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Cardiovascular Involvement, an Overlooked Feature of Erdheim-Chester Disease: Report of 6 New Cases and a Literature Review

Haroche, Julien MD, PhD; Amoura, Zahir MD; Dion, Elisabeth MD; Wechsler, Bertrand MD; Costedoat-Chalumeau, Nathalie MD; Cacoub, Patrice MD; Isnard, Richard MD; Généreau, Thierry MD; Wechsler, Janine MD; Weber, Nina MD; Graef, Claire MD; Cluzel, Philippe MD; Grenier, Philippe MD; Piette, Jean-Charles MD

doi: 10.1097/01.md.0000145368.17934.91
Article

Abstract: Erdheim-Chester disease (ECD) is a rare, non-Langerhans form of histiocytosis of unknown origin. It is characterized by xanthomatous or xanthogranulomatous infiltration of tissues by spumous ("foamy") histiocytes. As of this writing, 178 cases have been reported. ECD is characterized by heterogeneous systemic manifestations. Bone pain is the most frequent symptom. About half of all patients have extraskeletal manifestations. Cardiovascular manifestations of ECD remain underestimated. We report 6 new cases of ECD associated with periaortic fibrosis. In 4 of these cases, the whole aorta had a "coated" aspect. A literature review revealed 66 cases of ECD with cardiovascular involvement. We therefore analyzed 72 ECD patients with cardiovascular involvement: 40 (55.6%) had periaortic "fibrosis," 32 (44.4%) had pericardial involvement, and 22 (30.6%) had myocardial involvement. Six had a right atrial tumor. Symptomatic valvular heart disease (3 aortic and 3 mitral regurgitations) was found in 6 patients. Nineteen patients (26.4%) had heart failure, leading to death in 8 cases. Six patients had renovascular hypertension related to perirenal artery stenosis. Data concerning follow-up were available for 58 (80.6%) patients. Of these, 35 (60.3%) patients died, confirming the severe prognosis of ECD. Cardiovascular complications were responsible for the death of 11 of the 35 patients (31.4%).

Abbreviations: CRP = C-reactive protein, CT = computed tomography, ECD = Erdheim-Chester disease, ESR = erythrocyte sedimentation rate, MRI = magnetic resonance imaging, 99Tc = technetium-99.

From Service de Médecine Interne (JH, ZA, BW, NCC, P Cacoub, JCP), Service de Radiologie Générale (ED, CG, P Cluzel, PG), and Institut de Cardiologie (RI), Hôpital Pitié-Salpêtrière, Paris; Service de Médecine Interne (TG), Hôpital Saint-Antoine, Paris; Département de Pathologie (JW), Hôpital Henri-Mondor, Créteil; Département de Pathologie (NW), Hôpital Victor Dupouy, Argenteuil, France.

Address reprint requests to: Julien Haroche, MD, PhD, Service de Médecine Interne, Hôpital Pitié-Salpêtrière, Paris, France. Fax: 33 1 42 17 80 32; e-mail: julien.haroche@psl.ap-hop-paris.fr.

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INTRODUCTION

Erdheim-Chester disease (ECD) is a rare, non-inherited, non-Langerhans form of histiocytosis of unknown origin. It is characterized by xanthomatous or xanthogranulomatous infiltration of tissues by spumous histiocytes, "lipid-laden" macrophages or histiocytes, surrounded by fibrosis. ECD can be distinguished from Langerhans cell histiocytosis by the immunohistologic and microscopic characteristics of histiocytes. ECD patients are constantly positive for CD68 and negative for CD1a, and ultrastructural studies show no Birbeck granules. Some patients are negative for the S-100 protein, whereas others are positive20,66.

Jakob Erdheim's pupil, William Chester, first described "lipoid granulomatose" in 193014. Between 1930 and October 2003, 178 cases were reported2,11,17,32-34,38,45,46,48,52,53,55,56,58,76,81,83. ECD is characterized by heterogeneous systemic manifestations. Bone pain is the most frequent symptom. Symmetrical radiodensities in the metaphyseal and diaphyseal portions of long bones, and abnormally increased labeling in the long bones of the lower limbs on technetium-99 (99Tc) bone scans are typical hallmarks. About half of all patients have extraskeletal manifestations including exophthalmos, diabetes insipidus, xanthelasma, interstitial lung disease, bilateral adrenal enlargement, retroperitoneal fibrosis with perirenal and/or ureteral obstruction, renal impairment, testis infiltration, central nervous system, and/or cardiovascular involvement78.

The cardiovascular manifestations of ECD, particularly the "coated aorta" aspect, were redescribed in 2000 by Serratrice et al69. They had been known to exist since the disease was first described, but remained largely unrecognized. Their occurrence is probably still underestimated. We report 6 cases of ECD associated with periaortic fibrosis. In 4 of these cases, the whole aorta had a "coated" aspect. Two of these patients had renovascular hypertension due to ostial stenosis of the renal artery. Two patients had major valvular regurgitation (1 mitral, 1 aortic) responsible for cardiac insufficiency. One patient had infiltration of the pericardium and a right atrial tumor. We found frequent infiltration around aortic collaterals, notably with perifibrosis of the mesenteric superior artery in all 6 patients and of the renal arteries in 5 of the 6 patients. We also reviewed the 66 histologically confirmed cases of ECD with cardiovascular involvement found in the literature.

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PATIENTS AND METHODS

We report 6 new cases of histologically proven ECD with cardiovascular involvement. Two men (Cases 1 and 2) and 3 women (Cases 3, 5, and 6) were referred to the internal medicine department of Pitié-Salpêtrière Hospital (Paris), and 1 man (Case 4) was followed in the internal medicine department of Saint-Antoine Hospital (Paris).

The following criteria were used to diagnose ECD in our new cases and for literature review observations:

  1. typical histologic findings (Figure 1): 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;
  2. FIGURE 1

    FIGURE 1

  3. typical skeletal findings with 1) X-rays showing bilateral and symmetric cortical osteosclerosis of the diaphyseal and metaphyseal regions in the long bones and/or 2) symmetric and abnormally increased labeling of the distal ends of the long bones of the lower limbs, and sometimes the upper limbs, on 99Tc bone scintigraphy.

These ECD criteria were those used for our previous literature review78 published in 1996. All new cases fulfilled criterion (a) and all but 1 fulfilled criterion (b).

For the literature review, we performed a MEDLINE (National Library of Medicine, Bethesda, MD) search for ECD of all papers published until October 2003. Among all published cases of ECD (included in our 1996 survey78 and reported since), we sought descriptions of cardiovascular involvement, characterized clinically and/or radiologically and/or by autopsy findings. We found 66 such cases, all of which met criterion (a) and 56 of which met criterion (b). Using the data available in these articles, we tried to determine the precise topography of the cardiovascular involvement. This was not always easy, as numerous case reports focused only on specific clinical patterns of ECD, and data regarding vascular involvement were often incomplete. Most data concerning aortic and pericardium infiltration were obtained by computed tomography (CT) scan.

For statistical analysis, we used contingency tables and the Fisher exact test to compare percentages of patients exhibiting clinical symptoms of ECD.

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CASE REPORTS

Case 1 (Figures 2-5)

FIGURE 2

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FIGURE 5

In February 2000, a 46-year-old man was diagnosed with renal insufficiency (serum creatinine = 182 μmol/L) following a routine blood test. Retroperitoneal and periaortic fibrosis with bilateral hydronephrosis was diagnosed based on an abdominal CT scan. He had an 11-year history of hyperlipemia; this was initially treated by fibrates and then by hMG-cOA reductase inhibitors. He had suffered from severe back pain for 3 years. This was attributed to a possible ankylosing spondylitis (he was HLA B27-positive). He had been hypertensive for 3 years. Despite treatment with calcium inhibitors and beta blockers, his condition had recently worsened (220/120 mm Hg). First-hour erythrocyte sedimentation rate (ESR) was elevated (71 mm in August 1997 and 121 mm in March 2000) with a C-reactive protein (CRP) concentration of 57 mg/L. Silicone double-pigtail ureteral stents were inserted on both sides, leading to normalization of serum creatinine level. Prednisone was initiated in April 2000 (1 mg/kg per day). This dose was decreased to 20 mg/d in September 2000, but did not improve the "fibrosis" on CT scan evaluation. In November 2000, he developed a xanthelasma of the left eyelid. He was referred to our hospital in January 2001. Skeletal X-rays revealed symmetrical osteosclerosis of the long bones of the lower limbs. Bone scintigraphy with 99mTc-HMDP showed diffuse hyperfixation in the lower limbs. A thoracoabdominal CT scan revealed a "coated aorta" aspect, sparing the origin and ascending part of the aorta, with predominance around the arch, the thoracoabdominal junction, and at the celiomesenteric level. It was not always circumferential and was sometimes symmetrical. The brachiocephalic trunk, left common carotid artery, and left subclavian artery were surrounded by circumferential, regular, and nonstenotic fibrosis. The celiac trunk and mesenteric superior artery were surrounded by regular circumferential fibrosis. We also detected ostial stenosis of the right renal artery. Both kidneys had circumferential perirenal infiltration. In this context, a full histologic diagnosis of ECD was possible based on perirenal soft tissue and bone biopsies; this revealed spumous histiocytes that were CD68 positive and S-100 negative. The right renal artery was stented, which had a good effect on blood pressure. In February 2001, he was treated with 45 mg/m2 of vesanoid (b.i.d.) (or all-trans-retinoic acid [ATRA], an important regulator of gene expression in neoplasms, and during growth and development) for 6 weeks. The same regimen was subsequently repeated 15 days each month. This treatment was discontinued in May 2001 because of cramps, dry mouth, and lack of effect on the "fibrosis," which had progressed according to the CT scan. In June 2001, peripheral blood stem-cell rescue was carried out and alpha interferon treatment (3 million units subcutaneously 3 times a week) was initiated. This treatment was well tolerated. In December 2003, after 30 months of this regimen, the patient was in stable condition. His blood pressure was normal under treatment with calcium inhibitors and beta blockers, and the xanthelasma was stable. The periaortic "fibrosis" had regressed slightly (10%-20%) according to CT scans. CRP was normal and the creatinine concentration was 120 μmol/L.

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Case 2 (Figures 6 and 7)

FIGURE 6

FIGURE 6

FIGURE 7

FIGURE 7

A 54-year-old man was referred to our hospital in November 2001 for hypertension, malaise, bilateral hydronephrosis, and increased levels of acute inflammatory protein. His medical history was unremarkable except for hypertriglyceridemia discovered a few years ago. Hypertriglyceridemia was controlled by diet, resulting in the loss of 13 kg in 2 years. Hypertension was discovered in August 2000. This was initially treated by bisoprolol and nifedipine-atenolol, and subsequently treated by amlodipine and atenolol-chlorthalidone. Since December 2000, he suffered from malaise, sometimes at night, each lasting less than a minute. During these periods of malaise he was pale, perspired, and experienced incomplete loss of consciousness and problems walking. The frequency of the periods of malaise had increased during the few months before admission, reaching up to 3 every 2 weeks. For 1 year, he showed signs of inflammation: CRP = 80 mg/L, fibrinogen = 7 g/L, and increased platelet count = 563,000/mm3. First-hour ESR was 76 mm. Serum creatinine was normal. Abdominal CT scan revealed bilateral hydronephrosis, and renal angiography showed ostial stenosis of the right renal artery. A temporal arterial biopsy revealed no signs of giant cell arteritis. He had no orthostatic hypotension. At admission, vascular murmurs affecting the carotids and subclavian arteries were found. Hypertension was poorly controlled (170/110 mm Hg). He also had hepatomegaly.

Re-examination of the abdominal CT scan revealed perirenal infiltration and thickening of the aortic wall. This was confirmed by total aorta CT scan, which revealed infiltration involving the mediastinum, the retroperitoneum, the perirenal space, and the mesentery. Periaortic infiltration started at the origin of the supra-aortic vessels and continued around the arch, across the roof of the left atrium, and behind the right atrium. The pericardium and left coronary artery were surrounded by fibrosis, as were the pulmonary trunk and the right pulmonary artery. Infiltration of the aorta started at its origin and was not circumferential. It reached the arch, where it became circumferential and continued around the descending part of the aorta, where it was asymmetrical and sometimes pseudonodular. The abdominal aorta was infiltrated, almost circumferentially but not concentrically, up to the bifurcation. The iliac arteries were not affected. The brachiocephalic trunk, left common carotid artery, left subclavian artery, celiac trunk, and mesenteric superior artery were surrounded by circumferential and regular nonstenotic fibrosis. The right renal artery was within tight ostial regular circumferential stenosis. Doppler analysis of the supra-aortic vessels found diffuse nonstenotic atheromatous infiltration of both carotids. Doppler analysis also confirmed tight stenosis of the origin of the right renal artery. A skeletal X-ray revealed osteosclerosis of the distal extremities of both femurs, and bone scintigraphy showed diffuse intense hyperfixation in the lower limbs.

An echographically guided percutaneous perirenal soft tissue biopsy led to a diagnosis of ECD. The right renal stenosis was stented, resulting in normalization of blood pressure and complete resolution of malaise. Prednisone (initially at 1 mg/kg per day) was started in January 2002, but had no effect on inflammation or periaortic "fibrosis." The patient subsequently developed diabetes mellitus. He was then treated with alpha interferon (3 million units subcutaneously 3 times a week), which led to the disappearance of inflammation and improvement of his general status. The perivascular infiltration had not progressed in September 2003, 10 months after initiation of this therapy.

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Case 3 (Figures 8-12)

FIGURE 8

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FIGURE 12

A 57-year-old woman was referred to our hospital in August 2002 with a 2-year history of thoracic and retroperitoneal corticosteroid-resistant fibrosis. She had a long history of migraine (for which she had never taken methysergide). She also had hypertension, which was treated by angiotensin-converting enzyme inhibitor. She was first hospitalized in another hospital in February 2000 for dyspnea, with inability to walk more than 500 meters. At this time, she mentioned a 1-year history of vesperal febricula, persistent nonproductive cough, episodes of tracheitis and sinusitis, and a 20-kg weight loss (from 113 to 93 kg). A thoracic CT scan revealed mediastinal fibrosis. She underwent thoracotomy in April 2000: histology revealed dense collagenous tissue suggestive of mediastinal primary fibrosis. At this time, an abdominal CT scan revealed retroperitoneal fibrosis including both ureters, responsible for mild hydronephrosis and periaortitis. She received 2 intravenous pulses of 1 g of methylprednisolone, followed by oral prednisone (0.5 mg/kg per d). In July 2000 tamoxifen was added. Clinical examination and CT scans revealed no improvement of the mediastinal fibrosis in September 2000.

In June 2001, she had acute pulmonary edema due to mitral regurgitation, which progressively worsened throughout 2002 leading to NYHA class III-IV. The dose of steroids was decreased to 5 mg/d in July 2002 and azathioprine was initiated. Mediastinal fibrosis worsened and pleural fibrosis was observed on a CT scan in July 2002. She had biologic inflammation with CRP = 78 mg/L. Re-reading of different CT scans revealed "coated aorta" and "hairy perirenal infiltration" aspects. Bone scintigraphy revealed hyperfixation of the sacroiliac joints, inferior parts of femurs, inferior metaphyses of tibias, superior part of the right tibia, and distal extremity of the left radius. A perirenal soft tissue biopsy showed mild inflammatory fibrosis with CD68-positive and S-100-negative spumous histiocytes. This result, along with the clinical and radiologic findings, enabled us to diagnose ECD.

Doppler examination of the supra-aortic vessels revealed right internal jugular vein thrombosis and circumferential perifibrosis of the left carotid bulb. Thrombosis of the right internal jugular vein was confirmed on thoracic magnetic resonance imaging (MRI), which revealed diffuse signal anomalies in the mediastinum and pleura. The hyposignal surrounding the ascending aorta observed on T2-weighted sequences was suggestive of a noninflammatory fibrotic infiltration, whereas signal anomalies surrounding the superior vena cava, right pulmonary artery, and pleura seemed more inflammatory. The superior vena cava was within fibrosis and stenosed near the right atrium. The right cardiac cavities were also infiltrated. The pericardium facing the left ventricle was thickened. Transthoracic and transesophageal echocardiography showed massive mitral regurgitation associated with major pulmonary hypertension (pulmonary artery systolic pressure = 80 mm Hg). Like ultrasonography, CT scan and MRI detected a 4.5 × 3.7 cm mass in the right atrium. Cardiac catheterization and quantitative angiography confirmed the severity of the mitral regurgitation and pulmonary hypertension (pulmonary artery pressure 70/45 mm Hg, pulmonary wedge pressure 30 mm Hg with a v wave at 70 mm Hg). Alpha interferon treatment (3 million units subcutaneously 3 times a week) was initiated in October 2002. Inflammation resolved, general status improved significantly, and dyspnea disappeared. In September 2003, the perivascular involvement was stable.

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Case 4

A 52-year-old man was hospitalized in December 1999 for global cardiac insufficiency due to aortic regurgitation stage III with a bicuspid aortic valve. A decision was made to replace the valve. He had a long history of hypertension, stabilized by verapamil. A preoperative blood test revealed major biologic inflammation (CRP = 161 mg/L). He had no fever or apparent infections. Transesophageal echocardiography and blood cultures ruled out endocarditis. An abdominal CT scan showed perirenal and left ureteral fibrosis with no hydronephrosis, and a circumferential regular nonstenotic infiltration of the subrenal abdominal aorta and of the medial and distal parts of the mesenteric superior artery. "Fibrosis" also surrounded the right primitive iliac artery and the intrarenal part of the left renal artery. Bone scintigraphy showed hyperfixation of the lower limbs. Perirenal biopsy found xanthogranulomatous tissue with spumous histiocytes, suggestive of ECD. Pericardial and periaortic samples were collected during surgery (February 2000). Both contained spumous histiocytes. Between July 2000 and February 2001, the patient was treated with vinblastine (10 mg/week for 6 weeks, then 10 mg every 3 weeks for 4 months). He also received prednisone, initially at 1 mg/kg per day and gradually decreased between July 2000 and January 2001. Inflammation rapidly disappeared after initiation of treatment, but periaortic "fibrosis" persisted. At last follow-up the patient was receiving 10 mg of vinblastine every 6 weeks.

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Case 5

A 72-year-old woman was referred to our department in February 2003 with biologic inflammation and periaortitis. She had a long history of depression (since she was aged 25 yr) and a 3-year history of diarrhea concomitant with treatment by venlafaxine. Diarrhea stopped with discontinuation of this medication. Inflammation was first noted in 1999 with first-hour ESR at 55 mm, reaching 120 mm in October 2002. In October 2002, CRP was 120 mg/L and in February 2003 it was 94 mg/L. Infective endocarditis and temporal arteritis were ruled out. Thoracoabdominal CT scan revealed a tissular right paravertebral mass and a circumferential nonstenotic thickening of the perivascular wall of the ascending arch and descending parts of the aorta, of the arterial brachiocephalic trunk, of the left primitive carotid artery, and of the left subclavian artery. "Fibrosis" encased the abdominal aorta where it was regular but not circumferential. It reached the aortic bifurcation and iliac arteries and also surrounded the superior mesenteric artery where it was regular, circumferential, and stenotic. Both renal arteries were surrounded by "fibrosis" with ostial stenosis of the right renal artery. She had no fever and her blood pressure was normal. She only complained of right knee pain and was asthenic. A 99mTc-HMDP bone scintigraphy showed intense and symmetrical uptake by sacroiliac joints, by the lower thirds of the femurs, and by the upper thirds of the tibias. MRI of the knee bones revealed a hyposignal of the medullary bone canal corresponding to the loss of the fat signal. A CT-guided biopsy of retroperitoneal periaortic tissue showed spumous histiocytic infiltration with a strong staining of CD68 and a weak positivity for S-100 protein. ECD was diagnosed and prednisone treatment was prescribed (0.5 mg/kg per day).

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Case 6 (Figure 13)

FIGURE 13

FIGURE 13

A 41-year-old woman was referred to our department in February 2001 for mediastinal fibrosis and mesenteric angina. These conditions were responsible for a weight loss of 14 kg since September 2000. She had severe biologic inflammation with CRP = 161 mg/L. A CT scan revealed infiltration of the mediastinum including the aortic arch, the left primitive carotid artery, and the left subclavian artery, which were all surrounded by circumferential and regular nonstenotic fibrosis. The superior mesenteric artery was surrounded by a regular and circular "fibrosis," which started a few centimeters after the ostium. Explorative thoracotomy was carried out, but tissue biopsies did not allow a diagnosis. Doppler examination showed thickening of the vessel wall, which reached 5 mm in places, and also revealed a nonstenotic infiltration of the celiac trunk followed by a narrowing of the origin of the common hepatic artery and major stenosis of the left intrahepatic artery branch. Transthoracic echocardiography found a mild to moderate circumferential pericarditis. Re-examination of the mediastinal tissue samples and of a bone marrow biopsy found xanthogranulomatous tissue with spumous histiocytes. These histiocytes were CD68 positive, CD1a negative, and S-100 negative, consistent with ECD. Bone scintigraphy did not reveal any increased labeling of the long bones of the lower limbs. The patient initially received high-dose methylprednisolone pulses intravenously, followed by oral steroids. Under this regimen, mesenteric angina disappeared and the patient regained weight. Inflammation resolved and by September 2001 the steroids dose was reduced to 10 mg/d. The patient was totally asymptomatic in October 2003 under 5 mg/d of steroids, but the mediastinal mass did not decrease in size on further CT scans.

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RESULTS

Literature Review

We found 66 cases of ECD with cardiovascular involvement. Twenty-six of these were reported in our 1996 study78 (listed here by first author of the original report): Chester14 (2 cases), Alper3 (2 cases), Fink25 (1 case), Wechsler80 (1 case), Caparros-Lefebvre12 (3 cases), Cavanagh13 (2 cases), Rozenberg64,65 (1 case), Sandrock67 (1 case), Valdez77 (1 case), Resnick63 (1 case), Elian21 (1 case), Shields72 (2 cases), Sherman71 (2 cases), Freyschmidt26 (1 case), Heine31 (1 case), Masshoff49 (1 case), Miyachi51 (1 case), Mergancova50 (1 case), and Kujat41,42 (1 case). Some of the patients were described in several different articles focusing on different aspects of ECD: the third patient reported by Capparos-Lefebvre et al12 was also described by Remy-Jardin et al62 and Farre et al23. The same applies to the following reports: references 44 and 35; reference 69 (second case) and reference 43; reference 67 (first case) and reference 77; reference 63 (second case) and reference 68; reference 66 and reference 3 (second case); references 15, 82, and 10; and references 30 and 4.

We previously analyzed 58 cases of ECD78. Five of the 7 cases reported therein (listed here by first author of the original report)-Rozenberg64,65 (1 case), Caparros-Lefebvre12 (3 cases), and Wechsler80 (1 case)-were reported to have periaortic fibrosis, but this lesion was not considered to be a feature of ECD at that time. Eight other cases of ECD with periaortic involvement were also included in the 1996 study3,13,21,25,50,51,66. Pericardial effusion, leading to tamponade in 1 case77, was described in 7 patients in that study3,25,41,51,63,67,77, and pericardial infiltration was reported in 3 patients66,71,80. Three case reports25,50,51 also described involvement of other major blood vessels, including the basilar artery, vertebral artery, carotid artery, and medial cerebral artery, and infiltration of the heart (right atrial tumor). Twelve patients were reported to have heart failure3,13,14,21,25,26,51,71,72,77,80. Although hypertension was also described, we decided not to include 2 patients from the previous study because of the lack of information concerning cardiovascular histiocyte infiltration8,40.

Since our 1996 study, 120 cases of ECD have been reported in the literature11. Cardiovascular involvement was described in 40 of these. In 2000, Serratrice et al69 observed the "coated aorta" aspect on CT scans of 3 patients with ECD and concentric encasement of the whole aorta. Thus, counting the 26 patients from our 1996 study78 and the 40 patients from the literature since then, and including the 6 new cases reported above, we reviewed 72 ECD patients with cardiovascular involvement. We did not include the patient said to have hypertension without description of cardiovascular involvement reported by Amrith et al6. The main characteristics of the cases, including description of the heart and perivascular infiltration, are reported in Tables 1 and 2.

TABLE 1

TABLE 1

TABLE 1

TABLE 1

TABLE 1

TABLE 1

TABLE 2

TABLE 2

TABLE 2

TABLE 2

TABLE 2

TABLE 2

TABLE 2

TABLE 2

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Demographics

The current study includes 40 men and 32 women. This sex distribution is concordant with the slight male preponderance observed in the 1996 study (32 males: 26 females). Mean age at diagnosis in the current series was 54.7 years ± standard deviation (range, 28-84 yr), which is similar to previous findings.

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Vascular Involvement

Aorta

Forty (56%) of the 72 patients had periaortic "fibrosis"; this involved the whole aorta in 20 cases, was limited to the thoracic aorta in 10 cases, and was limited to the abdominal aorta in 10 cases. Periaortitis was demonstrated by CT scan in 25 patients, and/or by MRI in 7 cases. Autopsy findings confirmed periadventitial, xanthogranulomatous, perivascular infiltration of the aorta in 15 cases1,12,13,18,21,22,25,31,50,60,66,80. Surgery also provided valuable data concerning periaortic infiltration in 2 cases: in the first patient reported by Serratrice et al69 a glossy aspect of the aorta was noted during aortobifemoral bypass with difficult retroperitoneal tunneling of the prosthesis due to local inflammation; in the study by Kenn et al37, the surgeon found a condensed periaortal tissue during aortic valve replacement and bypass surgery. This tissue showed remarkable histiocytic infiltration and a foamy appearance of the cytoplasm on pathologic specimen from the aortic valve and ascending aorta.

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Aorta Branches and Other Arteries

Major blood vessels apart from the aorta were involved in 13 of the 66 cases described in the literature: basilar artery (n = 3)22,25,51, vertebral arteries (n = 2)22,50, carotids (n = 3)39,50,66, innominate artery (n = 1)39, anterior iliac arteries (n = 3)60,69, right renal artery (n = 3)1,18,69, left renal artery (n = 2)44,69, celiac trunk stenosis (n = 2)18,69, right popliteal artery (n = 1)49, and right medial cerebral artery (n = 1)50. However, as mentioned above, these data are certainly incomplete, and it is highly probable that other arteries were surrounded by "fibrosis." Indeed, among our 6 personal cases with aortic involvement reported here, the superior mesenteric artery (6/6), left common carotid artery (5/6), left subclavian artery (5/6), left renal artery (5/6), right renal artery (4/6), brachiocephalic trunk (4/6), pulmonary trunk (3/6), celiac trunk (3/6), and left (2/6) or right coronary artery (1/6) were surrounded by fibrosis (Table 3).

TABLE 3

TABLE 3

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Venous Involvement

Venous involvement was reported much less frequently in the 66 cases from the literature: 2 patients had deep vein thrombosis with pulmonary embolism49,70, 2 patients had superior sagittal sinus thrombosis49,51 and 1 patient had superior vena cava obstruction77. Venous involvement was also observed in 3 of our 6 personal cases: fibrosis around the right pulmonary artery and coronary sinus was observed in Cases 2 and 3; the patient described in Case 3 had fibrosis around the superior vena cava (with a stenosis near the right atrium) and the thoracic portion of the inferior vena cava and thrombosis of the right internal jugular vein; the patient described in Case 6 had fibrosis surrounding the pulmonary trunk.

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Heart Involvement

Pericardium

Although ECD may involve the myocardium and endocardium, pericardial involvement is by far the most frequent heart lesion4. In the current series, 32 of the 72 patients (44%) had pericardial involvement, 9 of whom also had periaortic "fibrosis." Pericardial effusion was found in 17 patients1,3,4,7,9,17,20,27,28,33,36,39,57,63,67,77 including our Case 6, leading to tamponade in 5 cases4,7,27,57,77. Detailed analysis of pericardial fluid was available in 3 patients only: clusters of mesothelial cells, foamy macrophages and eosinophils, lymphocytes and polymorphonuclear leukocytes were observed in the second patient described by Resnick et al63; mesothelial cells in their third patient63; and histiocytes and inflammatory cells in the patient reported by Gupta et al30. In most cases, other causes of pericarditis were ruled out and pericardial effusion could be attributed to ECD. Pericardial involvement was mainly identified by imaging techniques (CT scan, echocardiography) in the absence of histologic proof. In our Case 3, the pericardium was infiltrated as attested by its thickened aspect on CT scan and on MRI. Including our Case 4, histologic analysis of the pericardium revealed histiocyte infiltration in 15 patients1,3,4,7,18,20,47,51,63,66,70,71,75,77. This was discovered at autopsy in 6 cases. In 6 cases (including our Case 4), spumous histiocytes were reported in pericardial tissue4,47,66,70,75, and in only 1 case foamy histiocytes were reported to be positive for CD68, negative for CD1a, and partially positive for S-1004.

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Myocardium

Twenty-two patients had myocardial involvement1,5,14,18,19,21,25,28,31,35,37,39,50,53,58,60,66,69,72,82 including our Cases 2 and 3. Six of these patients (including our Case 3) had a right atrial tumor5,25,28,50,58. Deep myocardial involvement was found in 1 case, as attested by myocardial thickening on echocardiography39. Endomyocardial biopsy revealed histiocyte infiltration in the first patient reported by Serratrice et al69. Epicardial involvement was seen in 4 patients14,21,26,31 as demonstrated by autopsy findings: epicardial atrial thickening14, extensive epicardial fibrosis21, subepicardial fat tissue thickening31, and microscopic foci of epicardial infiltration26.

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Heart Valves

Symptomatic heart valve diseases (3 aortic and 3 mitral regurgitations) were found in 6 patients37,39,61,69 including our Cases 3 and 4. Valve replacement was required in 3 patients, revealing histiocyte infiltration of the aortic valve in 2 patients37 including our Case 4.

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Coronary Arteries

Myocardial infarction was reported in 6 cases15,19,25,53,60,72, leading to death in 219,25. Mean age of the first myocardial infarction was 60.8 years (range, 33-86 yr). Coronary infiltration was noted in 5 patients: stenosis of the interventricular artery that was stented35, obstruction of the circumflex artery60, severe "2-vessel coronaropathy stage II"37, "fibrosis" around the left coronary (our Case 2), and fibrosis around both the left and right coronary arteries (our Case 3).

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Heart Failure

Nineteen patients had heart failure, leading to death in 11% of cases (8/72). In 2 cases, heart failure could be attributed to dilated cardiomyopathy39,74. In 1 case, it was due to "constrictive and restrictive" cardiomyopathy with paroxysmal atrial flutter77, and in 1 case to "decreased systolic function of the myocardium"17.

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Systemic Hypertension

In our literature review, blood pressure was surprisingly not reported in 42 cases (58%). Twenty-two patients had systemic hypertension. Six of these patients had renovascular hypertension related to perirenal artery stenosis1,18,44,69, as described in our Cases 1 and 2. However, in reports it was not always possible to correlate the presence of hypertension with imaging of renal arteries.

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Lipid Profile

We found no data regarding lipid profile for 42 of the 72 patients in this series. For 22 patients, cholesterol and triglyceride profiles were within the normal range; 5 had hypertriglyceridemia (including our Cases 1 and 2); and 3 had hypercholesterolemia.

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Association of ECD Cardiovascular Involvement With Other Clinical Features

Other organs were frequently infiltrated in our 72 ECD patients: 32 (44%) displayed exophthalmos, 28 (39%) had "xanthelasma" or "xanthoma-like lesions," 25 (35%) had neurologic involvement, and 25 (35%) had diabetes insipidus. Among the 58 patients with all forms of ECD included in the 1996 study, we found that cardiovascular involvement was significantly associated with exophthalmos, neurologic involvement, and xanthelasma (p = 0.006, 0.0153, and 0.03 according to the Fisher exact test, respectively). There was a trend toward an association between cardiovascular involvement and diabetes insipidus (p = 0.06).

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Follow-Up With Special Focus on Cardiovascular Involvement

Data concerning follow-up were available for 58 of the 72 (81%) patients: 35 of these 58 (60%) patients died, which is consistent with our prior findings, that is, 22 deaths (59%) out of 37 available patients in the 1996 report (21 deaths being included in both series), confirming the severe prognosis of ECD. Cardiovascular complications were responsible for death in 11 of these 35 patients (31%): 7 died of heart failure3,13,18,19,69,71,72. Of these 7 patients, 2 died of right-sided heart failure secondary to extensive bilateral pulmonary fibrosis3,71; 1 died of tamponade27; 2 died of myocardial infarction19,25; 1 died following occlusion of the abdominal aorta due to severe atherosclerosis22; and 1 died of colic ischemia following surgery60. The other 24 patients seemed to die from infiltration of other organs and/or treatment-related complications, that is, death was not directly related to cardiovascular involvement.

Data were available for 34 of the 35 patients who died; mean survival time was 19.2 months after diagnosis (range, 0-120 mo). Considering all 55 patients for whom follow-up duration was known (35 deaths, 14 patients reported alive with variable follow-up periods, and our 6 cases), the mean follow-up time was 28.9 months (range, 0-300 mo), which is shorter than the mean follow-up reported in the 1996 series (32 mo).

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DISCUSSION

Although cardiovascular involvement was reported in the first case of ECD14, its importance has been largely overlooked. Improvements in radiologic imaging techniques have clearly increased the likelihood of detecting cardiovascular involvement in recent case reports. We found cardiovascular infiltration in about 40% of the 178 cases of ECD reported in literature. This is probably an underestimation as data regarding cardiovascular involvement were often incomplete, emphasizing the lack of recognition of this manifestation of ECD.

Periaortic "fibrosis" is the most frequent cardiovascular involvement in ECD. We found 40 cases of ECD with periaortic fibrosis (including our 6 cases), 20 of which had a "coated aorta" aspect. When the whole aorta is infiltrated, this "coated aorta" aspect can give the impression of a lead pipe39,69. Analysis of samples obtained during autopsy or surgery has shown that this "fibrosis" is due to periaortic infiltration by histiocytes37,69. Fibrosis is mainly located in the adventitia1,13,22,23,60. Nevertheless, as seen on the CT scans of Cases 1 and 3, the intima can appear irregular, suggesting an intimal tropism of histiocytes. When faced with this type of periaortic infiltration, physicians should consider the diagnosis of ECD. Indeed, this particular aspect seems to be specific to ECD, as it has not been reported in other forms of histiocytosis particularly, Langerhans cell histiocytosis.

Complete radiologic data for our personal cases reported here showed that the perivascular infiltration frequently spread around all aortic collaterals. This feature of ECD has been mentioned rarely in other cases, and probably has been overlooked3,66. Modern imaging techniques highlight the general perivascular tropism of ECD "fibrosis," which is clearly not limited to the aorta wall. This finding supports the hypothesis that the xanthogranulomatous process is diffused from the aorta to all aortic collaterals. The significant association found between cardiovascular involvement and extraskeletal manifestations of ECD is consistent with this hypothesis. Nevertheless, 2 of our personal cases displayed "isolated" infiltration of an aortic collateral in the absence of adjacent periaortic "fibrosis": Case 4 with abdominal periaortic "fibrosis" and distal infiltration around the left renal artery, sparing the ostium; and Case 6 with 2 distinct involved sites, the superior mesenteric artery and the aortic arch.

These findings stress the clinical consequences of cardiovascular involvement in ECD. Infiltration of arteries can lead to ischemic manifestations like myocardial infarction25, mesenteric angina18,69, or cerebral ischemia22,50,66. Renal artery stenosis caused hypertension in 6 patients1,18,44,69 including our Cases 1 and 2. Angioplasty and stenting normalized blood pressure in 4 of these cases, but follow-up data remain limited. Arterial infiltration was not always associated with clinical symptoms. Indeed, although all our personal cases had regular infiltration surrounding mesenteric superior artery, only Case 5 had stenosis and mesenteric angina. Similarly, neither of our 2 personal cases with pericoronary infiltration were symptomatic. Heart infiltration by ECD may affect the pericardium, myocardium, valves, and/or coronary arteries. Although frequent, pericardial infiltration with pericardial effusion sometimes leading to tamponade was recognized only recently as a feature of ECD. Clinicians should be aware of the possible occurrence of right atrial tumors, given that the usual means of diagnosing ECD does not involve heart biopsy. Heart involvement was found to be responsible for one-quarter of all deaths in our series.

Due to the major clinical implications of heart abnormalities and the fact that they were identified in 30 patients by echocardiography, we suggest that echocardiography should be performed systematically when evaluating patients with ECD, especially those with vascular involvement. The following echographic signs should be sought: presence of pericardial effusion or of a thickened pericardium, a thickened myocardium and the presence of a right atrial infiltration, the existence of mitral or aortic regurgitation, and infiltration of the aortic arch and descending aorta (the latter is most easily seen on transesophageal echocardiography). Although most of the cases with echocardiographic data reported in the literature focused on pericardial involvement, no data on cardiac hypertrophy or ventricular dilation were available (emphasizing the unrecognized status of these abnormalities). However, Cases 1 and 2 from the present series had mild septal hypertrophy, and Case 5 had mild concentric hypertrophy. None of our cases had ventricular dilation.

Venous manifestations were less frequent (7 cases, including personal Cases 2 and 3). However, unlike arterial involvement, it was generally due to a thrombotic complication of a venous compression by the xanthomatous process rather than to direct infiltration of the vessel wall.

ECD should be added to the list of diseases that physicians consider when faced with 1 of the above-mentioned clinical manifestations or radiologic aspects. However, most of these symptoms are common and unspecific when considered alone. As we found that cardiovascular manifestations of ECD are significantly associated with exophthalmos, neurologic involvement, and xanthelasma, the presence of any of these 3 should prompt clinicians to evoke the diagnosis of ECD.

Parietal aortic wall thickening with diffusion to the main aortic branches can be observed in Takayasu arteritis, which mainly affects young women. However, the radiologic findings of Takayasu arteritis and ECD are different (Table 4). The entire wall, that is, adventitia, media, and intima, is affected in Takayasu arteritis, whereas the adventitial and periadventitial periaortic spaces but not the wall itself are affected in ECD patients. Radiologic abnormalities can also be used to distinguish ECD from mediastinal and retroperitoneal fibrosis. Typically, retroperitoneal fibrosis is not circumferential and infiltrates the anterior and the lateral sides of the aorta, sparing the posterior side. Retroperitoneal fibrosis, but not ECD, may involve the inferior vena cava (which may be stenosed or occluded) or the pelvic ureters. Extravascular images observed in ECD and not in retroperitoneal fibrosis, such as bilateral infiltration of the perirenal space ("hairy kidneys" appearance), can be useful for differential diagnosis.

TABLE 4

TABLE 4

It is important to note that the concomitant presence of an acute inflammatory response is not helpful for the differential diagnosis because our 6 patients all exhibited elevated levels of acute-phase protein despite receiving high-dose steroid treatment. Strikingly, inflammation resolved after alpha interferon therapy. Although CRP levels decreased, periaortic infiltration remained largely unchanged. Numerous treatments for ECD have been proposed, including steroids78, multiple chemotherapy drugs65,69,70,73,78, alpha interferon therapy78, biphosphonate52, and radiation therapy48. It is difficult to evaluate these treatments, however, as most of them have been tested only in a small number of patients or in combination with other drugs. Furthermore, the follow-up period in most of these reports is too short to make it possible to assess their real long-term efficacy.

In conclusion, cardiovascular involvement of ECD is much more frequent than previously thought. Clinical manifestations, such as heart failure, valvular dysfunction, renovascular hypertension, and pericarditis possibly leading to tamponade, are encountered with variable frequencies. Cardiovascular involvement accounts for a significant proportion of the deaths associated with ECD, and thus should be sought systematically.

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