Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2006-2018
The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 6 2007-2012
Copyright © 2007 by The Endocrine Society
Bilateral Adrenal Infiltration in Erdheim-Chester Disease. Report of Seven Cases and Literature Review
Julien Haroche,
Zahir Amoura,
Philippe Touraine,
Danielle Seilhean,
Claire Graef,
Béatrice Birmelé,
Bertrand Wechsler,
Philippe Cluzel,
Philippe A. Grenier and
Jean-Charles Piette
Service de Médecine Interne (J.H., Z.A., B.W., J.-C.P.), Service d’Endocrinologie et Médecine de la Reproduction (P.T.), Service de Neuropathologie (D.S.), and Service de Radiologie (C.G., P.C., P.A.G.), Hôpital Pitié-Salpêtrière, 75013 Paris, and Université Pierre et Marie Curie, Paris 6, France; and Service de Néphrologie-Immunologie Clinique (B.B.), Hôpital Bretonneau, 37044 Tours, France
Address all correspondence and requests for reprints to: Julien Haroche, M.D., Ph.D., Service de Médecine Interne, Hôpital Pitié-Salpêtrière, 47-83 Bld de l’Hôpital, 75013 Paris, France. E-mail: julien.haroche{at}psl.aphp.fr.
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Abstract
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Context: Erdheim-Chester disease (ECD) is a rare non-Langerhans form of histiocytosis characterized by xanthomatous tissue infiltration with CD68+ CD1a– foamy histiocytes. Endocrine problems, such as diabetes insipidus and hypogonadotropic hypogonadism, frequently occur in ECD, but bilateral adrenal infiltration has rarely been reported in this disease.
Objective: The aim of the study was to describe adrenal and periadrenal infiltration in ECD.
Patients: A total of 22 patients with ECD undergoing systematic computed tomography to search for signs of adrenal enlargement participated in the study.
Results: Of the 22 patients with ECD, seven (31.8%) displayed adrenal infiltration on computed tomography. In one case, autopsy confirmed that the adrenal enlargement was due to foamy histiocyte infiltration in the adrenal glands. Possible adrenal insufficiency was assessed in five of the seven patients. One developed signs of adrenal insufficiency, which was confirmed by adrenocorticotropin stimulation tests. Adrenal involvement was reported in only 15 of the 240 ECD cases published up to May 2006. This frequency is significantly lower than that in our series (P = 0.0008; Fisher’s exact test).
Conclusion: Physicians should be aware of ECD as a possible cause of morphological changes in adrenal size and infiltration.
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Introduction
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ERDHEIM-CHESTER DISEASE (ECD) is a rare non-Langerhans form of histiocytosis characterized by the xanthomatous infiltration of tissues with foamy histiocytes. In immunohistochemical analyses, these cells consistently stain positively for CD68 and negatively for CD1a, whereas staining for S-100 protein may be negative or positive.
Bone pain is the most frequent symptom of ECD. About half of all ECD patients have extraskeletal manifestations, including exophthalmos, xanthelasma, interstitial lung disease, retroperitoneal "fibrosis" with perirenal and/or ureteral obstruction, renal failure, and central nervous system and cardiovascular involvement (1).
The infiltration of the pituitary gland by foamy non-Langerhans histiocytes, leading to diabetes insipidus, is the main endocrine manifestation of ECD (2). Pituitary or hypothalamic infiltration leading to other endocrine manifestations, such as hyperprolactinemia, gonadotropin insufficiency, and abnormally low levels of IGF-I, has been reported in rare cases (3, 4). Adrenal gland infiltration has also been reported (5), but its occurrence is probably underestimated.
We report here seven cases of adrenal gland enlargement in a personal series of 22 ECD patients. The diagnosis was radiological in all cases and was confirmed by autopsy in one case. One of these patients had adrenal insufficiency. We also reviewed the 240 ECD cases reported in the literature up to May 2006 (1, 2), checking for signs of adrenal involvement.
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Patients and Methods
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All the patients were referred to the Internal Medicine Department of Pitié-Salpêtrière Hospital, Paris, between November 1995 and May 2006. One patient developed signs of adrenal insufficiency. We performed a MEDLINE search for ECD on all papers published until May 2006, looking for descriptions of adrenal involvement, characterized clinically and/or radiologically and/or on autopsy. In the seven cases reported in this personal series and in published studies, ECD was diagnosed based on: 1) typical histological findings: infiltration with foamy histiocytes nested among polymorphic granuloma and fibrosis or xanthogranulomatosis with CD68-positive and CD1a-negative immunohistochemical staining, which is typical of ECD histiocytes; and 2) typical skeletal findings with x-rays showing bilateral and symmetrical cortical osteosclerosis of the diaphyseal and metaphyseal regions in the long bones and/or; symmetrical and abnormally strong labeling of the distal ends of the long bones of the legs, and in some cases of the arms, on technetium 99 bone scintigraphy.
These criteria for ECD were used in our previous literature reviews published in 1996 and 2004 (2).
Hormonal evaluation
The synacthen test was performed as follows: 250 µg tetracosactide (Novartis, Basel, Switzerland) was injected iv into the subject, and cortisol concentration was determined after 30 and 60 min. Cortisol and ACTH levels were measured with Immulite 2000 chemiluminescence assay equipment (Diagnostics Products Corp., Los Angeles, CA). RIA (CIS Bio Int., Gif-sur Yvette, France) determined renin. Aldosterone was determined with the ALDO-RIACT RIA (CIS Bio Int.).
Case reports
All seven of our cases met both the diagnostic criteria for ECD. Four of these cases were partly described in our previous series focusing on cardiovascular involvement (1), which did not consider adrenal infiltration in ECD patients. For all case reports, the site of the biopsy confirming ECD, the size of the adrenal glands, and adrenal function testing are summarized in Table 1
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Case no. 1.
A 65-yr-old man with a history of myocardial infarction and idiopathic thrombocytopenic purpura was referred for unilateral hydronephrosis resulting in impaired renal function. He also had essential hypertension, for which he took several antihypertensive drugs (bumetanide, perindopril, nebivolol, and nicorandil). The patient had undergone left nephrectomy, leading to the diagnosis of ECD. The surgeon found periadrenal infiltration with foamy histiocytes on the left side. Computed tomography (CT) revealed periaortic fibrosis of the entire aorta (known as "coated aorta"), and showed right perirenal and right periadrenal infiltration, and enlargement of the adrenal gland. Adrenal insufficiency was excluded by a synacthen test in July 2005, in which values increased from 16.2–26.5 µg/dl at 1 h. Interferon-
treatment was initiated in October 2005, at a dose of 3 x 106 U administered sc three times per week. After 3 months, the patient reported feeling more tired than usual and presented recurrent hyperkalemia, up to 6.3 mmol/liter, for which he regularly had to take Kayexalate (Sanofi-Synthelabo, Paris, France). This hyperkalemia could not be accounted for by renal function impairment because creatinine concentration remained between 90 and 124 µmol/liter. The patient was assessed at another hospital in February 2006, at which time another synacthen test showed an increase in cortisol concentration from 11.7–18.8 µg/dl at 30 min and 14.4 µg/dl at 60 min (normal > 21 µg/dl). Hydrocortisone treatment was initiated and resolved asthenia; kalemia returned to normal values. It was not possible to perform an ACTH assay on the day of diagnosis of adrenal insufficiency. However, we nonetheless concluded that the patient had adrenal insufficiency of adrenal origin, based principally on the ACTH assay value obtained at 0800 h, after 2 months of hydrocortisone treatment, when the patient was referred to us in April 2006 (32.6 pg/ml; normal range 10–46). It was also very difficult to assess mineralocorticoid function in this case because the patient was taking several antihypertensive drugs. Interestingly, the patient had noticed that his kalemia increased when he forgot to take his hydrocortisone or if attempts were made to taper the dose to less than 20 mg/d, necessitating further Kayexalate treatment. This observation provides further evidence to support the adrenal origin of adrenal insufficiency in this patient. Based on surgical findings, this patient was considered to display bilateral adrenal involvement.
Case no. 2.
A 46-yr-old man with renal failure and severe renovascular hypertension (1) was diagnosed with retroperitoneal and periaortic fibrosis and bilateral hydronephrosis on abdominal CT. Steroid treatment (1 mg/kg·d) was initiated in April 2000 and gradually tapered to 20 mg/d in September. In November, the patient developed xanthelasma of the left eyelid. A thoracic/abdominal CT scan revealed a "coated aorta" and ostial stenosis of the right renal artery. Circumferential infiltration was observed around both kidneys. CT also showed unilateral periadrenal infiltration, with an enlarged adrenal gland on the right side of the body. Steroid treatment was stopped in June 2001, and a synacthen test performed at that time was normal. In February 2005, CT of the periaortic fibrosis showed a 50% decrease in maximum diameter at two locations, but no decrease in right adrenal gland infiltration was observed.
Case no. 3.
A 54-yr-old man was referred to our hospital in November 2001 for a malaise due to tight ostial stenosis of the right renal artery (1). His serum creatinine level was within the normal range. A CT scan revealed bilateral hydronephrosis with perirenal infiltration and a "coated aorta." CT also showed symmetric, bilateral periadrenal infiltration. Both adrenal glands were enlarged and symmetric, and were surrounded by an infiltrate. Prednisone (1 mg/kg·d) treatment was initiated in January 2002 but did not reduce periaortic fibrosis. Steroid levels were then tapered to 5 mg/d. Synacthen tests were not performed because steroid treatment was continuous. Despite treatment, the patient developed severe multi-vessel ischemic cardiomyopathy and died of myocardial infarction in March 2005. No autopsy was performed.
Case no. 4.
A 57-yr-old woman was referred to our hospital in August 2002 for a 2-yr history of mediastinal and retroperitoneal fibrosis that did not respond to continuous glucocorticoid therapy (1). Congestive heart failure developed due to frank mitral regurgitation. Steroid treatment was progressively tapered. On reinterpretation, a previous CT scan was found to show a "coated aorta" and extensive perirenal infiltration highly suggestive of ECD, together with bilateral, symmetrical periadrenal infiltration. In April 2004, perivascular involvement was stable, but the patient’s mitral insufficiency worsened. Mitral valve replacement was attempted in May 2004 but was unsuccessful due to extensive pericardial and myocardial fibrosis. A few days later, the patient underwent tamponade. She was transferred to the intensive care unit where respiratory distress developed due to severe pulmonary infection requiring mechanical ventilation. She died of pulmonary infection in October 2004. Autopsy findings confirmed the infiltration of all the organs identified as involved on the basis of clinical and radiological data: very thick pericardium (1 cm); a firm, yellowish pseudo-atrial mass 8 x 3 cm in size; periaortic fibrosis; and perirenal infiltration. It also showed massive periadrenal histiocyte infiltration, leading to an 8-fold increase in adrenal gland volume (Fig. 1). Pathological examination of the adrenal area showed massive infiltration of the periadrenal tissue, with large cells with small nuclei shown to be histiocytes by immunostaining for CD68+ (Fig. 2).
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FIG. 1. ECD infiltration of the adrenal glands (A) and of the aortic lumen together with both adrenal glands (B).
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FIG. 2. A, Hematoxylin-eosin staining of adrenal tissue (macroscopic view). B, CD68 staining of adrenal tissue (macroscopic view) from a patient with ECD. C, Infiltration of the periadrenal tissue by histiocytes hematoxylin-eosin (magnification, x100). D, Anti-CD68 immunohistochemistry (magnification, x100).
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Case no. 5.
A 52-yr-old man was admitted to the hospital in December 1999 for global cardiac insufficiency due to stage III aortic regurgitation and a bicuspid aortic valve (1). It was decided to replace the valve. The patient had a long history of hypertension, and a preoperative blood test revealed major biological inflammation (C-reactive protein 161 mg/liter; normal < 5 mg/liter). Abdominal CT showed perirenal and left ureteral fibrosis with no hydronephrosis and also revealed bilateral, symmetrical periadrenal infiltration with bilateral, symmetrical enlargement of the adrenal glands (Fig. 3). Between July 2000 and February 2001, the patient was treated with vinblastine (10 mg/wk for 6 wk, then 10 mg every 3 wk for 4 months). He also received prednisone, initially at 1 mg/kg·d, but was gradually weaned off this drug between July 2000 and January 2001. No change in periadrenal infiltration was observed on the CT scan taken in September 2005. Synacthen test results were normal.
Case no. 6.
A 37-yr-old man with ECD presented with right exophthalmos and eyelid xanthelasma. A CT scan revealed bilateral, symmetrical periadrenal infiltration and bilateral, symmetrical adrenal gland enlargement. Synacthen test results were normal.
Case no. 7.
A 57-yr-old man with Down’s syndrome was referred for focal neurological symptoms and respiratory distress. Magnetic resonance imaging revealed multiple brainstem tumors. Stereotaxic biopsy was consistent with ECD. CT showed a "coated aorta," and bilateral, symmetrical periadrenal infiltration with bilateral and symmetrical adrenal gland enlargement and bilateral hydronephrosis. The patient also displayed moderate pericardial effusion, sinusal dysfunction, bone involvement, and lung fibrosis, all specific to ECD. Adrenal insufficiency was excluded based on the results of adrenal stimulation tests. The patient was treated with high-dose steroids due to the severity of the disease. An assessment 6 months after initiation of the steroid treatment showed this treatment to be effective.
Literature review
There were 15 additional cases of adrenal involvement in ECD patients identified in published studies (Table 1
). Eight of the patients were male, and seven were female. Mean age at diagnosis was 51.9 yr. At least 12 of these patients died, confirming the poor overall prognosis of ECD. No data were available for adrenal function tests in 13 of the 15 cases, and in one case, only the results of the synacthen test were normal. None of these cases presented signs of adrenal tumor. No signs of adrenal failure were reported in these 15 cases of ECD and adrenal involvement. In 10 of these cases, evidence for adrenal and/or periadrenal infiltration was provided by autopsy findings. Various types of adrenal involvement were observed: bilateral adrenal enlargement (n = 9), unilateral adrenal infiltration (n = 1), and periadrenal infiltration in the absence of adrenal involvement (n = 5).
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Discussion
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We reinterpreted CT scans to search systematically for possible adrenal enlargement in 22 patients with ECD. Adrenal enlargement was detected in seven (31.8%) of these patients, and was bilateral in six cases and unilateral in one. None of the seven patients displayed any sign of an adrenal tumor. In one case (no. 4), autopsy confirmed that the observed enlargement was due to adrenal infiltration with foamy histiocytes. Adrenal function was assessed in five patients (nos. 1, 2, 5, 6, and 7). One patient (no. 1) had clinical and biological signs of adrenal insufficiency. This patient is the first reported case of adrenal insufficiency due to ECD. Despite adrenal enlargement, adrenal stimulation test results were normal in three cases. Two patients (nos. 3 and 4) were on steroid treatment for ECD and could not be tested. All patients, except no. 7, received interferon- treatment because we have recently shown this treatment to be a valuable first-line therapy for prolonged ECD (6). Our findings clearly suggest that adrenal infiltration is not rare in ECD patients and may even lead to adrenal insufficiency.
We reviewed the 240 cases of ECD reported in previous studies. Adrenal involvement was mentioned in 15 (6.25%) cases. This frequency is significantly lower (P = 0.0008; by Fisher’s exact test) than that in our series. This is probably because we systematically searched for adrenal infiltration, whereas the data for published cases were often incomplete, highlighting the lack of recognition of this manifestation of ECD. Therefore, adrenal enlargement should be sought systematically in proven cases of ECD because it may lead to adrenal insufficiency. No cases of adrenal insufficiency were reported in published studies, but stimulation tests were described in only one case. The main characteristics of previously reported cases and of the cases from our series (Table 1) were similar. Adrenal involvement was found in all ECD patients with diffuse multisystemic disease, and unilateral infiltration was rare. It appears clearly, in the light of our results and those from previous studies, that adrenal steroidogenesis should be systematically investigated to generate sufficient data for firm conclusions to be drawn on the prevalence of adrenal abnormalities in patients with ECD.
Of the 22 patients with ECD and adrenal involvement, 14 (63.6%; 12 from the literature review and 2 personal cases) died of ECD-related causes, confirming the poor overall prognosis of ECD. Indeed, in our 2004 survey of follow-up data for 58 of the 72 (80.6%) patients studied, 35 (60.3%) patients died (1). It is important for physicians to be familiar with ECD because this life-threatening condition, like lymphoma, sites of metastases, tuberculosis (7), histoplasmosis (8), cryptococcosis (9), cytomegalovirus infection, bilateral hemorrhages (10), systemic vasculitis (11), sarcoidosis, amyloidosis, bilateral pheochromocytoma (12), and bilateral adrenal macro-nodular hyperplasia (13), may be responsible for bilateral adrenal enlargement.
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Footnotes
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Disclosure Statement: The authors have nothing to declare.
First Published Online April 3, 2007
Abbreviations: CT, Computed tomography; ECD, Erdheim-Chester disease.
Received September 14, 2006.
Accepted March 27, 2007.
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Abstract
Introduction
