Scandinavian Journal of Infectious Diseases, 2014; 46: 76–79

CASE REPORT

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Erdheim–Chester disease: A rare cause of recurrent fever of unknown origin mimicking lymphoma

ANUSIYANTHAN MARIAMPILLAI1, ABIRAMI SIVAPIRAGASAM1, AMIT KUMAR1, ALEXANDER HINDENBURG1, BURKE A. CUNHA2,4 & JIANHONG ZHOU3 From the 1Division of Hematology–Oncology, 2Division of Infectious Disease, 3Department of Pathology, Winthrop-University Hospital, Mineola, New York, and 4State University of New York School of Medicine, Stony Brook, New York, USA

Abstract We report the case of a patient with recurrent fever of unknown origin (FUO) with prominent back pain, hepatosplenomegaly, and abdominal/pelvic adenopathy suggesting lymphoma. A bone biopsy showed histiocytic infiltration. Studies for lymphoma were negative, but immunohistochemical stains were diagnostic of Erdheim–Chester disease (ECD). ECD should be included as a rare cause of recurrent FUO with bone involvement.

Keywords: Recurrent FUO, histiocytic disorders, non-Langerhans cell histiocytosis, infiltrative bone lesions

Introduction Fever of unknown origin (FUO) refers to a variety of disorders that have prolonged fever ⬎ 38°C for 3 or more weeks and that remain undiagnosed after a focused FUO workup. Since Petersdorf ’s initial description in 1961 defining FUO and the various disease categories responsible for FUO, i.e. infectious, malignant/neoplastic, rheumatic/inflammatory, and miscellaneous disorders, the most common category of FUO is currently malignant/neoplastic disorders [1,2]. Among malignant/neoplastic disorders, there are relatively few disorders with the potential to present as prolonged/difficult to diagnose fever. The most common malignant/neoplastic causes of FUO in adults are lymphoma, pre-leukemia (due to acute myelogenous leukemia), renal cell carcinoma, central nervous system or liver metastases, and colon cancer [3]. Rarely, other miscellaneous disorders, particularly histiocytic disorders, may present as FUO and not uncommonly as recurrent FUO [4]. Recurrent FUO is difficult to diagnose, but recurrent FUO is diagnostically even more problematic since the disorders associated with recurrent FUO are rare

and most clinicians are not familiar with their clinical manifestations [5]. Erdheim–Chester disease (ECD) is a rare, nonLangerhans form of histiocytosis of unknown origin first described in 1930 by the pathologist William Chester in the laboratory of Jakob Erdheim in Vienna. Originally described as a ‘lipoid granulomatosis’, a third case was reported by Ronald Jaffe in 1972 who coined the term ‘Erdheim–Chester disease’ [6–8]. ECD may present with a wide range of multisystemic manifestations [8–13]. We describe here an extremely rare case of FUO due to ECD with unusual manifestations.

Case A 20-y-old African American male presented with a 3-month history of recurrent fever (maximum temperature 40°C), chills, and a 22.5-kg weight loss. He also reported low back pain and developed lower extremity weakness, transient visual and hearing loss, and intermittent light-headedness. A physical examination was unremarkable, except for

Correspondence: B. A. Cunha, Infectious Disease Division, Winthrop-University Hospital, Mineola, NY 11501, USA. Tel: ⫹ 1 516 663 2505. Fax: ⫹ 1 516 663 2753. E-mail: [email protected] (Received 19 August 2013 ; accepted 4 September 2013) ISSN 0036-5548 print/ISSN 1651-1980 online © 2014 Informa Healthcare DOI: 10.3109/00365548.2013.844352

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Recurrent FUO due to Erdheim – Chester disease lumbar spinal tenderness. Neurological examinations including muscle strength, deep tendon reflexes, and urinary/bowel function, were intact. Importantly, there was no hepatosplenomegaly, lymphadenopathy, rash, or mucosal lesions. Laboratory abnormalities included a white blood cell (WBC) count of 23.2 ⫻ 103/mm3 and platelet count of 425 ⫻ 103/mm3 (normal 160–392 ⫻ 103/mm3). His erythrocyte sedimentation rate (ESR) was 73 mm/h (normal 1–16 mm/h), C-reactive protein was 86 mg/l (normal ⬍ 3 mg/l), and lactate dehydrogenase (LDH) was 262 IU/l (normal 100–250 IU/l). Liver function tests were within normal limits. Iron studies showed a ferritin level of 1253 ng/ml (normal 14–235 ng/ml). Serum protein electrophoresis showed a normal pattern without monoclonal or polyclonal gammopathy. The serum kappa/lambda ratio was 1.13 (normal 0.26–1.65). The coagulation profile revealed an elevated partial thromboplastin time (PTT) of 40.2 s (normal 27–38 s) and prothrombin time (PT) of 21 s (normal 10.34–12.97 s), and the PT inhibitor assay was negative. The patient was found to have a Factor 2 level of 84% (normal 50–150%), Factor 5 level of 83% (normal 50– 150%), Factor 7 level of 29% (normal 50–150%), and Factor 10 level of 68% (normal 50–150%). His alpha-fetoprotein level was found to be ⬍ 1.3 ng/ml (normal 1–9 ng/ml). An extensive workup for infectious causes of recurrent FUO was done, including HIV-1 RNA PCR, HIV antibodies, human T-cell lymphotropic virus (HTLV)-I/II quantitative antibodies, T.SPOT tuberculosis test, Histoplasma antibodies and antigen, Coccidioides titers, Blastomyces titers, Cryptococcus antibodies and antigen, and Ehrlichia chaffeensis titers. Blood cultures were repeatedly negative. A bone marrow biopsy of the iliac crest was done, and acid-fast bacilli stain/culture and Gomori– Grocott methenamine silver stain were negative for mycobacteria and fungi, but showed aggregates of hemosiderin-laden macrophages with increased numbers of histiocytes. Magnetic resonance imaging (MRI) revealed diffuse lesions in the lumbosacral region and abdominal/pelvic lymphadenopathy. Small pulmonary nodules were seen on chest computer axial tomography (CT). Positron emission tomography showed intense hypermetabolic uptake in several vertebral bodies and the sacrum (Figure 1). A repeat MRI of the lumbar spine revealed an infiltrative process with diffusely abnormal hypointense T1 signal throughout the vertebral bodies due to marrow replacement, and non-specific hyperintense T2 signal in multiple vertebral bodies (L3, L4, and S2). An epidural soft tissue mass was also noted at S2–3.

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Figure 1. Fluorodeoxyglucose positron emission tomography (FDG-PET) scan showing increased uptake in the vertebral bodies and sacrum.

Repeat CT of the chest, thorax, and abdomen revealed calcified granulomas, hepatomegaly, and necrotic peri-vena caval, mediastinal, hilar, and intraperitoneal adenopathy. CT-guided core biopsy of the L3 lumbar body showed abnormal proliferation and replacement of marrow with numerous benign-appearing histiocytes admixed with small lymphocytes, eosinophils, plasma cells, and neutrophils, with the absence of maturation of hematopoietic cell lineage. Immunohistochemical stains were positive for CD1a, Factor XIIIA, and CD68, and negative for S100 and CD1a, diagnostic of ECD (Figure 2).

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Figure 2. Immunohistochemical (IHC) stains of bone marrow. (A) Hematoxylin and eosin stain of bone marrow showing absence of trilineage hematopoiesis (⫻ 10). (B) IHC stains for CD68 showing diffuse positivity suggesting the presence of macrophage lineage (⫻ 40). (C) Lack of staining seen on CD1a IHC (⫻ 40) and (D) S100 IHC (⫻ 40), diagnostic of Erdheim–Chester disease.

Discussion The diagnostic approach to adults with FUO involves determining the pattern of organ involvement, which provides differential diagnostic clues to the possible FUO etiologies, e.g., adult FUO with splenomegaly has a different differential diagnosis to that with localized adenopathy [1,2]. The case presented here was that of a 20-y-old African American male with a 3-month history of recurrent fever, chills, and a 22.5-kg weight loss, with transient visual and hearing loss. Only lumbar/spinal tenderness was present on examination. His nonspecific laboratory tests included highly elevated ESR, thrombocytosis, elevated LDH, and a highly elevated serum ferritin level [2,14]. The differential diagnosis of an FUO with such findings includes malignant/neoplastic disorders, e.g., lymphoma or one of the obscure, rare malignant neoplastic disorders, e.g., lymphoma mimics [4]. Among the rheumatic/inflammatory disorders, sarcoidosis was a consideration, but the presence of high fever with chills and the absence of other findings eliminated sarcoidosis from further diagnostic consideration.

The cause of this patient’s recurrent FUO was likely infectious, and the pattern of organ involvement and non-specific laboratory abnormalities made brucellosis, histoplasmosis, and tuberculosis likely diagnostic possibilities [1,2]. These infectious diseases all involve bone, and vertebral tenderness was a key diagnostic clue to his recurrent FUO. Bone pain prompted imaging, which showed extensive bone involvement and suggested the possibility of a lymphoma-like disorder, i.e. a histiocytic disorder [8–12,15]. After infectious disease etiologies were ruled out, bone marrow biopsy ruled out lymphoma, and findings were diagnostic of ECD [6,15]. The differential diagnosis of an FUO in a young adult with bone pain is broad, including infectious, rheumatic/inflammatory, and malignant/neoplastic disorders (including histiocytic disorders, e.g., Langerhans cell histiocytosis (LCH), Rosai–Dorfman disease (RDD), and ECD). The clinical manifestations of ECD are varied with multiple systemic symptoms including persistent fever, weight loss, weakness, dysuria, abdominal pain, and ataxia, making the diagnosis of ECD especially challenging [10–13].

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Recurrent FUO due to Erdheim – Chester disease Unusual manifestations of ECD include long bone pain (50%), peri-aortic infiltration (66%), and pericardial (42%), pulmonary (53%), and CNS involvement with cranial nerve palsies and sensory disturbances (25%) [10–13]. On imaging, ECD most commonly presents as bilateral and symmetrical osteosclerosis of the diaphyseal and metaphyseal regions of long bones with epiphyseal sparing. In contrast to LCH, axial skeleton manifestations are rare with ECD. In cases of vertebral body involvement with ECD lytic lesions with sclerotic margins with cortical thickening/periostitis are typical and margins between cortex and medullary bone are indistinct secondary to the medullary infiltrative process resulting in fibrosis and osteosclerosis [11–13]. The diagnosis of ECD is based on histopathological findings and the immunohistochemical profile. Histologically, ECD is characterized by the xanthomatous/xanthogranulomatous infiltration of tissues by spumous histiocytes, ‘lipid-laden’ macrophages or histiocytes, surrounded by areas of fibrosis. Bone marrow replacement by a diffuse proliferation of benign-appearing histiocytes, admixed with small lymphocytes, plasma cells, eosinophils, and few scattered neutrophils, may be seen. Immunohistochemical staining in ECD is positive for markers of macrophage lineage including CD68 and CD163, and negative for CD1a. In most cases of ECD, staining for S100 protein is negative [6,13]. Clinically, ECD should be distinguished from other histiocytic and dendritic cell disorders, hematopoietic neoplasms, hemophagocytic, lymphohistiocytic, and macrophage activation syndromes [4,15]. LCH and RDD are 2 important histiocytic disorders to be considered in the differential diagnosis of recurrent FUO. LCH has a different immunophenotype from ECD (CD68⫹, CD1a⫹, and S100⫹) and RDD, which presents with fever and lymphadenopathy, and histopathological examination shows emperipolesis. A distinguishing clinical feature of RDD is sinus involvement, which is lacking in ECD [15]. Our patient exhibited findings not previously reported in ECD, i.e., young age of onset, along with axial skeletal and mandible involvement (usually spared in ECD vs LCH). Paraneoplastic syndromes such as diabetes insipidus (30% of cases) secondary to pituitary involvement have been associated with ECD, but were not present in our patient [13]. An elevated PTT/PT and international normalized ratio (INR) suggestive of acquired Factor 5 deficiency were present in laboratory studies. While our patient’s pathological findings were diagnostic of ECD, the clinical presentation of recurrent FUO poses a most difficult challenge for clinicians [1,2,16]. We conclude that

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after infectious etiologies have been ruled out, ECD should be included as a rare cause of recurrent FUO with bone involvement. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

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Erdheim-Chester disease: a rare cause of recurrent fever of unknown origin mimicking lymphoma.

We report the case of a patient with recurrent fever of unknown origin (FUO) with prominent back pain, hepatosplenomegaly, and abdominal/pelvic adenop...
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