Fever of unknown origin as the first manifestation of Erdheim-Chester disease

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Vol.2, No.6, 351-357 (2013) Case Reports in Clinical Medicine

http://dx.doi.org/10.4236/crcm.2013.26095

Fever of unknown origin as the first manifestation of

Erdheim-Chester disease

Ning Li1*, Mingquan Chen1*, Huaping Sun2, Yun Bao3, Jiming Zhang1#

1Department of Infectious Diseases, Huashan Hospital, Fudan University, Shanghai, China;

#Corresponding Author: [email protected]

2Department of Radiology, Huashan Hospital, Fudan University, Shanghai, China

3Department of Pathology, Huashan Hospital, Fudan University, Shanghai, China

Received 8 July 2013; revised 1 August 2013; accepted 10 August 2013

Copyright © 2013 Ning Li et al. This is an open access article distributed under the Creative Commons Attribution License, which

permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

ABSTRACT

Erdheim-Chester disease (ECD) is an uncom-

mon non-Langerhans cell histiocytosis that af-

fects multiple body systems and can present

clinically in a my riad of ways. W e re port the cas e

of a 29-year-old man presented with fever and

diffuse bone pain. Physical examination showed

bilateral and symmetrical long bone pain, espe-

cially the knees. Radiographs showed multiple

mixed bone lesions with sclerotic and ly tic areas

of the femora, tibiae, and fibula. Biopsy of the

tibial area displayed foamy lipid-laden histio-

cytes, confirming the diagnosis of ECD.

Keywords: Erdheim-Chester Dise ase; Histio cytosi s ;

Osteoarthropathy

1. INTRODUCTION

Erdheim-Chester disease (also known as Erdheim-

Chester syndrome or polyostotic sclerosing histiocytosis,

ECD) is a rare form of non-Langerhans-cell histiocytosis

with particular tropism for connective and adipose tis-

sues. To date, about 450 distinct cases of ECD have been

described in the medical literature [1,2]. The number of

new cases has dramatically increased over the past 10

years because of the better recognition of this condition.

ECD is a systemic disease characterized by proteiform

manifestations, including skeletal involvement with bone

pain, exophthalmos, diabetes insipidus, xanthelasma, in-

terstitial lung disease, bilateral adrenal enlargement, re-

troperitoneal fibrosis with perirenal and/or ureteral ob-

struction, renal impairment, testis infiltration, central ner-

vous system, and/or cardiovascular involvements. The

pathology is characterized by foamy histiocytes or lipid-

laden macrophages or histiocytes, surrounded by fibrosis,

which are those with immunohistochemical findings de-

monstrating the presence of non-Langerhans histiocytes

markers, namely, positivity for anti-CD68 labeling, little

or no protein S100 labeling, and negativity for anti-

CD1a labeling [3,4].

We present the case of a 29-year-old male patient,

who presented initially with decreased vision, diagnosis

of VKHS. To the best of our knowledge, it is the first

description of ECD with VKHS as the initial presenta-

tion. Leveled equations, graphics, and tables are not pre-

scribed, although the various table text styles are provid-

ed. The formatter will need to create these components,

incorporating the applicable criteria that follow.

2. CASE REPORT

A 29-year-old man was admitted to our hospital

because of fevers, chills, cough, and pain in the both

lower limbs. He presented a 10-month history of inter-

mittent fevers (about 39˚C), progressive pain in both

lower limbs, and nonproductive cough. There were nu-

merous mildly enlarged bilateral cervical and supracla-

vicular lymph nodes. A doppler B scan system-guided

fine-needle aspiration biopsy of the left cervical lymph

nodes was performed, and pathological examination of

the biopsy specimen revealed reactive lymphoid hyper-

plasia. A radiograph reportedly showed infection-related

lesions in the tibia and fibula. Antibiotics sulperazon and

vancomycin were administered without any improve-

ment. Six days later, twice myeloid culture reportedly

showed Human staphylococcus aureus, and bone scan

reportedly showed lesions with increased activity involv-

ing the large joints. Antibiotics rifampicin, clindamycin,

teicoplanin, or linezolid were sequentially administered,

and the patient was running a mid to high fever, accom-

panied by lower limbs pain and discomfort. Antibiotics

*Ning Li and Mingquan Chen contributed equally to this work.

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N. Li et al. / Case Reports in Clinical Medicine 2 (2013) 35 1-35 7

352

were discontinued, and antipyretic-analgesic was admi-

nistrated. He had no prior medical history, and no expo-

sure to occupational, dust, or animal hazards. He had no

known allergies to medications. Medications included

antipyretic-analgesic as needed for pain and fever, pred-

nisone, potassium chloride sustained-release tablets, and

pantoprazole. Laboratory examination results revealed

erythrocyte sedimentation rate (ESR) of 90 mm/h and C-

reactive protein (CRP) 96.5 mg/l (reference range, <8).

Approximately 8 weeks before admission, increased

severe persistent pain in his right frontal, temporal, and

occipital lobs were suffer from. Specimens of cerebro-

spinal fluid were stained for acid-fast bacilli, and cultur-

ed for bacteria, mycobacteria, and fungi and remained

sterile. At the time of admission to our ward he appeared

unwell, still fever, increasing fatigue, malaise, weakness,

sweats, myalgias, and leg pain developed. The patient

reported that the pain was located primarily in the region

of both leg, occurred at rest, and awoke him at night. He

described it as a constant aching and throbbing and gave

it a score of 5 (on a scale of 1 to 10, where 10 is the most

severe pain). The pain lessened with rest and narcotic

analgesia and increased when the patient walked and

moved his leg.

His temperature was 39.5˚C, blood pressure 125/65,

pulse 106 per minute, respiratory rate 22 per minute. He

had peripheral lymphadenopathy. B-ultrasound of the

superficial lymph node showed multiple nodules through-

out both bilateral cervical (up to 1.6 cm in diameter),

supraclavicular lymph nodes (up to 2.1 cm in diameter),

axillae (up to 1.4 cm in diameter) and the abdomen (up

to 1.6 cm in diameter), and a thyroid nodule (1.3 cm). On

abdominal examination, liver and spleen tip was not

palpable. In our laboratory findings, results were normal

for measurements of red and white blood cell count,

platelets, glucose, plasma electrolytes, total protein, albu-

min, globulin, bilirubin, lactate dehydrogenase, immu-

noglobulins, and urine Bence Jones protein; studies of

serum protein electrophoresis and tests of renal and liver

function were also normal, as were serum levels of an-

giotensinconverting enzyme, antinuclear antibodies, rheu-

matoid factor, antineutrophil cytoplasmic antibodies

(ANCA). Repeated culture of blood, sputum, urine, and

stool were negative for possible pathogens.

To evaluate the extent of the disease, positron emis-

sion tomography/computed tomography (PET/CT) was

performed 1 h after administration of 370 MBq 18F-fluo-

rodeoxyglucose (FDG), which showed asystematic lytic

bone lesion in the long bone and the pelvis with in-

tensively FDG uptake (standardize uptake value, SUV

approximately 15.5 to 17.1) (Figures 1(A)-(C)). There

was mild FDG uptake (SUV, 2.4) with hyperdense

nodules in bilateral posterior chamber of eyeball around

optic nerves (Figure 1(D)). Malignant tumor was con-

Figure 1. FDG PET/CT scan showed involvement of various organ systems in patients with Erdheim-Chester

disease. (A)-(C) Typical bilateral and symmetric uptake in the diaphyseal and metaphyseal regions of the long

bones was seen; (D) Neurologic involvement, with multiple nodules in bilateral posterior chamber of eyeball

around optic nerves, is demonstrated; (E) A Tc-99m bone scintigraphy displayed a symmetrically increased up-

take in the epiphyses of long bones, sparing the middiaphysis and the axial skeleton.

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N. Li et al. / Case Reports in Clinical Medicine 2 (2013) 35 1-35 7 353

sidered via PET/CT scan. However, anterior and post-

erior whole-body images of Tc-99m bone scintigraphy

displayed the characteristic findings of ECD with sym-

metric increased radionuclide uptake in the epiphyses of

long bones (Figure 1(E)). Findings of MRI showed re-

placement of the normal fatty bone marrow of the dia-

physeal and metaphyseal bone segments by a markedly

low signal intensity (hypointense compared with muscle

and heterogeneous signal intensity on T1-weighted ima-

ges) and heterogeneous intermediate or high signal in-

tensity (isointense or hyperintense compared with muscle)

on fatsuppressed T2-weighted images. Areas of high ir-

regular signal intensity on T1-weighted images after con-

trast (Figure 2).

The patient had not been to rural areas or been ex-

posed to animals recently. He reported no highrisk sexual

activity, occupational exposures. Tests for histoplasma

antigen were negative.

Five days later, at a follow-up visit, the patient re-

ported increased leg pain. During the next 3 days, He

was readmitted to this hospital. The vital signs were

normal. There was mild percussion pain on both lower

extremities, the remainder of the examination was un-

changed. An electrocardiogram was normal. The white-

cell count was 9200 per cubic millimeter, with a normal

differential count. Specimens of blood and sputum were

cultured for bacteria, mycobacteria, and fungi and re-

mained sterile. Tests for respiratory viruses and anti-

bodies to HIV were negative, as were multiple specimens

of sputum stained for acid-fast bacilli. Two days later, an

open excisional biopsy and curettage of the lesion of the

left tibia were performed at this hospital; cefazolin was

administered before and after the surgery; pathological

examination of the biopsy specimen revealed infiltration

of foamy histiocytes with irregular spindle cell prolife-

ration and infiltration of mononuclear inflammatory cells

Figure 2. MRI findings. (A) Diffuse low signal intensity on axial T1-weighted images; and (B)

intermediate enhancement on T1-weighted images after contrast are visible in diaphysis and

metaphysis of distal femora; (C) Diffuse low signal intensity on axial T1-weighted images;

and (D) with heterogeneous enhancement on T1-weighted images enhanced after gadolinium

injection are visible in diaphysis and metaphysis of bilateral fibulas and tibias; (E) Diffuse low

signal intensity on coronal T1-weighted images; and (F) irregular enhancement on T1-

weighted images after gadolinium injection are visible in diaphysis and metaphysis of distal

femora and proximal tibiae; (G) Fat-suppressed T1-weighted images after contrast show he-

terogeneous signal intensity, irregular stippled fat-suppressed signal (arrow).

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N. Li et al. / Case Reports in Clinical Medicine 2 (2013) 35 1-35 7

354

and eosinophils (Figure 3). Immunohistochemical stain-

ing showed infiltrating cells to be positive for CD68,

lysozyme (LYS), but negative for S-100, CD1a. Based on

the imaging and pathologic data, the diagnosis of ECD

was made.template measures proportionately more than

is customary. This measurement and others are deliberate,

using specifications that anticipate your paper as one part

of the entire journals, and not as an independent docu-

ment. Please do not revise any of the current designa-

tions.

3. DISCUSSION

The first case of ECD was reported by W. Chester and

Jakob Erdheim in 1930 [5]. ECD is a rare systemic non-

Langerhans cell histiocytosis (LCH) with distinguishing

clinicopathologic and radiographic features of unknown

etiology. It is associated with many clinical presentations

with involvement of 1 or more organ systems. In parti-

cular, bone is affected, but skin, soft tissue, central ner-

vous system, heart, lungs, or abdominal viscera can also

be involved.

While the exact ontogeny is incompletely understood,

histiocytes are believed to arise from a common CD-34

positive progenitor stem cell within the bone marrow.

Two major types of histiocytes are described. Dendritic

cells (e.g., Langerhans cells in skin and bronchial epi-

thelium; and interdigitating and dendritic reticulum cells

in spleen and lymph nodes) are the main antigen-present-

ing cells and are characterized by immunoreactivity to

S-100 protein and CD1a [6]. The second main histologic

cell type includes cells of the monocyte/macrophage line-

age (e.g., circulating monocytes, alveolar macrophages, he-

patic Kupffer cells, osteoclasts, and microglia) [7]. These

antigen-phagocytosing cells are characterized by immu-

noreactivity to CD68. The causative cell of Langerhans

cell histiocytosis (LCH) is derived from the Langerhans

Figure 3. Histological photomicrographs. (A), (B) Intraoperative smear

preparation showing foamy histiocytes (arrows) and small numbers of

lymphocytes. Note presence of multinucleate giant cells (arrows) and

emperipolesis. Paraffin-embedded, HE stain, 100× original magnifica-

tion; (C) CD68 immunohistochemitry. Many of the foamy cells are im-

munoreactive. 100× original magnification; (D) CD1a immunohisto-

chemistry. There is scarce immunoreactivity to CD1a, a marker for cer-

tain dendritic cells. 100× original magnification; (E) S-100 immunohis-

tochemistry. Only rare isolated cells are S-100 immunoreactive. 100×

original magnification; (F) LYS immunohistochemistry. The cells are

immunoreactive to LYS, 100× original magnification.

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N. Li et al. / Case Reports in Clinical Medicine 2 (2013) 35 1-35 7 355

dendritic cell line and that of ECD is from the mono-

cyte-macrophage lineage, however, the clinical presenta-

tions can be similar, with bony involvement most fre-

quent in both disease states. There are several key fea-

tures, particularly immunohistochemical profile, that al-

low LCH and ECD to be distinguished.

The diagnosis of ECD is based on the combination of

radiographic features, nuclear medicine features and

nearly pathognomonic immunohistochemical profile as

follow: evidence of bilateral and symmetrical cortical

osteosclerosis of the diaphyseal and metaphyseal regions

of the long bones and/or the symmetrical and strong

uptake on the distal ends of the long bones of the legs

and in some cases of the arms, on technetium-99 skeletal

scintigraphy; and typical histological findings: xantho-

granulomatous infiltration with foamy histiocytes sur-

rounded by fibrosis; CD68-positive and CD1a-negative

immunohistochemical labelling.

Patients with ECD typically develop characteristic

multifocal osteosclerotic lesions of long bones [8] and

may also develop extraskeletal histiocytic infiltrates [9].

Extra-osseous manifestations are numerous: central ner-

vous system involvement may lead to diabetes insipidus

[10], cerebellar symptoms, venous sinus thrombosis [11],

and dural based masses, which may mimic multiple

meningiomas [12,13]. Exopthalmos, which may be bila-

teral, occurs secondary to orbital infiltration. Pulmonary

involvement is manifest as worsening dyspnoea, with

interstitial infiltrates seen on chest radiographs [14]. Re-

troperitoneal fibrosis is a well-recognized sequela, and

can cause bilateral adrenal infiltration [15], and also can

lead to ureteric obstruction and progressive renal failure,

which is a common cause of death in these patients.

When our case presented with only blurred and de-

creased vision involvement diagnosis of VKHS, after

that persistent fever, increasing fatigue, malaise, weak-

ness, and leg pain developed. The diagnosis of ECD was

made until this case biopsy and curettage, according to

the results of immunophenotypic analysis, which mat-

ches the ECD description. We think that immune factors

may serve as an important stimulus for VKHS. Mean-

while, ECD lesions express a wide array of cyto-che-

mokines, which may orchestrate histiocyte recruitment

and activation [16,17], and which is also related with

immune factors. One of the unique points in our case is

the progression from VKHS to ECD. The three most

frequent clinical features of ECD are bone pain, diabetes

insipidus and exophthalmos, these features are called the

classic ECD triad. This patient only present with bone

pain companied by fever, and twice myeloid culture

reportedly showed Human staphylococcus aureus, which

might have contributed to the delayed diagnosis; ECD is

a very rare disease and difficult to diagnose, even with

classic symptoms. However, the diagnosis of ECD can

be made with near certainty because of the characteristic

radiographic findings. The bilateral diffuse or patchy

symmetric sclerosis of the medullary cavity of the major

long bones, with relative epiphyseal sparing, is almost

pathognomonic for ECD and can be confirmed by PET-

CT. The distinct histological findings of ECD are also

useful in making the diagnosis. Biopsy samples from the

organs involved will reveal diffuse infiltrations of foamy

histiocytes, Touton giant cells, lymphocytes and plasma

cells, associated with dense fibrosis and reactive sclero-

sis of the cortical and cancellous bone. Immunohisto-

chemistry of the biopsy samples confirms the monocyte/

macrophage lineage of the histiocytes by their expression

of CD68, LYS, and S100 protein (variable), and by their

lack of the Langerhans cell marker CD1a. This patient’s

biopsy material exhibited diffuse infiltration of CD68-

and LYS-expressing foamy histiocytes, and were nega-

tive for CD1a and S100. These findings were associated

with dense fibrosis, which matches the ECD description.

In this patient, additional immunohistochemical staining

with antibodies against CD68 and CD1a supplemented

the original histological findings. The present data, which

are, to the best of our knowledge, it is the first de-

scription of ECD with VKHS as the initial presentation.

It was difficult to assess the exact relationship between

these 2 conditions.

ECD is a rare non-Langerhans histiocytosis of un-

known etiology. The outcome of patients with ECD is

worse than that for Langerhans-cell histiocytosis with

59% of patients in the former group dead after a mean

follow-up of 32 months [3]. Although our study was not

designed to assess the efficacy of treatments in ECD

complicated by VKHS, these data suggest that corti-

costeroids which have been recognized as effective in

other literature of VKHS, and have only a minor impact

on the course of morbid involvement in ECD patients.

Treatment strategies for ECD have been challenged by

rare occurrence and poor understanding of etiopathology.

Therapy with interferon-α (IFN-α) effective in ECD

appear to have minimal benefit [18-20]. A rationale for

this approach is that IFN-α induces terminal differen-

tiation of some histiocytes and dendritic cells. Target-

ing interleukin-1 (IL-1), a proinflammatory cytokine ex-

pressed by ECD histiocytes, with recombinant inter-

leukin-1 receptor (IL-1R) has also recently been reported

as a promising therapeutic strategy [1]. Arnaud and col-

leagues quantitatively analyze 23 cytokines in serum

samples from 37 patients with ECD, and studied the

impact of treatment on cytokine production [21]. They

found no significant difference between cytokine levels

measured in untreated and IFN-α-treated patients. This

suggests that IFN-α has limited impact on the systemic

immunologic perturbations that are characteristic of ECD.

They also found many significant differences in cyto-

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N. Li et al. / Case Reports in Clinical Medicine 2 (2013) 35 1-35 7

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kine/chemokine levels in ECD patients compared with

controls, with principal component analysis identifying

an ECD-specific signature based on increased expression

of IFN-α, IL-1/IL-1RA, IL-6, IL-12, monocyte chemo-

tactic protein-1, and decreased expression of IL-4 and

IL-7. The authors conclude that the systemic immune

Th-1-oriented perturbation associated with this condition,

and provides clues for the choice of more focused

therapeutic agents.

4. CONCLUSION

ECD is a rare form of non-Langerhans’ cell histiocy-

tosis. ECD appears to be the pathognomonic clinical,

radiographic and histological features. Diagnosis of ECD

is based on the identification in tissue biopsy of histio-

cytes, which are typically foamy and immunostain for

CD68+ CD1a−. Central nervous system involvement is a

major prognostic factor in ECD. Because the incidence

of ECD is low, the data from literature remains limited.

More case data for this histiocytosis need therefore be

obtained for a better understanding of its characteristics

and an exploration of appropriate therapy.

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