CASE REPORT
Nagoya J. Med. Sci. 85. 150–156, 2023
doi:10.18999/nagjms.85.1.150

A case of Erdheim–Chester disease with the BRAF V600E
mutation diagnosed via endoscopic sinus surgery
Takaharu Matsuhisa1, Masaaki Teranishi2, Yuta Tsuyuki3,
Michihiko Sone2 and Juichi Sato1
21
Department of General Medicine, Nagoya University Hospital, Nagoya, Japan
Department of Otorhinolaryngology, Nagoya University Graduate School of Medicine, Nagoya, Japan3
Department of Pathology and Laboratory Medicine, Nagoya University Hospital, Nagoya, JapanABSTRACT
Erdheim–Chester disease is characterized by the infiltration of foamy histiocytes in tissues. Lesional
tissue biopsy is recommended to confirm diagnosis and establish the BRAF mutational status. A 52-yearold man presented to our hospital with hydronephrosis. Computed tomography showed enhancement ofsoft shadows around the left renal pelvis transition area and the aorta. He was treated with prednisolone
0.2 mg/kg for 1 year; however, no improvement was observed. 18Fluorodeoxyglucose–positron emission
tomography/computed tomography revealed increased fluorodeoxyglucose uptake in various body parts,including the maxillary sinuses, indicative of Erdheim–Chester disease. He refused further examination,and the maxillary sinus lesions were treated with antibiotics and intranasal steroids, but no improvement
was observed. Two years later, he underwent biopsy with endoscopic sinus surgery of the maxillary sinus,
which showed the highest increase in fluorodeoxyglucose uptake on repeat 18fluorodeoxyglucose–positronemission tomography/computed tomography. Endoscopic findings showed only nonspecific inflammatory
findings, but pathological findings revealed the proliferation of cells with abundant foamy cytoplasms.
Sufficient tumor volume was available to perform PCR for BRAF V600E mutation analysis, which waspositive and resulted in a diagnosis of Erdheim–Chester disease with the BRAF V600E mutation. This is
the first case of a patient with Erdheim–Chester disease with the BRAF V600E mutation identified in asinus lesion. Endoscopic sinus surgery biopsy of the paranasal sinuses was considered to contribute to thehistological and genetic diagnosis of Erdheim–Chester disease, particularly following the notable increasein fluorodeoxyglucose uptake.
Keywords: Erdheim–Chester disease, BRAF V600E mutation, endoscopic sinus surgery
Abbreviations:
ECD: Erdheim–Chester disease
ESS: endoscopic sinus surgery
CT: computed tomography
FDG-PET: fluorodeoxyglucose–positron emission tomography
SUVmax: maximum standardized uptake value
This is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
License. To view the details of this license, please visit (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Received: December 16, 2021; accepted: February 28, 2022
Corresponding Author: Takaharu Matsuhisa, MD, PhD
Department of General Medicine, Nagoya University Hospital, 65 Tsurumai-Cho, Showa-ku, Nagoya
466-8560, Japan
Tel: +81-52-744-2951, Fax: +81-52-744-2951 E-mail: matsukyuu413@med.nagoya-u.ac.jp
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A case of ECD diagnosed via ESS

INTRODUCTION
Erdheim–Chester disease (ECD) is characterized by the infiltration of tissues by foamy
CD68(+), CD1a(–) histiocytes.1 Only 1,500 cases of ECD have been reported worldwide as ofJuly 2019.1 ECD affects most systems and organs, including the long bones, skin, cardiovascularsystem, retroperitoneum, and paranasal sinuses, with lesions of the maxillary and sphenoid sinuses
being identified in 47% of cases.1 ECD is diagnosed via the identification of characteristic
histopathological findings in appropriate clinical and radiological examinations.2
In recent years, a high rate of detection of the BRAF V600E mutation has been reported in
ECD, and BRAF inhibitor therapy has been introduced in some countries.3 Tissue biopsies arenecessary to identify relevant mutations to broaden the treatment choice, as well as to confirm
the diagnosis. However, selecting a specimen biopsy site is often difficult because of low tumor
cellularity and lesion heterogeneity.3 To date, there are no reported cases of ECD in which theBRAF V600E mutation was confirmed by a biopsy of the sinuses. We herein describe a case inwhich a tissue biopsy of the maxillary sinus was performed via endoscopic sinus surgery (ESS)
and was confirmed to be positive for the BRAF V600E mutation.

CASE REPORTA 52-year-old man with no medical history presented to our hospital with left hydronephrosis,
which was revealed by abdominal echography during an annual checkup. He had no subjectivesymptoms, and blood samples showed a C-reactive protein level of 0.11 mg/dL and immu-Fig. 1 Positron emission tomography
Fig. 1A: At initial examination, bilateral maxillary sinuses showed increased FDG uptake (SUVmax, 6.28).
Fig. 1B: The lateral right atrium also showed increased FDG uptake (SUVmax, 5.54).
Fig. 1C: Two years later, despite the use of nasal steroids and macrolide antibiotics, bilateral maxillary sinuses
showed worsening of the accumulation and expansion of the area with a SUVmax of 8.5.
Fig. 1D: The retroperitoneum and mesentery showed pale and sparse FDG uptake and thickening of both renal
capsules.
Fig. 1E: The bilateral distal femur, proximal tibia, and distal tibia showed hyperintensity and typical findings ofECD.
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Takaharu Matsuhisa et al

noglobulin G4 level of 64.2 mg/dL (normal range <117 mg/dL). Computed tomography (CT)showed enhancement of soft shadows around the left renal pelvis transition area and the aorta.
Retroperitoneal fibrosis was suspected, and he was treated with prednisolone 0.2 mg/kg for 1year. However, no improvement was noted on imaging.
One year later, repeat CT showed gradual worsening of the perirenal and periaortic soft tissue
shadows, and he was referred to the General Medicine department. 18F-fluorodeoxyglucose–positron emission tomography (FDG-PET) /CT showed a maximum standardized uptake value(SUVmax) of 6.28 in the bilateral maxillary sinuses (Figure 1A), SUVmax of 5.54 in the lateralright atrium (Figure 1B), SUVmax of 3.39 in the periaortic region, infiltrative perinephric soft tissue
thickening, and increased FDG uptake in the orbit and bone lesions. ECD was suspected on thebasis of these findings. Biopsy was recommended for definitive diagnosis, but the patient refused
further examination because he was asymptomatic. CT of the paranasal sinuses showed mucosal

Fig. 2 Endoscopic examination of the maxillary sinus
Fig. 2A: The posterior wall of the left maxillary sinus. Nonspecific inflammatory findings were observed, including
erythema, granulation, and some angiogenesis (arrow).
Fig. 2B–2C: Pathological findings of the posterior wall of the left maxillary sinus. The proliferation of cellswith abundant foamy cytoplasms were observed in fibrous tissue, accounting for the sufficient tumor
content by area for the cobas 4800 BRAF V600 mutation test. Hematoxylin and eosin staining,original magnification: B, ×100; C, ×400).
PW: posterior wall
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A case of ECD diagnosed via ESS

thickening of the bilateral maxillary sinus, and the lesions were treated as chronic sinusitis.
Specifically, macrolide antibiotics were used for 6 months, and expectorants and steroid nasal
drops for 9 months. However, imaging findings revealed no improvement in mucosal thickeningof the maxillary sinus.
Over the next year, the patient gradually developed bilateral proptosis and pericardial effusion,
which was treated with pericardiocentesis. His C-reactive protein level increased to 7.30 mg/dL.
FDG-PET/CT showed a maxillary sinus SUVmax of 8.5 (Figure 1C), bilateral orbital SUVmax of
7.5, aortic arch SUVmax of 3.6, right atrial SUVmax of 5.3, pale and sparse accumulation of theretroperitoneum, infiltrative perinephric soft tissue thickening (Figure 1D), and increased FDG
uptake in bone lesions (Figure 1E). We obtained consent for a tissue biopsy and performed it
via ESS from the posterior wall of the maxillary sinus, wherein the highest increase in FDG
uptake was observed on FDG-PET/CT. The posterior wall of the maxillary sinus showed only
nonspecific inflammatory findings (redness, granulation, and some angiogenesis) via endoscopy(Figure 2A). Pathological findings of the posterior wall of the left maxillary sinus revealed theproliferation of cells with abundant foamy cytoplasms in the fibrous tissue (Figure 2B and Figure2C). The proliferating cells were positive for CD68 and negative for S-100 and CD1a expression,consistent with ECD. The obtained tumor content (by area) in the tissue sample was >50%, andBRAF V600 mutation analysis PCR using the cobas 4800 BRAF V600 mutation test kit (Roche
Diagnostics, Indianapolis, IN, USA) on formalin-fixed paraffin-embedded tissue was positive.
He was diagnosed with ECD with the BRAF V600E mutation. He is under careful observationin an outpatient setting, but in the absence of medical insurance coverage is not being treatedwith a BRAF inhibitor.

DISCUSSION
We encountered a case of ECD with the BRAF V600E mutation diagnosed using histologicaland genetic analyses of the maxillary sinus via ESS. To the best of our knowledge, this is thefirst case of ECD with the BRAF V600E mutation identified in a sinus lesion. This demonstrates
that sinus biopsy via ESS can be used as an alternative diagnostic method for patients withsuspected ECD who show increased FDG uptake in the sinuses on FDG-PET/CT.
Identifying BRAF mutations in patients with ECD is clinically important because their mutation status directly affects treatment choice.4 The BRAF inhibitor vemurafenib is approved by
the US Food and Drug Administration and the European Medicines Agency for the treatmentof ECD with the BRAF V600E mutation.5,6 However, the use of BRAF inhibitors for the treatment of ECD is not currently covered by Japanese medical insurance despite their reportedsuccess.7-9 Identifying BRAF mutations could help the expansion of future treatment optionsin Japan. Although the cobas 4800 BRAF V600 mutation test kit relies on standard molecular
genetic diagnostic methods, it requires a high tumor content by area.10,11 Therefore, biopsy site
selection can be challenging3 if ECD lesions contain tissues with a high percentage of fibrosis
to histiocytes, making them unsuitable for BRAF testing.12
Few studies have reported biopsies of the paranasal sinuses in cases of ECD; of these, manyrequired multiple biopsies for diagnosis,13,14 and none identified BRAF mutations.13-15 Paranasal
sinus lesions are commonly observed in patients with ECD, particularly in the maxillary andsphenoidal sinuses.1 In the present case, FDG-PET/CT revealed the highest FDG uptake in theposterior wall of the maxillary sinus. Furthermore, ESS endoscopic findings showed only nonspecific inflammatory findings, with no obvious tumor-related findings (Figure 2A). We performeda biopsy of the posterior wall of the maxillary sinus at the site of the highest increase in FDG
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Takaharu Matsuhisa et aluptake. Although we were unsure from the endoscopic findings whether we had successfully
biopsied the ECD lesion, pathological findings revealed sufficient tumor content by area (Figure2B), and genetic testing confirmed the presence of the BRAF V600E mutation. This indicatesthe value of testing for the BRAF V600E mutation in sinus specimens of patients with ECD.
FDG-PET/CT is best completed before biopsy, and biopsy should be performed at a safe andaccessible site showing the highest FDG uptake.3 SUV accumulation in FDG-PET/CT has been
associated with tumor lesion differentiation and proliferation,16 and a higher SUVmax correlateswith BRAF V600E mutation positivity.12,17 We biopsied the maxillary sinus, which showed thehighest accumulation on FDG-PET/CT. However, an abnormal accumulation of FDG in theparanasal sinuses on FDG-PET/CT is also observed in benign diseases such as sinusitis,18 making
it difficult to differentiate between these diseases and to determine the best biopsy site. Althoughprevious studies have shown that sinus lesions in cases of ECD have a high mean SUVmax of
5.7 (range, 2.6–10),12 we could not rule out the possibility of chronic sinusitis from the imagingfindings. Therefore, our patient was treated with antibiotics for 6 months and nasal steroids for 9
months, but no improvement was observed on imaging, and the SUVmax worsened further (Figure1A, C). We recommend treating for sinusitis in cases where it is difficult to differentiate disease,but suggest that ECD should be suspected if there is little improvement.
The pathologic diagnosis of ECD has often involved biopsy of skin, bone, or soft tissue
perirenal invasion.3 Most patients with ECD present with long bone osteosclerosis,19 but bonelesions usually require tissue processing involving demineralization. Because most demineralization reagents contain strong acids that damage nucleic acids, DNA degradation is common somolecular testing is not possible.20 Therefore, particular demineralization techniques such as theethylenediaminetetraacetic acid-based decalcification method must be used.3 Skin lesions (mainlyxanthelasma-like lesions) and perirenal tissues are also suitable sites for biopsy as they are more
appropriate for molecular studies than bone lesions.19 They are also the easiest to access andleast invasive, but they are observed in fewer than half of ECD patients.19 No skin lesions werepresent in our case. Although the safety of CT-guided biopsy of perinephric tissue has been
established,21 FDG-PET/CT of the perinephric to the retroperitoneal area showed a low SUV andsparse lesions in our patient (Figure 1D). This prompted us not to use the perinephric tissue
biopsy sample for further analyses.

CONCLUSION
We report a case of ECD with the BRAF V600E mutation diagnosed via ESS. ESS is a useful
method for performing tissue biopsy, including identification of the BRAF V600E mutation incases of ECD. Although the endoscopic findings of ECD are nonspecific, ESS biopsy samples
are suitable for histological analysis and can provide sufficient tissue content for genetic testing.
We recommend selecting the biopsy site based on FDG-PET/CT findings.

ACKNOWLEDGEMENTS
We thank Sarah Williams, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft ofthis manuscript.

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A case of ECD diagnosed via ESSDISCLOSURE STATEMENT
This study did not receive any specific grant from funding agencies in the public, commercial,or not-for-profit sectors. The authors declare no conflicts of interest.
This study was approved by the ethical committee of Nagoya University (approval number2021-0263). All procedures completed were in accordance with the ethical standards laid down in
the 1964 Declaration of Helsinki and its later amendments. Oral informed consent was obtained
from the patient for publication of this case report and any accompanying images.

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