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Erdheim–Chester disease presenting as an intracardiac mass and pericardial effusion confirmed by biopsy: a case report

Abstract Background Erdheim–Chester disease (ECD) is a rare non-Langerhans cell histiocytosis that can affect the bones, heart, lungs, brain, and other organs. Cardiovascular involvement is common in ECD and is associated with a poor prognosis. Here, we report a case of ECD presenting as an intracardiac mass and pericardial effusion confirmed by biopsy with sternotomy. Case summary A 54-year-old man was admitted because of dyspnoea. He was previously diagnosed with bilateral hydronephrosis and retroperitoneal fibrosis. Echocardiography revealed a large amount of pericardial effusion and echogenic mass on the right atrial (RA) side and atrioventricular (AV) groove. Cardiac magnetic resonance imaging and positron emission tomography-computed tomography (CT) revealed infiltrative mass-like lesions in the RA and AV groove. Pericardial window formation and pericardial biopsy were performed, and the pathologic results showed only pericardial fibrosis with no specific findings. Bone scan revealed increased uptake in the long bones. Considering the high probability of ECD based on the patient’s manifestations and the imaging findings, we performed a cardiac biopsy with median sternotomy despite initial insufficient pathologic results in the pericardial biopsy. The surgical findings included multiple irregular and firm masses on the cardiac wall and large vessels; after obtaining a large amount of suspicious mass, ECD accompanied with CD68 (+) and BRAF V600E mutation was confirmed. Discussion Erdheim–Chester disease can be associated with various forms of cardiovascular involvement. Considering the multi-systemic manifestations and difficulty in identifying this rare disease, a comprehensive and meticulous diagnostic work-up is crucial.


Introduction
Erdheim-Chester disease (ECD) is a systemic disease and rare form of non-Langerhans cell histiocytosis. 1 The characteristic pathologic finding of ECD is tissue infiltration by foamy non-Langerhans histiocytes surrounded by fibrosis, which leads to systemic xanthogranulomatous infiltration. 2 This disease was first described by Jakob Erdheim and William Chester in 1930. 3 The majority of ECD patients are diagnosed between the ages of 40 and 70 years, with a slight male predominance. 1 Although approximately 550 cases have been reported, the number of case reports of ECD dramatically increased in the last 20 years due to increased recognition of this disease and a wider availability of diagnostic methods. 1,2 Erdheim-Chester disease is a multisystem disease affecting the bones, heart, lungs, kidneys, brain, skin, and other organs. 4 The most common clinical manifestation is bone pain due to bony involvement. Cardiovascular involvement is also common, but not always clinically evident as it is often asymptomatic. 5,6 However, cardiovascular involvement in ECD is associated with poor prognosis, and cardiac complications are a major cause of death in this disease. 1,7,8 Herein, we report a case of ECD presenting as an intracardiac mass and pericardial effusion confirmed by biopsy with sternotomy despite initial negative pathologic findings in the pericardial biopsy.

Case presentation
A 54-year-old man was admitted to our hospital because of dyspnoea. He had a past medical history of diabetes mellitus and Stage 3 chronic kidney disease. He was diagnosed with heart failure with reduced ejection fraction (HFrEF) in 2010. The aetiology of HFrEF was suspected to be idiopathic dilated cardiomyopathy with comprehensive evaluation, including transthoracic echocardiography (TTE), coronary angiography, and cardiac magnetic resonance imaging (MRI). He was followed up in a cardiology outpatient clinic with guideline-directed medical therapy for 10 years. In 2012, he was diagnosed with a ureter stone, and abdominal pelvic computed tomography (CT) revealed bilateral hydronephrosis and bilateral fat infiltration in the perirenal and periureteric spaces ( Figure 1). Diagnostic ureteroscopy and biopsy were performed, and the pathology results showed chronic non-specific inflammation. He was referred to a rheumatologic clinic, and the diagnosis was suspected to be idiopathic retroperitoneal fibrosis. Oral steroids and azathioprine for immunosuppression were started and followed up in the outpatient clinic.
On admission, his vital signs were: blood pressure 119/63 mmHg, pulse rate of 60 beats/min, respiratory rate of 16 breaths/min, and body temperature of 37.0 C. He had a little dehydrated tongue, but  He underwent subxiphoid pericardial window formation and pericardial biopsy to drain the pericardial effusion and obtain a sample of suspicious tissue. In the operating room, there was a large amount of serous pericardial effusion. In addition, firm and irregular cardiac masses were observed in the pericardial space and on the right ventricle (RV) surface. We could only obtain some pericardial tissue due to the limitations of the surgical field; pathological examination revealed only pericardial fibrosis with no specific findings. Immunohistochemical staining with IgG and IgG4 showed negative results, and BRAF mutation analysis revealed the patient had the wildtype.
However, bone radiography revealed suspicious heterogeneous radiolucency in the distal femur and proximal tibia, and a whole-body bone scan revealed increased uptake in both distal femurs and proximal tibiae (Figure 4). Considering the pericardial effusion, cardiac masses, hydronephrosis, retroperitoneal fibrosis, and multifocal bone lesion, we believed that that the patient likely had ECD despite initial insufficient pathologic results (Supplementary material online, Figure  S1). After a multidisciplinary team approach, we performed a cardiac biopsy with median sternotomy; multiple irregular and firm masses were found on the surface of RA, RV, AV groove, inferior vena cava, superior vena cava, and aorta ( Figure 5). We obtained a large amount of suspicious mass, and pathological examination found chronic inflammation, fibrosis, and CD68 positivity on immunohistochemical staining (Supplementary material online, Figure S2). In addition, the BRAF V600E mutation was detected. Finally, the patient was diagnosed with ECD.
He was referred to the haematology department and started chemotherapy with etoposide and dexamethasone. After the 2 months of initial chemotherapy, he was started with vemurafenib, an inhibitor of BRAF harbouring the V600E mutation. Treatment response will be assessed after 2 or 3 months of vemurafenib treatment.

Discussion
Erdheim-Chester disease can affect any organ; therefore, its manifestations vary among patients, making it difficult to diagnose. Cardiovascular involvement is important because it is common and associated with a poor prognosis. 4,7,8 Cardiovascular manifestations are the major cause of death in ECD since 60% of patients with ECD die due to cardiovascular complications including heart failure and myocardial infarction. 8,9 The prognosis of ECD was reported as poor, with 57% of patients dead after an average follow-up of 32 months. 1 Erdheim-Chester disease may affect the myocardium, pericardium, cardiac valves, aorta, coronary arteries, and conduction system. 10 Pericardial involvement is frequent, occurring in 40-45% of patients when evaluated using TTE, and it can be totally asymptomatic or can lead to pericarditis, effusion, and even tamponade. 11 Pathological histiocytes can also infiltrate the heart wall, thus producing a pseudotumour typically localized to the RA or AV groove. 8 Erdheim-Chester disease can also affect the aorta, causing circumferential infiltration, which can be detectable in a CT scan. 8 This radiologic finding in the aorta is referred to as a 'coated aorta'. 12 In this case, pericardial effusion and cardiac mass were cardiac manifestations of ECD.
Diagnosing ECD is very challenging because the most common clinical manifestations (e.g. bone pain) usually lack adequate specificity. In this multi-systemic disease, various multi-modal imaging   approaches, including CT, brain MRI, cardiac MRI, PET-CT, and bone scan, can be helpful in the diagnosis. 13 For this rare and complex disease, it is essential that clinicians know the main features of the disease so that they can perform an early and comprehensive diagnostic investigation. 14 An accurate diagnosis of ECD is made by identifying the pathological histiocytes in the tissue. Nonetheless, selection of the biopsy site and histopathologic confirmation of ECD remains challenging. 1 Because the yield of a single biopsy is low due to histologic changes from field to field, efforts should be made to obtain several samples, regardless of the biopsy site. 15 In this case, the patient presented with pericardial effusion and cardiac masses. Multi-modal imaging, including CT, MRI, PET-CT, and bone scan, was beneficial for diagnosis. Although the initial pathologic results from the pericardial biopsy showed non-specific findings, the cardiac biopsy with sternotomy allowed a large amount of suspicious masses to be obtained, which confirmed ECD.

Conclusion
We report a patient with ECD presenting as an intracardiac mass, pericardial effusion, retroperitoneal fibrosis, and multifocal bone lesions. He was diagnosed with ECD after performing a cardiac biopsy with median sternotomy despite initial insufficient pathologic results from pericardial biopsy. Because the yield of a single biopsy is low, obtaining a large amount of samples or re-biopsy may be helpful if ECD is clinically highly suspected. Considering the various clinical manifestations and the difficulty in identifying this rare disease, a comprehensive and meticulous diagnostic work-up is crucial.

Lead author biography
Minjae Yoon was born in 1989 in Seoul, Republic of Korea. He received the MD degree from Yonsei University in 2013. He completed one year of internship and four years of resident program at Severance Hospital (2013-18). Currently, he is working as a cardiologist in Severance Cardiovascular Hospital. His research interest is focused on heart failure and heart transplantation.

Supplementary data
Supplementary material is available at European Heart Journal-Case Reports online.
Slide sets: A fully edited slide set detailing these cases and suitable for local presentation is available online as Supplementary data.

Consent:
The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.