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Erdheim-Chester disease

Erdheim-Chester disease
Authors:
Eric Jacobsen, MD
Gaurav Goyal, MD
Section Editor:
Arnold S Freedman, MD
Deputy Editor:
Alan G Rosmarin, MD
Literature review current through: May 2025. | This topic last updated: Jun 18, 2025.

INTRODUCTION — 

Erdheim-Chester disease (ECD) is a rare histiocytic neoplasm that most commonly manifests multifocal sclerotic lesions of the long bones. A biopsy of ECD lesions reveals sheets of foamy histiocytes (ie, xanthogranulomatous infiltration), with or without involvement of extraosseous tissues.

ECD was previously considered an inflammatory/autoimmune disorder, but it is now recognized as a clonal hematopoietic neoplasm that is usually associated with mutations of BRAF or other components of the MAPK pathway.

The clinical manifestations, pathologic features, diagnosis, and management of ECD are discussed here.

Related topics include:

●(See "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis".)

●(See "Pulmonary Langerhans cell histiocytosis".)

EPIDEMIOLOGY — 

ECD is rare, but the actual incidence is not well defined.

Fewer than 1000 cases have been reported in the published literature [1,2], but the detection of ECD is expected to increase due to greater awareness and improved diagnostic precision.

ECD is most common in adult male patients, with a mean age of 40 to 60 years at diagnosis; the male predominance is estimated to be 3:1 [1,3,4]. While ECD is primarily a disease of adults, onset before age 18 years has been reported; this highlights the overlap between ECD and juvenile xanthogranuloma (JXG) [5]. ECD generally affects White individuals, but cases have been reported among the Asian population and those of Hispanic ethnicity.

PATHOGENESIS — 

ECD is a malignancy of myeloid cells in which mutated BRAF or other signaling molecules drive increased expression of inflammatory cytokines [6].

●ECD mutations – The mutations associated with ECD are acquired (ie, not germline); there is no evidence that ECD is a heritable disorder. No infectious etiology or other environmental causes for ECD have been identified.

Somatic mutations of BRAF or other components of the MAPK signaling pathway are found in most patients with ECD. Mutations in NRAS, KRAS, ARAF, PIK3CA, MAP2K1, and CSF1R are reported [6-15]. In some studies, BRAF V600E was found in one-half of ECD cases, but the frequency is likely higher if more sensitive techniques are used [16-22].

The role of targetable mutations in the management of ECD is discussed below. (See 'Management' below.)

●Pathophysiology – Mutant BRAF enhances cell proliferation and survival by activating the RAS/RAF/MEK/MAPK signaling pathway [6-9]. Histiocytes in ECD express a pattern of proinflammatory cytokines and chemokines that accelerate further histiocyte recruitment and activation [23]. One study reported that, compared with controls, 37 untreated patients with ECD had higher serum levels of interleukin (IL)-6, interferon (IFN) alpha, and MCP-1 (monocyte chemoattractant protein-1; also called CCL2), and lower levels of IL-4 and IL-7; this pattern suggests perturbation of T cell helper 1 (Th-1) lymphocytes in ECD [3]. Another study reported that IFN gamma-expressing Th-1 lymphocytes were prominent in the cellular infiltrate of ECD [23].

●Myeloid origin of malignant cells – The myeloid origin of ECD is demonstrated by the detection of BRAF V600E in subsets of dendritic cells, mature monocytes, committed myeloid progenitors, and CD34-positive cells of affected patients [24,25]. Hematopoietic cells that carry the BRAF V600E mutation can recapitulate the phenotype of ECD in vitro and in a mouse xenograft model.

Lesions that histopathologically resemble ECD but have ALK gene fusions are classified as ALK-positive histiocytosis by the World Health Organization 5th edition and the International Consensus Classification [26-28].

CLINICAL MANIFESTATIONS — 

The clinical presentation of ECD varies with the extent and distribution of involved sites. Most patients have bony involvement at diagnosis, and the vast majority also has at least one extraosseous site of involvement.

A subset of patients is asymptomatic, with disease detected by imaging for unrelated conditions. Some patients with multisystemic involvement may have a rapidly progressive clinical course.

A review of 259 patients with histologically proven ECD reported that the most common clinical presentations were bone pain (26 percent), neurologic findings (23 percent), arginine vasopressin deficiency (AVP-D; ie, central diabetes insipidus; 22 percent), and constitutional symptoms (20 percent) [1]. A single-center review of 165 patients reported that the most common sites of clinical involvement were long bones (80 percent), retroperitoneum (58 percent), vascular (64 percent), heart (53 percent), central nervous system (CNS; 37 percent), and skin (33 percent) [29]. Another study of 60 patients reported similar patterns of organ involvement [30].

Bone

●Clinical findings – Bone pain is present in approximately one-half of patients, even though bony involvement is nearly universal [29,30]. Mild, persistent juxta-articular pain, particularly in the lower extremities, is typical.

●Imaging – Symmetric diaphyseal and metaphyseal osteosclerosis of the lower extremities is present in 85 to 90 percent of cases with ECD [22,29,30]. While long bone involvement was previously a diagnostic criterion, there is increasing recognition of "non-classic" cases (ie, no bone involvement).

The typical manifestation is bilateral symmetric osteosclerosis of the long bones (image 1 and image 2). Osteosclerosis of the skull bones, particularly the facial bones, is also described [31]. The pattern of bony involvement distinguishes ECD from Langerhans cell histiocytosis (LCH), in which the axial skeleton (limbs, pelvis, scapula, and skull) is more commonly involved.

Positron emission tomography (PET), computed tomography (CT), magnetic resonance imaging (MRI), or bone scintigraphy can detect bony lesions that are not apparent on plain radiographs. PET/CT is highly sensitive for bony involvement, can be used to identify a site for a diagnostic biopsy, and is an important component of the evaluation for organ involvement [4]. MRI, which demonstrates replacement of the normal fatty bone marrow by heterogeneous signal intensity on T1- and T2-weighted spin-echo images (image 3) and bone scintigraphy, detects all bone lesions visible on radiographs (image 4).

Cardiovascular — Cardiac involvement can be a significant source of morbidity and mortality and is present in 50 to 60 percent of patients, often associated with BRAF V600E [32]. Cardiovascular involvement can include valve abnormalities, rhythm or conduction defects, and periaortic fibrosis along the entire course of the vessel, the latter often mimicking vasculitis. Cardiac involvement was previously considered a marker of poor prognosis, but this is less significant since targeted agents are used for treatment [32].

Among 37 patients with ECD who were systematically screened with electrocardiogram (ECG), cardiac MRI, and/or CT, 70 percent had abnormal heart imaging, and 40 percent had an abnormal ECG [33]. One-half of the patients had infiltration of the right heart (including pseudotumors); periaortic fibrosis, periarterial infiltration of the coronary arteries, and pericardial thickening/effusion were also common.

MRI was more sensitive for cardiac involvement than other imaging modalities in a study of 23 consecutive patients with ECD; 10 patients had evidence of cardiac involvement by MRI (9 with myocardial involvement and 9 with pericardial involvement) [34]. Heart disease most often manifests a posterior right atrial pseudotumor; infiltration of the right atrioventricular sulcus with asymptomatic infiltration of the right coronary artery was also common. Six patients had thoracic large-vessel involvement together with cardiac lesions, whereas only one patient had thoracic aorta involvement without cardiac involvement. Coronary artery involvement can lead to myocardial infarction [35,36].

Circumferential soft tissue sheathing of the thoracic and abdominal aorta ("coated aorta") is seen by CT in two-thirds of patients [35,37]. Involvement of the renal arteries can cause renal artery hypertension.

Central nervous system — Neurologic involvement (including hypothalamus/pituitary) is seen in 40 to 50 percent of ECD cases. Some series included the hypothalamus and pituitary as endocrine manifestations, thereby leading to lower prevalence estimates of CNS involvement.

Histiocytes can infiltrate all areas of the CNS, including intra-axial and extra-axial compartments [29,38,39]. CNS manifestations are pleiotropic but most commonly manifest T2 hyperintensities of the posterior fossa (cerebellum, pons) or brainstem without gadolinium enhancement [38]. CNS involvement, whether symptomatic or asymptomatic, is an independent predictor of inferior outcomes with ECD [40].

Exophthalmos (with unilateral or bilateral infiltration of the orbits), retro-orbital pain, oculomotor palsies, and/or blindness occur in one-quarter of patients [41,42]. Neurologic involvement may also manifest excessive thirst or urination in association with AVP-D, loss of libido, headache, weakness, ataxia, dysarthria, exophthalmos, seizures, cognitive impairment, cranial nerve palsies, or spinal cord compression [43,44].

Cerebellar involvement and other CNS mass lesions are often multifocal. CNS lesions typically enhance with gadolinium on MRI [16,45]. ECD can infiltrate the dura, in which case it may be confused with a meningioma [46]. Cognitive impairments have been described in the absence of imaging abnormalities. In a study of 11 patients, volumetric MRI demonstrated diffuse reduction in cortical thickness and subcortical gray matter compared with age-matched controls [47].

Pituitary involvement commonly manifests AVP deficiency and other endocrinopathies, such as hyperprolactinemia, gonadotropin insufficiency, or hypotestosteronemia. Pre-existing AVP-D and endocrinopathies typically persist despite a radiographic response to treatment [1].

The management of CNS involvement and associated endocrinopathies is discussed below. (See 'Complications and emergencies' below.)

Other organ systems — Infiltration of nearly every organ system has been reported with ECD [16].

●Endocrinopathies – In addition to AVP-D, 30 to 40 percent of patients with ECD have deficiencies of anterior and/or posterior pituitary hormones (eg, growth hormone, gonadotropin, thyrotropin, corticotropin, prolactin); other endocrinopathies associated with ECD include primary hypogonadism and adrenal insufficiency [48]. Pituitary endocrinopathies may or may not be accompanied by imaging abnormalities. A study of 61 patients with ECD reported that 28 percent had hypothyroidism requiring levothyroxine therapy [49].

●Kidney – Kidney involvement may manifest renovascular hypertension, hydronephrosis, and occasional kidney failure [1]. Infiltration of perinephric tissues with a rind or mass-like lesion leading to "hairy kidney" is common and can cause hydronephrosis, ureteral narrowing, and slowly progressive kidney insufficiency [16,50]. Percutaneous nephrostomy tubes are often required to alleviate ureteral obstruction. (See "Clinical manifestations and diagnosis of urinary tract obstruction (UTO) and hydronephrosis".)

●Lungs – Up to one-half of patients have involvement of the pleura, lung parenchyma, or both [51]. Pulmonary involvement may be asymptomatic or may present with dyspnea or cough [16]. Although dyspnea and progressive fibrosis leading to respiratory failure can occur, a large study reported that lung involvement was not an independent predictor of decreased survival [52].

Plain chest radiographs are often normal in patients with ECD, but spirometry may show restrictive features and decreased diffusion capacity. CT findings include mediastinal infiltration, pleural thickening/effusion, centrilobular nodular opacities, ground glass opacities, or lung cysts [53,54]. Fluid from bronchoalveolar lavage may contain macrophages and foamy histiocytes [16]. Open-lung biopsies have demonstrated histiocytic infiltrates in a lymphangitic pattern with associated fibrosis and lymphoplasmacytic inflammatory infiltrates.

●Skin – Skin is involved in one-quarter of cases of ECD; this contrasts with LCH, which frequently affects the skin [55]. One-third of patients have yellow plaques under the skin (xanthelasma), most commonly on the eyelids [16,56]. Other skin lesions are generally multifocal, reddish-brown, and papulonodular in appearance but have few other distinguishing characteristics. Pruritus can occur but is not a universal feature.

●Other organs – Involvement of other structures (breast, thyroid, testis, gingiva, kidneys, and spleen) is rare. Breast involvement usually presents as a palpable mass or nodule in one or both breasts [57]. Liver involvement may be detected on radiographic staging or manifest with abnormalities in transaminases, bilirubin, and/or alkaline phosphatase [58].

●Mixed histiocytosis – ECD can present concurrently or metachronously with LCH or Rosai-Dorfman disease (RDD); these rare entities are known as mixed histiocytosis. In mixed LCH/ECD, LCH usually precedes ECD lesions and is driven by BRAF V600E in 70 to 80 percent of cases [59]. RDD lesions can also occur in patients with ECD, commonly involving the testicular tissue in older male patients and driven by mutated MAP2K1 [60].

Associated myeloid malignancies — Patients with ECD and mixed ECD/LCH have an increased risk for concurrent or subsequent myeloid neoplasms.

The incidence of myeloid malignancies in patients with ECD is higher than in the general population. A retrospective study of 189 patients with biopsy-proven ECD reported that 10 percent had an overlapping myeloid neoplasm (eg, myeloproliferative neoplasm [MPN], myelodysplastic syndrome/neoplasm [MDS], chronic myelomonocytic leukemia, or other MDS/MPN overlap syndrome) [61]. Compared with patients who had ECD alone, patients with coexistent ECD and an associated myeloid neoplasm were older at the diagnosis of ECD (68 versus 57 years, respectively) and had inferior survival (82 versus 364 months).

Hallmark driver mutations of myeloid neoplasms (eg, JAK2 V617F, CALR) may coexist with mutations associated with ECD (eg, BRAF V600E, MAP2K1).

Monitoring for myeloid malignancies is a component of follow-up care. (See 'Response assessment and monitoring' below.)

INITIAL EVALUATION — 

The evaluation must document the diagnosis, define the extent and sites of disease and end-organ compromise, assess the mutational status, and determine the patient's functional status. The evaluation includes clinical assessment of the central nervous system (CNS), heart, and other organs; laboratory studies; genetic testing, and imaging [4,62].

Clinical

●History – The medical history should assess constitutional symptoms (eg, fever, night sweats, weight loss), bone pain, skin lesions (eg, xanthelasma, rash), and findings that may indicate organ involvement (eg, dyspnea, dysrhythmias, polydipsia/polyuria, gynecomastia, decreased libido, double vision, ataxia, dysarthria, falls, depression, mood lability).

●Examination – Physical examination should evaluate potential neurologic, cardiac, pulmonary, and cutaneous findings, as described above. Neurologic manifestations can be particularly underappreciated and often require specialist evaluation. (See 'Clinical manifestations' above.)

Functional status is assessed by Eastern Cooperative Oncology Group (ECOG) or Karnofsky Performance Status (table 1).

Laboratory — Baseline laboratory studies include:

●Hematology – Complete blood count (CBC) with differential count.

●Chemistries – Serum electrolytes, liver and kidney function tests, and vitamin B12.

●Inflammation – C-reactive protein (CRP).

●Endocrine – Morning urine osmolality and morning serum cortisol, followed by a water deprivation test if arginine vasopressin deficiency (AVP-D) is suspected [63]; thyroid-stimulating hormone (TSH) and free T4; morning plasma cortisol and adrenocorticotropic hormone (ACTH); prolactin, luteinizing hormone, follicle-stimulating hormone; insulin-like growth factor-1 (IGF-1); testosterone (in males), estradiol (in females). (See "Clinical manifestations of hypopituitarism" and "Evaluation of patients with polyuria".)

●Bone marrow aspiration and biopsy should be performed in cases with an abnormal CBC.

Electrocardiogram (ECG) should be performed in patients who may receive a BRAF inhibitor, and an echocardiogram should be obtained in those starting an MEK inhibitor, or if clinically indicated.

Imaging — We perform the following studies at diagnosis:

●Positron emission tomography (PET)/CT – PET/CT should include the full body (vertex to toes); it is important to include the lower extremities to assess osteosclerosis around the knees.

Bone scintigraphy can demonstrate the iconic radiologic features (image 4), but unlike PET/CT, bone scintigraphy does not identify extraosseous involvement.

●CT – CT of chest, abdomen, and pelvis, including the entire aorta. (See 'Cardiovascular' above.)

●MRI – MRI of the brain with contrast, including detailed examination of the sella turcica.

●Cardiac MRI – MRI is superior to an echocardiogram for assessing cardiac infiltration [34].

Pathology — An adequate tissue biopsy is required to diagnose ECD, distinguish it from other conditions, and identify mutations that may be amenable to targeted therapies.

For many patients, a shave biopsy of a cutaneous lesion yields adequate diagnostic material, but a biopsy of bone or another organ may be required in other cases. Regardless of the tissue source, we obtain multiple biopsy specimens because histologic involvement may vary from field to field. Recognize that decalcification of a bone specimen will render the sample unsuitable for molecular analysis.

In addition to standard histologic and immunophenotypic analysis, biopsy specimens should undergo molecular testing with a gene panel or next-generation sequencing to identify BRAF V600E and other relevant mutations (eg, NRAS, KRAS, ARAF, PIK3CA, MAP2K1, ALK). If a mutation is not detected, we repeat the testing using another involved site and/or genotyping modality. (See 'No mutation detected' below.)

Lipid-laden, "foamy" histiocytes with a distinctive immunophenotype in an inflammatory and/or fibrotic milieu are a typical histopathologic appearance. Involved tissues are infiltrated by sheets of lipid-laden (xanthomatous) histiocytes that typically have small nuclei and foamy cytoplasm (picture 1). Multinucleated giant histiocytes (Touton cells) with a central ring of nuclei are commonly seen, and there may be interspersed inflammatory cells and fibrosis, similar to that seen in xanthogranulomas (picture 2 and picture 3) [64,65]. Reactive small lymphocytes, plasma cells, and neutrophils are frequently admixed. Histopathologic findings may be highly variable, including the absence of classic foamy histiocytic infiltrate, nonspecific inflammation admixed with fibrosis, or fibrosis alone with scant histiocytes [6].

ECD cells express CD14 (a receptor for lipopolysaccharide), CD68 (a lysosomal macrosialin), CD163 (a hemoglobin- and haptoglobin-scavenging receptor), Factor XIIIa (tissue glutaminase), and fascin (an actin-binding protein) (picture 4) [2,66]. ECD cells do not express the Langerhans cell markers, CD1a or langerin, and S100 is rarely positive [16,67].

DIAGNOSIS — 

ECD is a rare disease that may be suspected in a patient with unexplained bone pain (especially of distal extremities) in association with cutaneous, cardiac, endocrine, or neurologic findings and abnormal imaging of bone. ECD has protean manifestations, is often challenging to diagnose, and delayed or erroneous diagnoses are common.

Diagnosis is based on the distinctive histopathologic findings in an appropriate clinical and radiologic context [4,16]. Lesions typically demonstrate foamy or lipid-laden histiocytes admixed with reactive inflammatory cells and/or fibrosis. (See 'Pathology' above.)

Symmetric osteosclerosis of the knees can be pathognomonic, especially in the presence of other clinical or pathologic features. Other histopathology, immunohistochemical, and radiologic features that can distinguish ECD from other histiocytoses are discussed below. (See 'Differential diagnosis' below.)

Our approach to evaluation and diagnosis of ECD is consistent with published guidelines [16].

DIFFERENTIAL DIAGNOSIS — 

ECD must be distinguished from other histiocytic and dendritic cell disorders, metastatic solid tumors, and hematopoietic neoplasms.

●Juvenile xanthogranuloma (JXG) and adult xanthogranuloma (AXG) – JXG and AXG are primarily cutaneous disorders that are histologically and immunophenotypically indistinguishable from ECD. JXG belongs to the broad group of non-Langerhans cell histiocytoses and is typically seen in early childhood. By contrast, ECD usually occurs in adults of middle age or older. JXG presents in the first two years of life as a solitary reddish or yellowish skin papule or nodule (picture 5), most often on the head, neck, and upper trunk.

JXG generally follows a benign course with spontaneous resolution over a period of a few years. Multiple skin lesions are uncommon with JXG (picture 6). Extracutaneous or systemic forms (brain, lung, kidney, spleen, liver, bone marrow, and retro-orbital tumors) are exceedingly rare and can cause considerable morbidity. Some cases of CNS-JXG with BRAF V600E may represent pediatric ECD [68].

Distinguishing AXG from ECD is challenging, as both affect adults. AXG mostly involves the skin and rarely presents with isolated systemic organ involvement. ECD generally manifests classic bone involvement, but often has more widespread systemic involvement, such as posterior fossa lesions, perinephric infiltration, coated aorta, and right atrial pseudotumor.

Management of systemic involvement by JXG or AXG is like that for ECD. (See "Juvenile xanthogranuloma (JXG)".)

●Langerhans cell histiocytosis – Langerhans cell histiocytosis (LCH) and ECD are both histiocytic diseases that can involve multiple sites, most often bones. Skin involvement is more common in LCH. These entities can usually be distinguished by morphologic and immunohistochemical findings. Unlike LCH, ECD tumor cells lack central nuclear grooves and do not express CD1a or S100 [69]. Cases of concomitant LCH and ECD (ie, mixed histiocytosis) have been described [70]. (See "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis".)

●Rosai-Dorfman disease – Rosai-Dorfman disease (RDD; sinus histiocytosis with massive lymphadenopathy) is a macrophage-related disorder that usually involves lymph nodes, skin, and other organs [71-77]. Unlike ECD, the skin lesions of RDD are firm, indurated papules. Although the pathologic cells in RDD are macrophages (CD14 positive, CD1a negative, S100 positive-negative, CD68 positive), RDD is histologically distinct from the other histiocytic diseases because the macrophages have normal-appearing lymphocytes residing in the macrophage cytoplasm (emperipolesis) [78]. (See "Peripheral lymphadenopathy in children: Etiology", section on 'Rosai-Dorfman disease'.)

●Paget's disease and POEMS syndrome – The osteosclerotic lesions of bone in ECD can be confused for various metabolic bone disorders, including Paget's disease and POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes), the latter of which also causes endocrine abnormalities.

While the ECD bone abnormalities are confined to bilateral and symmetric osteosclerosis of the diaphysis of the long bones, Paget's disease and POEMS syndrome generally cause less symmetric bone abnormalities and less specific localization. ECD can readily be distinguished from Paget's disease and POEMS syndrome by histologic and immunophenotypic findings on biopsy. (See "POEMS syndrome" and "Clinical manifestations and diagnosis of Paget disease of bone".)

●Other disorders

•Central nervous system (CNS) involvement by ECD can be confused with metastatic solid or hematopoietic neoplasms, or primary CNS tumors (including meningioma). (See 'Central nervous system' above.)

•Cutaneous involvement by ECD can mimic vasculitis, cutaneous lymphoma, or cutaneous involvement with LCH. (See 'Other organ systems' above.)

•Abdominal involvement by ECD should be distinguished from primary or secondary retroperitoneal fibrosis, sclerosing mesenteritis, and various retroperitoneal neoplasms, including lymphomas and germ cell tumors. (See 'Other organ systems' above.)

•Cardiac involvement can mimic other infiltrative cardiovascular processes, including sarcoidosis, and pulmonary involvement can have the clinical appearance of any number of interstitial lung diseases. (See 'Cardiovascular' above.)

MANAGEMENT — 

ECD is a rare condition. Outcomes data come primarily from retrospective series and case reports because there are few treatment studies and no randomized clinical trials. The management of organ effects and complications from ECD benefits from multidisciplinary collaboration.

While most patients with ECD have symptomatic disease that requires treatment at the time of diagnosis, asymptomatic patients with no evidence of CNS or organ dysfunction may be candidates for a period of observation, as discussed below. (See 'Asymptomatic patients' below.)

Our approach is consistent with society guidelines and recommendations from an international panel of physicians with expertise in ECD [4]. (See 'Society guideline links' below.)

Symptomatic patients — For patients with symptoms related to ECD, symptomatic or asymptomatic central nervous system (CNS) involvement, or other organ dysfunction, we suggest treatment with a mutation-guided targeted agent, based on the favorable balance of benefit and toxicity. We encourage enrollment in a clinical trial when possible.

When no mutation is detected, we perform a biopsy from an alternative site or use another genotyping modality. (See 'Pathology' above.)

Treatment with immunosuppressive or cytotoxic therapy (eg, interferon [IFN] alfa, glucocorticoids, systemic chemotherapy) is acceptable when a suitable targeted agent is not available. (See 'Other systemic treatments' below.)

BRAF mutation — For ECD with BRAF V600E, we suggest vemurafenib rather than immunosuppressive or cytotoxic therapy, based on the balance of efficacy and toxicity.

Vemurafenib is a potent inhibitor of V600E (and other activating mutations in BRAF), and treatment resistance is uncommon. For patients who lack access to vemurafenib or are intolerant of treatment, management is individualized according to toxicity profile, comorbidities, and patient preference. The risks and benefits of treatment should be discussed because vemurafenib is effective but may be associated with an increased risk of secondary cancers.

Acceptable alternatives to vemurafenib include:

●An alternative BRAF inhibitor (eg, dabrafenib). (See 'BRAF inhibitors' below.)

●An MEK inhibitor (eg, cobimetinib). (See 'MEK inhibition' below.)

●Pegylated IFN alfa. (See 'Interferons' below.)

●Systemic chemotherapy (eg, cladribine) or biologic agents (eg, anakinra) may be considered in selected cases. (See 'Other systemic therapies' below.)

●Administration – We attempt to begin with vemurafenib 480 mg twice daily by mouth, but this generally requires dose adjustment for toxicity. Treatment should continue until disease progression or the development of unacceptable toxicity. Disease relapse is common after the discontinuation of vemurafenib.

For patients with CNS involvement or other critical organ dysfunction, we consider dual therapy (eg, a BRAF inhibitor plus an MEK inhibitor), although there is no evidence that combining a BRAF inhibitor with another targeted agent is more efficacious than either alone and is likely to be more toxic [4]. Regardless of the starting dose, vemurafenib generally requires dose adjustment or a brief treatment interruption to lessen toxicity.

Concomitant administration of vemurafenib with strong CYP3A4 inhibitors or inducers (table 2) should be avoided, if possible.

Vemurafenib is approved by the US Food and Drug Administration (FDA) for ECD with BRAF V600E. It is approved by the European Medicines Agency (EMA) for the treatment of adults with unresectable or metastatic melanoma with BRAF V600E mutation.

●Toxicity – Mild or moderate arthralgia, alopecia, fatigue, rash, skin papilloma, or QT interval prolongation are seen in more than one-half of patients. Due to the risk of photosensitivity, patients should reduce sun exposure and use sunscreen with SPF ≥30.

Grade ≥3 adverse effects (AEs) that occur in ≥10 percent of patients include squamous cell skin cancer, hypertension, maculopapular rash, and arthralgia. BRAF inhibitors may increase the risk of second cancers, presumably due to the activation of RAS signaling in BRAF wild-type cells [61,79,80]. RAS activation may also lead to rare AEs, such as sarcoidosis [81].

Among patients treated with BRAF inhibitors, 61 percent discontinued therapy, mostly due to toxicity [82]. Some AEs can be managed effectively by reducing the dose further, while others may require switching to an alternate BRAF inhibitor or an MEK inhibitor. (See 'MEK inhibition' below.)

●Outcomes – Treatment with vemurafenib 960 mg twice daily in 26 patients with BRAF V600 (22 with ECD and 4 with Langerhans cell histiocytosis [LCH]) was associated with 96 percent two-year overall survival (OS), 86 percent two-year progression-free survival (PFS), and 62 percent overall response rate (ORR; including 100 percent response among patients evaluated by positron emission tomography [PET]/CT) [83]. Most patients required a dose reduction to 480 mg twice daily due to AEs.

Comparable responses to vemurafenib were reported in other studies of ECD and/or LCH [84-87]. ECD can respond rapidly to vemurafenib at all disease sites, including reversal of critical illness from ECD in some cases [88].

In a report of >50 patients taking vemurafenib or dabrafenib (an alternative BRAF inhibitor), most patients relapsed after the BRAF inhibitor was interrupted, but all responses were recaptured after the resumption of treatment with a BRAF inhibitor [89].

Other MAPK or ERK pathway mutations — For other mutations that activate the MAPK pathway (eg, NRAS, KRAS, ARAF, PIK3CA, MAP2K1) or BRAF gene fusions, we suggest cobimetinib (MEK inhibitor).

●Administration – We attempt to begin with cobimetinib 40 mg once daily by mouth for 21 days in 28-day cycles, but this often requires dose adjustment for toxicity.

Cobimetinib is approved by the FDA as a single agent for the treatment of adults with histiocytic neoplasms.

●Toxicity – Common AEs include mild or moderate rash, diarrhea, nausea, fever, leg edema, elevated liver transaminases or creatine phosphokinase, and low magnesium. The skin rash is typically acneiform; mild cases can be managed with over-the-counter topical acne medications (eg, benzoyl peroxide 10 percent), while oral doxycycline or minocycline and/or consultation with dermatology can be useful for more extensive or severe rashes. Less common but severe AEs include reduced left ventricular function and retinal changes; echocardiograms and retinal examinations by optical coherence tomography (OCT) are useful for screening for these AEs.

We generally treat patients who do not respond or are intolerant of cobimetinib with trametinib (another MEK inhibitor) or IFN alfa.

●Outcomes – The following studies reported treatment of ECD with MEK inhibitors:

•A study of 18 patients with histiocytic neoplasms (including 12 with ECD) reported that cobimetinib was effective independent of genotype (including mutations of ARAF, BRAF, RAF1, NRAS, KRAS, MEK1, and MEK2) [90]. The response rate by PET was 89 percent (including 72 percent complete response [CR]). At one year, 100 percent of responses were ongoing, and 94 percent of patients remained progression-free.

•Comparable efficacy was also reported with trametinib (MEK inhibitor) in ECD patients without BRAF V600E [61,91,92].

•Trametinib plus dabrafenib (a BRAF inhibitor) resulted in an excellent response in a case report of relapsed ECD with an activating KRAS Q61H mutation [93]. Another case report demonstrated the efficacy of cobimetinib in ECD with wild-type BRAF [94].

Non-MAPK or non-ERK pathway mutations — Treatment for mutations outside of the MAPK-ERK pathway is individualized according to the molecular findings. We consider it acceptable to treat with a targeted agent that has demonstrated efficacy with the specific mutation in another disorder, or use other systemic treatments, such as pegylated IFN alfa, cladribine, or anakinra. (See 'Other systemic therapies' below.)

BRAF and MEK inhibitors appear to be relatively ineffective for mutations outside of the MAPK-ERK pathway, such as mutated CSF1R and gene fusions involving NTRK or RET. Among 20 patients with ECD treated with an MEK inhibitor, the ORR was 40 percent in the 5 patients with no mutations of the MAPK-ERK pathway, compared with 93 percent ORR in the other patients [95]. Nonresponding patients had FLT3::MEF2C or mutated CSF1R, and they responded well to pexidartinib and sorafenib, respectively; one patient with BRAF V471F (a class II BRAF mutation that is expected to be resistant to MEK inhibitors) also did not respond.

No mutation detected — When no mutation is detected, we repeat the biopsy or use an alternative method for mutation detection. Failure to detect a mutation may be related to low cellularity in the biopsy specimen, a low yield of deoxyribonucleic acid (DNA), or a low variant allele fraction of the mutation from the biopsy specimen.

When no mutation is identified after a repeat biopsy, we suggest initial treatment with an MEK inhibitor, based on reported responses in some cases [95]. Other acceptable options include pegylated IFN alfa, cladribine, or anakinra. Note that IFN alfa may not be effective for patients with mixed histiocytosis (ECD/LCH overlap) because the non-ECD component may not respond to IFN therapy [70]. Administration, toxicity, and outcomes with IFN therapy are discussed below. (See 'Interferons' below.)

Asymptomatic patients — For asymptomatic patients with no evidence of CNS involvement or organ dysfunction, we suggest a period of observation rather than immediate treatment. It is uncertain if targeted therapies alter the natural history of ECD or delay the onset of symptoms, and a period of observation avoids treatment-related toxicity.

Patients should be thoroughly evaluated to detect subclinical CNS or organ involvement. A decision to observe rather than initiate treatment should take place after a discussion of the risks and benefits with an informed patient. A minimally symptomatic patient with involvement of bone or another nonvital organ may instead choose to receive a less toxic treatment, such as anakinra. (See 'Other systemic therapies' below.)

Asymptomatic patients should be followed with periodic clinical evaluation, but it is not necessary to perform routine imaging or repeat biopsies unless new clinical or laboratory findings emerge. Follow-up of patients with ECD is described below. (See 'Response assessment and monitoring' below.)

COMPLICATIONS AND EMERGENCIES — 

Patients with ECD are at risk of developing potentially life-threatening complications due to central nervous system (CNS) involvement, cardiovascular involvement, or ureteral compression. (See 'Clinical manifestations' above.)

●Neurologic involvement – CNS involvement requires a prompt clinical response to avoid neurologic complications. Patients with CNS involvement and BRAF V600E may benefit from a higher initial dose of a BRAF inhibitor or dual agent therapy, as discussed above. (See 'BRAF mutation' above.)

Patients with neurologic involvement often have substantial fatigue and pain that requires specialized evaluation and management, along with neoplasm-directed therapy. Some patients benefit from referral to palliative care, physical therapy, and/or occupational therapy to maintain functional status. Patients may experience late neurologic adverse effects from neurologic involvement.

●Compression/obstruction of vital structures – Heart valve replacement or percutaneous nephrostomy may also be necessary in selected patients.

SYSTEMIC THERAPIES — 

Management of ECD is informed by the underlying mutation, as discussed above. (See 'Symptomatic patients' above.)

ECD is rare, and no prospective studies have directly compared outcomes with various treatments. There is no consensus for the treatment of patients who did not respond to a targeted agent, had intolerable adverse effects (AEs), or do not have access to such treatments. In such settings, treatment is informed by the toxicity profile, comorbidities, and availability, as discussed below. (See 'Other systemic treatments' below.)

BRAF inhibitors — Vemurafenib is a potent inhibitor of the kinase domain of mutant BRAF and has activity against activating mutations in BRAF (eg, V600E). Administration, toxicity, and outcomes with vemurafenib for BRAF-mutated ECD are discussed above. (See 'BRAF mutation' above.)

There is little experience with other BRAF inhibitors for ECD. Dabrafenib is active against BRAF V600E and other activating kinase mutations in melanoma, but it is not currently approved for the treatment of ECD [96]. In a case report, a patient with BRAF V600E responded to dabrafenib but experienced a recurrence 14 months later; BRAF V600E was not detected on a repeat biopsy, but a KRAS mutation was found [93].

MEK inhibition — There is no preferred MEK inhibitor, but the greatest experience in ECD is with cobimetinib for mutations of NRAS, PIK3CA, or components of the RAS-PI3K-AKT signaling pathway.

Cobimetinib may also be effective for patients who did not respond to, progressed on, or were intolerant of a BRAF inhibitor, and it may have efficacy for selected patients with wild-type (unmutated) BRAF. Administration, toxicity, and outcomes with cobimetinib are discussed above. (See 'Other MAPK or ERK pathway mutations' above.)

Other MEK inhibitors (eg, trametinib) may also be effective against ECD with mutations of NRAS, PIK3CA, or components of the RAS-PI3K-AKT signaling pathway. Trametinib is approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of melanoma, but it is not labeled for ECD. Treatment with trametinib for melanoma is discussed separately. (See "Systemic treatment of metastatic melanoma with BRAF and other molecular alterations".)

Other systemic treatments — For patients who are not suitable for a targeted agent, we suggest pegylated interferon alfa-2b based on prolonged survival compared with other systemic therapies.

Patients may not be suitable for a targeted agent because they did not respond adequately, had intolerable AEs, or did not have access to such treatments. Pegylated IFNa has good efficacy and modest toxicity, but no prospective studies have directly compared it with targeted agents or other systemic treatments for ECD. (See 'Interferons' below.)

Other systemic options are discussed below. (See 'Other systemic therapies' below.)

Interferons — Interferon alfa (IFNa) is a pharmaceutical product obtained from human leukocytes that contains several naturally occurring subtypes of interferon alpha. Ropeginterferon alfa-2b (pegylated IFNa) provides a more favorable toxicity profile than conventional IFNa, with prolonged activity compatible with once-weekly dosing.

Pegylated IFNa is our preferred treatment for patients with symptomatic ECD who are not eligible for, unable to tolerate, or unresponsive to a targeted agent. Conventional (unpegylated) IFNa is no longer available in the United States.

●Administration – We generally begin with pegylated IFNa 135 micrograms weekly and titrate the dose upward to a maximum dose of 200 micrograms weekly, as tolerated, if the patient is not responding to the initial dose.

Treatment should continue until disease progression or intolerable side effects occur, but the risk-benefit ratio should be revisited periodically after ≥2 years of treatment. Prolonged treatment is generally required because ECD is likely to relapse at the discontinuation of IFNa.

Patients should be monitored for infections, liver function abnormalities, thyroid abnormalities, and depression.

Conventional IFNa may be started at 3 million international units three times per week, with the dose titrated upwards (to a maximum dose of 9 million international units three times a week) as tolerated, if patients are not responding to the initial dose.

Note that IFNa should not be used for patients with mixed histiocytosis (ie, ECD/LCH overlap) because the non-ECD component is unlikely to respond to IFNa [70].

●Toxicity – Common AEs include fatigue, flu-like symptoms, headache, myalgia, and depression. In a study of 24 patients with ECD receiving high-dose IFNa or pegylated IFNa, only 13 percent experienced AEs that required switching to standard doses [97].

●Outcomes

•In a French registry study of 165 patients with ECD, IFN therapy was associated with longer survival than other treatments; approximately one-half of the patients had mutated BRAF, but testing for other mutations was not performed [29]. For the entire cohort, five-year overall survival (OS) was 83 percent, and the median OS was 162 months. Patients treated with IFNa or pegylated IFNa had improved OS (hazard ratio [HR] 0.38 [95% CI 0.16-0.89]) compared with other treatments. Central nervous system (CNS) involvement was independently associated with mortality in multivariate analysis (HR 2.43 [95% CI 1.33-4.94]).

•Conventional IFNa or pegylated IFNa was associated with 96 percent one-year OS and 68 percent five-year OS in 53 patients with ECD [40]. Compared with other treatments, IFN was associated with improved OS (HR 0.32 [95% CI 0.14-0.70]), while CNS involvement was an independent predictor of inferior survival.

•In a Chinese study, high-dose IFNa was associated with an 88 percent response rate, and it offered a cost-effective alternative to targeted therapies [98].

Other systemic therapies — The choice of other systemic therapies for ECD is guided by the severity of symptoms, extent of organ involvement, toxicity profile, comorbidities, availability, and patient preference.

●Cladribine – Cladribine is a purine analog that offers the potential for sustained remission with limited duration therapy.

Cladribine is our preferred cytotoxic chemotherapy for ECD, based on case reports and our own clinical experience [99,100]. Treatment with cladribine in 21 patients with ECD (9 treated in front-line and 12 in later lines of treatment) reported a 52 percent overall clinical response rate (including 6 percent complete responses [CR]) and 9 months median duration of response [100].

We typically administer two cycles of cladribine and then restage with positron emission tomography (PET)/CT and/or other imaging. If there is at least a partial response, we administer two more cycles of treatment, but limit treatment to ≤6 cycles total. We change therapy if there is no response after two cycles.

Patients may become profoundly lymphopenic, and prophylaxis is generally given for Pneumocystis jirovecii pneumonia, varicella zoster, and herpes simplex virus.

●Anakinra – Anakinra is a recombinant interleukin 1 receptor antagonist (IL-1RA) that requires subcutaneous administration. Anakinra can be effective for nonsevere forms of ECD, such as patients with no CNS involvement.

There are case reports of recombinant IL-1RA (anakinra, canakinumab) inducing responses in patients who could not tolerate IFN [101-107]. There is more published experience with anakinra. Anakinra can be helpful for less severe disease or for constitutional symptoms and bone pain, but there is limited experience with it for CNS and cardiac disease [108,109]. The most common AE is a reaction at the site of subcutaneous injection.

●Sirolimus – We offer sirolimus when the agents above are not efficacious or are poorly tolerated. In an open-label trial of 10 patients with ECD using sirolimus plus prednisone, 6 patients had a partial response, 2 had stable disease, and 2 had progressive disease [110].

●Others

•Methotrexate – Low-dose oral methotrexate may not have much activity in ECD as demonstrated by a case series [111]. In a case report of ECD with CNS involvement, high-dose systemic methotrexate with leucovorin rescue was utilized successfully (given the ability of methotrexate to cross the blood-brain barrier) [112].

•Cytarabine – Intermediate-dose cytarabine was successful for ECD, especially among patients with CNS involvement [113].

Localized therapies — Surgery and radiation therapy (RT) have limited roles in the management of ECD. They are used primarily to manage local and/or mechanical complications.

●Surgery has no clear role in the management of ECD except for mechanical complications, such as ureteral obstruction or repair/replacement of cardiac valves.

●RT can provide local palliation, but ECD seems to be much less responsive to RT than Langerhans cell histiocytosis (LCH); lack of response or in-field recurrence is fairly common [114]. The optimal dose and field for RT are unknown. We generally use doses appropriate for aggressive lymphomas (40 to 50 Gray) when feasible, rather than the much lower doses utilized for LCH.

RESPONSE ASSESSMENT AND MONITORING — 

Patients are monitored for treatment response by clinical evaluation, laboratory studies, and imaging. The monitoring schedule is individualized according to disease status, treatment, comorbidities/complications, and concerns of the patient and clinicians.

An international panel of experts has published guidelines for response assessment and disease monitoring [4], and the United States National Comprehensive Cancer Network created guidelines for the management of histiocytic neoplasms, including ECD [62].

Patients should be clinically assessed at least every three to six months, but it may be more frequent, if needed, to monitor symptoms and organ function. Follow-up visits should seek evidence of central nervous system (CNS) and organ involvement. The interval between visits can be increased as warranted by the individual's clinical status.

●Clinical and laboratory – Clinical examination and laboratory testing are used to assess responses of skin and endocrine manifestations. Routine laboratory studies include a complete blood count (CBC), differential count, and serum chemistry studies. We obtain an annual electrocardiogram (ECG) and echocardiogram for patients who are taking a targeted agent.

•Hematology – ECD can infiltrate the bone marrow, and it is associated with other myeloid neoplasms or clonal hematopoiesis of indeterminate potential (CHIP) [61]. We routinely monitor blood counts and consider bone marrow examination with myeloid gene panels to assess hematologic abnormalities.

•Biomarkers – C-reactive protein is elevated in most patients at diagnosis [115], and a decline with treatment suggests a favorable response. However, the inflammatory effects of targeted therapies and interferon must be considered in the interpretation of biomarker results.

•Endocrine – Endocrinopathies in patients with ECD are typically permanent. We monitor pituitary hormone abnormalities every one to two years because additional endocrinopathies may develop during treatment [48].

●Imaging – Positron emission tomography (PET)/CT is the preferred imaging modality for assessing treatment response. A modified PET Response Criteria in Solid Tumors (PERCIST) can be used to assess the response to therapy [83,90,116].

•PET imaging to assess metabolic response should be obtained three to four months after the initiation of therapy. For patients receiving chemotherapy, a restaging PET/CT should be performed after two to three cycles. A complete metabolic response (CMR) is considered the optimal treatment response, but the degree of metabolic response varies by patient and treatment, and a CMR may take several months.

•Organ-specific imaging with CT or MRI (eg, of heart, brain, orbit) should be performed every 3 to 6 months initially, and every 6 to 12 months once disease stabilizes. However, treated lesions may not fully regress because of associated fibrosis, and the shrinkage of lesions by CT or MRI may not accurately reflect disease activity or response to treatment. This is particularly characteristic of longstanding lesions in the retroperitoneum, abdomen, orbits, and sinuses.

An international panel of experts published guidelines for response assessment and disease monitoring [4] and the United States National Comprehensive Cancer Network created guidelines for the management of histiocytic neoplasms, including ECD [62].

PROGNOSIS — 

Historically the prognosis in patients with ECD has been poor. There is no cure for ECD, and long-term effects of targeted agents are not well defined.

A large case series from France reported 82 percent five-year overall survival [29]. In the same series, involvement of the central nervous system and retroperitoneum was associated with adverse outcomes, while BRAF mutation status was not associated with prognosis.

CLINICAL TRIALS — 

Often there is no better therapy to offer a patient than enrollment in a well-designed, scientifically valid, peer-reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the National Institutes of Health, ECD Global Alliance, Histiocyte Society, or the National Cancer Institute.

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Histiocytic and dendritic cell neoplasms, including Langerhans cell histiocytosis".)

SUMMARY AND RECOMMENDATIONS

●Description – Erdheim-Chester disease (ECD) is a rare histiocytic neoplasm manifest as multifocal osteosclerotic lesions of the long bones. Pathologically, ECD demonstrates sheets of foamy histiocytes, with or without histiocytic infiltration of extraosseous tissues.

●Pathogenesis – ECD is a malignancy of myeloid progenitor cells in which a somatic mutation of BRAF or another signaling molecule appears to drive the malignant process and create an inflammatory tissue milieu. (See 'Pathogenesis' above.)

●Clinical manifestations – The presentation of ECD varies with the extent and distribution of involved sites. Most patients have symmetrical bony involvement of long bones and one or more nonosseous sites of involvement (eg, heart, central nervous system [CNS], skin, other organs). Most patients have multisystemic involvement with a progressive clinical course, but occasional patients are asymptomatic. (See 'Clinical manifestations' above.)

●Evaluation – Evaluation requires a history and physical examination, baseline laboratory studies, and imaging to assess organ involvement, as discussed above. (See 'Initial evaluation' above.)

●Diagnosis – ECD may be suspected in patients with unexplained bone pain (especially of distal extremities) in association with cutaneous, cardiac, or neurologic findings and abnormal bone imaging. Delayed or erroneous diagnosis is common because of the protean manifestations. (See 'Diagnosis' above.)

Diagnosis requires a characteristic histopathologic appearance (ie, foamy or lipid-laden histiocytes admixed with reactive inflammatory cells and/or fibrosis) in an appropriate clinical and radiologic context. The biopsy specimen should provide sufficient material to enable mutation testing and to distinguish ECD from other histiocytic and dendritic cell disorders, metastatic solid or hematopoietic neoplasms, and other conditions. (See 'Diagnosis' above and 'Differential diagnosis' above.)

●Management

•Symptomatic – For ECD-related symptoms, symptomatic or asymptomatic CNS involvement, or evidence of organ dysfunction, we suggest a targeted agent directed against the underlying mutation, rather than immunosuppressive or cytotoxic therapy (Grade 2C). (See 'Symptomatic patients' above.)

-BRAF – For BRAF V600E mutation, we suggest vemurafenib (BRAF inhibitor) (Grade 2C). (See 'BRAF inhibitors' above.)

-Other MAPK-ERK mutations – For other mutations that affect signaling molecules in the MAPK/ERK pathways (eg, NRAS, KRAS, ARAF, PIK3CA, and MAP2K1) and BRAF fusions, we suggest cobimetinib (MEK inhibitor) (Grade 2C). (See 'MEK inhibition' above.)

-Non-MAPK-ERK mutations – For molecular abnormalities outside of the MAPK-ERK pathway (CSF1R mutations, fusions in NTRK, RET), we consider either known inhibitors of the specific abnormality or pegylated interferon alfa acceptable. (See 'Non-MAPK or non-ERK pathway mutations' above.)

-No mutation detected – For patients with no detected mutations, we repeat a biopsy from an alternate site or using an alternate genotyping modality.

If no mutation is detected with repeat biopsy, we suggest initial treatment with an MEK inhibitor (Grade 2C). (See 'No mutation detected' above.)

•Asymptomatic – For asymptomatic patients with no evidence of organ dysfunction or CNS involvement, we suggest observation rather than immediate treatment (Grade 2C), reserving treatment for the development of symptoms. Patients should be clinically assessed at least every three to six months for evidence of CNS or other organ involvement. (See 'Asymptomatic patients' above.)

●Response assessment – The schedule and protocol for clinical, laboratory, and imaging to assess treatment response are discussed above. (See 'Response assessment and monitoring' above.)

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Topic 13942 Version 38.0

References

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