Advertisement
Mayo Clinic Proceedings Home

Erdheim-Chester Disease: Characteristics and Management

      Abstract

      Erdheim-Chester disease is a rare CD68+, CD1a non-Langerhans cell histiocytosis with multiorgan involvement. The etiology of Erdheim-Chester disease is unclear; there are no known associated infectious or hereditary genetic abnormalities. However, somatic BRAF mutations have recently been identified in these patients. Historically, the literature regarding the management of Erdheim-Chester disease consisted of case reports and small case series with anecdotal therapeutic responses to agents including, but not limited to, cytotoxic chemotherapy, bone marrow transplantation, cladribine, corticosteroids, IFN-α, the BCR-ABL/KIT inhibitor imatinib mesylate, the IL-1 receptor antagonist anakinra, the TNF-inhibitor infliximab, and recently the BRAF inhibitor vemurafenib. We performed a search of the literature using PubMed with the terms Erdheim Chester disease, without date limitations, including case reports, case series, original articles, and previous review articles. In the absence of large-scale studies, experience-based management prevails. The present review details our approach to the management of patients with Erdheim-Chester disease.

      Abbreviations and Acronyms:

      CNS (central nervous system), ECD (Erdheim-Chester disease), PDGF (platelet-derived growth factor)
      Article Highlights
      • Erdheim-Chester disease is a rare non-Langerhans cell histiocytosis.
      • Common features include bone sclerosis, orbital infiltration with proptosis, diabetes insipidus, cardiac involvement, and pulmonary infiltration.
      • Somatic BRAF mutations have been recently identified.
      • Treatment options (although some based on anecdotal evidence) include IFN-α, imatinib, anakinra, infliximab, vemurafenib, bone marrow transplantation, cladribine, and steroids.
      • This condition serves as an example of the salutary effects of targeted therapy across malignancies that bear the cognate target. In particular, several case reports document excellent responses to vemurafenib, a BRAF kinase inhibitor, in patients with Erdheim-Chester disease harboring BRAF mutations.
      Erdheim-Chester disease (ECD) is an uncommon non-Langerhans cell histiocytosis that was initially described by William Chester and his tutor, the Viennese pathologist Jakob Erdheim, in 1930.
      • Arnaud L.
      • Hervier B.
      • Néel A.
      • et al.
      CNS involvement and treatment with interferon-alpha are independent prognostic factors in Erdheim-Chester disease: a multicenter survival analysis of 53 patients.
      Langerhans histiocytosis may coexist with ECD.
      • Marchal A.
      • Cuny J.F.
      • Montagne K.
      • Haroche J.
      • Barbaud A.
      • Schmutz J.L.
      Associated Langerhans cell histiocytosis and Erdheim-Chester disease [in French].
      Diverse organs are often affected. The most common presentation includes diffuse sclerotic lesions, which reveal foamy lipid-laden histiocytes on biopsy, present especially on the diaphysis of appendicular long bones, and generally sparing the epiphyses. The etiology of ECD has not been elucidated. A systemic derangement of cytokine and chemokine networks such as IL-6 and IFN-α do, however, appear to be involved in its pathogenesis.
      • Arnaud L.
      • Gorochov G.
      • Charlotte F.
      • et al.
      Systemic perturbation of cytokine and chemokine networks in Erdheim-Chester disease: a single-center series of 37 patients.
      We performed a review of the literature using PubMed searching the terms Erdheim Chester disease, without date limitations, including case reports, case series, original articles, and previous review articles. Because of the rarity of this disease, most of the therapeutic literature is anecdotal and randomized trials would be difficult to perform. There are therefore no clear-cut guidelines to direct optimal treatment. However, of special interest in this regard is the detection of BRAF mutations in patients with ECD.
      • Haroche J.
      • Charlotte F.
      • Arnaud L.
      • et al.
      High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses.
      The effect of BRAF inhibitors in ECD has, however, not been confirmed in larger trials despite promising reports.
      • Haroche J.
      • Cohen-Aubart F.
      • Emile J.F.
      • et al.
      Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation.
      To our knowledge, the largest case series of ECD is composed of 53 patients in whom treatment with IFN-α was shown, in a multivariate retrospective analysis, to predict a more favorable outcome.
      • Arnaud L.
      • Hervier B.
      • Néel A.
      • et al.
      CNS involvement and treatment with interferon-alpha are independent prognostic factors in Erdheim-Chester disease: a multicenter survival analysis of 53 patients.
      We have followed 14 patients with this uncommon disease in the Clinical Center for Targeted Therapy at MD Anderson Cancer Center. In addition to chemotherapy with cladribine
      • Adam Z.
      • Koukalová R.
      • Sprláková A.
      • et al.
      Successful treatment of Erdheim-Chester disease by 2-chlorodeoxyadenosine-based chemotherapy. Two case studies and a literature review [in Czeck].
      and steroids, we have administered IFN-α,
      • Esmaeli B.
      • Ahmadi A.
      • Tang R.
      • Schiffman J.
      • Kurzrock R.
      Interferon therapy for orbital infiltration secondary to Erdheim-Chester disease.
      • Braiteh F.
      • Boxrud C.
      • Esmaeli B.
      • Kurzrock R.
      Successful treatment of Erdheim-Chester disease, a non-Langerhans-cell histiocytosis, with interferon-alpha.
      imatinib,
      • Janku F.
      • Amin H.M.
      • Yang D.
      • Garrido-Laguna I.
      • Trent J.C.
      • Kurzrock R.
      Response of histiocytoses to imatinib mesylate: fire to ashes.
      and anakinra.
      • Aouba A.
      • Georgin-Lavialle S.
      • Pagnoux C.
      • et al.
      Rationale and efficacy of interleukin-1 targeting in Erdheim-Chester disease.
      • Tran T.A.
      • Pariente D.
      • Lecron J.C.
      • Delwail A.
      • Taoufik Y.
      • Meinzer U.
      Treatment of pediatric Erdheim-Chester disease with interleukin-1-targeting drugs.
      Herein, we provide an overview of the characteristics, outcomes, and our experience regarding the management of ECD (Figure 1). Of note, this algorithm depicts our current therapeutic recommendations based on our personal experience. As an example, there have not been randomized controlled trials comparing IFN with newer therapies (as BRAF inhibitors) to this date; nevertheless, we still often use IFN as our frontline approach (Figure 1) because we have more experience with this regimen.
      Figure thumbnail gr1
      Figure 1Algorithm showing our management of ECD. We consult with the respective specialists (in ophthalmology, endocrinology, and cardiology) to comanage multiple specific derangements present in these patients. CBC = complete blood cell count; CT = computed tomography; ECD = Erdheim-Chester disease; ECG = electrocardiogram; PET = positron emission tomography; MRI = magnetic resonance imaging.

      Diagnosis

      Differential diagnosis: Langerhans cell histiocytosis vs non-Langerhans cell histiocytosis

      ECD is a non-Langerhans cell histiocytosis; however, it may coexist with Langerhans histiocytosis.
      • Marchal A.
      • Cuny J.F.
      • Montagne K.
      • Haroche J.
      • Barbaud A.
      • Schmutz J.L.
      Associated Langerhans cell histiocytosis and Erdheim-Chester disease [in French].
      As an example, Haroche et al
      • Haroche J.
      • Arnaud L.
      • Amoura Z.
      Erdheim-Chester disease.
      reported overlapping histiocytosis in 12 of the 75 (16%) patients who have been followed at their institution. Mononuclear phagocytic cells are divided into macrophages and dendritic cells. The latter are thought to be the abnormal cells that trigger Langerhans cell histiocytosis.
      • Arceci R.J.
      The histiocytoses: the fall of the Tower of Babel.
      In contrast, non-Langerhans cell histiocytosis is believed to stem from an abnormal monocyte-macrophage ancestry.
      • Arceci R.J.
      The histiocytoses: the fall of the Tower of Babel.
      In 1868, Paul Langerhans
      • Arceci R.J.
      The histiocytoses: the fall of the Tower of Babel.
      • Jolles S.
      Paul Langerhans.
      described skin histiocytes that, although these cells call skin their “home,” are found in many organs. These cutaneous “Langerhans cells” are thus frontline antigen-presenting cells that engulf noxious foreign bodies, present antigens to lymphocytes, and trigger an immune-protective response. Because of their cutaneous predilection, Langerhans cell histiocytosis has a higher rate of skin infiltration than does ECD (Table 1). The heterogeneous systemic histiocytoses (both Langerhans cell histiocytosis and non-Langerhans cell histiocytosis such as ECD) are susceptible to infiltrate the pituitary stalk and hypothalamus, with subsequent development of central diabetes insipidus.
      Table 1Langerhans vs Non-Langerhans Cell Histiocytosis
      The population affected by a particular entity is also dependent on the institutional referral pattern due to the rarity of these conditions.
      VariableLangerhans cell histiocytosisErdheim-Chester disease
      Cell of originDendriticMononuclear-phagocyte
      PopulationChildrenAdults
      CD68++
      CD1a+
      S100+
      Birbeck granules+
      T6 protein+
      Bone involvementOsteolytic/axialOsteosclerosis/appendicular
      Lung involvementPeribronchialLymphangitic
      Skin involvementCommonUncommon
      a The population affected by a particular entity is also dependent on the institutional referral pattern due to the rarity of these conditions.
      As with other orphan diseases, the classification of histiocytosis is evolving (Table 2).
      • Vassallo R.
      • Ryu J.H.
      • Colby T.V.
      • Hartman T.
      • Limper A.H.
      Pulmonary Langerhans'-cell histiocytosis.
      • Windebank K.
      Advances in the management of histiocytic disorders.
      Histologically, the presence of CD1a+ and S100+ raises clinical suspicion for Langerhans cell histiocytosis.
      • Arceci R.J.
      The histiocytoses: the fall of the Tower of Babel.
      However, a lipid-laden histiocytic foamy infiltrate that immunochemically reveals CD1a and S100 better fits the diagnosis of ECD (Table 1). The T6 protein, or so-called Langerhans cells antigen, is not expressed in ECD.
      • Offret H.
      • Hannouche D.
      • Frau E.
      • Doyon D.
      • Quillard J.
      • Schaison G.
      Orbital Erdheim-Chester disease.
      CD68+, a histiocyte marker, is present in both histiocytic conditions, as expected. The differential diagnosis of sclerotic bony lesions includes Paget disease, although it lacks the systemic manifestations of ECD, and it does not incorporate a symmetric predilection for the diaphysis of the appendicular long bones.
      • Breuil V.
      • Brocq O.
      • Pellegrino C.
      • Grimaud A.
      • Euller-Ziegler L.
      Erdheim-Chester disease: typical radiological bone features for a rare xanthogranulomatosis.
      Table 2Suggested Classification of Histiocytosis
      Terms previously used for Langerhans cell histiocytosis included histiocytosis X, eosinophilic granuloma (single organ), Hans-Schüller-Christian disease, and Letterer-Siwe disease.
      Non-Langerhans cell histiocytoses
       Juvenile xanthogranuloma family
      Cutaneous: juvenile xanthogranuloma
      Cutaneous and systemic: xanthoma disseminatum
      Systemic: Erdheim-Chester disease
       Nonjuvenile xanthogranuloma family
      Cutaneous: solitary reticulohistiocytoma
      Cutaneous and systemic: multicentric reticulohistiocytosis
      Systemic: Rosai-Dorfman disease
      Langerhans cell histiocytosis
       Single-organ involvement
       Multiorgan disease with pulmonary involvement
       Multiorgan disease without pulmonary involvement
       Multiorgan histiocytic disorder
      a Terms previously used for Langerhans cell histiocytosis included histiocytosis X, eosinophilic granuloma (single organ), Hans-Schüller-Christian disease, and Letterer-Siwe disease.
      It has been noted that some patients demonstrate clinical and pathological features compatible with both Langerhans cell histiocytosis and ECD, suggesting possible overlap or simultaneous appearance of both diagnostic entities.
      • Kenn W.
      • Eck M.
      • Allolio B.
      • et al.
      Erdheim-Chester disease: evidence for a disease entity different from Langerhans cell histiocytosis? Three cases with detailed radiological and immunohistochemical analysis.
      Interestingly, the authors have treated patients whose clinical manifestations and overlap in histology results were compatible with both Langerhans cell histiocytosis and ECD, similar to experiences reported elsewhere,
      • Marchal A.
      • Cuny J.F.
      • Montagne K.
      • Haroche J.
      • Barbaud A.
      • Schmutz J.L.
      Associated Langerhans cell histiocytosis and Erdheim-Chester disease [in French].
      suggesting that both diseases can occur concomitantly or sequentially as a disease continuum. All referrals deemed to have histiocytic disorders have central pathology review at MD Anderson Cancer Center.

      Clinical Subtypes and Radiographic Presentation: Diverse Organ Involvement

      Phenotypically (Table 3), ECD has many faces. In our experience, a very common characteristic is bone involvement (Table 4), which is usually combined with infiltration of at least 1 more organ system. Patients who are incidentally diagnosed when imaging occurs because of an unrelated cause have been reported.
      • Egan A.J.
      • Boardman L.A.
      • Tazelaar H.D.
      • et al.
      Erdheim-Chester disease: clinical, radiologic, and histopathologic findings in five patients with interstitial lung disease.
      Our practice is to obtain a baseline positron emission tomography scan, with an optional bone scan. Bilateral symmetric sclerosis of peripheral long bones is frequently observed (Figure 2, A). We pay attention particularly to critical areas, such as the neck of the femur, which is susceptible to pathologic fractures. Central axial bone involvement (Figure 2, B) is possible, although less common. A baseline echocardiogram may be considered and, if abnormal, an early cardiology consultation and cardiac magnetic resonance imaging to rule out cardiac involvement, an important cause of ECD-related morbidity and mortality.
      • Haroche J.
      • Amoura Z.
      • Dion E.
      • et al.
      Cardiovascular involvement, an overlooked feature of Erdheim-Chester disease: report of 6 new cases and a literature review.
      Cardiovascular anomalies include “pseudo-tumor” of the right side of the heart, pericardial fibrosis (Figure 2, C), valvular infiltration, and fibrous encasement of the aorta, which has been coined “coated aorta.”
      • Haroche J.
      • Amoura Z.
      • Wechsler B.
      • Veyssier-Belot C.
      • Charlotte F.
      • Piette J.C.
      Erdheim-Chester disease [French].
      In addition, a “hairy kidney” (Figure 2, D), due to perinephric infiltration of histiocytes, is sometimes observed on abdominal imaging studies.
      • Haroche J.
      • Amoura Z.
      • Wechsler B.
      • Veyssier-Belot C.
      • Charlotte F.
      • Piette J.C.
      Erdheim-Chester disease [French].
      Such retroperitoneal infiltration can cause hydronephrosis (Figure 2, E).
      Table 3Manifestations of Patients With Erdheim-Chester Disease
      CharacteristicDescription
      ClinicalCentral nervous system: diabetes insipidus
      Ophthalmologic: proptosis
      Pulmonary involvement
      Adrenal infiltration
      Cutaneous
      Skeletal: osteolytic lesions
      RadiologicalStellate intracranial lesions
      Coated aorta
      Hairy kidney
      PathologicalCD68+, CD1a
      Non-Langerhans histiocytosis
      May coexist with Langerhans histiocytosis
      BRAF mutations in 54% (13 of 24)
      Table 4Characteristics of 14 Patients With Erdheim-Chester Disease
      CNS = central nervous system; ECD = Erdheim-Chester disease; F = female; LCH = Langerhans cell histiocytosis; M = male; RT = radiation.
      Patients with adequate follow-up were included.
      PathologySexAge at diagnosis (y)Initial presentationInvolvementTreatmentComments (best response)
      ECDM55Retro-orbital painRetro-orbital, bone, retroperitoneum, CNSIFN-αIFN April 2000 to October 2010 then lost to follow-up
      ECDM48New-onset atrial fibrillationCardiac (valve and pericardiac), retroperitoneum, omental, bone, diabetes insipidusSteroids, imatinib, IFN-α, anakinraImatinib (follow-up unclear)

      IFN January 2011 until January 2014 (ongoing)

      Anakinra February 2012 until January 2014 (ongoing)
      ECDM36AscitesPerihepatic, pericardiac, renal, bone, pleural, bone marrowIFN-αIFN May 2008 until at least December 2009 (then lost to follow-up)
      ECDM44Slurred speechCNS, retroperitoneum, hydropnephrosis, boneCladribine, imatinibCladribine for 5 cycles from 2008 to 2009 (no response). Imatinib from 2009 until January 2014 (ongoing)
      ECD/LCHF31AtaxiaCNS, bone, lungs, diabetes insipidus, panhypopituitarismRT to brain, IFN-α, imatinibIFN January 2005 to March 2009. Imatinib April 2009 to at least until September 2011 (then lost to follow-up)
      ECDF64Shortness of breathLung, subcutaneous, skin, cecal, adrenal, hilar, boneImatinibImatinib July 2009 to December 2009 (then lost to follow-up)
      ECDF51Bone painBone, lung, diabetes insipidus, panhypopituitarismSteroids, RT, IFN-α, cladribine, imatinibIFN April 2002 until April 2007 (at which time there was progression)

      Cladribine for 5 d in 2008

      Imatinib from July 2009 until November 2009

      Patient now deceased
      ECDF46Mental status changesCNS, bone, retro-orbital, lungsIFN-α, steroids, RT, imatinibIFN 2007 to 2010 (at which time there was progression)

      Imatinib from July 2010 to August 2010

      Patient now deceased
      ECDF60Subcutaneous nodulesBone, subcutaneousIFN-α, imatinib, IFN-α, anakinra, cladribineIFN June 2010 to August 2010 (stopped because of toxicity)

      Imatinib August 2010 to October 2010 (then progression)

      IFN November 2010 until 2012

      Anakinra February 2012 until 2013

      Cladribine April 2013 to November 2013 (then progression)
      ECD/LCHF76Bone painBone, carotid arteryVemurafenib, IFN-αVemurafenib July 2012 to September 2012 (stopped because of toxicity)

      IFN October 2012 to March 2013 (stopped because of toxicity)
      ECDF44PolydispsiaBone, CNS, diabetes insipidus, hydronephrosisIFN-αIFN December 2008 until at least February 2012 (then lost to follow-up)
      ECDM68Abdominal painBone, cardiac, retro-orbital, perirenalIFN-αIFN September 2010 until unknown (then lost to follow-up)
      ECDF43PolydipsiaBone, diabetes insipidusAnakinraAnakinra May 2012 until January 2014 (ongoing)
      ECDM27Skin lesionsSkinImatinib, IFN-α, anakinra, PUVAImatinib May 2012 to June 2012 (then progression)

      IFN October 2012 until September 2013 (then progression)

      Anakinra added to IFN from March 2013 to September 2013 (then progression)

      PUVA for skin lesions from September 2013 to January 2014 (ongoing)
      a CNS = central nervous system; ECD = Erdheim-Chester disease; F = female; LCH = Langerhans cell histiocytosis; M = male; RT = radiation.
      b Patients with adequate follow-up were included.
      Figure thumbnail gr2
      Figure 2A, Whole-body technetium bone scan: Erdheim-Chester disease manifested as diffuse sclerotic lesions, particularly on the diaphysis of appendicular long bones. Scattered foci of abnormal radiotracer activity were also seen, with the most conspicuous sites of abnormality in the right sacrum and bilateral tibiae and distal femora. B, Magnetic resonance imaging showing lesions on T9, L1, and L5 vertebral bodies with no evidence of acute compression fracture. C, Computed tomography of the chest showing an infiltrative mass involving the pericardium and the wall of the right atrium. D, Computed tomography of the abdomen showing a perirenal infiltrative mass compatible with “hairy kidney.” Note the wall thickening surrounding the abdominal aorta. E, Positron emission tomography showing activity within the enlarged thickened kidneys and renal tissues. F, Magnetic resonance imaging showing dural-based masses and a central heterogeneous mass displacing the cingulate gyrus, corpus callosum, and lateral ventricles. G, Computed tomography of the chest showing chronic interstitial changes throughout both lungs. H, Positron emission tomography showing multiple hypermetabolic lesions in the subcutaneous tissues.
      Many patients have central nervous system (CNS) involvement (Figure 2, F), resulting in central diabetes insipidus. We consult with our endocrinology colleagues to manage electrolyte and hormonal derangements. Central nervous system involvement confers a worse prognosis
      • Arnaud L.
      • Hervier B.
      • Néel A.
      • et al.
      CNS involvement and treatment with interferon-alpha are independent prognostic factors in Erdheim-Chester disease: a multicenter survival analysis of 53 patients.
      ; thus, we suggest obtaining a baseline brain magnetic resonance imaging. We recently reported various radiological presentations of CNS involvement in ECD, including stellate intracranial lesions and diffuse vertebral involvement.
      • Sedrak P.
      • Ketonen L.
      • Hou P.
      • et al.
      Erdheim-Chester disease of the central nervous system: new manifestations of a rare disease.
      In many disorders, pulmonary involvement denotes a worse prognosis and contributes greatly to the patient's demise; ECD might be an exception. Pulmonary fibrosis from ECD was not an independent factor associated with a worse outcome in a recent case series.
      • Arnaud L.
      • Hervier B.
      • Néel A.
      • et al.
      CNS involvement and treatment with interferon-alpha are independent prognostic factors in Erdheim-Chester disease: a multicenter survival analysis of 53 patients.
      However, some smaller previous case series suggested a grim prognosis associated with interstitial lung involvement (Figure 2, G).
      • Shamburek R.D.
      • Brewer Jr., H.B.
      • Gochuico B.R.
      Erdheim-Chester disease: a rare multisystem histiocytic disorder associated with interstitial lung disease.
      Space-occupying orbital ECD results in proptosis, which can threaten vision and requires evaluation by an ophthalmologist. From a cosmetic standpoint, dermatologic infiltration can be distressing to patients with multiple subcutaneous nodules (Figure 2, H) and a similar unsettling effect is also experienced by patients with localized (Figure 3) or diffuse (Figure 4) cutaneous lesions. The diverse clinical involvement of ECD translates into unique radiographic features that have been described elsewhere.
      • Esmaeli B.
      • Ahmadi A.
      • Tang R.
      • Schiffman J.
      • Kurzrock R.
      Interferon therapy for orbital infiltration secondary to Erdheim-Chester disease.
      • Sedrak P.
      • Ketonen L.
      • Hou P.
      • et al.
      Erdheim-Chester disease of the central nervous system: new manifestations of a rare disease.
      • Arnaud L.
      • Pierre I.
      • Beigelman-Aubry C.
      • et al.
      Pulmonary involvement in Erdheim-Chester disease: a single-center study of thirty-four patients and a review of the literature.
      • Dion E.
      • Graef C.
      • Miquel A.
      • et al.
      Bone involvement in Erdheim-Chester disease: imaging findings including periostitis and partial epiphyseal involvement.
      • Haroche J.
      • Cluzel P.
      • Toledano D.
      • et al.
      Images in cardiovascular medicine. Cardiac involvement in Erdheim-Chester disease: magnetic resonance and computed tomographic scan imaging in a monocentric series of 37 patients.
      Figure thumbnail gr3
      Figure 3Localized cutaneous involvement of Erdheim-Chester disease with bilateral palpebral infiltration.
      Figure thumbnail gr4
      Figure 4Diffuse cutaneous involvement of Erdheim-Chester disease.
      In summary, ECD is a systemic condition involving multiple organs. Because of its rarity and diverse presentations, it can be extremely difficult to diagnose. In our experience, patients have at times sought help for years before a diagnosis is made. Therefore, referral for pathology review or treatment recommendations to tertiary centers should be considered.

      Prognosis

      Poorer prognosis is dictated by the degree of organ involvement, particularly the CNS.
      • Arnaud L.
      • Hervier B.
      • Néel A.
      • et al.
      CNS involvement and treatment with interferon-alpha are independent prognostic factors in Erdheim-Chester disease: a multicenter survival analysis of 53 patients.
      Sequelae range from asymptomatic bone sclerosis to life-threatening visceral infiltration. Although ECD is not curable, we have seen prolonged responses in our clinic after various agents. Survival in recent larger series
      • Arnaud L.
      • Hervier B.
      • Néel A.
      • et al.
      CNS involvement and treatment with interferon-alpha are independent prognostic factors in Erdheim-Chester disease: a multicenter survival analysis of 53 patients.
      is better than previously described in other older smaller series.
      • Shamburek R.D.
      • Brewer Jr., H.B.
      • Gochuico B.R.
      Erdheim-Chester disease: a rare multisystem histiocytic disorder associated with interstitial lung disease.
      Indeed, Arnaud et al
      • Arnaud L.
      • Hervier B.
      • Néel A.
      • et al.
      CNS involvement and treatment with interferon-alpha are independent prognostic factors in Erdheim-Chester disease: a multicenter survival analysis of 53 patients.
      reported 1- and 5-year survival rates of 96% and 68%, respectively, which is compatible with our experience.
      • Braiteh F.
      • Boxrud C.
      • Esmaeli B.
      • Kurzrock R.
      Successful treatment of Erdheim-Chester disease, a non-Langerhans-cell histiocytosis, with interferon-alpha.
      • Janku F.
      • Amin H.M.
      • Yang D.
      • Garrido-Laguna I.
      • Trent J.C.
      • Kurzrock R.
      Response of histiocytoses to imatinib mesylate: fire to ashes.
      However, 26% of the patients die by 27 months after their diagnosis; CNS involvement is an independent variable that predicts poor prognosis.
      • Arnaud L.
      • Hervier B.
      • Néel A.
      • et al.
      CNS involvement and treatment with interferon-alpha are independent prognostic factors in Erdheim-Chester disease: a multicenter survival analysis of 53 patients.

      Pathophysiology

      The underlying pathophysiology of ECD is largely unknown, although it seems to be associated with cytokine disturbances.
      • Arnaud L.
      • Gorochov G.
      • Charlotte F.
      • et al.
      Systemic perturbation of cytokine and chemokine networks in Erdheim-Chester disease: a single-center series of 37 patients.
      • Tsuji Y.
      • Kogawa K.
      • Imai K.
      • Kanegane H.
      • Fujimoto J.
      • Nonoyama S.
      Evans syndrome in a patient with Langerhans cell histiocytosis: possible pathogenesis of autoimmunity in LCH.
      • Dagna L.
      • Corti A.
      • Langheim S.
      • et al.
      Tumor necrosis factor α as a master regulator of inflammation in Erdheim-Chester disease: rationale for the treatment of patients with infliximab.
      • Stoppacciaro A.
      • Ferrarini M.
      • Salmaggi C.
      • et al.
      Immunohistochemical evidence of a cytokine and chemokine network in three patients with Erdheim-Chester disease: implications for pathogenesis.
      • Mossetti G.
      • Rendina D.
      • Numis F.G.
      • Somma P.
      • Postiglione L.
      • Nunziata V.
      Biochemical markers of bone turnover, serum levels of interleukin-6/interleukin-6 soluble receptor and bisphosphonate treatment in Erdheim-Chester disease.
      Serum samples from 37 patients with ECD were assessed for 23 cytokines. It was found that IL-6 and IFN-α levels (TH-1–induced pro-inflammatory chemokines) were elevated in untreated patients; IL-1 and IFN-γ levels were high in patients treated with IFN-α.
      • Arnaud L.
      • Gorochov G.
      • Charlotte F.
      • et al.
      Systemic perturbation of cytokine and chemokine networks in Erdheim-Chester disease: a single-center series of 37 patients.
      Earlier attempts to elucidate the etiology of ECD did not focus on the balance among cytokines, an approach that may shed new light on and identify novel targets for this disease.
      Of special interest, the V600E BRAF mutation has been identified in patients with ECD but not in patients with other non-Langerhans histiocytosis.
      • Haroche J.
      • Charlotte F.
      • Arnaud L.
      • et al.
      High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses.
      BRAF mutations are also detected in patients with Langerhans histiocytosis.
      • Badalian-Very G.
      • Vergilio J.A.
      • Degar B.A.
      • et al.
      Recurrent BRAF mutations in Langerhans cell histiocytosis.
      This is a drug-responsive mutation, with responses reported in other BRAF-positive diseases such as melanoma, thyroid cancer, and hairy cell leukemia after treatment with the BRAF inhibitors vemurafenib
      • Chapman P.B.
      • Hauschild A.
      • Robert C.
      • et al.
      Improved survival with vemurafenib in melanoma with BRAF V600E mutation.
      • Tiacci E.
      • Trifonov V.
      • Schiavoni G.
      • et al.
      BRAF mutations in hairy-cell leukemia.
      and dabrafenib,
      • Falchook G.S.
      • Long G.V.
      • Kurzrock R.
      • et al.
      Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial.
      as well as with the MEK inhibitor trametinib.
      • Falchook G.S.
      • Lewis K.D.
      • Infante J.R.
      • et al.
      Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial.

      Therapy

      Systemic treatment is deemed not to have curative potential, though, on the basis of retrospective analysis, it can improve symptoms as well as outcomes.
      • Arnaud L.
      • Hervier B.
      • Néel A.
      • et al.
      CNS involvement and treatment with interferon-alpha are independent prognostic factors in Erdheim-Chester disease: a multicenter survival analysis of 53 patients.
      There is no standard of care (approved therapies), and no randomized trials have been performed for ECD. Until recently, treatment included diverse approaches such as steroids, cladribine-based chemotherapy,
      • Adam Z.
      • Koukalová R.
      • Sprláková A.
      • et al.
      Successful treatment of Erdheim-Chester disease by 2-chlorodeoxyadenosine-based chemotherapy. Two case studies and a literature review [in Czeck].
      and cytokine-based agents. The recent reports of BRAF mutations in patients with ECD support testing BRAF inhibitors in the clinic.
      • Haroche J.
      • Cohen-Aubart F.
      • Emile J.F.
      • et al.
      Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation.
      The therapeutic story of ECD is interesting because IFN-α was first used in this condition in a “clinic-to-bench” fashion. Initial anecdotal reports in other histiocytosis led to its application to ECD.
      • Arnaud L.
      • Hervier B.
      • Néel A.
      • et al.
      CNS involvement and treatment with interferon-alpha are independent prognostic factors in Erdheim-Chester disease: a multicenter survival analysis of 53 patients.
      • Esmaeli B.
      • Ahmadi A.
      • Tang R.
      • Schiffman J.
      • Kurzrock R.
      Interferon therapy for orbital infiltration secondary to Erdheim-Chester disease.
      • Braiteh F.
      • Boxrud C.
      • Esmaeli B.
      • Kurzrock R.
      Successful treatment of Erdheim-Chester disease, a non-Langerhans-cell histiocytosis, with interferon-alpha.
      • Jakobson A.M.
      • Kreuger A.
      • Hagberg H.
      • Sundstrom C.
      Treatment of Langerhans cell histiocytosis with alpha-interferon.
      After the success seen with IFN-α, the IL-1 pathway was examined in laboratory investigations and led to anakinra's (IL-1 receptor antagonist) translation from the “bench to clinic” where it was made available to patients.
      • Aouba A.
      • Georgin-Lavialle S.
      • Pagnoux C.
      • et al.
      Rationale and efficacy of interleukin-1 targeting in Erdheim-Chester disease.
      • Tran T.A.
      • Pariente D.
      • Lecron J.C.
      • Delwail A.
      • Taoufik Y.
      • Meinzer U.
      Treatment of pediatric Erdheim-Chester disease with interleukin-1-targeting drugs.
      Other treatments successfully used include imatinib, cladribine, zoledronic acid, and transplantation.
      • Adam Z.
      • Koukalová R.
      • Sprláková A.
      • et al.
      Successful treatment of Erdheim-Chester disease by 2-chlorodeoxyadenosine-based chemotherapy. Two case studies and a literature review [in Czeck].
      • Janku F.
      • Amin H.M.
      • Yang D.
      • Garrido-Laguna I.
      • Trent J.C.
      • Kurzrock R.
      Response of histiocytoses to imatinib mesylate: fire to ashes.
      • Haroche J.
      • Amoura Z.
      • Charlotte F.
      • et al.
      Imatinib mesylate for platelet-derived growth factor receptor-beta-positive Erdheim-Chester histiocytosis.
      • Srikulmontree T.
      • Massey H.D.
      • Roberts W.N.
      Treatment of skeletal Erdheim-Chester disease with zoledronic acid: case report and proposed mechanisms of action.
      • Boissel N.
      • Wechsler B.
      • Leblond V.
      Treatment of refractory Erdheim-Chester disease with double autologous hematopoietic stem-cell transplantation.
      Treatment, which has often been palliative rather than curative, is not necessarily needed for asymptomatic patients with an indolent disease course. However, patients with ECD who face imminent organ compromise or CNS infiltration have a worse outcome.
      • Arnaud L.
      • Hervier B.
      • Néel A.
      • et al.
      CNS involvement and treatment with interferon-alpha are independent prognostic factors in Erdheim-Chester disease: a multicenter survival analysis of 53 patients.
      We often “watch and wait” with serial imaging to document disease status in asymptomatic patients. If treatment is warranted, there are several choices available (Figure 1).

      IFN-α

      Studies have shown increased serum IFN-α levels in treatment-naive patients with ECD.
      • Arnaud L.
      • Gorochov G.
      • Charlotte F.
      • et al.
      Systemic perturbation of cytokine and chemokine networks in Erdheim-Chester disease: a single-center series of 37 patients.
      Even so, IFN-α can be an effective therapeutic approach to ECD. Multivariate retrospective analysis suggested increased survival with the use of this agent; however, no prospective randomized trials are available.
      • Arnaud L.
      • Hervier B.
      • Néel A.
      • et al.
      CNS involvement and treatment with interferon-alpha are independent prognostic factors in Erdheim-Chester disease: a multicenter survival analysis of 53 patients.
      • Esmaeli B.
      • Ahmadi A.
      • Tang R.
      • Schiffman J.
      • Kurzrock R.
      Interferon therapy for orbital infiltration secondary to Erdheim-Chester disease.
      • Braiteh F.
      • Boxrud C.
      • Esmaeli B.
      • Kurzrock R.
      Successful treatment of Erdheim-Chester disease, a non-Langerhans-cell histiocytosis, with interferon-alpha.
      Interferon should be used with caution in patients with mental illness, especially depression, owing to possible exacerbation of the problem.
      • Schaefer M.
      • Sarkar R.
      • Knop V.
      • et al.
      Escitalopram for the prevention of peginterferon-alpha2a-associated depression in hepatitis C virus-infected patients without previous psychiatric disease: a randomized trial.
      • Haroche J.
      • Amoura Z.
      • Trad S.G.
      • et al.
      Variability in the efficacy of interferon-alpha in Erdheim-Chester disease by patient and site of involvement: results in eight patients.
      In our experience, patients with ECD have a poor tolerance for conventional IFN-α doses, such as the 3 million units subcutaneously 3 times per week, though these doses are well tolerated in patients with hairy cell leukemia.
      • Benz R.
      • Siciliano R.D.
      • Stussi G.
      • Fehr J.
      Long-term follow-up of interferon-alpha induction and low-dose maintenance therapy in hairy cell leukemia.
      • Kurzrock R.
      • Strom S.S.
      • Estey E.
      • et al.
      Second cancer risk in hairy cell leukemia: analysis of 350 patients.
      • Seymour J.F.
      • Estey E.H.
      • Keating M.J.
      • Kurzrock R.
      Response to interferon-alpha in patients with hairy cell leukemia relapsing after treatment with 2-chlorodeoxyadenosine.
      Patients with ECD often develop intolerable fatigue at this dose level. It is conceivable that this poor tolerance is driven by the already elevated endogenous IFN-α levels detected in these patients.
      • Arnaud L.
      • Gorochov G.
      • Charlotte F.
      • et al.
      Systemic perturbation of cytokine and chemokine networks in Erdheim-Chester disease: a single-center series of 37 patients.
      Consequently, we use a lower dose of IFN-α (1 million units subcutaneously 3 times per week). In our experience, patients tolerate this dose well, and about half will have durable responses. Pegylated IFN-α can be offered as an alternative to conventional IFN-α. Its advantages may include decreased constitutional adverse effects and, with weekly dosing, increased convenience.
      • Husken A.C.
      • Tsianakas A.
      • Hensen P.
      • et al.
      Comparison of pegylated interferon alpha-2b plus psoralen PUVA versus standard interferon alpha-2a plus PUVA in patients with cutaneous T-cell lymphoma.
      It has been suggested that IFN-α lacks effect in patients with CNS and/or cardiac involvement.
      • Suzuki H.I.
      • Hosoya N.
      • Miyagawa K.
      • et al.
      Erdheim-Chester disease: multisystem involvement and management with interferon-alpha.
      However, the authors have seen responses in this population of patients. Importantly, our current choice of using IFN as a frontline agent (Figure 1) is based on our greater personal experience with such agents because there are no randomized controlled trials comparing IFN with other therapies to the date of this publication. Other groups have also recommended frontline IFN although using different dosage. Haroche et al
      • Haroche J.
      • Amoura Z.
      • Trad S.G.
      • et al.
      Variability in the efficacy of interferon-alpha in Erdheim-Chester disease by patient and site of involvement: results in eight patients.
      treated multisystemic ECD with subcutaneous IFN-α at a dosage of 3 to 9 million units 3 times weekly for a median duration of 23 months. Hervier et al
      • Hervier B.
      • Arnaud L.
      • Charlotte F.
      • et al.
      Treatment of Erdheim-Chester disease with long-term high-dose interferon-alpha.
      used high-dose IFN-α (IFN-α 18 million international units per week or pegylated IFN-α 180 μg per week) in severe ECD and suggested prolonged therapy because some patients may be slow responders.

      Imatinib Mesylate

      Imatinib mesylate is a tyrosine kinase inhibitor that selectively targets KIT, BCR-ABL, and platelet-derived growth factor (PDGF).
      • Utikal J.
      • Ugurel S.
      • Kurzen H.
      • et al.
      Imatinib as a treatment option for systemic non-Langerhans cell histiocytoses.
      In addition to the landmark discovery that the inhibition of the fusion kinase BCR-ABL by this agent can be exploited to treat chronic myeloid leukemia,
      • Druker B.J.
      • Sawyers C.L.
      • Kantarjian H.
      • et al.
      Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome.
      several orphan diseases have shown remarkable responses to imatinib mesylate. These include mastocytosis with a KITD816V mutation,
      • Pardanani A.
      Systemic mastocytosis in adults: 2011 update on diagnosis, risk stratification, and management.
      dermatofibrosarcoma protuberans with a COL1A1-PDGFR-β fusion gene,
      • Rutkowski P.
      • Wozniak A.
      • Switaj T.
      Advances in molecular characterization and targeted therapy in dermatofibrosarcoma protuberans.
      c-KIT– positive gastrointestinal stromal tumors,
      • Reichardt P.
      • Reichardt A.
      • Pink D.
      Molecular targeted therapy of gastrointestinal stromal tumors.
      • Joensuu H.
      Adjuvant treatment of GIST: patient selection and treatment strategies.
      FIP1L1-PDGFR-α–positive hypereosinophilic syndromes,
      • Baccarani M.
      • Cilloni D.
      • Rondoni M.
      • et al.
      The efficacy of imatinib mesylate in patients with FIP1L1-PDGFRalpha-positive hypereosinophilic syndrome. Results of a multicenter prospective study.
      and c-ABL–positive rhabdoid tumors.
      • Koos B.
      • Jeibmann A.
      • Lünenbürger H.
      • et al.
      The tyrosine kinase c-Abl promotes proliferation and is expressed in atypical teratoid and malignant rhabdoid tumors.
      More recently, successful treatment of ECD has been demonstrated.
      • Janku F.
      • Amin H.M.
      • Yang D.
      • Garrido-Laguna I.
      • Trent J.C.
      • Kurzrock R.
      Response of histiocytoses to imatinib mesylate: fire to ashes.
      The biology behind ECD response remains unclear. In our experience, about a third of the patients given imatinib respond even though our numbers are small and some patients were lost to follow-up (Table 4).
      It has been postulated that imatinib penetrates the CNS inadequately
      • Fielding A.K.
      How I treat Philadelphia chromosome-positive acute lymphoblastic leukemia.
      • Goldman J.M.
      How I treat chronic myeloid leukemia in the imatinib era.
      ; whether disruption of the blood-brain barrier occurs in patients with ECD with CNS involvement is unclear. Haroche et al
      • Haroche J.
      • Amoura Z.
      • Charlotte F.
      • et al.
      Imatinib mesylate for platelet-derived growth factor receptor-beta-positive Erdheim-Chester histiocytosis.
      treated 6 patients with ECD positive for platelet-derived growth factor receptor (PDGFR)-β with imatinib starting at 100 mg/d, increasing progressively up to 800 mg/d in 1 patient. Imatinib was used safely with stable cardiovascular involvement; nevertheless, it led to worsening of the disease with CNS involvement; thus, the disease was deemed to be stable in 2 cases and worsening in 4 cases. Overall, imatinib is well tolerated in our experience at doses of 400 mg/d orally. In some patients, a dose increase may be needed. The role of other tyrosine kinase inhibitors in the management of ECD is currently unknown. To conclude, anecdotal data and our experience suggest that imatinib can be a reasonable option in the arsenal against ECD, particularly if other options have been exhausted.

      Anakinra: IL-1 Receptor Antagonist

      Anakinra, a recombinant human IL-1 receptor antagonist approved by the Food and Drug Administration in 2001 as treatment for rheumatoid arthritis, has been reported to ameliorate ECD.
      • Aouba A.
      • Georgin-Lavialle S.
      • Pagnoux C.
      • et al.
      Rationale and efficacy of interleukin-1 targeting in Erdheim-Chester disease.
      Tran et al
      • Tran T.A.
      • Pariente D.
      • Lecron J.C.
      • Delwail A.
      • Taoufik Y.
      • Meinzer U.
      Treatment of pediatric Erdheim-Chester disease with interleukin-1-targeting drugs.
      reported a response to anakinra, that is, weight gain and resolution of fever and bone pain, in a pediatric patient with ECD. A 43-year-old woman with progressive multisystemic ECD including diabetes insipidus and widespread cutaneous lichen planus was started on 100 mg/d of anakinra subcutaneously with improvement in most of her skin lesions and resolution of her pruritus.
      • Cohen P.R.
      • Kurzrock R.
      Anakinra-responsive lichen planus in a woman with Erdheim-Chester disease: a therapeutic enigma.
      Despite initial case reports, the utility of anakinra has subsequently been questioned.
      • Haroche J.
      • Arnaud L.
      • Cohen-Aubart F.
      • et al.
      Erdheim-Chester disease.
      The IL-1 machinery orchestrates the signaling cascade that includes IL-1R–associated kinases and mitogen-activated protein kinases in histiocytes.
      • Gabay C.
      • Lamacchia C.
      • Palmer G.
      IL-1 pathways in inflammation and human diseases.
      It has also been documented that there is a high level of expression of IL-1α on the membrane of monocytes
      • Aouba A.
      • Georgin-Lavialle S.
      • Pagnoux C.
      • et al.
      Rationale and efficacy of interleukin-1 targeting in Erdheim-Chester disease.
      and IL-1β abnormal infiltrating histiocytes
      • Kannourakis G.
      • Abbas A.
      The role of cytokines in the pathogenesis of Langerhans cell histiocytosis.
      in histiocytic disorders, supporting anakinra's role as a therapeutic target. Of interest, IFN-α stimulates the production of natural IL-1 receptor antagonist, which apparently then abrogates the inflammatory pathways leading to histiocytic proliferation.
      • Tran T.A.
      • Pariente D.
      • Lecron J.C.
      • Delwail A.
      • Taoufik Y.
      • Meinzer U.
      Treatment of pediatric Erdheim-Chester disease with interleukin-1-targeting drugs.
      Other IL-1–mediated effects include monocyte/macrophage lineage activation
      • Gabay C.
      • Lamacchia C.
      • Palmer G.
      IL-1 pathways in inflammation and human diseases.
      and osteoclast stimulation.
      • Geyer M.
      • Muller-Ladner U.
      Actual status of antiinterleukin-1 therapies in rheumatic diseases.
      Anakinra, a recombinant mimic of the naturally occurring receptor antagonists of IL-1, is usually started at 100 mg/d subcutaneously. It is well tolerated, though there can be mild local injection site tenderness, which usually subsides with continued drug administration. Reactivation of infections,
      • Singh J.A.
      • Wells G.A.
      • Christensen R.
      • et al.
      Adverse effects of biologics: a network meta-analysis and Cochrane overview.
      such as tuberculosis, may occur. There is insufficient safety data regarding the use of anakinra during pregnancy.
      • Ostensen M.
      • Förger F.
      Treatment with biologics of pregnant patients with rheumatic diseases.
      Because of its excellent toxicity profile, we favor using anakinra, especially for patients who are elderly or have comorbidities, and particularly if other options have been exhausted.

      Vemurafenib

      BRAF V600E mutations were found in 38% (11 of 29) to 57% (35 of 61) of the patients with Langerhans cell histiocytosis.
      • Haroche J.
      • Charlotte F.
      • Arnaud L.
      • et al.
      High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses.
      • Badalian-Very G.
      • Vergilio J.A.
      • Degar B.A.
      • et al.
      Recurrent BRAF mutations in Langerhans cell histiocytosis.
      • Sahm F.
      • Capper D.
      • Preusser M.
      • et al.
      BRAFV600E mutant protein is expressed in cells of variable maturation in Langerhans cell histiocytosis.
      Subsequently, BRAF mutations were detected in 54% (13 of 24) of the patients with ECD.
      • Haroche J.
      • Charlotte F.
      • Arnaud L.
      • et al.
      High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses.
      The therapeutic implications of BRAF mutations in histiocytic disorders remain unknown. Of interest, BRAF mutations also occur in hairy cell leukemia, and our recent experience suggests that this disease can be very responsive to the BRAF inhibitor vemurafenib.
      • Munoz J.
      • Schlette E.
      • Kurzrock R.
      Rapid response to vemurafenib in a heavily pretreated patient with hairy cell leukemia and a BRAF mutation.
      We recently treated a BRAF-positive patient with vemurafenib with stable disease after 2 cycles of therapy (unpublished data); unfortunately, treatment had to be discontinued because of poor tolerability including fatigue and diarrhea. Haroche et al
      • Haroche J.
      • Cohen-Aubart F.
      • Emile J.F.
      • et al.
      Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation.
      described dramatic responses in 3 patients with refractory ECD, which serves as a proof of principle for targeted therapy in this rare disease.

      Steroids

      Chen et al
      • Chen M.T.
      • Wang S.M.
      • Lin S.Y.
      • et al.
      Pericardial effusion as a crucial presentation of Erdheim-Chester disease in a hemodialysis patient: an overlooked diagnosis.
      reported a patient with a diagnosis of ECD whose pericardial effusion responded to intravenous pulse methylprednisolone followed by oral prednisolone. Taguchi et al
      • Taguchi T.
      • Iwasaki Y.
      • Asaba K.
      • et al.
      Erdheim-Chester disease: report of a case with PCR-based analysis of the expression of osteopontin and survivin in Xanthogranulomas following glucocorticoid treatment.
      described a patient with ECD and multiple xanthogranulomas that improved in response to glucocorticoids. However, Mahnel et al
      • Mahnel R.
      • Tan K.H.
      • Fahlbusch R.
      • et al.
      Problems in differential diagnosis of non Langerhans cell histiocytosis with pituitary involvement: case report and review of literature.
      presented a case of pituitary histiocytosis that did not respond to systemic steroids or local radiation and the patient continued to decline neurologically.

      Cytotoxic Chemotherapy

      A regimen combining vinblastine, etoposide, prednisone, and 6-mercaptopurine has been successfully tried in patients with multisystem Langerhans cell histiocytosis.
      • Gadner H.
      • Grois N.
      • Pötschger U.
      • et al.
      Improved outcome in multisystem Langerhans cell histiocytosis is associated with therapy intensification.
      The activity of such combinations in ECD is unknown. Broccoli et al
      • Broccoli A.
      • Stefoni V.
      • Faccioli L.
      • et al.
      Bilateral orbital Erdheim-Chester disease treated with 12 weekly administrations of VNCOP-B chemotherapy: a case report and a review of literature.
      reported a patient with bilateral orbital ECD that responded to VNCOP-B chemotherapy (etoposide, mitoxantrone, cyclophosphamide, vincristine, bleomycin, and prednisone). High-dose chemotherapy has also been attempted, with cyclophosphamide given on day 1 and etoposide administered on days 1 to 3, and subsequently monthly doses of 2-chlorodeoxyadenosine on days 1 to 5.
      • Adam Z.
      • Balsíková K.
      • Pour L.
      • et al.
      Diabetes insipidus followed, after 4 years, with dysarthria and mild right-sided hemiparesis–the first clinical signs of Erdheim-Chester disease. Description and depiction of a case with a review of information on the disease [in Czeck].
      Intrathecal or high-dose intravenous methotrexate has been suggested to be a reasonable option for patients with ECD and CNS involvement.
      • Lachenal F.
      • Cotton F.
      • Desmurs-Clavel H.
      • et al.
      Neurological manifestations and neuroradiological presentation of Erdheim-Chester disease: report of 6 cases and systematic review of the literature.

      Cladribine (2-Chlorodeoxyadenosine)

      Adam et al
      • Adam Z.
      • Balsíková K.
      • Krejcí M.
      • et al.
      Central diabetes insipidus in adult patients–the first sign of Langerhans cell histiocytosis and Erdheim-Chester disease. Three case studies and literature review [in Czeck].
      described a patient with ECD whose pituitary stalk infiltration went into radiological remission after 4 cycles of 2-chlordeoxyadenosine, also known as cladribine, a purine analogue that is toxic to monocytes. This drug is approved for hairy cell leukemia, a disease that almost universally responds to it. The same group tried a combination of 2-chlorodeoxyadenosine and cyclophosphamide during the initial 5 days of a 28-day cycle and achieved a complete response that persisted at 16 months.
      • Adam Z.
      • Koukalová R.
      • Sprláková A.
      • et al.
      Successful treatment of Erdheim-Chester disease by 2-chlorodeoxyadenosine-based chemotherapy. Two case studies and a literature review [in Czeck].
      Interestingly, partial response of CNS lesions to cladribine
      • Adam Z.
      • Sprláková A.
      • Rehák Z.
      • et al.
      Partial regression of CNS lesions of Erdheim-Chester disease after treatment with 2-chlorodeoxadenosine and their full remission following treatment with lenalidomide [in Czeck].
      has been reported in a patient with ECD, with subsequent complete remission of CNS disease when the regimen was switched to lenalidomide,
      • Adam Z.
      • Sprláková A.
      • Rehák Z.
      • et al.
      Partial regression of CNS lesions of Erdheim-Chester disease after treatment with 2-chlorodeoxadenosine and their full remission following treatment with lenalidomide [in Czeck].
      though bone involvement persisted. Overall, cladribine has activity in the treatment of histiocytic disorders.
      • Adam Z.
      • Szturz P.
      • Pour L.
      • et al.
      Cladribine is highly effective in the treatment of Langerhans cell histiocytosis and rare histiocytic disorders of the juvenile xanthogranuloma group [in Czeck].

      Bone Marrow Transplantation

      Boissel et al
      • Boissel N.
      • Wechsler B.
      • Leblond V.
      Treatment of refractory Erdheim-Chester disease with double autologous hematopoietic stem-cell transplantation.
      reported an 18-year-old man with ECD who achieved a partial response to his first autologous bone marrow transplantation (etoposide and melphalan as conditioning regimen); a second autologous bone marrow transplantation (carmustine, etoposide, and melphalan as conditioning regimen) rendered the patient stable for 2 years. The authors of this article also suggested that etoposide is cytotoxic for monocytic lineage cells.
      • Boissel N.
      • Wechsler B.
      • Leblond V.
      Treatment of refractory Erdheim-Chester disease with double autologous hematopoietic stem-cell transplantation.
      Gaspar et al
      • Gaspar N.
      • Boudou P.
      • Haroche J.
      • et al.
      High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation for adult histiocytic disorders with central nervous system involvement.
      reported the use of high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation for 6 adult patients with histiocytic disorders and CNS involvement. Three of these 6 patients had ECD, and their overall survival was reported to be 97, 14, and 8 months, respectively. The patients were alive at the time of such publication, although they were facing progressive disease.
      • Gaspar N.
      • Boudou P.
      • Haroche J.
      • et al.
      High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation for adult histiocytic disorders with central nervous system involvement.

      Bone-Remodeling Agents

      The role of bisphosphonates to prevent skeletal-related events in ECD has not been defined in clinical trials; however, some investigators use bisphosphonates, extrapolating data from other malignancies. Denosumab, a human monoclonal antibody directed against receptor activator of NF-κB ligand, is an attractive agent for patients with ECD because high serum levels of soluble receptor activator of NF-κB ligand have been reported in patients with Langerhans cell histiocytosis.
      • Ishii R.
      • Morimoto A.
      • Ikushima S.
      • et al.
      High serum values of soluble CD154, IL-2 receptor, RANKL and osteoprotegerin in Langerhans cell histiocytosis.
      Because most patients with ECD have sclerotic bone lesions, the potential salutary effects of these agents may be limited to a subset of individuals.

      Infliximab: An Anti–TNF-α Antibody

      Tumor necrosis factor alpha seems to regulate the recruitment of histiocytes, which has been documented in lesions of patients with ECD. Dagna et al
      • Dagna L.
      • Corti A.
      • Langheim S.
      • et al.
      Tumor necrosis factor α as a master regulator of inflammation in Erdheim-Chester disease: rationale for the treatment of patients with infliximab.
      used this rationale to treat 2 patients with severe ECD-related cardiovascular disease with the TNF-α inhibitor infliximab. Resolution of pericardial effusion and improvement in cardiac function were demonstrated.

      Future Directions

      Erdheim-Chester disease is an uncommon non-Langerhans histiocytosis that may coexist with Langerhans histiocytosis.
      • Janku F.
      • Munoz J.
      • Subbiah V.
      • Kurzrock R.
      A tale of two histiocytic disorders.
      It involves diverse organs, and it is often difficult to diagnose. Common features include bone sclerosis, orbital infiltration with proptosis, CNS involvement with diabetes insipidus, cardiac involvement, and pulmonary infiltration. Deregulation of cytokine pathways has been implicated in the pathogenesis of ECD. Responses have been seen with steroids, cytotoxic chemotherapy, bone-remodeling agents, and bone marrow transplantation. For many diseases, rational and biologic-based therapeutic targeting (Figure 5) often improves outcomes.
      • Janku F.
      • Garrido-Laguna I.
      • Petruzelka L.B.
      • Stewart D.J.
      • Kurzrock R.
      Novel therapeutic targets in non-small cell lung cancer.
      • Munoz J.
      • Kurzrock R.
      Targeted therapy in rare cancers–adopting the orphans.
      Bedside observations are often crucial as well, especially for very rare disorders. There are now well-documented responses, even though in small numbers of patients with ECD, to various easy-tolerated agents such as low-dose IFN-α, the kinase inhibitor imatinib mesylate, 2-chlorodeoxyadenosine, the IL-1 receptor antagonist anakinra, and the TNF-α antibody infliximab. There are no prospective randomized trials in this disease, nor have any therapies been approved for it. Furthermore, such trials and approvals will be difficult because of its rarity; nevertheless, international organizations, such as the ECD global alliance (www.erdheim-chester.org), foster research in orphan diseases and will be a vehicle to perform larger prospective therapeutic trials. Recently, BRAF mutations have been identified in 58% of the patients with ECD, suggesting that this entity is also a possible target for BRAF inhibitors.
      • Haroche J.
      • Cohen-Aubart F.
      • Emile J.F.
      • et al.
      Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation.
      Figure thumbnail gr5
      Figure 5Possible mechanism of action of drugs used in Erdheim-Chester disease. It has been suggested that imatinib mesylate may inhibit the differentiation of normal CD34+ stem cells into dendritic cells. Histiocytes of patients with Erdheim-Chester disease have been reported to express PDGFR-β, providing a rationale for the use of imatinib in this population; however, the mechanism of action of imatinib in this condition remains largely unknown. Abnormal histiocytes seem to have IL-1 expression, thus supporting the rationale of using the IL-1 receptor antagonist anakinra in ECD. BRAF mutations seem to be relatively common in patients with histiocytosis; hence, clinical trials using BRAF inhibitors in this condition are awaited. Infliximab seems to regulate the recruitment of histiocytes.

      Conclusion

      ECD is an uncommon multisystem non-Langerhans histiocytosis. Rare diseases are uniquely challenging from a therapeutic point of view, though increasingly many cancers may be stratified into small molecular subsets.
      • Munoz J.
      • Swanton C.
      • Kurzrock R.
      Molecular profiling and the reclassification of cancer: divide and conquer.
      • Braiteh F.
      • Kurzrock R.
      Uncommon tumors and exceptional therapies: paradox or paradigm?.
      • Tsimberidou A.M.
      • Iskander N.G.
      • Hong D.S.
      • et al.
      Personalized medicine in a phase I clinical trials program: the MD Anderson Cancer Center initiative.
      The present review details our approach to the management of ECD.

      Acknowledgments

      Drs Munoz and Janku share first authorship because they contributed equally to this work.

      References

        • Arnaud L.
        • Hervier B.
        • Néel A.
        • et al.
        CNS involvement and treatment with interferon-alpha are independent prognostic factors in Erdheim-Chester disease: a multicenter survival analysis of 53 patients.
        Blood. 2011; 117: 2778-2782
        • Marchal A.
        • Cuny J.F.
        • Montagne K.
        • Haroche J.
        • Barbaud A.
        • Schmutz J.L.
        Associated Langerhans cell histiocytosis and Erdheim-Chester disease [in French].
        Ann Dermatol Venereol. 2011; 138: 743-747
        • Arnaud L.
        • Gorochov G.
        • Charlotte F.
        • et al.
        Systemic perturbation of cytokine and chemokine networks in Erdheim-Chester disease: a single-center series of 37 patients.
        Blood. 2011; 117: 2783-2790
        • Haroche J.
        • Charlotte F.
        • Arnaud L.
        • et al.
        High prevalence of BRAF V600E mutations in Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses.
        Blood. 2012; 120: 2700-2703
        • Haroche J.
        • Cohen-Aubart F.
        • Emile J.F.
        • et al.
        Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation.
        Blood. 2013; 121: 1495-1500
        • Adam Z.
        • Koukalová R.
        • Sprláková A.
        • et al.
        Successful treatment of Erdheim-Chester disease by 2-chlorodeoxyadenosine-based chemotherapy. Two case studies and a literature review [in Czeck].
        Vnitr Lek. 2011; 57: 576-589
        • Esmaeli B.
        • Ahmadi A.
        • Tang R.
        • Schiffman J.
        • Kurzrock R.
        Interferon therapy for orbital infiltration secondary to Erdheim-Chester disease.
        Am J Ophthalmol. 2001; 132: 945-947
        • Braiteh F.
        • Boxrud C.
        • Esmaeli B.
        • Kurzrock R.
        Successful treatment of Erdheim-Chester disease, a non-Langerhans-cell histiocytosis, with interferon-alpha.
        Blood. 2005; 106: 2992-2994
        • Janku F.
        • Amin H.M.
        • Yang D.
        • Garrido-Laguna I.
        • Trent J.C.
        • Kurzrock R.
        Response of histiocytoses to imatinib mesylate: fire to ashes.
        J Clin Oncol. 2010; 28: e633-e636
        • Aouba A.
        • Georgin-Lavialle S.
        • Pagnoux C.
        • et al.
        Rationale and efficacy of interleukin-1 targeting in Erdheim-Chester disease.
        Blood. 2010; 116: 4070-4076
        • Tran T.A.
        • Pariente D.
        • Lecron J.C.
        • Delwail A.
        • Taoufik Y.
        • Meinzer U.
        Treatment of pediatric Erdheim-Chester disease with interleukin-1-targeting drugs.
        Arthritis Rheum. 2011; 63: 4031-4032
        • Haroche J.
        • Arnaud L.
        • Amoura Z.
        Erdheim-Chester disease.
        Curr Opin Rheumatol. 2012; 24: 53-59
        • Arceci R.J.
        The histiocytoses: the fall of the Tower of Babel.
        Eur J Cancer. 1999; 35 (discussion 767-769): 747-767
        • Jolles S.
        Paul Langerhans.
        J Clin Pathol. 2002; 55: 243
        • Vassallo R.
        • Ryu J.H.
        • Colby T.V.
        • Hartman T.
        • Limper A.H.
        Pulmonary Langerhans'-cell histiocytosis.
        N Engl J Med. 2000; 342: 1969-1978
        • Windebank K.
        Advances in the management of histiocytic disorders.
        Paediatr Child Health. 2008; 18: 129-135
        • Offret H.
        • Hannouche D.
        • Frau E.
        • Doyon D.
        • Quillard J.
        • Schaison G.
        Orbital Erdheim-Chester disease.
        J Francais D'Ophtalmologie. 1995; 18: 220-225
        • Breuil V.
        • Brocq O.
        • Pellegrino C.
        • Grimaud A.
        • Euller-Ziegler L.
        Erdheim-Chester disease: typical radiological bone features for a rare xanthogranulomatosis.
        Ann Rheum Dis. 2002; 61: 199-200
        • Kenn W.
        • Eck M.
        • Allolio B.
        • et al.
        Erdheim-Chester disease: evidence for a disease entity different from Langerhans cell histiocytosis? Three cases with detailed radiological and immunohistochemical analysis.
        Hum Pathol. 2000; 31: 734-739
        • Egan A.J.
        • Boardman L.A.
        • Tazelaar H.D.
        • et al.
        Erdheim-Chester disease: clinical, radiologic, and histopathologic findings in five patients with interstitial lung disease.
        Am J Surg Pathol. 1999; 23: 17-26
        • Haroche J.
        • Amoura Z.
        • Dion E.
        • et al.
        Cardiovascular involvement, an overlooked feature of Erdheim-Chester disease: report of 6 new cases and a literature review.
        Medicine (Baltimore). 2004; 83: 371-392
        • Haroche J.
        • Amoura Z.
        • Wechsler B.
        • Veyssier-Belot C.
        • Charlotte F.
        • Piette J.C.
        Erdheim-Chester disease [French].
        La Presse Médicale. 2007; 36: 1663-1668
        • Sedrak P.
        • Ketonen L.
        • Hou P.
        • et al.
        Erdheim-Chester disease of the central nervous system: new manifestations of a rare disease.
        AJNR. Am J Neuroradiol. 2011; 32: 2126-2131
        • Shamburek R.D.
        • Brewer Jr., H.B.
        • Gochuico B.R.
        Erdheim-Chester disease: a rare multisystem histiocytic disorder associated with interstitial lung disease.
        Am J Med Sci. 2001; 321: 66-75
        • Arnaud L.
        • Pierre I.
        • Beigelman-Aubry C.
        • et al.
        Pulmonary involvement in Erdheim-Chester disease: a single-center study of thirty-four patients and a review of the literature.
        Arthritis Rheum. 2010; 62: 3504-3512
        • Dion E.
        • Graef C.
        • Miquel A.
        • et al.
        Bone involvement in Erdheim-Chester disease: imaging findings including periostitis and partial epiphyseal involvement.
        Radiology. 2006; 238: 632-639
        • Haroche J.
        • Cluzel P.
        • Toledano D.
        • et al.
        Images in cardiovascular medicine. Cardiac involvement in Erdheim-Chester disease: magnetic resonance and computed tomographic scan imaging in a monocentric series of 37 patients.
        Circulation. 2009; 119: e597-e598
        • Tsuji Y.
        • Kogawa K.
        • Imai K.
        • Kanegane H.
        • Fujimoto J.
        • Nonoyama S.
        Evans syndrome in a patient with Langerhans cell histiocytosis: possible pathogenesis of autoimmunity in LCH.
        Int J Hematol. 2008; 87: 75-77
        • Dagna L.
        • Corti A.
        • Langheim S.
        • et al.
        Tumor necrosis factor α as a master regulator of inflammation in Erdheim-Chester disease: rationale for the treatment of patients with infliximab.
        J Clin Oncol. 2012; 30: e286-e290
        • Stoppacciaro A.
        • Ferrarini M.
        • Salmaggi C.
        • et al.
        Immunohistochemical evidence of a cytokine and chemokine network in three patients with Erdheim-Chester disease: implications for pathogenesis.
        Arthritis Rheum. 2006; 54: 4018-4022
        • Mossetti G.
        • Rendina D.
        • Numis F.G.
        • Somma P.
        • Postiglione L.
        • Nunziata V.
        Biochemical markers of bone turnover, serum levels of interleukin-6/interleukin-6 soluble receptor and bisphosphonate treatment in Erdheim-Chester disease.
        Clin Exp Rheumatol. 2003; 21: 232-236
        • Badalian-Very G.
        • Vergilio J.A.
        • Degar B.A.
        • et al.
        Recurrent BRAF mutations in Langerhans cell histiocytosis.
        Blood. 2010; 116: 1919-1923
        • Chapman P.B.
        • Hauschild A.
        • Robert C.
        • et al.
        Improved survival with vemurafenib in melanoma with BRAF V600E mutation.
        N Engl J Med. 2011; 364: 2507-2516
        • Tiacci E.
        • Trifonov V.
        • Schiavoni G.
        • et al.
        BRAF mutations in hairy-cell leukemia.
        N Engl J Med. 2011; 364: 2305-2315
        • Falchook G.S.
        • Long G.V.
        • Kurzrock R.
        • et al.
        Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial.
        Lancet. 2012; 379: 1893-1901
        • Falchook G.S.
        • Lewis K.D.
        • Infante J.R.
        • et al.
        Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial.
        Lancet Oncol. 2012; 13: 782-789
        • Jakobson A.M.
        • Kreuger A.
        • Hagberg H.
        • Sundstrom C.
        Treatment of Langerhans cell histiocytosis with alpha-interferon.
        Lancet. 1987; 2: 1520-1521
        • Haroche J.
        • Amoura Z.
        • Charlotte F.
        • et al.
        Imatinib mesylate for platelet-derived growth factor receptor-beta-positive Erdheim-Chester histiocytosis.
        Blood. 2008; 111: 5413-5415
        • Srikulmontree T.
        • Massey H.D.
        • Roberts W.N.
        Treatment of skeletal Erdheim-Chester disease with zoledronic acid: case report and proposed mechanisms of action.
        Rheumatol Int. 2007; 27: 303-307
        • Boissel N.
        • Wechsler B.
        • Leblond V.
        Treatment of refractory Erdheim-Chester disease with double autologous hematopoietic stem-cell transplantation.
        Ann Int Med. 2001; 135: 844-845
        • Schaefer M.
        • Sarkar R.
        • Knop V.
        • et al.
        Escitalopram for the prevention of peginterferon-alpha2a-associated depression in hepatitis C virus-infected patients without previous psychiatric disease: a randomized trial.
        Ann Intern Med. 2012; 157: 94-103
        • Haroche J.
        • Amoura Z.
        • Trad S.G.
        • et al.
        Variability in the efficacy of interferon-alpha in Erdheim-Chester disease by patient and site of involvement: results in eight patients.
        Arthritis Rheum. 2006; 54: 3330-3336
        • Benz R.
        • Siciliano R.D.
        • Stussi G.
        • Fehr J.
        Long-term follow-up of interferon-alpha induction and low-dose maintenance therapy in hairy cell leukemia.
        Eur J Haematol. 2009; 82: 194-200
        • Kurzrock R.
        • Strom S.S.
        • Estey E.
        • et al.
        Second cancer risk in hairy cell leukemia: analysis of 350 patients.
        J Clin Oncol. 1997; 15: 1803-1810
        • Seymour J.F.
        • Estey E.H.
        • Keating M.J.
        • Kurzrock R.
        Response to interferon-alpha in patients with hairy cell leukemia relapsing after treatment with 2-chlorodeoxyadenosine.
        Leukemia. 1995; 9: 929-932
        • Husken A.C.
        • Tsianakas A.
        • Hensen P.
        • et al.
        Comparison of pegylated interferon alpha-2b plus psoralen PUVA versus standard interferon alpha-2a plus PUVA in patients with cutaneous T-cell lymphoma.
        J Eur Acad Dermatol Venereol. 2012; 26: 71-78
        • Suzuki H.I.
        • Hosoya N.
        • Miyagawa K.
        • et al.
        Erdheim-Chester disease: multisystem involvement and management with interferon-alpha.
        Leuk Res. 2010; 34: e21-e24
        • Hervier B.
        • Arnaud L.
        • Charlotte F.
        • et al.
        Treatment of Erdheim-Chester disease with long-term high-dose interferon-alpha.
        Semin Arthritis Rheum. 2012; 41: 907-913
        • Utikal J.
        • Ugurel S.
        • Kurzen H.
        • et al.
        Imatinib as a treatment option for systemic non-Langerhans cell histiocytoses.
        Arch Dermatol. 2007; 143: 736-740
        • Druker B.J.
        • Sawyers C.L.
        • Kantarjian H.
        • et al.
        Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome.
        N Engl J Med. 2001; 344: 1038-1042
        • Pardanani A.
        Systemic mastocytosis in adults: 2011 update on diagnosis, risk stratification, and management.
        Am J Hematol. 2011; 86: 362-371
        • Rutkowski P.
        • Wozniak A.
        • Switaj T.
        Advances in molecular characterization and targeted therapy in dermatofibrosarcoma protuberans.
        Sarcoma. 2011; 2011: 959132
        • Reichardt P.
        • Reichardt A.
        • Pink D.
        Molecular targeted therapy of gastrointestinal stromal tumors.
        Curr Cancer Drug Targets. 2011; 11: 688-697
        • Joensuu H.
        Adjuvant treatment of GIST: patient selection and treatment strategies.
        Nat Rev Clin Oncol. 2012; 9: 351-358
        • Baccarani M.
        • Cilloni D.
        • Rondoni M.
        • et al.
        The efficacy of imatinib mesylate in patients with FIP1L1-PDGFRalpha-positive hypereosinophilic syndrome. Results of a multicenter prospective study.
        Haematologica. 2007; 92: 1173-1179
        • Koos B.
        • Jeibmann A.
        • Lünenbürger H.
        • et al.
        The tyrosine kinase c-Abl promotes proliferation and is expressed in atypical teratoid and malignant rhabdoid tumors.
        Cancer. 2010; 116: 5075-5081
        • Fielding A.K.
        How I treat Philadelphia chromosome-positive acute lymphoblastic leukemia.
        Blood. 2010; 116: 3409-3417
        • Goldman J.M.
        How I treat chronic myeloid leukemia in the imatinib era.
        Blood. 2007; 110: 2828-2837
        • Cohen P.R.
        • Kurzrock R.
        Anakinra-responsive lichen planus in a woman with Erdheim-Chester disease: a therapeutic enigma.
        Dermatol Online J. 2014; 20: 21241
        • Haroche J.
        • Arnaud L.
        • Cohen-Aubart F.
        • et al.
        Erdheim-Chester disease.
        Rheum Dis Clin North Am. 2013; 39: 299-311
        • Gabay C.
        • Lamacchia C.
        • Palmer G.
        IL-1 pathways in inflammation and human diseases.
        Nat Rev Rheumatol. 2010; 6: 232-241
        • Kannourakis G.
        • Abbas A.
        The role of cytokines in the pathogenesis of Langerhans cell histiocytosis.
        Br J Cancer Suppl. 1994; 23: S37-S40
        • Geyer M.
        • Muller-Ladner U.
        Actual status of antiinterleukin-1 therapies in rheumatic diseases.
        Curr Opin Rheumatol. 2010; 22: 246-251
        • Singh J.A.
        • Wells G.A.
        • Christensen R.
        • et al.
        Adverse effects of biologics: a network meta-analysis and Cochrane overview.
        Cochrane Database Syst Rev. 2011; : CD008794
        • Ostensen M.
        • Förger F.
        Treatment with biologics of pregnant patients with rheumatic diseases.
        Curr Opin Rheumatol. 2011; 23: 293-298
        • Sahm F.
        • Capper D.
        • Preusser M.
        • et al.
        BRAFV600E mutant protein is expressed in cells of variable maturation in Langerhans cell histiocytosis.
        Blood. 2012; 120: e28-e34
        • Munoz J.
        • Schlette E.
        • Kurzrock R.
        Rapid response to vemurafenib in a heavily pretreated patient with hairy cell leukemia and a BRAF mutation.
        J Clin Oncol. 2013; 31: e351-e352
        • Chen M.T.
        • Wang S.M.
        • Lin S.Y.
        • et al.
        Pericardial effusion as a crucial presentation of Erdheim-Chester disease in a hemodialysis patient: an overlooked diagnosis.
        Clin Nephrol. 2012; 78: 81-84
        • Taguchi T.
        • Iwasaki Y.
        • Asaba K.
        • et al.
        Erdheim-Chester disease: report of a case with PCR-based analysis of the expression of osteopontin and survivin in Xanthogranulomas following glucocorticoid treatment.
        Endocr J. 2008; 55: 217-223
        • Mahnel R.
        • Tan K.H.
        • Fahlbusch R.
        • et al.
        Problems in differential diagnosis of non Langerhans cell histiocytosis with pituitary involvement: case report and review of literature.
        Endocr Pathol. 2002; 13: 361-368
        • Gadner H.
        • Grois N.
        • Pötschger U.
        • et al.
        Improved outcome in multisystem Langerhans cell histiocytosis is associated with therapy intensification.
        Blood. 2008; 111: 2556-2562
        • Broccoli A.
        • Stefoni V.
        • Faccioli L.
        • et al.
        Bilateral orbital Erdheim-Chester disease treated with 12 weekly administrations of VNCOP-B chemotherapy: a case report and a review of literature.
        Rheumatol Int. 2012; 32: 2209-2213
        • Adam Z.
        • Balsíková K.
        • Pour L.
        • et al.
        Diabetes insipidus followed, after 4 years, with dysarthria and mild right-sided hemiparesis–the first clinical signs of Erdheim-Chester disease. Description and depiction of a case with a review of information on the disease [in Czeck].
        Vnitr Lek. 2009; 55: 1173-1188
        • Lachenal F.
        • Cotton F.
        • Desmurs-Clavel H.
        • et al.
        Neurological manifestations and neuroradiological presentation of Erdheim-Chester disease: report of 6 cases and systematic review of the literature.
        J Neurol. 2006; 253: 1267-1277
        • Adam Z.
        • Balsíková K.
        • Krejcí M.
        • et al.
        Central diabetes insipidus in adult patients–the first sign of Langerhans cell histiocytosis and Erdheim-Chester disease. Three case studies and literature review [in Czeck].
        Vnitr Lek. 2010; 56: 138-148
        • Adam Z.
        • Sprláková A.
        • Rehák Z.
        • et al.
        Partial regression of CNS lesions of Erdheim-Chester disease after treatment with 2-chlorodeoxadenosine and their full remission following treatment with lenalidomide [in Czeck].
        Klin Onkol. 2011; 24: 367-381
        • Adam Z.
        • Szturz P.
        • Pour L.
        • et al.
        Cladribine is highly effective in the treatment of Langerhans cell histiocytosis and rare histiocytic disorders of the juvenile xanthogranuloma group [in Czeck].
        Vnitr Lek. 2012; 58: 455-465
        • Gaspar N.
        • Boudou P.
        • Haroche J.
        • et al.
        High-dose chemotherapy followed by autologous hematopoietic stem cell transplantation for adult histiocytic disorders with central nervous system involvement.
        Haematologica. 2006; 91: 1121-1125
        • Ishii R.
        • Morimoto A.
        • Ikushima S.
        • et al.
        High serum values of soluble CD154, IL-2 receptor, RANKL and osteoprotegerin in Langerhans cell histiocytosis.
        Pediatr Blood Cancer. 2006; 47: 194-199
        • Janku F.
        • Munoz J.
        • Subbiah V.
        • Kurzrock R.
        A tale of two histiocytic disorders.
        Oncologist. 2013; 18: 2-4
        • Janku F.
        • Garrido-Laguna I.
        • Petruzelka L.B.
        • Stewart D.J.
        • Kurzrock R.
        Novel therapeutic targets in non-small cell lung cancer.
        J Thorac Oncol. 2011; 6: 1601-1612
        • Munoz J.
        • Kurzrock R.
        Targeted therapy in rare cancers–adopting the orphans.
        Nat Rev Clin Oncol. 2012; 9: 631-642
        • Munoz J.
        • Swanton C.
        • Kurzrock R.
        Molecular profiling and the reclassification of cancer: divide and conquer.
        Am Soc Clin Oncol Educ Book. 2013; 33: 127-134
        • Braiteh F.
        • Kurzrock R.
        Uncommon tumors and exceptional therapies: paradox or paradigm?.
        Mol Cancer Ther. 2007; 6: 1175-1179
        • Tsimberidou A.M.
        • Iskander N.G.
        • Hong D.S.
        • et al.
        Personalized medicine in a phase I clinical trials program: the MD Anderson Cancer Center initiative.
        Clin Cancer Res. 2012; 18: 6373-6383