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Erdheim-Chester disease
Author: Eric Jacobsen, MD
Section Editor: Arnold S Freedman, MD
Deputy Editor: Alan G Rosmarin, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2021. | This topic last updated: Nov 19, 2020.
INTRODUCTION
Erdheim-Chester disease (ECD) is a rare non-Langerhans histiocytic multisystem disorder.

ECD is most commonly manifest as multifocal sclerotic lesions of the long bones
demonstrating sheets of foamy histiocytes on biopsy, with or without histiocytic infiltration of
extra-osseous tissues. Since 1930, when ECD was first described by Erdheim and Chester,
fewer than 1000 cases have been reported in the medical literature [1,2].
Histiocytic disorders are thought to be derived from mononuclear phagocytic cells

(macrophages and dendritic cells) or histiocytes. This group has generally been divided into
Langerhans cell histiocytosis (LCH) and non-Langerhans histiocytosis. LCH is so-named for its
presumed derivation from the Langerhans cells (specialized dendritic cells found in the skin
and mucosa). In contrast, non-Langerhans histiocytoses are thought to be derived from the
monocyte-macrophage lineage.
The epidemiology, clinical manifestations, pathologic features, diagnosis, and management

of ECD will be presented here.
Diagnosis and management of LCH are presented separately. (See "Clinical manifestations,
pathologic features, and diagnosis of Langerhans cell histiocytosis" and "Pulmonary
Langerhans cell histiocytosis".)
SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC
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The coronavirus disease 2019 (COVID-19) pandemic has increased the complexity of cancer
care. Important issues include balancing the risk from treatment delay versus harm from
COVID-19, ways to minimize negative impacts of social distancing during care delivery, and
appropriately and fairly allocating limited health care resources. These issues and
recommendations for cancer care during the COVID-19 pandemic are discussed separately.
● (See "COVID-19: Cancer screening, diagnosis, post-treatment surveillance in uninfected

patients during the pandemic, and issues related to COVID-19 vaccination in cancer
patients".)
● (See "COVID-19: Risks for infection, clinical presentation, testing, and approach to
infected patients with cancer".)
EPIDEMIOLOGY
ECD is rare, but the actual incidence is unknown. Fewer than 1000 cases have been reported
in the published literature [2,3]. However, detection of ECD is expected to increase due to
greater awareness and improved diagnostic precision.
ECD is most common in adult men, with a mean age of 50 to 60 years at diagnosis; the male
predominance is estimated to be 3:1 [3,4]. Rare pediatric cases (<15 years of age) have been
reported.
PATHOGENESIS
ECD is a malignancy of myeloid progenitor cells. Somatic mutation of BRAF and/or other
signaling molecules appears to drive the malignant process, which is associated with
increased expression of inflammatory cytokines. No infectious etiology or other
environmental cause for ECD has been identified and there is no evidence that ECD is
inherited; the mutations associated with ECD are acquired (ie, somatic, not germline).
ECD is caused by clonal proliferation of myeloid progenitor cells, as demonstrated by

detection of the characteristic BRAF V600E mutation in subsets of dendritic cells, mature
monocytes, committed myeloid progenitors, and CD34+ cells of affected patients [5,6].
Hematopoietic cells that carry the BRAF V600E mutation can recapitulate the phenotype of
ECD in vitro and in a mouse xenograft model.
Somatic mutations of BRAF or other components of the MAPK signaling pathway are present
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in most patients with ECD. In some studies, BRAF V600E has been detected in approximately
half of ECD cases, but the incidence is likely higher with more sensitive techniques [7-12].
Mutant BRAF enhances cell proliferation and survival by activating the RAS/RAF/MEK/MAPK
signaling pathway [13-16]. Mutations in NRAS, KRAS, ARAF, PIK3CA, MAP2K1, and ALK are also
reported in ECD [13-22]. The role of targetable mutations in disease management is
described below. (See 'Management' below.)
ECD histiocytes express a pattern of proinflammatory cytokines and chemokines that

accelerate 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 alpha, and MCP-1 and lower levels of IL-4 and IL-7; this pattern suggests
perturbation of T cell helper 1 (Th-1) lymphocytes in ECD [4]. Another study reported that
interferon gamma-expressing Th-1 lymphocytes were prominent in the cellular infiltrate of
ECD [23].
CLINICAL MANIFESTATIONS
The clinical presentation varies with the extent and distribution of involved sites. Most
patients have bony involvement at the time of diagnosis and the vast majority also have at
least one extra-osseous site of involvement. A subset of patients is asymptomatic, with
disease detected by imaging for unrelated conditions. Other patients with multisystemic
involvement may have a rapidly progressive clinical course.
In a literature review that included data from 259 patients with histologically-proven ECD, the
most common clinical presentations were bone pain (26 percent), neurologic findings (23
percent), diabetes insipidus (22 percent), and constitutional symptoms (20 percent) [3].
A retrospective case series of 37 patients reported involvement of the following sites, in

order of decreasing frequency [4]:
● Long bones (95 percent)

● Maxillary sinus, large vessels, and retroperitoneum (59 percent each)
● Heart (57 percent)
● Lungs (46 percent)
● Central nervous system (41 percent)
● Skin (27 percent)
● Pituitary gland and orbit (22 percent each)
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Another case series reported a similar pattern of clinical manifestations [24].
Bone — Symmetric diaphyseal and metaphyseal osteosclerosis of the lower extremities is

nearly always present in ECD but, in one study, pain was reported by only half of the patients
[25]. Bone pain is most commonly manifest as mild, persistent juxta-articular pain,
particularly in the lower extremities. Radiographically, the typical presentation is bilateral and
symmetric osteosclerosis of the long bones ( image 1 and image 2). Osteosclerosis of
the skull bones, particularly the facial bones, is also described [26]. The pattern of bony
involvement distinguishes ECD from Langerhans cell histiocytosis (LCH), in which proximal
limbs, pelvis, scapula, and skull involvement is more common.
Bone lesions that are not apparent on plain radiographs can be detected by bone
scintigraphy, computed tomography (CT), magnetic resonance imaging (MRI), or positron
emission tomography (PET). A retrospective series of 11 patients with biopsy-proven ECD
reported bilateral and symmetric osteosclerosis of the diaphysis of the long bones in 98
percent of bone lesions visible on conventional radiographs; 83 percent of the lesions also
involved the metaphysis [27]. Osteosclerosis was homogeneous in 35 percent and
heterogeneous in the others. Partial epiphyseal involvement with sparing of the subchondral
bone was also common, as were periostitis and endosteitis. Bone scintigraphy detects all
bone lesions visible on radiographs ( image 3). MRI detected all abnormalities noted by
plain radiograph and scintigraphy, and also depicted replacement of the normal fatty bone
marrow by heterogeneous signal intensity on T1- and T2-weighted spin-echo images (
image 4).
Cardiovascular — Cardiac involvement with ECD is a significant source of morbidity and

mortality and is present in the majority of patients. Cardiovascular involvement can include
valve abnormalities, rhythm or conduction defects, and periaortic fibrosis along the entire
course of the vessel. In a retrospective series of 72 patients with ECD, 31 percent of ECD-
related deaths were secondary to cardiac involvement, including myocardial infarction,
cardiomyopathy, and symptomatic valve disease [28].
In a series of 37 patients with ECD who were systematically screened with electrocardiogram
(ECG), cardiac MRI, and/or CT, 70 percent had abnormal heart imaging and 12 of 32 had an
abnormal ECG [29]. The most common finding was infiltration of the right heart (including
pseudo-tumor) in half of the patients; periaortic fibrosis, periarterial infiltration of the
coronary arteries, and pericardial thickening/effusion were also common. A study of 23
consecutive patients with ECD who underwent cardiac MRI corroborated these findings [30].
Ten patients had evidence of cardiac involvement by MRI (myocardial involvement in nine,
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pericardial involvement in nine). Heart disease was most commonly manifest as a posterior
right atrial pseudotumor; also common was infiltration of the right atrioventricular sulcus
with asymptomatic infiltration of the right coronary artery. Six patients had thoracic large-
vessel involvement together with cardiac lesions, whereas only one patient had thoracic
aorta involvement without cardiac disease.
Circumferential soft tissue sheathing of the thoracic and abdominal aorta ("coated aorta") is
visualized by CT in two-thirds of patients [28,31]. Renal artery hypertension may result from
involvement of the renal arteries, and coronary artery involvement may lead to myocardial
infarction [31-33].
Central nervous system (CNS) — Neurologic involvement is seen in up to half of cases

[3,25,26]. Infiltration can involve the entire CNS, including intra-axial and extra-axial
compartments. CNS involvement, whether symptomatic or asymptomatic, is an independent
predictor of a worse outcome in patients with ECD [34]. CNS manifestations are pleiotropic,
but neurodegenerative cerebellar disease is the most common neurologic complication (in
up to 20 percent of patients) [2].
Unilateral or bilateral infiltration of the orbits, manifest as exophthalmos, retro-orbital pain,

oculomotor palsies, or blindness, occurs in one-quarter of patients [35,36]. Neurologic
involvement may also be manifest as excessive thirst or urination, loss of libido, headache,
weakness, ataxia, dysarthria, exophthalmos, seizures, cognitive impairment, cranial nerve
palsies, or spinal cord compression [37,38]. Cerebellar involvement and other CNS mass
lesions are often multifocal. CNS lesions typically enhance with gadolinium on MRI [7]. ECD
can infiltrate the dura, in which case it may be confused with a meningioma [39]. Cognitive
impairments have been described in the absence of imaging abnormalities. In one study of
11 patients, volumetric MRI demonstrated diffuse reduction in cortical thickness and
subcortical gray matter compared with age-matched controls [40].
Pituitary involvement commonly manifests as central diabetes insipidus and other

endocrinopathies (eg, hyperprolactinemia, gonadotropin insufficiency, hypotestosteronism).
Pre-existing diabetes insipidus and endocrinopathies typically persist despite a radiographic
response to treatment, whereas diabetes insipidus rarely develops late in the disease course
[3].
Management of CNS involvement and associated endocrinopathies is discussed below. (See

'Management of complications' below.)
Other organs — Infiltration of nearly every organ system has been reported with ECD [7].
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● Kidney – Infiltration of perinephric tissues with a rind or mass-like lesion leading to

"hairy kidney" is common and may cause hydronephrosis, ureteral narrowing, and
slowly progressive renal insufficiency [7,41]. Acute renal insufficiency occurs less
commonly. Percutaneous nephrostomy tubes are often required to alleviate ureteral
obstruction. (See "Clinical manifestations and diagnosis of urinary tract obstruction and
hydronephrosis".)
● Pulmonary – One-quarter to one-half of patients have involvement of the pleura, lung

parenchyma, or both [42]. Pulmonary involvement may be asymptomatic or may be
manifest as dyspnea and/or cough [7]. Although dyspnea and progressive fibrosis
leading to respiratory failure can occur, in one large series pulmonary involvement was
not an independent predictor of decreased survival [43]. Plain films are often normal,
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 [44]. Fluid from bronchoalveolar
lavage may contain macrophages and foamy histiocytes [7]. 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, in contrast to LCH, which

frequently affects the skin [45]. One-third of patients have yellow plaques under the
skin (xanthelasma), most commonly on the eyelids [7]. 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 – 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 [46]. Liver involvement may be detected on radiographic staging or
manifest with abnormalities in transaminases, bilirubin, and/or alkaline phosphatase
[47]. Renal involvement may manifest as renal failure, renovascular hypertension, or
hydronephrosis [3].
Associated myeloid malignancies — There is an increased incidence of myeloid neoplasms

among patients with ECD.
An international retrospective study of 189 patients with biopsy-proven ECD reported that 10
percent had an overlapping myeloid neoplasm (eg, myeloproliferative neoplasm [MPN],
myelodysplastic syndrome [MDS], chronic myelomonocytic leukemia, or other MDS/MPN
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overlap syndrome) [48]. The incidence of myeloid malignancies is much higher than is
encountered in the general population. Compared with patients who had ECD alone, patients
with coexistent ECD and an associated myeloid neoplasm were older at the time of 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 'Patient follow-
up' below.)
INITIAL EVALUATION
Initial evaluation must document the diagnosis, define the extent and sites of disease, and
determine the patient's functional status. This includes clinical assessment of the central
nervous system (CNS), heart, and other organs; laboratory studies; and imaging.
Clinical — The medical history should assess the patient for constitutional symptoms (eg,
fever, night sweats, weight loss), bone pain, skin lesions (eg, xanthelasma, rash), and possible
organ involvement (eg, dyspnea, dysrhythmias, polydipsia/polyuria, gynecomastia,
decreased libido, double vision, neuropsychiatric findings). Physical examination should also
evaluate the patient for potential neurologic, cardiac, pulmonary, and cutaneous findings.
Clinical manifestations are described above. (See 'Clinical manifestations' above.)
The patient's functional status should be assessed by Eastern Cooperative Oncology Group
(ECOG) or Karnofsky Performance Status ( table 1).
Laboratory — Baseline laboratory studies should include:
● Complete blood count (CBC) with differential

● Serum electrolytes, liver and renal function tests, vitamin B12 and thiamine levels
● C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)
● Morning urine osmolality and morning serum cortisol; thyroid-stimulating hormone
(TSH) and free T4; prolactin, luteinizing hormone (LH), follicle-stimulating hormone
(FSH); testosterone (in males) (see "Clinical manifestations of hypopituitarism" and
"Evaluation of patients with polyuria")
● Electrocardiogram (ECG)
Imaging — We suggest the following studies at the time of diagnosis:
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● Computed tomography (CT) of chest, abdomen, and pelvis to include the entire aorta
(see 'Cardiovascular' above)
● Positron emission tomography (PET)/CT; although bone scintigraphy can demonstrate
the iconic radiologic features ( image 3), unlike PET, bone scintigraphy does not
assess extra-osseous involvement
● Magnetic resonance imaging (MRI) with contrast of the brain (with detailed examination
of the sella turcica) and heart
● Echocardiogram or radionuclide ventriculography
Pathology — An adequate tissue biopsy is required to establish the diagnosis of ECD,

distinguish it from other conditions, and identify mutations that may be amenable to
targeted therapies. The biopsy should demonstrate the characteristic histopathologic
findings of lipid-laden, "foamy" histiocytes with a distinctive immunophenotype in a proper
cellular and/or fibrotic milieu.
For many patients, a shave biopsy of a cutaneous lesion can yield adequate diagnostic
material and is the least invasive procedure. For other patients, biopsy of bone or another
organ may be required. Regardless of the tissue source, we suggest multiple samples
because histologic involvement may vary from field to field. It is important to 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 that can identify
BRAF V600E and other relevant mutations (eg, NRAS, KRAS, ARAF, PIK3CA, MAP2K1, ALK). If a
mutation is not detected, we suggest repeat testing using another involved site and/or
genotyping modality. (See 'Pathogenesis' above.)
Involved tissues are infiltrated by sheets of lipid-laden (xanthomatous) histiocytes that

typically have small nuclei and foamy cytoplasm. Multinucleated giant histiocytes (Touton
cells) with a central ring of nuclei are commonly seen and there may be interspersed
inflammatory cells and fibrosis ( picture 1 and picture 2 and picture 3) [49,50].
Reactive small lymphocytes, plasma cells, and neutrophils are frequently admixed.
Histopathologic findings may be highly variable, including absence of classic foamy
histiocytic infiltrate, nonspecific inflammation admixed with fibrosis, or fibrosis alone with
scant histiocytes [14].
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 (actin-binding protein) [2,51]. ECD cells do not express the
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Langerhans cell markers, CD1a or langerin ( picture 4 and picture 1); Birbeck granules
(an ultrastructural finding on electron microscopy in Langerhans cell histiocytosis) are absent
and S100 is rarely positive [7].
DIAGNOSIS
ECD is a rare disease with protean manifestations that is often challenging to diagnose;
delayed or erroneous diagnosis is common.
ECD may be suspected in a patient with unexplained bone pain (especially of distal
extremities) in association with cutaneous, cardiac, or neurologic findings and abnormal
imaging of bone [7,50,52]. (See 'Clinical manifestations' above.)
Diagnosis of ECD is based on identifying the distinctive histopathologic findings in an

appropriate clinical and radiologic context [7]. Lesions typically demonstrate foamy or lipid-
laden histiocytes admixed with reactive inflammatory cells and/or fibrosis. Symmetric
osteosclerosis of the legs is nearly always present. Further description of the histopathology,
immunohistochemical, and radiologic features that distinguish ECD from other histiocytoses
are described in the differential diagnosis. (See 'Pathology' above and 'Differential diagnosis'
below.)
DIFFERENTIAL DIAGNOSIS
ECD must be distinguished from other histiocytic and dendritic cell disorders, metastatic
solid or hematopoietic neoplasms, and hemophagocytic lymphohistiocytosis/macrophage
activation syndromes.
● Langerhans cell histiocytosis – Langerhans cell histiocytosis (LCH) and ECD are both
histiocytic diseases that can involve multiple sites, most commonly bones. Skin
involvement is more common in LCH. The two entities can usually be distinguished by
morphologic and immunohistochemical evaluation. ECD tumor cells lack central nuclear
grooves and Birbeck granules typical of LCH cells, and unlike LCH, they do not express
CD1a or S100 [53]. Cases of concomitant LCH and ECD (ie, mixed histiocytosis) have
been described [54]. (See "Clinical manifestations, pathologic features, and diagnosis of
Langerhans cell histiocytosis".)
● Paget's disease and POEMS syndrome – The osteosclerotic lesions of bone in ECD can
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be confused for a variety of metabolic bone disorders, including Paget's disease and
the POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal
protein, skin changes), the latter of which also causes endocrine abnormalities. While
the bone abnormalities of ECD often 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".)
● Hemophagocytic lymphohistiocytosis – Hemophagocytic lymphohistiocytosis (HLH)

and the related macrophage activation syndrome are systemic disorders that
demonstrate tissue infiltration by non-neoplastic histiocytes. Unlike ECD, these
disorders demonstrate prominent hemophagocytic activity in the biopsy and are also
characterized by a number of other findings including fever, hypertriglyceridemia,
hypofibrinogenemia, hyperferritinemia, and bicytopenia. (See "Clinical features and
diagnosis of hemophagocytic lymphohistiocytosis", section on 'Laboratory and
radiographic abnormalities'.)
● Juvenile xanthogranuloma (JXG) – Juvenile xanthogranuloma (JXG) is a non-malignant

proliferative disorder of histiocytic cells of the dermal dendrocyte phenotype. JXG
belongs to the broad group of non-Langerhans cell histiocytoses and is typically a
disorder of early childhood; by contrast, ECD typically occurs in middle-age or older
adults. 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.
Histologically and immunophenotypically, JXG is indistinguishable from ECD. JXG
generally follows a benign course with spontaneous resolution over a period of a few
years. Less commonly, skin lesions can be multiple ( picture 6). Extracutaneous or
systemic forms (brain, lung, kidney, spleen, liver, bone marrow, and retro-orbital
tumors) are exceedingly rare and can be associated with considerable morbidity. (See
"Juvenile xanthogranuloma (JXG)".)
● Rosai-Dorfman disease – Rosai-Dorfman disease (RDD, sinus histiocytosis with massive

lymphadenopathy) is a macrophage-related disorder that most often presents as a
systemic disorder involving lymph nodes and other organs [55-57] or rarely can be
limited to the skin [58,59]. Unlike ECD, skin lesions are firm, indurated papules.
Although the pathologic cells in RDD are the macrophages (CD14+, CD1a-, S100+/-,
CD68+), RDD is histologically distinct from the other histiocytic diseases because the
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macrophages have normal-appearing lymphocytes residing in the macrophage

cytoplasm (emperipolesis) [60]. (See "Peripheral lymphadenopathy in children:
Etiology", section on 'Rosai-Dorfman disease'.)
● Other disorders
• Central nervous system involvement can be confused for metastatic solid or

hematopoietic neoplasms or primary central nervous system tumors (including
meningioma). (See 'Central nervous system (CNS)' above.)
• Cutaneous involvement by ECD can mimic vasculitis, cutaneous lymphoma, or

cutaneous involvement with LCH. (See 'Other organs' above.)
• Abdominal involvement is frequently confusing with primary or secondary

retroperitoneal fibrosis, sclerosing mesenteritis, or a variety of retroperitoneal
neoplasms including lymphoma and germ cell tumor. (See 'Other organs' 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
Not all patients with ECD require treatment at the time of diagnosis. Treatment is typically
reserved for patients with symptoms or those with evidence of central nervous system (CNS)
involvement or organ dysfunction, as discussed below. (See 'Symptomatic patients' below.)
Treatment in the context of a clinical trial is recommended, whenever possible. (See 'Clinical
trials' below.)
Prior to treatment, the patient should be evaluated with history and physical examination,
laboratory testing, and imaging, as described above. (See 'Initial evaluation' above.)
Asymptomatic patients — For asymptomatic patients who have no evidence of organ

dysfunction or CNS involvement (either symptomatic or asymptomatic), we suggest a period
of observation rather than immediate treatment. For asymptomatic patients with evidence of
CNS involvement or organ dysfunction, we suggest management as described for
symptomatic patients. (See 'Symptomatic patients' below.)
Asymptomatic or minimally symptomatic disease is uncommon, but some cases of ECD
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follow an indolent clinical course. All patients should be thoroughly evaluated to detect
subclinical CNS or organ involvement, as described above. (See 'Initial evaluation' above.)
Because there is no known cure for ECD and it is uncertain if targeted therapies alter the
natural history of ECD, we suggest a period of observation in asymptomatic individuals to
assess the trajectory of the illness and avoid adverse effects of treatment. 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 the patient with ECD is described below. (See 'Patient follow-up' below.)
Symptomatic patients — For patients with symptoms related to ECD and/or evidence of

organ dysfunction or CNS involvement (either symptomatic or asymptomatic), we suggest
treatment rather than observation alone. No treatment is optimal for all patients with
symptomatic ECD and we encourage enrollment in a clinical trial, when possible.
Outside of a clinical trial, our approach is to initially treat with a targeted therapy (informed
by the underlying mutation) rather than interferon alfa, glucocorticoids, or systemic
chemotherapy, based on the favorable balance of benefit and toxicity.
Our approach follows:
● BRAF – For patients with a BRAF V600E mutation, we suggest initial treatment with
vemurafenib (BRAF inhibitor). (See 'BRAF inhibition' below.)
For patients who do not respond to vemurafenib, we suggest enrollment in a clinical

trial, treatment with another BRAF inhibitor (if available) or MEK inhibitor, or interferon
alfa.
For patients who are responding to vemurafenib but are having substantial treatment-
related toxicity, we suggest dose reduction or a brief treatment interruption to lessen
adverse effects.
● Other mutations – For patients with mutations that affect other signaling molecules
(eg, NRAS, KRAS, ARAF, PIK3CA, MAP2K1, and ALK), we suggest initial treatment with
cobimetinib (or another MEK inhibitor). (See 'MEK inhibition' below.)
For patients who do not respond to or are intolerant of an MEK inhibitor, we suggest an
alternate MEK inhibitor (if available) or interferon alfa.
● No mutation detected – For patients with no detected mutations, we suggest a repeat
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biopsy from an alternate site or using an alternate genotyping modality. If no mutation

is detected with repeat biopsy, we suggest initial treatment with interferon alfa rather
than a targeted therapy or systemic chemotherapy. We suggest not treating patients
initially with systemic chemotherapy. (See 'Interferon alfa' below.)
There are few prospective therapeutic studies and no randomized clinical trials for ECD.
Outcomes data come primarily from retrospective case series, as described below. Our
approach is generally consistent with that proposed by an international panel of physicians
with expertise in ECD and society guidelines [7]. (See 'Society guideline links' below.)
TARGETED AGENTS
Targeted agents are available that are active against many of the mutations that are found in
ECD.
BRAF inhibition — Vemurafenib is a potent inhibitor of the kinase domain of mutant BRAF

and has activity in ECD with activating mutations in BRAF (eg, V600E) [61-64]. Vemurafenib is
approved by the US Food and Drug Administration (FDA) and the European Medicines Agency
(EMA) for treatment of ECD with BRAF V600E mutation [64,65].
For patients with BRAF V600E, we suggest initial treatment with vemurafenib 480 mg twice
daily by mouth; some experts suggest initial treatment with 960 mg twice daily. Regardless of
the starting dose, the dose may require adjustment due to toxicity [64]. Treatment with
vemurafenib should continue until disease progression or development of unacceptable
toxicity.
The most common (>50 percent) adverse reactions are arthralgia, alopecia, fatigue, rash, skin
papilloma, and electrocardiogram QT interval prolongation [64]. The most common serious
adverse reactions (grade ≥3, seen in ≥10 percent) were squamous cell skin cancer,
hypertension, maculopapular rash, and arthralgia. Concomitant administration with strong
CYP3A4 inhibitors or inducers ( table 2) should be avoided, if possible.
FDA approval was based on a study of 22 patients with BRAF V600 mutation positive ECD, 15
of whom had received prior systemic therapies [64]. Treatment with vemurafenib 960 mg
twice daily achieved 55 percent overall response (OR; 5 percent with complete response [CR]).
All patients required dose reduction to either 720 mg or 480 mg twice daily, but efficacy was
maintained after dose reduction in responding patients. In another study, vemurafenib
demonstrated at least a partial response (PR) in 6 of 18 patients with BRAF V600E positive
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ECD or Langerhans cell histiocytosis (LCH), and the remainder had stable disease [63]. In a
study that evaluated treatment interruption in more than 50 patients taking vemurafenib or
dabrafenib (an alternative BRAF inhibitor), most patients relapsed after BRAF inhibitor
interruption, but all patients improved after the treatment was resumed [66].
Dabrafenib is a kinase inhibitor that is active against BRAF V600E and other kinase mutations
in melanoma but is not currently approved for treatment of ECD [67]. 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 [68].
MEK inhibition — Inhibitors of the MAPK/extracellular signal regulated kinase (MEK)

pathway are active in melanoma that is resistant to BRAF inhibitors and they hold promise
for treatment of ECD with mutations of other signaling molecules (eg, NRAS, PIK3CA, or the
RAS-PI3K-AKT signaling pathway).
There is no consensus regarding a preferred MEK inhibitor or regimen. Cobimetinib has been
granted breakthrough therapy designation for ECD. Trametinib has been approved by the
FDA and EMA for treatment of melanoma, but is not labeled for ECD. Limited data are
available regarding treatment of ECD with MEK inhibitors. We consider treatment with a MEK
inhibitor reasonable for patients who have not responded to or progressed on BRAF
inhibitors, have mutations that predict sensitivity to a MEK inhibitor, or have wild-type BRAF.
The following are studies of MEK inhibitors in ECD:
● A study of 18 patients with histiocytic neoplasms (12 with ECD) reported that
cobimetinib was effective independent of genotype (including mutations of ARAF, BRAF,
RAF1, NRAS, KRAS, MEK1, and MEK2) [69]. The rate of OR, measured by positron emission
tomography (PET), was 89 percent, with 72 percent CR and 17 percent PR. At one year,
100 percent of responses were ongoing and 94 percent remained progression-free.
● In a case report of relapsed ECD with an activating KRAS Q61H mutation, trametinib plus
dabrafenib (BRAF inhibitor) resulted in an excellent response [68].
● Another case report demonstrated efficacy of cobimetinib in ECD with wild-type BRAF
[70].
OTHER TREATMENTS
Interferon alfa — Interferon alfa is our preferred treatment for patients with newly
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diagnosed, symptomatic ECD who are not eligible, able to tolerate, or responsive to a
targeted agent. Either conventional or pegylated interferon alfa may be used. The optimal
regimen and duration of treatment are not defined, but patients are usually treated until
disease progression or intolerable side effects occur. The risk-benefit ratio of interferon
should be revisited periodically in patients who are on treatment for more than two years.
We suggest beginning pegylated interferon alfa at 135 micrograms weekly, and we titrate
the dose upward to a maximum dose of 200 micrograms weekly as tolerated, if patients are
not responding to the initial dose. Alternatively, conventional interferon alfa may be started
at 3 million international units (MIU) three times a week and the dose is titrated upwards (to
a maximum dose of 9 MIU three times a week) as tolerated, if patients are not responding to
the initial dose. Patients on interferon should be monitored for infection, liver function
abnormalities, thyroid abnormalities, and depression. (See "Neuropsychiatric side effects
associated with interferon-alfa plus ribavirin therapy: Treatment and prevention".)
In a series of 53 patients with ECD, 87 percent received interferon alfa for a median of 19
months [34]. Doses ranged from 3 MIU to 9 MIU three times weekly with conventional
interferon, or 135 to 200 micrograms weekly with pegylated interferon. The one-year and
five-year survival rates were 96 and 68 percent, respectively. In this study, treatment with
interferon alfa was an independent predictor of improved survival (hazard ratio 0.32; 95% CI
0.14-0.70), while central nervous system (CNS) involvement was an independent predictor of
inferior survival.
Glucocorticoids — Glucocorticoids have demonstrated clinical activity in ECD, but have not

demonstrated a survival benefit [34]. Glucocorticoids are generally reserved for patients who
cannot tolerate more aggressive systemic therapies or who have very mild symptoms. For
such patients, we consider prednisone 60 mg daily for two to four weeks followed by a slow
taper over three to six months. Patients on long-term glucocorticoids should receive
prophylaxis for Pneumocystis jirovecii (previously Pneumocystis carinii) infection and may
benefit from prophylaxis for gastrointestinal ulcers. (See "Treatment and prevention of
Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis' and "Major side
effects of systemic glucocorticoids", section on 'Gastrointestinal effects'.)
Other systemic therapies — Treatment with systemic chemotherapy or an alternate

biologic agent should not be considered for initial therapy of ECD. We consider these agents
appropriate only for patients who fail to respond or develop intolerable side effects to
targeted agents and/or interferon alfa. (See 'Management' above.)
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It is difficult to judge the relative efficacy of various systemic agents for ECD because most
reports are restricted to case reports or small case series. We consider the utility of systemic
chemotherapy in ECD to be limited. We generally reserve cytotoxic chemotherapy for
medically fit patients (eg, Eastern Cooperative Oncology Group [ECOG] performance status
≤2) ( table 1) with substantial systemic disease. For other patients, we favor use of biologic
agents.
● Cytotoxic chemotherapy – Cladribine is our preferred cytotoxic chemotherapy for ECD,

based on case reports and our own clinical experience [71,72]. The largest reported
experience with cladribine included 21 patients with ECD (9 treated in front-line, and 12
in later lines of treatment) [72]. The overall clinical response rate was 52 percent,
including 6 percent complete response (CR) and 46 percent partial response (PR);
median duration of response was 9 months. Cyclophosphamide plus prednisolone led
to improved pulmonary findings in a patient who did not previously respond to
prednisolone alone [73].
● Methotrexate – Low dose oral methotrexate may have activity in ECD [74]. High dose
systemic methotrexate with leucovorin rescue may be useful in ECD with CNS
involvement (given the ability of methotrexate to cross the blood brain barrier),
although this approach has not been studied.
● IL-1-receptor antagonist – IL-1-receptor antagonist (IL-1RA) production is stimulated

by interferon alfa, and there are case reports of recombinant IL-1RA (anakinra,
canakinumab) inducing responses in a small group of patients who could not tolerate
interferon alfa [75-81].
● Sirolimus – In an open-label trial of sirolimus plus prednisone in 10 patients with ECD,

six patients had a partial response, two had stable disease, and two had progressive
disease [82]. We offer sirolimus when the agents mentioned above have not proven
efficacious or are poorly tolerated.
● Infliximab – A report described clinical responses to infliximab in two patients with

cardiac involvement [83].
● ALK inhibitors – ALK rearrangements and recurrent kinase fusions of ALK and NTRK1
have been described in ECD [14]. There is limited clinical experience with these agents
for ECD. Use of ALK inhibitors for lung cancer is described separately. (See "Anaplastic
lymphoma kinase (ALK) fusion oncogene positive non-small cell lung cancer", section
on 'First-line treatment'.)
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● Imatinib – Imatinib has activity for ECD, but its role is unclear now that effective kinase
inhibitors (eg, vemurafenib) are available [84,85].
Localized therapies — Surgery and radiation therapy (RT) have limited roles in the
management of ECD and are used primarily to manage local and/or mechanical
complications.
Surgery has no clear role in the management of ECD except to address mechanical
complications, such as ureteral obstruction or repair/replacement of cardiac valves. RT has
been used for local palliation, but ECD seems to be much less responsive to RT than
Langerhans cell histiocytosis (LCH), and lack of response or in-field recurrence is fairly
common [86]. The optimal dose and field are unknown. We generally use doses appropriate
for aggressive lymphomas (40 to 50 Gy) when feasible, rather than the much lower doses
utilized for LCH.
PATIENT FOLLOW-UP
There is no consensus regarding an optimal schedule or protocol for follow-up or monitoring

response to therapy. We consider clinical evaluation more useful than routine repeated
imaging, which may be discordant with symptoms.
Patients should be clinically assessed a minimum of every three to six months or more
frequently as symptoms and organ dysfunction require. Follow-up visits should seek
evidence of central nervous system (CNS) and organ involvement. Laboratory studies should
include a complete blood count and differential and routine serum chemistry studies. We
suggest routine annual electrocardiogram (ECG) and echocardiogram, even if no heart
involvement was detected at the time of diagnosis. The frequency and mode of imaging is
dictated by baseline disease status, organ involvement, and requirement for ongoing
treatment. As an example, affected organs might be imaged every three to six months until
stability is documented; the interval between studies should be increased as warranted by
the clinical status. Because of an increased incidence of myeloid neoplasms in patients with
ECD, bone marrow examination or other evaluation should be considered in patients with
symptoms related to unexplained cytopenias or other hematologic abnormalities [48].
MANAGEMENT OF COMPLICATIONS
Complications of ECD may include mechanical compression of organs, and involvement of
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the central nervous system (CNS) may cause a variety of endocrinopathies. (See 'Clinical
manifestations' above.)
Patients with ECD are at risk of developing potentially life-threatening complications due to
the compression of normal structures (eg, cardiovascular involvement, ureteral
compression). Mechanical measures such as heart valve replacement or percutaneous
nephrostomy may also be necessary in selected patients.
CNS involvement may be subtle and difficult to recognize [38]. There is no consensus
regarding optimal management of CNS involvement, but options include surgical resection,
radiation therapy, high dose steroids, targeted agents, and other systemic treatments. A high
percentage of patients with ECD will develop diabetes insipidus (DI) and other
endocrinopathies due to hypopituitarism. Regardless of other therapies, endocrinopathies
such as DI should be corrected. Pre-existing DI and endocrinopathies typically persist, even
after radiographic regression of disease. (See "Clinical manifestations of hypopituitarism"
and "Evaluation of patients with polyuria".)
PROGNOSIS
There is no known cure for ECD and historically the prognosis has been poor. However, the
long-term effects of targeted agents are not well-defined. Case series of patients treated with
interferon therapy have reported five-year overall survival rates of approximately 70 percent
[34]. In the same series, involvement of the central nervous system was associated with
adverse outcomes.
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
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dendritic cell neoplasms".)
SUMMARY AND RECOMMENDATIONS
● Erdheim-Chester disease (ECD) is a rare non-Langerhans histiocyte disorder that is most

commonly characterized by multifocal osteosclerotic lesions of the long bones
demonstrating sheets of foamy histiocytes on biopsy, with or without histiocytic
infiltration of extraskeletal tissues.
● 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.)
● The clinical presentation varies with the extent and distribution of involved sites. Most
patients with ECD have osseous involvement and at least one non-osseous site of
involvement (eg, heart, central nervous system [CNS], skin, other organs). Occasional
patients are asymptomatic, but most have multisystemic involvement with a
progressive clinical course. (See 'Clinical manifestations' above.)
● Evaluation requires a history and physical examination, baseline laboratory studies, and
imaging to assess the extent of organ involvement. (See 'Initial evaluation' above.)
● Diagnosis requires a characteristic histopathologic appearance in an appropriate

clinical and radiologic context. Lesions typically demonstrate foamy or lipid-laden
histiocytes admixed with reactive inflammatory cells and/or fibrosis. The biopsy
specimen should provide sufficient material to enable mutation testing and distinguish
ECD from other histiocytic and dendritic cell disorders, metastatic solid or
hematopoietic neoplasms, and other conditions. (See 'Diagnosis' above and 'Differential
diagnosis' above.)
● Asymptomatic – Not all patients with ECD require treatment at the time of diagnosis.
For the occasional asymptomatic patient who has no evidence of organ dysfunction or
CNS involvement (either symptomatic or asymptomatic), we suggest a period of
observation rather than immediate treatment. (See 'Asymptomatic patients' above.)
● Symptomatic – For patients with symptoms related to ECD and/or evidence of organ
dysfunction or CNS involvement (either symptomatic or asymptomatic), we suggest
treatment with a targeted therapy (selected according to the underlying mutation)
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rather than interferon alfa, glucocorticoids, or systemic chemotherapy, based on the

favorable balance of benefit and toxicity (Grade 2C). (See 'Symptomatic patients' above.)
• BRAF – For patients with a BRAF V600E mutation, we suggest initial treatment with
vemurafenib (BRAF inhibitor). (See 'BRAF inhibition' above.)
• Other mutations – For patients with mutations that affect other signaling
molecules (eg, NRAS, KRAS, ARAF, PIK3CA, MAP2K1, and ALK), we suggest initial
treatment with an MEK inhibitor (eg, cobimetinib). (See 'MEK inhibition' above.)
• No mutation detected – For patients with no detected mutations, we suggest a

repeat biopsy from an alternate site or using an alternate genotyping modality. If no
mutation is detected with repeat biopsy, we suggest initial treatment with interferon
alfa rather than a targeted therapy or systemic chemotherapy, based on the balance
of benefit and toxicity (Grade 2C). We suggest not treating patients initially with
systemic chemotherapy. (See 'Interferon alfa' above.)
● For patients who do not respond to or are intolerant to initial treatment, management
suggestions are discussed above. (See 'Symptomatic patients' above.)
● The schedule and protocol for follow-up and monitoring response to therapy are
discussed above. (See 'Patient follow-up' above.)
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Topic 13942 Version 34.0
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GRAPHICS
Osteosclerosis and osteolysis in Erdheim-Chester

disease
X-ray of left femur revealed diffuse osteosclerosis with focal osteolysis

in the diaphysis and metaphysis of the left distal femur.
Reproduced with permission from: Kim MS, Kim CH, Choi SJ, et al. Erdheim-Chester
disease. Ann Dermatol 2010; 22:439. Copyright © 2010 Korean Dermatological
Association.
Graphic 77396 Version 3.0
27 of 40 12/13/2021, 8:46 PM
Computed tomography imaging of the leg in Erdheim-

Chester disease
Computed tomography imaging of the left leg in a 48-year-old male with

Erdheim-Chester disease shows an expansile lytic lesion in the distal tibia with
lobulated endosteal scalloping, and multiple foci of calcified matrix. There is
mild subcutaneous soft tissue stranding anteriorly and medially. Within the
fibula, the marrow also appears abnormal, but there is no endosteal
scalloping.
Kindly provided by German Pihan, MD, Department of Pathology, Beth Israel Deaconess Medical
Center, Boston, MA.
28 of 40 12/13/2021, 8:46 PM
Multiple areas of increased uptake on bone scan in

Erdheim-Chester disease
Bone scan showed multiple increased uptakes in both maxillae,

mandible, right temporal bone, both radii, both ulnae, both distal
femurs, both proximal and distal tibiae, both calcanei, left second rib,
right ninth rib, both tenth ribs, left posterior iliac crest and right
acetabulum.
Reproduced with permission from: Kim MS, Kim CH, Choi SJ, et al. Erdheim-Chester
disease. Ann Dermatol 2010; 22:439. Copyright © 2010 Korean Dermatological
Association.
29 of 40 12/13/2021, 8:46 PM
Magnetic resonance imaging of the leg in Erdheim-

Chester disease
(A) T1.
(B) T2.
Magnetic resonance imaging of the left leg in a 48-year-old male with

Erdheim-Chester disease shows abnormal signaling in the distal tibia with
surrounding soft tissue edema. There is a heterogeneous signal in the bone
marrow on T1 and T2 with areas of patchy enhancement post-gadolinium.
The bone marrow signal abnormality extends more proximally than the
lesion itself. There is a mild periosteal reaction, but no overt abnormality of
true tumor extending out from the bone.
Kindly provided by German Pihan, MD, Department of Pathology, Beth Israel Deaconess
Medical Center, Boston, MA.
30 of 40 12/13/2021, 8:46 PM
Karnofsky and Eastern Cooperative Oncology Group (ECOG) performance

status measures
Karnofsky ECOG
Score Definition Score Definition
100 Normal, no complaints, no evidence of 0 Fully active; no performance restrictions

disease
1 Strenuous physical activity restricted;
90 Able to carry on normal activity, minor fully ambulatory and able to carry out
signs or symptoms of disease light work
80 Normal activity with effort, some signs 2 Capable of all self-care but unable to
or symptoms of disease carry out any work activities; up and
about >50% of waking hours
70 Cares for self, unable to carry on normal
activity or to do active work 3 Capable of only limited self-care;
confined to bed or chair >50% of waking
60 Requires occasional assistance but is
hours
able to care for most needs
4 Completely disabled; cannot carry out
50 Requires considerable assistance and
any self-care; totally confined to bed or
frequent medical care
chair
40 Disabled, requires special care and
5 Dead
assistance
30 Severely disabled, hospitalization is

indicated, although death is not
imminent
20 Hospitalization is necessary, very sick,

active supportive treatment necessary
10 Moribund, fatal processes progressing

rapidly
0 Dead
31 of 40 12/13/2021, 8:46 PM
Bone curettage samples in Erdheim-Chester disease
Bone curettage samples (panels A and B) from a patient with Erdheim-Chester

disease demonstrate tissue infiltration by sheets of foamy (xanthomatous)
histiocytes with interspersed inflammatory cells and multinucleate giant cells
(Touton cells). The histiocytes express the histiocyte markers CD68 (panel C)
and CD163 (panel D), but do not express CD1a (panel E) or Langerin (panel F).
Kindly provided by German Pihan, MD, Department of Pathology, Beth Israel Deaconess Medical
Center, Boston, MA.
32 of 40 12/13/2021, 8:46 PM
Erdheim-Chester disease lesion biopsy
The figure demonstrates a representative hematoxylin/eosin-stained

ECD lesion biopsy sample from a retroperitoneal, perinephric
infiltrate (400x magnification). It shows the bland histiocytic infiltrate
with foamy (xanthomatous) cytoplasm and interspersed
inflammatory cells.
Reproduced with permission of the American Society of Hematology, from Allen CE,
McClain KL, Erdheim-Chester: beyond the lesion, Blood 2011; 117:2745, Copyright ©
2011; permission conveyed through Copyright Clearance Center, Inc.
33 of 40 12/13/2021, 8:46 PM
Skin biopsy in Erdheim-Chester disease
(A) Left temporal lesion showed dermal infiltration of foamy histiocytes with giant cells
(H&E, x100).
(B) Scalp lesion also showed infiltrating histiocytes and multiple Touton-type giant cells
with dermal fibrosis (H&E, x100).
Reproduced with permission from: Kim MS, Kim CH, Choi SJ, et al. Erdheim-Chester disease. Ann Dermatol
2010; 22:439. Copyright © 2010 Korean Dermatological Association.
34 of 40 12/13/2021, 8:46 PM
Infiltration of CD68 positive, S100 negative histiocytes in Erdheim-

Chester disease
(A) The biopsy obtained from perirenal tissue showed an infiltration of numerous
histiocytes (H&E, x100). The histiocytes were CD68-positive (B: x100) and S100-negative
(C: x100).
Reproduced with permission from: Kim MS, Kim CH, Choi SJ, et al. Erdheim-Chester disease. Ann Dermatol
2010; 22:439. Copyright © 2010 Korean Dermatological Association.
35 of 40 12/13/2021, 8:46 PM
Juvenile xanthogranuloma
Typical solitary lesion on the abdomen of an infant.
Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights

reserved.
36 of 40 12/13/2021, 8:46 PM
Juvenile xanthogranuloma
Multiple scalp lesions in a young child.
Reproduced with permission from: www.visualdx.com. Copyright VisualDx. All rights

reserved.
37 of 40 12/13/2021, 8:46 PM
Cytochrome P450 3A (including 3A4) inhibitors and inducers
Strong inhibitors Moderate Strong inducers Moderate inducers

Atazanavir
inhibitors Apalutamide Bexarotene
Ceritinib Amiodarone* Carbamazepine Bosentan
Clarithromycin Aprepitant Enzalutamide Cenobamate
Cobicistat and Berotralstat Fosphenytoin Dabrafenib

cobicistat- Cimetidine* Lumacaftor Dexamethasone ¶
containing
Conivaptan Lumacaftor- Dipyrone
coformulations
Crizotinib ivacaftor
Darunavir Efavirenz
Cyclosporine* Mitotane
Idelalisib Elagolix, estradiol,
Diltiazem Phenobarbital and norethindrone
Indinavir
therapy pack Δ
Duvelisib Phenytoin
Itraconazole
Eslicarbazepine
Dronedarone Primidone
Ketoconazole
Etravirine
Erythromycin Rifampin
Lonafarnib
(rifampicin) Lorlatinib
Fedratinib
Lopinavir
Modafinil
Fluconazole
Mifepristone
Nafcillin
Fosamprenavir
Nefazodone
Pexidartinib
Fosaprepitant*
Nelfinavir
Rifabutin
Fosnetupitant-
Ombitasvir-
palonosetron Rifapentine
paritaprevir-
ritonavir Grapefruit juice Sotorasib
Ombitasvir- Imatinib St. John's wort

paritaprevir-
Isavuconazole
ritonavir plus
(isavuconazonium
dasabuvir
sulfate)
Posaconazole
Lefamulin
Ritonavir and
Letermovir
ritonavir-containing
coformulations Netupitant
Saquinavir Nilotinib
Telithromycin Ribociclib
Tucatinib Schisandra
38 of 40 12/13/2021, 8:46 PM
Voriconazole Verapamil
▪ For drug interaction purposes, the inhibitors and inducers of CYP3A metabolism listed above can
alter serum concentrations of drugs that are dependent upon the CYP3A subfamily of liver
enzymes, including CYP3A4, for elimination or activation.
▪ These classifications are based upon US Food and Drug Administration (FDA) guidance. [1,2] Other
sources may use a different classification system resulting in some agents being classified
differently.
▪ Data are for systemic drug forms. Degree of inhibition or induction may be altered by dose,
method, and timing of administration.
▪ Weak inhibitors and inducers are not listed in this table with exception of a few examples. Clinically
significant interactions can occasionally occur due to weak inhibitors and inducers (eg, target drug
is highly dependent on CYP3A4 metabolism and has a narrow therapeutic index). Accordingly,
specific interactions should be checked using a drug interaction program such as the Lexicomp
drug interactions program included within UpToDate.
▪ Refer to UpToDate topics on specific agents and indications for further details.
* Classified as a weak inhibitor of CYP3A4 according to FDA system. [1]
¶ Classified as a weak inducer of CYP3A4 according to FDA system. [1]
Δ The fixed-dose combination therapy pack taken in the approved regimen has moderate CYP3A4

induction effects. When elagolix is used as a single agent, it is a weak CYP3A4 inducer. Norethindrone
and estradiol are not CYP3A4 inducers.
Data from: Lexicomp Online (Lexi-Interact). Copyright © 1978-2021 Lexicomp, Inc. All Rights Reserved.
References:
1. Clinical Drug Interaction Studies — Cytochrome P450 Enzyme- and Transporter-Mediated Drug Interactions Guidance
for Industry (January 2020) available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents
/clinical-drug-interaction-studies-cytochrome-p450-enzyme-and-transporter-mediated-drug-interactions.
2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers.
Available at: FDA.gov website.
39 of 40 12/13/2021, 8:46 PM
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Official reprint from UpToDate®

Erdheim-Chester disease (ECD) is a rare non-Langerhans histiocytic multisystem disorder.

Histiocytic disorders are thought to be derived from mononuclear phagocytic cells

The epidemiology, clinical manifestations, pathologic features, diagnosis, and management

SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC

● (See "COVID-19: Cancer screening, diagnosis, post-treatment surveillance in uninfected

ECD is caused by clonal proliferation of myeloid progenitor cells, as demonstrated by

ECD histiocytes express a pattern of proinflammatory cytokines and chemokines that

A retrospective case series of 37 patients reported involvement of the following sites, in

● Long bones (95 percent)

Another case series reported a similar pattern of clinical manifestations [24].

Bone — Symmetric diaphyseal and metaphyseal osteosclerosis of the lower extremities is

Cardiovascular — Cardiac involvement with ECD is a significant source of morbidity and

Central nervous system (CNS) — Neurologic involvement is seen in up to half of cases

Unilateral or bilateral infiltration of the orbits, manifest as exophthalmos, retro-orbital pain,

Pituitary involvement commonly manifests as central diabetes insipidus and other

Management of CNS involvement and associated endocrinopathies is discussed below. (See

● Kidney – Infiltration of perinephric tissues with a rind or mass-like lesion leading to

● Pulmonary – One-quarter to one-half of patients have involvement of the pleura, lung

● Skin – Skin is involved in one-quarter of cases of ECD, in contrast to LCH, which

Associated myeloid malignancies — There is an increased incidence of myeloid neoplasms

Laboratory — Baseline laboratory studies should include:

● Complete blood count (CBC) with differential

Imaging — We suggest the following studies at the time of diagnosis:

Pathology — An adequate tissue biopsy is required to establish the diagnosis of ECD,

Involved tissues are infiltrated by sheets of lipid-laden (xanthomatous) histiocytes that

Diagnosis of ECD is based on identifying the distinctive histopathologic findings in an

● Hemophagocytic lymphohistiocytosis – Hemophagocytic lymphohistiocytosis (HLH)

● Juvenile xanthogranuloma (JXG) – Juvenile xanthogranuloma (JXG) is a non-malignant

● Rosai-Dorfman disease – Rosai-Dorfman disease (RDD, sinus histiocytosis with massive

macrophages have normal-appearing lymphocytes residing in the macrophage

• Central nervous system involvement can be confused for metastatic solid or

• Cutaneous involvement by ECD can mimic vasculitis, cutaneous lymphoma, or

• Abdominal involvement is frequently confusing with primary or secondary

• Cardiac involvement can mimic other infiltrative cardiovascular processes, including

Asymptomatic patients — For asymptomatic patients who have no evidence of organ

Asymptomatic or minimally symptomatic disease is uncommon, but some cases of ECD

Symptomatic patients — For patients with symptoms related to ECD and/or evidence of

Our approach follows:

For patients who do not respond to vemurafenib, we suggest enrollment in a clinical

● No mutation detected – For patients with no detected mutations, we suggest a repeat

biopsy from an alternate site or using an alternate genotyping modality. If no mutation

BRAF inhibition — Vemurafenib is a potent inhibitor of the kinase domain of mutant BRAF

MEK inhibition — Inhibitors of the MAPK/extracellular signal regulated kinase (MEK)

The following are studies of MEK inhibitors in ECD:

Glucocorticoids — Glucocorticoids have demonstrated clinical activity in ECD, but have not

Other systemic therapies — Treatment with systemic chemotherapy or an alternate

● Cytotoxic chemotherapy – Cladribine is our preferred cytotoxic chemotherapy for ECD,

● IL-1-receptor antagonist – IL-1-receptor antagonist (IL-1RA) production is stimulated

● Sirolimus – In an open-label trial of sirolimus plus prednisone in 10 patients with ECD,

● Infliximab – A report described clinical responses to infliximab in two patients with

There is no consensus regarding an optimal schedule or protocol for follow-up or monitoring

Complications of ECD may include mechanical compression of organs, and involvement of

Often there is no better therapy to offer a patient than enrollment in a well-designed,

SOCIETY GUIDELINE LINKS

dendritic cell neoplasms".)

SUMMARY AND RECOMMENDATIONS