Case Report

Sustained Efficacy of Targeted Therapy with Vemurafenib in BRAF(V600e) - Mutated Erdheim - Chester Disease

Kimberly D. Tran, Juan Ayala-Haedo, Oliver Fischer, Sander R. Dubovy and Sara T. Wester*
Department of Ophthalmology, University of Miami, USA

*Corresponding author: Sara T. Wester, Department of Ophthalmology, Bascom Palmer Eye Institute, University of Miami, 900 NW 17th St. Miami, FL 33136, USA

Published: 06 Dec, 2016
Cite this article as: Tran KD, Ayala-Haedo J, Fischer O, Dubovy SR, Wester ST. Sustained Efficacy of Targeted Therapy with Vemurafenib in BRAF(V600e) - Mutated Erdheim - Chester Disease. Clin Surg. 2016; 1: 1230.


The authors report the case of a 45-year-old African American female with complex history of pituitary mass, diabetes insipidus, anasarca, congestive heart failure, right atrial mass, cardiac tamponade, pericardial effusions, retroperitoneal fibrosis, and lower extremity arthralgia, who presented for evaluation of bilateral exophthalmos and intraconal orbital masses. Orbital biopsy revealed histiocytic infiltrate with immunohistochemical staining positively for CD 68, and negatively for S100 and CD1a, as well as genetic testing positive for the proto-oncogene B-Raf protein (BRAFV600E) mutation. The presentation was suggestive of Erdheim-Chester Disease, and the patient was treated with Vemurafenib with significant sustained clinical improvement.
Keywords: Erheim-chester disease; Xanthogranuloma; Vemurafenib; BRAF(V600E)


Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis with multi-organ involvement, characterized by tissue infiltration by lipid-laden histiocytes. ECD presents a challenge for clinicians as the clinical presentation, course, and prognosis are all highly influenced by site of disease involvement. The severity of ECD course ranges from asymptomatic to life threatening, with a reported global 5-year mortality of 30-40% [1]. We describe a patient that presented to our clinical institution with a history of multi-organ disease and orbital involvement with worsening of disease despite one year of high dose corticosteroids and Methotrexate for systemic inflammatory disease of unknown etiology.

Case Presentation

A 45-year old African American female presented to the oculoplastics service due to a 4 month history of bilateral eye pain, proptosis, and diplopia. Her complex medical history began 3 years prior when she had a seizure episode due to pituitary tumor and diabetes insipidus (DI), for which she was treated medically. She was readmitted the following year for renal failure due to retroperitoneal fibrosis associated with hydronephrosis, and required nephrostomy tube and ureteral stent placement. A diagnosis of histiocytosis was raised at that time; however, biopsy of the retroperitoneal mass showed only non-specific fibrotic changes, and thus the diagnosis was not established. The patient was treated for one year with high dose steroids and Methotrexate, and the following year, despite treatment, she was re-hospitalized for pericardial tamponade due to a large pericardial effusion, requiring a pericardial window placement. Over the months following, the patient’s symptoms worsened. She developed marked anasarca and shortness of breath, and further workup revealed congestive heart failure due to a right atrial mass.
On presentation to the oculoplastics service, the patient was noted to have bilateral severe orbital pain and proptosis (Figure 1A and 1B). She demonstrated bilateral upper lid fullness, bilateral lower lid retraction, and limitation to supraduction and adduction in the right eye. The remaining ophthalmic exam was unremarkable. Best corrected visual acuity was 20/20 in both eyes, and there was no evidence of optic nerve compromise. MRI imaging revealed bilateral perioptic nerve sheath masses, displacing but not involving the optic nerves, in a pattern atypical of meningioma (Figure1C and 1D). There was also enlargement of intraconal and preseptal orbital tissues with radiographic evidence of lacrimal gland involvement. Due to concern for IgG4-related disease, the patient underwent a lacrimal gland biopsy which demonstrated non-specific inflammatory changes. Due to the inconclusive biopsy results as well as persistent concern for IgG4-related disease given her clinical and radiographic presentation, another biopsy was performed, this time of the medial intraconal orbital tissues. Histopathologic analysis revealed xanthogranulomatous inflammation with reactive fibrosis and a moderate amount of histiocytes which stained positively for CD-68, and negative for S-100 and CD1a (Figure 2A-2D). These histopathologic findings in the context of her clinical presentation were suggestive of ECD, and the patient was referred to Rheumatology and Hematology-Oncology for comanagement. While initial flow cytometric analysis of peripheral blood and bone marrow biopsy were unremarkable, the patient subsequently developed severe pain in both knees to the point of difficulty ambulating. Gallium scan showed evidence of increased absorption of the long bone juxtaarticular areas (Figure 3). Due to reports of the characteristic B-raf proto-oncogene mutation (BRAFV600E) in cases of ECD, the orbital biopsy sample was sent for genetic analysis. The biopsy sample was positive for the BRAFV600E mutation, and the patient who had initially started Interferon-alpha (IFNα) as initial empiric therapy, was switched to Vemurafenib, with subsequent improvement in her orbital pain, proptosis, and limited ductions. MRI at 9 months after induction of Vemurafenib therapy demonstrated persistent intraconal masses with interval improvement and more orbital fat visible. After 18 months of Vemurafenib therapy, no drug resistance has emerged, and her orbital and systemic disease remains stable without exacerbation or progression.

Figure 1

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Figure 1
Clinical presentation with (A, B) bilateral proptosis with lower lid retraction and upper eyelid fullness (C) Coronal and (D) Axial T1 Contrast enhanced MRI scans showing bilateral perioptic nerve sheath masses, displacing but not involving the optic nerves, in a pattern atypical of meningioma.

Figure 2

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Figure 2
Histopathologic specimen from right medial orbital lesion (40x). (A) Foamy histiocytes, lymphocytes, and proliferating fibroblasts. These cells are positive for (B) CD 68 (20x), and negative for (C) S100 and (D) CD1a.

Figure 3

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Figure 3
Whole bone scan showing increased uptake on long bones on juxta articular areas.


We present the case of a 45-year old female with ECD who was treated for years for multi-organ disease without a clear diagnosis, demonstrating the challenge for clinicians in diagnosing and managing this rare condition. The mean age of presentation is approximately 55 years, but it can present from adolescence until adulthood [2]. Men are more frequently affected than women [2]. ECD is included in a spectrum of adult xanthogrogranulomatous disease which includes Adult onset xanthogranuloma (AOX) (solitary lesion without systemic findings), Adult onset asthma and periocular xanthogranuloma (AAPOX), Necrobiotic xanthogranuloma (NBX), and ECD. While they share similar histopathologic findings of non-Langerhans histiocytosis, Touton giant cells, varying degrees of fibrosis, and possible necrosis, they are differentiated by their systemic disease manifestations, with ECD being associated with the worst morbidity and mortality.
The disease manifestation of ECD is determined by the organ system involved, and skeleton, retroperitoneum, and orbit are the most common sites of involvement, in addition to disease involving the cardiovascular, pulmonary, neurologic and endocrine systems. Cardiovascular manifestations include pericardial effusion, sheathing of the aorta, pericardial effusion, myocardial infarction, valvular heart disease, and heart failure. Neurologic manifestations include pituitary lesions associated with diabetes insipidus or other endocrinopathies, cerebellar or pyramidal syndromes, cognitive impairment, and cranial nerve palsies. Renal manifestations include retroperitoneal fibrosis, bilateral hydronephrosis, renovascular hypertension, ischemic injury and renal failure. Musculoskeletal manifestations including juxtaarticular involvement with histiocytic infiltration and sclerosis of long bones and pain in lower limbs [1,3,4]. Orbital involvement occurs in approximately 25% of cases, and may present as exophthalmos, retro-orbital pain, oculomotor palsies, or vision loss [4-5]. Other affected sites include the liver, spleen, thyroid, and skin [1].
While the organ systems involved may differ in each case of ECD, the common unifying diagnostic criteria for ECD, as proposed by Haroche et al. [6] confirmed histologically by tissue biopsy. In ECD, one finds characteristic lipid-laden histiocytes organized into polymorphic xanthogranulomas nested among fibrosis, with CD68-positive and CD1a negative immunostaining. The expression of markers of the macrophage lineage, such as CD14 and CD68, confirms the presence of histiocytic cells. In the majority of cases (80%), markers of dendritic lineage, such as CD1a and S-100 are not expressed [1]. These immunohistochemical features help distinguish ECD from Langerhans’ cell histiocytosis, which is a different type of histiocytosis with multiorgan involvement that may clinically demonstrate similarities with ECD [7]. A second adjunctive criterion as proposed by Haroche et al. [6] is the finding of bilateral and symmetric cortical osteosclerosis of the diaphyseal and metaphyseal parts of the long bones on X-rays, and/or symmetric and abnormally intense labeling of the distal ends of the long bones of the legs, and in some cases arms, as revealed by 99Tc bone scintigraphy. The second criterion is not strictly required for ECD diagnosis. More recently, a characteristic histiocyte-restricted mutation in the genetic sequence of the B-Raf proto-oncogene, which confers the amino acid substitution of glutamic acid for valine at position 600 of the B-Raf protein(BRAFV600E), has been associated in at least 50% of the cases [8-9], lending one additional diagnostic tool in characterizing this disease. The expression of ECD can range from focal indolent disease to fulminant multiorgan system dysfunction which in some cases may be fatal. Thus it is recommended that once the diagnosis is confirmed, baseline evaluation include computed tomography (CT) scans of the chest, abdomen, pelvis, positive emission tomography (PET) of the entire body, magnetic resonance imaging (MRI) of the brain with gadolinium and cardiac MRI to evaluate the extent of organ system involvement [3].
The pathogenesis of ECD is not fully understood, and current data suggest a clonal mechanism in the setting of a local and systemic pro-inflammatory cytokine-chemokine network which may be responsible for the recruitment and activation of histiocytes into ECD lesions [10-11]. BRAF is involved in the regulation of cell proliferation and survival as it contributes to the RAS-RAF-MEK-ERK protein kinase pathway. Mutations of BRAF lead to chronic activation of this pathway leading to cellular proliferation and survival of cells [12-13]. The BRAFV600E mutation, in particular, has oncogenic activity that has previously been described in melanomas, papillary thyroid cancers and hairy-cell leukemia [3,8,14,15]. Reports have described >50% of patients with ECD carrying the BRAFV600E mutation [8,9]. In this setting, BRAFV600E is thought not only to contribute to clonal proliferation of BRAFV600E histiocytes but also to contribute to the inflammatory milieu that is associated with further histiocytic recruitment to ECD lesions. BRAFV600E has been found to be associated with oncogeneinduced senescence (OIS), which is a protective mechanism against oncogenic events. In OIS, an activating mutation in an oncogene without complementary mutations leads to cell-cycle arrest and induction of pro-inflammatory molecules. Histiocytes carrying the BRAFV600E mutation have markers of OIS, thus while the BRAFV600E mutation promotes clonal proliferation of BRAFV600E histiocytes, it paradoxically also leads to OIS, and in this way contributes a key role to the inflammatory milieu observed in recruiting activated histiocytes to ECD lesions [16]. Activated foamy histiocytes have a high expression of chemokine/chemokine receptors (CCR) involved in monocyte migration process (CCR1, CCR2, CCR3, CCR5 and the ligands CCL4, CCL2, CCL20 and CCL5), and recruited T-helper lymphocyte demonstrate increased expression of IFNγ and the IFNγ induced chemokine (IP-10) on histiocytes with an auto feedback loop that in turn recruit more histiocytes and proinflammatory cells [3]. ECD is characterized by elevated levels of interferon alpha (IFNα), interleukin (IL)-6, IL-12, and monocyte chemotactic protein-1 as well as by decreased levels of IL-4 and IL-7 [4 and 10]. Il-6 is involved in osteoclast differentiation that can lead to osteosclerosis, [4] and IL-6 may also play a role in endothelial cell dysfunction and permeability seen in pericardial effusions of ECD [17].
There have been no randomized controlled trials in ECD. Case series have reported, with varying degrees of success, the use of steroids as well as other immunomodulatory agents. IFNα is currently considered first-line treatment, which induces activation of CD40 for immune-mediated destruction of histiocytes. Cladribine is a purine analogue that causes monocyte and T-lymphocyte depletion [18]. Anakinra is a recombinant non-glycosylated form of human IL- 1Ra that down regulates the activity of IL-1. Infliximab is a chimeric monoclonal antibody against TNFα. Recently, Vemurafenib therapy has been studied and it appears to be a highly promising treatment, [10] as it induces apoptosis in cell lines expressing the BRAFV600E mutation. Interestingly, it has also been effective in BRAFV600E mutated melanoma cell lines [10] and non-melanoma cancer [19]. Given the patient’s positive BRAFV600E genetic analysis, she was started on Vemurafenib with significant improvement in her symptoms, which is consistent with other reports of successful use of Vemurafenib for ECD [10,20-25]. After 18 months of Vemurafenib therapy, no drug resistance has emerged, and consistent with other prior reports, her orbital masses are markedly decreased in size on MRI, [22] and her systemic disease remains stable without exacerbation or progression.


ECD is a rare disease associated with multidisciplinary morbidity that presently poses a great challenge to the medical care team. The heterogeneity of case presentation due to multi-system involvement makes diagnosis and management particularly challenging, and ECD historically has demonstrated poor response to therapy. More recently, improved understanding into the clonal and pro-inflammatory mechanism of disease and central role of BRAF mutations in this disease may help guide clinicians in the use of anti-inflammatory, immunomodulatory, and anti-proliferative treatments. Long-term outcomes and side effects of these treatments remain important questions, and prospective clinical trials are needed to further guide treatment algorithms for ECD.


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