hervier B, Neel A, et al. CNS involvement and treatment with interferon-alpha are independent prognostic factors in Erdheim-Chester disease: a multicenter survival analysis of 53 patients. Blood. 2011;117:2778-2782. 11. Colin P, Ballereau C, Lambert M, et al. Retroperitoneal infiltration as the first sign of Erdheim-Chester disease. Int J Urol. 2008;15: 455-456. 12. Veyssier-Belot C, Cacoub P, Caparros-Lefebvre D, et al. ErdheimChester disease. Clinical and radiologic characteristics of 59 cases. Medicine (Baltimore). 1996;75:157-169. 13. Lee HJ, Lee KY, Shin DY, et al. A case of erdheim-chester disease with asymptomatic renal involvement. Cancer Res Treat. 2012;44: 146-150. 14. Wimpissinger TF, Schernthaner G, Feichtinger H, et al. Compression of kidneys in Erdheim-Chester disease of retroperitoneum: Open surgical approach. Urology. 2005;65:798.e29798.e31. 15. Surabhi VR, Menias C, Prasad SR, et al. Neoplastic and nonneoplastic proliferative disorders of the perirenal space: crosssectional imaging findings. Radiographics. 2008;28:1005-1017. 16. Castle EP, Humphreys MR, Andrews PE. Laparoscopic biopsy and ureterolysis in Erdheim-Chester disease. Mayo Clin Proc. 2005;80: 546-548. 17. Droupy S, Attias D, Eschwege P, et al. Bilateral hydronephrosis in a patient with Erdheim-Chester disease. J Urol. 1999;162:2084-2085. 18. Bohlega S, Alwatban J, Tulbah A, et al. Cerebral manifestation of Erdheim-Chester disease: clinical and radiologic findings. Neurology. 1997;49:1702-1705. 19. Weidauer S, von Stuckrad-Barre S, Dettmann E, et al. Cerebral Erdheim-Chester disease: case report and review of the literature. Neuroradiology. 2003;45:241-245.
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