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The Mayo Clinic Histiocytosis Working Group Consensus Statement for the Diagnosis and Evaluation of Adult Patients With Histiocytic Neoplasms: Erdheim-Chester Disease, Langerhans Cell Histiocytosis, and Rosai-Dorfman Disease

      Abstract

      Histiocytic neoplasms, a rare and heterogeneous group of disorders, primarily include Erdheim-Chester disease, Langerhans cell histiocytosis, and Rosai-Dorfman disease. Due to their diverse clinical manifestations, the greatest challenge posed by these neoplasms is the establishment of a diagnosis, which often leads to a delay in institution of appropriate therapy. Recent insights into their genomic architecture demonstrating mitogen-activated protein kinase/extracellular signal–regulated kinase pathway mutations have now enabled potential treatment with targeted therapies in most patients. This consensus statement represents a joint document from a multidisciplinary group of physicians at Mayo Clinic who specialize in the management of adult histiocytic neoplasms. It consists of evidence- and consensus-based recommendations on when to suspect these neoplasms and what tests to order for the diagnosis and initial evaluation. In addition, it also describes the histopathologic and individual organ manifestations of these neoplasms to help the clinicians in identifying their key features. With uniform guidelines that aid in identifying these neoplasms, we hope to improve the awareness that may lead to their timely and correct diagnosis.

      Abbreviations and Acronyms:

      ALT (alanine aminotransferase), AST (aspartate aminotransferase), BUN (blood urea nitrogen), CBC (complete blood cell), CNS (central nervous system), CT (computed tomography), DI (diabetes insipidus), ECD (Erdheim-Chester disease), FDG (18F-fluorodeoxyglucose), FNA (fine-needle aspiration), FSH (follicle-stimulating hormone), H&E (hematoxylin and eosin), HRCT (high-resolution computed tomography), IGF-1 (insulinlike growth factor-1), IHC (immunohistochemical), LCH (Langerhans cell histiocytosis), LDH (lactate dehydrogenase), LH (luteinizing hormone), LN (lymph node), MAP (mitogen-activated protein), MAPK/ERK (mitogen-activated protein kinase/extracellular signal–regulated kinase), MRI (magnetic resonance imaging), PET-CT (positron emission tomography–computed tomography), PI3K/AKT (phosphatidylinositol-3-kinase/protein kinase B), RDD (Rosai-Dorfman disease), T4 (thyroxine)
      Histiocytic neoplasms are rare neoplasms (annual incidence of <5 cases per million population) originating from cells of the myeloid lineage and primarily include Erdheim-Chester disease (ECD), Langerhans cell histiocytosis (LCH), and Rosai-Dorfman disease (RDD), but also several other disorders.
      • Emile J.F.
      • Abla O.
      • Fraitag S.
      • et al.
      Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages.
      Although ECD is mainly a disease of young adults (median age, 45 years), LCH and RDD may be seen in all age groups. These neoplasms may present clinically as focal or diffuse multiple organ disease. The disease spectrum varies from incidental lesions on imaging studies to critical illness arising from severe organ dysfunction.
      Historically, ECD and LCH were considered predominantly inflammatory diseases. The demonstration of clonal Langerhans cells in nonpulmonary LCH led to its designation as a neoplastic process.
      • Willman C.L.
      Detection of clonal histiocytes in Langerhans cell histiocytosis: biology and clinical significance.
      This was subsequently supported by the discovery of BRAF V600E mutations in more than 50% of patients with LCH 2 decades later.
      • Badalian-Very G.
      • Vergilio J.A.
      • Degar B.A.
      • et al.
      Recurrent BRAF mutations in Langerhans cell histiocytosis.
      More robust evidence for the clonal origin of LCH, as well as ECD, was brought to light by the demonstration of recurrent activating mutations in the mitogen-activated protein kinase/extracellular signal–regulated kinase (MAPK/ERK) pathway in more than 90% of the patients.
      • Diamond E.L.
      • Durham B.H.
      • Haroche J.
      • et al.
      Diverse and targetable kinase alterations drive histiocytic neoplasms.
      This has led to their inclusion in the 2016 World Health Organization classification of hematopoietic and lymphoid tumors.
      • Swerdlow S.H.
      • Campo E.
      • Pileri S.A.
      • et al.
      The 2016 revision of the World Health Organization classification of lymphoid neoplasms.
      Recently, similar MAPK/ERK pathway mutations were reported in 33% of patients with RDD as well, suggesting a clonal origin in a subset of these patients.
      • Garces S.
      • Medeiros L.J.
      • Patel K.P.
      • et al.
      Mutually exclusive recurrent KRAS and MAP2K1 mutations in Rosai-Dorfman disease.
      • Goyal G.
      • Lau D.
      • Nagle A.M.
      • et al.
      Tumor mutational burden and other predictive immunotherapy markers in histiocytic neoplasms.
      Discovery of such alterations also has therapeutic implications and led to the first Food and Drug Administration approval of a drug (vemurafenib) for the treatment of BRAF V600–mutant ECD.
      • Diamond E.L.
      • Subbiah V.
      • Lockhart A.C.
      • et al.
      Vemurafenib for BRAF V600-mutant Erdheim-Chester disease and Langerhans cell histiocytosis: analysis of data from the Histology-Independent, Phase 2, Open-label VE-BASKET Study.
      Owing to their rarity and diverse clinical manifestations mimicking other conditions, histiocytic neoplasms pose a major diagnostic challenge for many clinicians. The diagnosis is frequently delayed, often after multiple attempts at tissue biopsies of critical anatomical areas. Due to the high symptom burden related to pain or organ dysfunction, patients with these neoplasms generally receive empiric treatments resulting in adverse effects, and sometimes serious complications. A lack of diagnosis or misdiagnosis is common, which can be both frustrating for the clinician and psychologically disabling for the patients and their families. Suspecting these diseases in the appropriate clinical context and establishing a diagnosis are usually the greatest challenges. Hence, there is a need for the development of evidence- and experience-based guidelines for the diagnosis and evaluation of these rare disorders. In this context, we recently established the multidisciplinary Histiocytosis Working Group within Mayo Clinic, which led to the formulation of the consensus guidelines presented herein. We focused specifically on ECD, LCH, and RDD because they are the most commonly seen histiocytic neoplasms in adults and share similar biological pathways.

      Methods

      The multidisciplinary group meetings began in June 2017 and included experts in various subspecialties who were engaged in the evaluation and management of patients with histiocytic neoplasms for several years. Owing to the multifaceted presentation of these disorders, the group consisted of experts from dermatology, endocrinology, hematology, laboratory medicine, neurology, pathology, pulmonology, radiology, and rheumatology. A primary task undertaken by this multidisciplinary group was to develop a uniform and practical approach to assist clinicians with the diagnosis of these entities. Once a diagnosis is established, patients and clinicians can benefit from input provided by centers of excellence regarding further management.
      Each member of the multidisciplinary group contributed to a section on the manifestations of ECD, LCH, and RDD pertinent to their subspecialty by review of existing literature as well as experience with our own patient cohort. The data from the Mayo cohort were provided in situations in which they addressed gaps in the existing knowledge or countered the prevailing notions. The proposed recommendations were discussed at monthly group meetings to establish a consensus. Owing to the relative paucity of prospective studies in adult histiocytic disorders, the recommendations were not graded similar to guidelines for other diseases. These recommendations are specifically focused on the evaluation of adult patients with suspected histiocytic neoplasms to aid in diagnosis and are not aimed at discussing therapeutic recommendations or baseline evaluation of a newly diagnosed patient. The latter require comprehensive evaluation, and such recommendations already exist.
      • Abla O.
      • Jacobsen E.
      • Picarsic J.
      • et al.
      Consensus recommendations for the diagnosis and clinical management of Rosai-Dorfman-Destombes disease.
      • Diamond E.L.
      • Dagna L.
      • Hyman D.M.
      • et al.
      Consensus guidelines for the diagnosis and clinical management of Erdheim-Chester disease.
      • Girschikofsky M.
      • Arico M.
      • Castillo D.
      • et al.
      Management of adult patients with Langerhans cell histiocytosis: recommendations from an expert panel on behalf of Euro-Histio-Net.
      The following sections provide an in-depth review of the common as well as uncommon organ system manifestations of each disorder, which may help in specific clinical scenarios to arrive at a diagnosis. The key features of individual neoplasms are listed in Table 1 and depicted in Figure 1, Figure 2 through 3.
      Table 1Key Features of Histiocytic Neoplasms Based on the Literature and the Mayo Clinic Cohort
      FeatureECDLCHRDD
      Organ involvement (frequency and characteristic features)
       Bones95% (pathognomonic long-bone osteosclerosis at the metadiaphysis)60% (osteolytic lesions including skull)15% (cortex-based osteolytic lesions most common)
       Nervous system40% (brainstem/cerebellum masses; cerebral white matter enhancement; dural and pituitary stalk thickening)5% (MRI with globus pallidus/dentate nucleus T1 hyperintensity; brainstem/cerebellum T2 hyperintensity; dural lesion from intracranial extension of skull lesion; pituitary stalk thickening)10% (isolated dural or parenchymal lesion)
       Endocrine40%-70%

      DI 40% (may present years before diagnosis of ECD)
      40%-70%

      DI 20%-30% (may present years before diagnosis of LCH)
      Rarely reported

      DI never reported
       Respiratory50% (mediastinal infiltration; pleural, septal, and maxillary sinus thickening)50%-60% (mostly seen in smokers; HRCT shows pulmonary nodules in the early stage, cysts in the later stage)10%-20% (primarily involving large airways and sinuses; rarely interstitial pulmonary or sinus thickening; pleural or pulmonary nodule)
       Dermatologic25% (xanthelasma-like lesions around eyes, face, neck, inguinal folds)15%-30% (papular rash; rarely subcutaneous nodules or xanthelasma-like lesions)50% (more common subcutaneous nodules, may be seen as macular or papular rash)
       Cardiac40%-70% (right atrial and atrioventricular groove infiltration; pericardial and myocardial infiltration seen on cardiac MRI)Rarely reported<5% (infiltration of the right atrium, interatrial septum, and left ventricle)
       Arterial50%-80% (periaortic infiltration “coated aorta”; infiltration of the supra-aortic trunk branches, visceral arteries, renal artery stenosis, coronary arteries)Rarely reported<5% (infiltration of the periaortic and carotid sheath)
       Retroperitoneum, including kidneys40%-50% (perinephric infiltration “hairy kidneys” with extension to renal pelvis and ureters causing renal failure; adrenal infiltration)Rarely reported5%-10% (commonly hilar masses; subcapsular infiltration; rarely perinephric coating)
       Lymph nodesNever reported5%-10% (rarely isolated)30%-50% (may present as isolated or generalized lymphadenopathy)
       Orbits30% (orbital masses)Never reported5% (orbital masses, sometimes involving the optic nerve)
      Histopathologic characteristics
      When positive, the immunohistochemical markers generally highlight all the lesional histiocytes of ECD, RDD, and LCH while being negative in the background reactive infiltrate. Patients with overlap disease (ECD-LCH or ECD-RDD) may present with features of both disorders.
       CD68++–/+
       CD163+–/++
       S100–/++/–+
       CD1a+
       Langerin+
       Factor XIIIa+–/+
      BRAF V600E
      BRAF V600E testing by immunohistochemical analysis may have insufficient sensitivity to detect the mutant protein in histiocytic neoplasms. Molecular testing methods are recommended to definitely exclude a mutation.
      +/–+/–
      DI= diabetes insipidus; ECD = Erdheim-Chester disease; HRCT= high-resolution computed tomography; LCH = Langerhans cell histiocytosis; MRI= magnetic resonance imaging; RDD = Rosai-Dorfman disease.
      a When positive, the immunohistochemical markers generally highlight all the lesional histiocytes of ECD, RDD, and LCH while being negative in the background reactive infiltrate. Patients with overlap disease (ECD-LCH or ECD-RDD) may present with features of both disorders.
      b BRAF V600E testing by immunohistochemical analysis may have insufficient sensitivity to detect the mutant protein in histiocytic neoplasms. Molecular testing methods are recommended to definitely exclude a mutation.
      Figure thumbnail gr1
      Figure 1Key features of Erdheim-Chester disease. The illustration depicts clinical and radiographic features with frequencies and descriptions (top) and histopathologic features (bottom). H&E = hematoxylin and eosin; IHC = immunohistochemistry; RDD = Rosai-Dorfman disease.
      Figure thumbnail gr2
      Figure 2Key features of Langerhans cell histiocytosis. The illustration depicts clinical and radiographic features with frequencies and descriptions (top) and histopathologic features (bottom). FNA = fine-needle aspiration; H&E = hematoxylin and eosin; IHC = immunohistochemistry.
      Figure thumbnail gr3
      Figure 3Key features of Rosai-Dorfman disease (RDD). The illustration depicts clinical and radiographic features with frequencies and descriptions (top) and histopathologic features (bottom). ECD = Erdheim-Chester disease; H&E = hematoxylin and eosin; IHC = immunohistochemistry.

      Organ Involvement: Clinical and Radiographic Characteristics

      Bones

      In ECD, lower extremity bone pain is one of the most common presenting symptoms, occurring in approximately 50% of patients.
      • Haroche J.
      • Arnaud L.
      • Cohen-Aubart F.
      • et al.
      Erdheim-Chester disease.
      Ill-defined bilateral symmetrical osteosclerosis of the metadiaphyseal bones around the knees is very common (>95%) and pathognomonic of ECD.
      • Estrada-Veras J.I.
      • O'Brien K.J.
      • Boyd L.C.
      • et al.
      The clinical spectrum of Erdheim-Chester disease: an observational cohort study.
      However, involvement of the axial skeleton and even the small bones of the feet can be seen (47% and 9%, respectively).
      • Young J.R.
      • Johnson G.B.
      • Murphy R.C.
      • Go R.S.
      • Broski S.M.
      18F-FDG PET/CT in Erdheim-Chester disease: imaging findings and potential BRAF mutation biomarker.
      Reports of complications from bone involvement are scant, with 3 cases of nontraumatic fracture in the literature, 2 of which might have been insufficiency fractures.
      • Bindra J.
      • Lam A.
      • Lamba R.
      • VanNess M.
      • Boutin R.D.
      Erdheim-Chester disease: an unusual presentation of an uncommon disease.
      • Caglar E.
      • Aktas E.
      • Aribas B.K.
      • Sahin B.
      • Terzi A.
      Erdheim-Chester disease in thoracic spine: a rare case of compression fracture.
      • Ramos-Font C.
      • Rebollo Aguirre A.C.
      • Moral Ruiz A.
      • Bellon Guardia M.
      • Cabello Garcia D.
      • Llamas-Elvira J.M.
      Occult femoral neck fracture in a patient with Erdheim-Chester disease [in Spanish].
      Although whole-body bone scintigraphy is a sensitive screening test for ECD bone involvement, 18F-fluorodeoxyglucose (FDG) positron emission tomography–computed tomography (PET-CT) can be even more sensitive, with the ability to detect subtle vertebral involvement and the added benefit of directing the biopsy site.
      • Young J.R.
      • Johnson G.B.
      • Murphy R.C.
      • Go R.S.
      • Broski S.M.
      18F-FDG PET/CT in Erdheim-Chester disease: imaging findings and potential BRAF mutation biomarker.
      • Balink H.
      • Hemmelder M.H.
      • de Graaf W.
      • Grond J.
      Scintigraphic diagnosis of Erdheim-Chester disease.
      • Ceulemans G.
      • Keyaerts M.
      • Verbruggen L.
      • et al.
      Erdheim-Chester disease detected with 99mTc MDP bone SPECT/CT.
      • Zanglis A.
      • Valsamaki P.
      • Fountos G.
      Erdheim-Chester disease: symmetric uptake in the (99m)Tc-MDP bone scan.
      • Garcia-Gomez F.J.
      • Cambil-Molina T.
      • Rios-Martin J.J.
      • de la Riva-Perez P.A.
      • Calvo-Moron C.
      • Castro-Montano J.
      Bone scintigraphy as cornerstone in the diagnosis of Erdheim-Chester disease.
      Adult LCH commonly involves bones and may occur as a bone-limited disease (38%) or as a component of multisystem disease (66%).
      • Arico M.
      • Girschikofsky M.
      • Genereau T.
      • et al.
      Langerhans cell histiocytosis in adults: report from the International Registry of the Histiocyte Society.
      The skull is most commonly involved, followed by the axial and proximal appendicular skeleton.
      • Kilpatrick S.E.
      • Wenger D.E.
      • Gilchrist G.S.
      • Shives T.C.
      • Wollan P.C.
      • Unni K.K.
      Langerhans' cell histiocytosis (histiocytosis X) of bone: a clinicopathologic analysis of 263 pediatric and adult cases.
      • Howarth D.M.
      • Gilchrist G.S.
      • Mullan B.P.
      • Wiseman G.A.
      • Edmonson J.H.
      • Schomberg P.J.
      Langerhans cell histiocytosis: diagnosis, natural history, management, and outcome.
      Bone involvement usually manifests as pain or as a mass/swelling of the involved site.
      • Stull M.A.
      • Kransdorf M.J.
      • Devaney K.O.
      Langerhans cell histiocytosis of bone.
      Aggressive radiographic patterns of bone involvement are more common, with “moth-eaten” permeative and cortically based lytic lesions that may progress with possible laminated periosteal reaction, prone to fracture. As with ECD, PET-CT has overall superior detection of LCH bone lesions compared with conventional imaging such as radiographs, computed tomography (CT), and magnetic resonance imaging (MRI).
      • Phillips M.
      • Allen C.
      • Gerson P.
      • McClain K.
      Comparison of FDG-PET scans to conventional radiography and bone scans in management of Langerhans cell histiocytosis.
      • Albano D.
      • Bosio G.
      • Giubbini R.
      • Bertagna F.
      Role of 18F-FDG PET/CT in patients affected by Langerhans cell histiocytosis.
      • Obert J.
      • Vercellino L.
      • Van Der Gucht A.
      • et al.
      18F-fluorodeoxyglucose positron emission tomography-computed tomography in the management of adult multisystem Langerhans cell histiocytosis.
      However, MRI is superior in evaluating subtle vertebral lesions.
      • Phillips M.
      • Allen C.
      • Gerson P.
      • McClain K.
      Comparison of FDG-PET scans to conventional radiography and bone scans in management of Langerhans cell histiocytosis.
      Bone scintigraphy has little role in imaging for LCH.
      • Howarth D.M.
      • Mullan B.P.
      • Wiseman G.A.
      • Wenger D.E.
      • Forstrom L.A.
      • Dunn W.L.
      Bone scintigraphy evaluated in diagnosing and staging Langerhans' cell histiocytosis and related disorders.
      In contrast, bone involvement in RDD is less common (10%-20%) and rarely occurs in isolation.
      • Foucar E.
      • Rosai J.
      • Dorfman R.
      Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): review of the entity.

      Clinicopathological features, treatment approaches, and outcomes in Rosai-Dorfman disease. Haematologica. 2019 Apr 19. pii: haematol.2019.219626. https://doi.org/10.3324/haematol.2019.219626.

      When present, RDD of the bone is usually evident clinically as pain, compressive neuropathy with spinal disease, or headache with skull involvement.
      • Demicco E.G.
      • Rosenberg A.E.
      • Bjornsson J.
      • Rybak L.D.
      • Unni K.K.
      • Nielsen G.P.
      Primary Rosai-Dorfman disease of bone: a clinicopathologic study of 15 cases.
      Skeletal RDD lesions are usually lytic, yet less aggressive and centered in the medullary space. A unique feature is the lack of periosteal reaction and large soft tissue components.
      • Demicco E.G.
      • Rosenberg A.E.
      • Bjornsson J.
      • Rybak L.D.
      • Unni K.K.
      • Nielsen G.P.
      Primary Rosai-Dorfman disease of bone: a clinicopathologic study of 15 cases.
      Our preferred imaging evaluation for RDD bone disease is similar to that for LCH with PET-CT owing to increasing evidence of its utility.
      • Raslan O.A.
      • Schellingerhout D.
      • Fuller G.N.
      • Ketonen L.M.
      Rosai-Dorfman disease in neuroradiology: imaging findings in a series of 10 patients.
      • Albano D.
      • Bosio G.
      • Bertagna F.
      18F-FDG PET/CT follow-up of Rosai-Dorfman disease.
      • Hock A.T.
      • Long M.T.
      • Sittampalam K.
      • Eng D.N.
      Rosai-Dorfman disease: FDG PET/CT findings in a patient presenting with pyrexia and cervical adenopathy.
      • Huang J.Y.
      • Lu C.C.
      • Hsiao C.H.
      • Tzen K.Y.
      FDG PET/CT findings in purely cutaneous Rosai-Dorfman disease.
      • Deshayes E.
      • Le Berre J.P.
      • Jouanneau E.
      • Vasiljevic A.
      • Raverot G.
      • Seve P.
      18F-FDG PET/CT findings in a patient with isolated intracranial Rosai-Dorfman disease.
      • Tsang J.S.
      • Anthony M.P.
      • Wong M.P.
      • Wong C.S.
      The use of FDG-PET/CT in extranodal Rosai-Dorfman disease of bone.
      • Liu B.
      • Lee N.J.
      • Otero H.J.
      • Servaes S.
      • Zhuang H.
      Rosai-Dorfman disease mimics lymphoma on FDG PET/CT in a pediatric patient.
      • Dhull V.S.
      • Passah A.
      • Rana N.
      • Kaur K.
      • Tripathi M.
      • Kumar R.
      18F-FDG PET/CT of Widespread Rosai-Dorfman disease.
      • Mar W.A.
      • Yu J.H.
      • Knuttinen M.G.
      • et al.
      Rosai-Dorfman disease: manifestations outside of the head and neck.
      • Pucar D.
      • Laskin W.B.
      • Saperstein L.
      Isolated multinodular soft-tissue Rosai-Dorfman disease on FDG PET/CT.
      • Summers M.R.
      • Pettersson G.
      • Maalouf J.F.
      • Jaber W.A.
      Sinus histiocytosis with massive lymphadenopathy: extra-nodal Rosai-Dorfman disease presenting as a rare aetiology of a large intracardiac mass.
      • Xue Q.
      • Miao W.
      Spontaneous Recovery of Rosai-Dorfman disease on FDG PET/CT.

      Neurologic

      The identification of central nervous system (CNS) involvement in histiocytic neoplasms is important because it may be associated with an increased risk of mortality, especially in ECD.
      • Arnaud L.
      • Hervier B.
      • Neel A.
      • et al.
      CNS involvement and treatment with interferon-α are independent prognostic factors in Erdheim-Chester disease: a multicenter survival analysis of 53 patients.
      Note that in some patients, asymptomatic or paucisymptomatic central and peripheral nervous system involvement can be observed.
      Erdheim-Chester disease has a predilection for the posterior fossa brain parenchyma and spinal cord; however, it can also be associated with pituitary, dural, facial sinus, and orbital involvement.
      • Parks N.E.
      • Goyal G.
      • Go R.S.
      • Mandrekar J.
      • Tobin W.O.
      Neuroradiologic manifestations of Erdheim-Chester disease.
      Involvement of the CNS occurs in approximately 40% of patients with ECD, with clinical and radiologic signs/symptoms occurring in as many as 90%.
      • Estrada-Veras J.I.
      • O'Brien K.J.
      • Boyd L.C.
      • et al.
      The clinical spectrum of Erdheim-Chester disease: an observational cohort study.
      • Parks N.E.
      • Goyal G.
      • Go R.S.
      • Mandrekar J.
      • Tobin W.O.
      Neuroradiologic manifestations of Erdheim-Chester disease.
      Cognitive impairment, ataxia, and peripheral neuropathy occur in approximately 40% to 50% of patients. Headaches are present in 20% of patients.
      • Estrada-Veras J.I.
      • O'Brien K.J.
      • Boyd L.C.
      • et al.
      The clinical spectrum of Erdheim-Chester disease: an observational cohort study.
      White matter T2 hyperintensities, with and without postgadolinium enhancement, are common and likely result from direct tumor infiltration, small vessel disease, or a neurodegenerative process. Patients without evidence of intracranial ECD have a reduction in gray matter volumes on volumetric analysis independent of treatment and intracranial disease, raising the possibility of a secondary neurodegenerative process.
      • Diamond E.L.
      • Hatzoglou V.
      • Patel S.
      • et al.
      Diffuse reduction of cerebral grey matter volumes in Erdheim-Chester disease.
      Langerhans cell histiocytosis is associated with T2 hyperintense, gadolinium-enhancing lesions most commonly of the pituitary stalk, pineal gland, and other circumventricular regions (5%-10%).
      • Goyal G.
      • Hu M.
      • Young J.R.
      • et al.
      Adult Langerhans cell histiocytosis: A contemporary single-institution series of 186 patients.
      Parenchymal involvement can occur but is rare. Symmetrical, T2 hyperintense signal changes and hypointense or hyperintense signals on T1 can also be seen in the cerebellar gray matter, pons, basal ganglia, and globus pallidum.
      • Yeh E.A.
      • Greenberg J.
      • Abla O.
      • et al.
      Evaluation and treatment of Langerhans cell histiocytosis patients with central nervous system abnormalities: current views and new vistas.
      These lesions show variable FDG uptake, in contrast to tumefactive lesions,
      • Ribeiro M.J.
      • Idbaih A.
      • Thomas C.
      • et al.
      18F-FDG PET in neurodegenerative Langerhans cell histiocytosis: results and potential interest for an early diagnosis of the disease.
      • Calming U.
      • Bemstrand C.
      • Mosskin M.
      • Elander S.S.
      • Ingvar M.
      • Henter J.I.
      Brain 18-FDG PET scan in central nervous system langerhans cell histiocytosis.
      and can be asymptomatic or associated with progressive neurologic decline. The term neurodegenerative histiocytosis has been given to the MRI signal abnormalities and neurologic dysfunction associated primarily with LCH; some of these patients may have minimal or no clinical neurologic symptoms.
      • Yeh E.A.
      • Greenberg J.
      • Abla O.
      • et al.
      Evaluation and treatment of Langerhans cell histiocytosis patients with central nervous system abnormalities: current views and new vistas.
      Rosai-Dorfman disease involving the CNS is rare (10%) and involves the dura far more frequently than the brain parenchyma.

      Clinicopathological features, treatment approaches, and outcomes in Rosai-Dorfman disease. Haematologica. 2019 Apr 19. pii: haematol.2019.219626. https://doi.org/10.3324/haematol.2019.219626.

      • Andriko J.A.
      • Morrison A.
      • Colegial C.H.
      • Davis B.J.
      • Jones R.V.
      Rosai-Dorfman disease isolated to the central nervous system: a report of 11 cases.
      A potential clue to the diagnosis is emperipolesis (lymphocytes engulfed by histiocytes) in spinal fluid.
      • Kraeft S.K.
      • Honig M.
      • Krishnamurthy S.
      Emperipolesis in the cerebrospinal fluid from a patient with Rosai-Dorfman disease.

      Endocrine

      Endocrine manifestations are relatively common, particularly in ECD and LCH, and may commonly lead to permanent endocrinopathies in these patients.
      • Rigaud C.
      • Barkaoui M.A.
      • Thomas C.
      • et al.
      Langerhans cell histiocytosis: therapeutic strategy and outcome in a 30-year nationwide cohort of 1478 patients under 18 years of age.
      • Courtillot C.
      • Laugier Robiolle S.
      • Cohen Aubart F.
      • et al.
      Endocrine manifestations in a monocentric cohort of 64 patients with Erdheim-Chester disease.
      Infiltration of the hypothalamus or pituitary may lead to impairment of both the anterior and posterior pituitary hormones in 40% to 70% of patients. Hence, all patients with ECD and LCH should undergo endocrine evaluation at baseline and during follow-up (Figure 4). Growth hormone and corticotropin deficiencies may require dynamic testing for definitive diagnosis. Histiocytic neoplasms may also increase the risk of bone and metabolic abnormalities, and patients may benefit from screening for these complications at the time of diagnosis.
      Figure thumbnail gr4
      Figure 4Suggested algorithm for the diagnosis and initial evaluation of patients with histiocytic neoplasms. ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CBC = complete blood cell; ECD = Erdheim-Chester disease; FDG PET-CT = 18F-fluorodeoxyglucose positron emission tomography–computed tomography; FSH = follicle-stimulating hormone; HRCT = high-resolution computed tomography; IGF-1 = insulinlike growth factor-1; LCH = Langerhans cell histiocytosis; LDH = lactate dehydrogenase; LH = luteinizing hormone; MAP = mitogen-activated protein; MRI = magnetic resonance imaging; RDD = Rosai-Dorfman disease; T4 = thyroxine. aFDG PET-CT may help in determining a safe and high-yield biopsy site. Some patients would have already undergone other imaging studies, which may be sufficient to guide a biopsy and establish a diagnosis. For those patients, FDG PET-CT may be considered clinically as a staging test. bPerformed by immunohistochemical (IHC) analysis, polymerase chain reaction, or next-generation target capture sequencing. Confirm negative IHC analysis findings by at least 1 other molecular method. cMolecular profiling may aid in diagnosis in ambiguous cases, as well as identifying targets for treatment. dIn ECD only. ePulmonary LCH.
      The most common presenting endocrine disorder in ECD is diabetes insipidus (DI). The prevalence of DI in ECD ranges from 25% to 50% and may precede the diagnosis by many years.
      • Courtillot C.
      • Laugier Robiolle S.
      • Cohen Aubart F.
      • et al.
      Endocrine manifestations in a monocentric cohort of 64 patients with Erdheim-Chester disease.
      • Pertuiset E.
      • Laredo J.D.
      • Liote F.
      • Wassef M.
      • Jagueux M.
      • Kuntz D.
      Erdheim-Chester disease: report of a case, review of the literature and discussion of the relation to Langerhans-cell histiocytosis [in French].
      • Cives M.
      • Simone V.
      • Rizzo F.M.
      • et al.
      Erdheim-Chester disease: a systematic review.
      It is associated with anterior pituitary hormonal deficiencies in more than 50% of patients,
      • Kaltsas G.A.
      • Powles T.B.
      • Evanson J.
      • et al.
      Hypothalamo-pituitary abnormalities in adult patients with langerhans cell histiocytosis: clinical, endocrinological, and radiological features and response to treatment.
      • Kurtulmus N.
      • Mert M.
      • Tanakol R.
      • Yarman S.
      The pituitary gland in patients with Langerhans cell histiocytosis: a clinical and radiological evaluation.
      and patients can have anterior hormone deficiencies without DI. In one study, the most common anterior pituitary deficit was growth hormone (79%), followed by gonadotropin (22%), thyrotropin (10%), and corticotropin (3%) deficiencies. Hyperprolactinemia is found in approximately 40% of patients.
      • Courtillot C.
      • Laugier Robiolle S.
      • Cohen Aubart F.
      • et al.
      Endocrine manifestations in a monocentric cohort of 64 patients with Erdheim-Chester disease.
      Normal pituitary imaging does not necessarily exclude hormonal deficiency. However, most patients with abnormal pituitary stalk MRIs have hypopituitarism.
      In addition to the hypothalamic/pituitary involvement, ECD can infiltrate peripheral endocrine glands as well, which is more common than LCH.
      • Courtillot C.
      • Laugier Robiolle S.
      • Cohen Aubart F.
      • et al.
      Endocrine manifestations in a monocentric cohort of 64 patients with Erdheim-Chester disease.
      • Makras P.
      • Alexandraki K.I.
      • Chrousos G.P.
      • Grossman A.B.
      • Kaltsas G.A.
      Endocrine manifestations in Langerhans cell histiocytosis.
      Sonographic evidence of testicular infiltration can be seen in up to 30% of males but does not always correlate with testosterone levels or sperm count.
      • Courtillot C.
      • Laugier Robiolle S.
      • Cohen Aubart F.
      • et al.
      Endocrine manifestations in a monocentric cohort of 64 patients with Erdheim-Chester disease.
      In our experience, testicular infiltration in patients with ECD may be seen due to concomitant RDD. Adrenal infiltration is also frequent and seen in 20% to 40% of patients, most commonly bilateral.
      • Hurtado M.
      • Cortes T.
      • Goyal G.
      • et al.
      OR32-1 Endocrine Manifestations of Erdheim-Chester Disease: The Mayo Clinic Experience.
      Of patients with radiographic adrenal infiltration, less than 20% develop primary adrenal insufficiency.
      • Courtillot C.
      • Laugier Robiolle S.
      • Cohen Aubart F.
      • et al.
      Endocrine manifestations in a monocentric cohort of 64 patients with Erdheim-Chester disease.

      Maraka S, Shah MV, Go RS, Mundi MS, Clarke BL. Endocrine manifestations of Erdheim-Chester disease. Paper presented at: American Association of Clinical Endocrinologists (AACE) 23rd Annual Scientific and Clinical Congress; May 14-18, 2014; Las Vegas, NV.

      Thyroid involvement may present as an enlarging mass. The prevalence of primary hypothyroidism varies from 10% to 33%,
      • Courtillot C.
      • Laugier Robiolle S.
      • Cohen Aubart F.
      • et al.
      Endocrine manifestations in a monocentric cohort of 64 patients with Erdheim-Chester disease.

      O’Keeffe DT, Shah MV, Go RS, Mundi MS, Bart L. Clarke BL. Thyroid dysfunction in Erdheim-Chester disease. Paper presented at: 85th Annual Meeting of the American Thyroid Association; October 18-23, 2015; Lake Buena Vista, FL.

      although it is unclear what percentage of hypofunction is related to histiocytosis itself.
      • Courtillot C.
      • Laugier Robiolle S.
      • Cohen Aubart F.
      • et al.
      Endocrine manifestations in a monocentric cohort of 64 patients with Erdheim-Chester disease.

      Maraka S, Shah MV, Go RS, Mundi MS, Clarke BL. Endocrine manifestations of Erdheim-Chester disease. Paper presented at: American Association of Clinical Endocrinologists (AACE) 23rd Annual Scientific and Clinical Congress; May 14-18, 2014; Las Vegas, NV.

      Ovarian infiltration is extremely rare.
      • Dubach U.C.
      • Wiesli B.
      Histiocytosis “X” with diabetes insipidus, vulva ulcerations, spontaneous penumothorax, hypothyroidism and exitus from uremia: Hand-Schueller-Christian disease without skeletal involvement [in German].
      Endocrine abnormalities may be permanent, even with treatment of the disease.
      Similar to ECD, the most common permanent endocrinopathy in LCH is DI, which is present in 20% to 30% of patients.
      • Arico M.
      • Girschikofsky M.
      • Genereau T.
      • et al.
      Langerhans cell histiocytosis in adults: report from the International Registry of the Histiocyte Society.
      • Makras P.
      • Alexandraki K.I.
      • Chrousos G.P.
      • Grossman A.B.
      • Kaltsas G.A.
      Endocrine manifestations in Langerhans cell histiocytosis.
      Diabetes insipidus can either be present before the diagnosis or manifest many years later.
      • Kaltsas G.A.
      • Powles T.B.
      • Evanson J.
      • et al.
      Hypothalamo-pituitary abnormalities in adult patients with langerhans cell histiocytosis: clinical, endocrinological, and radiological features and response to treatment.
      The risk of developing DI is greater in patients with multisystem disease.
      • Arico M.
      • Girschikofsky M.
      • Genereau T.
      • et al.
      Langerhans cell histiocytosis in adults: report from the International Registry of the Histiocyte Society.
      Anterior pituitary deficiencies typically correlate with DI and can occur years after LCH diagnosis.
      • Garcia Gallo M.S.
      • Martinez M.P.
      • Abalovich M.S.
      • Gutierrez S.
      • Guitelman M.A.
      Endocrine manifestations of Langerhans cell histiocytosis diagnosed in adults.
      Reports from small cohorts have shown that of patients with LCH and DI, 70% to 90% develop a concomitant anterior pituitary hormone deficit within 5 years, the most common being growth hormone deficiency (40%-67%), followed by gonadotropin deficiency (33%-58%), whereas corticotropin and thyrotropin deficiencies are less frequent (11%-30%).
      • Kaltsas G.A.
      • Powles T.B.
      • Evanson J.
      • et al.
      Hypothalamo-pituitary abnormalities in adult patients with langerhans cell histiocytosis: clinical, endocrinological, and radiological features and response to treatment.
      • Kurtulmus N.
      • Mert M.
      • Tanakol R.
      • Yarman S.
      The pituitary gland in patients with Langerhans cell histiocytosis: a clinical and radiological evaluation.
      The prolactin level is elevated in approximately 20% of patients.
      • Kaltsas G.A.
      • Powles T.B.
      • Evanson J.
      • et al.
      Hypothalamo-pituitary abnormalities in adult patients with langerhans cell histiocytosis: clinical, endocrinological, and radiological features and response to treatment.
      • Kurtulmus N.
      • Mert M.
      • Tanakol R.
      • Yarman S.
      The pituitary gland in patients with Langerhans cell histiocytosis: a clinical and radiological evaluation.
      Less than 50% of patients with hypopituitarism have abnormal imaging findings; conversely, almost all patients with abnormal imaging findings have pituitary hormonal deficiencies.
      • Montefusco L.
      • Harari S.
      • Elia D.
      • et al.
      Endocrine and metabolic assessment in adults with Langerhans cell histiocytosis.
      Similar to ECD, anterior and posterior hormone deficits are generally permanent and do not improve or resolve, even when LCH is successfully treated.
      • Kaltsas G.A.
      • Powles T.B.
      • Evanson J.
      • et al.
      Hypothalamo-pituitary abnormalities in adult patients with langerhans cell histiocytosis: clinical, endocrinological, and radiological features and response to treatment.
      Involvement of other endocrine glands is rare in LCH and more frequent in the context of multisystem disease. Glands reported to be affected include the thyroid, parathyroids, ovaries, and adrenals.
      • Makras P.
      • Alexandraki K.I.
      • Chrousos G.P.
      • Grossman A.B.
      • Kaltsas G.A.
      Endocrine manifestations in Langerhans cell histiocytosis.
      • Montefusco L.
      • Harari S.
      • Elia D.
      • et al.
      Endocrine and metabolic assessment in adults with Langerhans cell histiocytosis.
      Endocrine manifestations are very infrequent in patients with RDD.
      • Demicco E.G.
      • Rosenberg A.E.
      • Bjornsson J.
      • Rybak L.D.
      • Unni K.K.
      • Nielsen G.P.
      Primary Rosai-Dorfman disease of bone: a clinicopathologic study of 15 cases.
      • Andriko J.A.
      • Morrison A.
      • Colegial C.H.
      • Davis B.J.
      • Jones R.V.
      Rosai-Dorfman disease isolated to the central nervous system: a report of 11 cases.
      • Mantilla J.G.
      • Goldberg-Stein S.
      • Wang Y.
      Extranodal Rosai-Dorfman disease clinicopathologic series of 10 patients with radiologic correlation and review of the literature.
      • Kong Y.Y.
      • Kong J.C.
      • Shi D.R.
      • et al.
      Cutaneous rosai-dorfman disease: a clinical and histopathologic study of 25 cases in China.
      Very few cases of thyroid, testicular, and adrenal infiltration or encasement have been reported, and some of these represented local extension from adjacent lymph nodes (LNs).
      • Foucar E.
      • Rosai J.
      • Dorfman R.
      Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): review of the entity.
      In our experience, most patients with testicular RDD had concomitant ECD.
      • Razanamahery J.
      • Diamond E.L.
      • Cohen-Aubart F.
      • et al.
      Erdheim-Chester Disease with concomitant Rosai-Dorfman like lesions: a distinct entity mainly driven by MAP2K1.

      Respiratory

      Respiratory system involvement may manifest in up to half of the patients with ECD.
      • Diamond E.L.
      • Dagna L.
      • Hyman D.M.
      • et al.
      Consensus guidelines for the diagnosis and clinical management of Erdheim-Chester disease.
      Unlike pulmonary LCH, there is no reported association with cigarette smoking. Common findings on chest CT include mediastinal infiltration, pleural thickening/effusions, and, less commonly, pulmonary parenchymal abnormalities (interlobular septal thickening, multifocal ground-glass opacities, nodules, or cysts). Pulmonary function abnormalities are commonly present in those with pulmonary involvement, although the pattern of abnormality varies. Histopathologic confirmation of ECD is usually made by biopsy from nonpulmonary sites. If lung tissue is required for diagnostic clarification, a surgical or bronchoscopic lung biopsy is generally needed, as percutaneous biopsies may have low diagnostic yield. Also, ECD may involve sinuses, leading to maxillary sinus wall thickening in up to 50% of patients.
      • Estrada-Veras J.I.
      • O'Brien K.J.
      • Boyd L.C.
      • et al.
      The clinical spectrum of Erdheim-Chester disease: an observational cohort study.
      Pulmonary LCH is the most common histiocytic disorder of the lungs. More than 90% of adults with pulmonary LCH are active or former smokers.
      • Vassallo R.
      • Ryu J.H.
      • Schroeder D.R.
      • Decker P.A.
      • Limper A.H.
      Clinical outcomes of pulmonary Langerhans'-cell histiocytosis in adults.
      Approximately one-third of patients are asymptomatic when diagnosed; the remaining two-thirds present with cough or dyspnea on exertion.
      • Vassallo R.
      • Ryu J.H.
      • Schroeder D.R.
      • Decker P.A.
      • Limper A.H.
      Clinical outcomes of pulmonary Langerhans'-cell histiocytosis in adults.
      Constitutional symptoms occur in up to 20% of patients. Lung examination findings may be normal or demonstrate signs of airflow limitation. Findings on chest radiography are frequently abnormal, although nonspecific (eg, nodular or reticulonodular opacities bilaterally). High-resolution CT of the chest should be performed in any patient suspected of having pulmonary LCH. Small nodules measuring several millimeters to 2 cm—some with central cavitation—are often observed in the early stages.
      • Hartman T.E.
      • Tazelaar H.D.
      • Swensen S.J.
      • Muller N.L.
      Cigarette smoking: CT and pathologic findings of associated pulmonary diseases.
      In more advanced disease, nodules are less commonly seen and cysts predominate. Pulmonary function testing may reveal a reduction in diffusing capacity (observed in up to two-thirds of patients at the time of diagnosis) together with changes of either obstructive, restrictive, or mixed physiologic abnormalities.
      • Vassallo R.
      • Ryu J.H.
      • Schroeder D.R.
      • Decker P.A.
      • Limper A.H.
      Clinical outcomes of pulmonary Langerhans'-cell histiocytosis in adults.
      However, spirometry and lung volumes may be completely normal, particularly in the early stages of disease. Bronchoscopic lung biopsy is associated with a diagnostic yield of up to 50%.
      • Baqir M.
      • Vassallo R.
      • Maldonado F.
      • Yi E.S.
      • Ryu J.H.
      Utility of bronchoscopy in pulmonary Langerhans cell histiocytosis.
      However, a surgical lung biopsy may be necessary if bronchoscopic biopsy is nondiagnostic. At the time of diagnosis, all patients should undergo echocardiographic assessment to screen for pulmonary hypertension. Right-sided heart catheterization and vasoreactivity testing should be considered in selected patients with echocardiographically demonstrated pulmonary hypertension to assess its severity and aid with further management.
      • Le Pavec J.
      • Lorillon G.
      • Jais X.
      • et al.
      Pulmonary Langerhans cell histiocytosis-associated pulmonary hypertension: clinical characteristics and impact of pulmonary arterial hypertension therapies.
      Pulmonary involvement is seen in up to 20% of patients with RDD and may present as cystic change, interstitial lung disease, focal pulmonary infiltrate/nodule, or airway disease on imaging.
      • Cartin-Ceba R.
      • Golbin J.M.
      • Yi E.S.
      • Prakash U.B.
      • Vassallo R.
      Intrathoracic manifestations of Rosai-Dorfman disease.
      There is no reported association with cigarette smoking. In addition, sinus involvement can be seen occasionally as well, with maxillary sinus wall thickening similar to that seen with ECD.

      Clinicopathological features, treatment approaches, and outcomes in Rosai-Dorfman disease. Haematologica. 2019 Apr 19. pii: haematol.2019.219626. https://doi.org/10.3324/haematol.2019.219626.

      Dermatologic

      Erdheim-Chester disease can affect the skin in up to 30% of patients. Half of these patients have cutaneous involvement at diagnosis. Typically, skin lesions are yellow-brown or xanthomatous papulonodules and indurated plaques ranging from a few millimeters to 1.5 cm in diameter.

      Kobic A, Shah KK, Schmitt AR, et al. Erdheim-Chester Disease: Expanding the spectrum of cutaneous manifestations [published online ahead of print May 23, 2019]. Br J Dermatol. http://doi.org/10.1111/bjd.18153.

      The most common location is around the eyes as xanthelasma-like lesions, but the face, neck, and inframammary, axillary, and inguinal folds can also be affected.
      • Chasset F.
      • Barete S.
      • Charlotte F.
      • et al.
      Cutaneous manifestations of Erdheim-Chester disease (ECD): clinical, pathological, and molecular features in a monocentric series of 40 patients.
      Some patients report pruritus.
      In LCH, cutaneous manifestations may occur as an erythematous papular rash located in the groin or on the abdomen, chest, or back. Scalp involvement may be misdiagnosed as seborrheic dermatitis. Other manifestations include subcutaneous nodules without epidermal changes. Xanthomatous lesions may be seen as red to purple nodules with a yellowish hue. Intraoral nodules, desquamative gingivitis, mucosal ulcers, and premature loss of primary dentition can be seen as well.
      • Annibali S.
      • Cristalli M.P.
      • Solidani M.
      • et al.
      Langerhans cell histiocytosis: oral/periodontal involvement in adult patients.
      Rosai-Dorfman disease involving the skin and subcutaneous tissue can be seen in a large proportion of patients (50%).

      Clinicopathological features, treatment approaches, and outcomes in Rosai-Dorfman disease. Haematologica. 2019 Apr 19. pii: haematol.2019.219626. https://doi.org/10.3324/haematol.2019.219626.

      Solitary or multiple red-to-brown macules or papules or xanthomatous papules, nodules, and plaques usually around the orbits (eyelids) or malar region can be seen. Panniculitis (tender subcutaneous nodules) and isolated cutaneous involvement have been reported as well.
      • Ruenngam P.
      • Juntongjin P.
      Rosai-Dorfman disease presenting as panniculitis-like.

      Cardiac

      Cardiac involvement is most commonly noted in ECD, less frequently in RDD, and almost never in LCH. Owing to a lack of systematic evaluation of cardiac involvement in patients with histiocytic neoplasms, reports on the frequency and location of abnormalities are incomplete. Among series in which thoracic imaging with CT or MRI was performed, 40% to 70% of patients with ECD had abnormal cardiac findings.
      • 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.
      • Brun A.L.
      • Touitou-Gottenberg D.
      • Haroche J.
      • et al.
      Erdheim-Chester disease: CT findings of thoracic involvement.
      • Gianfreda D.
      • Palumbo A.A.
      • Rossi E.
      • et al.
      Cardiac involvement in Erdheim-Chester disease: an MRI study.
      Although ECD can involve any cardiac layer, the most frequent finding is pericardial infiltration and effusion, which can be observed in up to 42% of patients.
      • 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.
      Rarely, massive pericardial effusion complicated by cardiac tamponade may occur.
      • Estrada-Veras J.I.
      • O'Brien K.J.
      • Boyd L.C.
      • et al.
      The clinical spectrum of Erdheim-Chester disease: an observational cohort study.
      • 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.
      Myocardial infiltration is detected in more than one-third of patients, with the most common and characteristic findings of right atrial pseudotumor (30%-37%) followed by infiltration of the atrioventricular sulcus (19%).
      • Estrada-Veras J.I.
      • O'Brien K.J.
      • Boyd L.C.
      • et al.
      The clinical spectrum of Erdheim-Chester disease: an observational cohort study.
      • 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.
      • Gianfreda D.
      • Palumbo A.A.
      • Rossi E.
      • et al.
      Cardiac involvement in Erdheim-Chester disease: an MRI study.
      • 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.
      The electrophysiologic effect of such involvement has not been systematically evaluated, but atrioventricular blocks requiring pacemaker insertion have been described.
      • 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.
      Malignant arrhythmias have not been reported. Endocardial disease resulting in valvular dysfunction is less common; however, symptomatic aortic and mitral valve abnormalities have been described.
      • 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.
      Cardiac involvement in ECD portends a poor prognosis, particularly if resulting in symptomatic heart failure.
      • 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.
      Cardiac lesions are exceedingly rare in LCH and if present should raise suspicion for an ECD/LCH overlap.
      • Pickens P.V.
      • Rosenshein M.
      Histiocytosis X with pericardial effusion.
      Cardiac involvement in RDD is rare but has been reported in 17 patients with infiltration of the atria, interatrial septum, left ventricle, and pericardium.
      • Heidarian A.
      • Anwar A.
      • Haseeb M.A.
      • Gupta R.
      Extranodal Rosai-Dorfman disease arising in the heart: clinical course and review of literature.
      Classical symptoms of RDD are present in a minority of such patients, and, therefore, a high index of suspicion and histologic confirmation are required. In our own cohort, cardiac involvement was seen in less than 5% of patients.

      Clinicopathological features, treatment approaches, and outcomes in Rosai-Dorfman disease. Haematologica. 2019 Apr 19. pii: haematol.2019.219626. https://doi.org/10.3324/haematol.2019.219626.

      Arterial

      Arterial involvement in histiocytic neoplasms rarely causes symptoms that lead to diagnosis.
      • Serratrice J.
      • Granel B.
      • De Roux C.
      • et al.
      “Coated aorta”: a new sign of Erdheim-Chester disease.
      • Cavalli G.
      • Guglielmi B.
      • Berti A.
      • Campochiaro C.
      • Sabbadini M.G.
      • Dagna L.
      The multifaceted clinical presentations and manifestations of Erdheim-Chester disease: comprehensive review of the literature and of 10 new cases.
      Nevertheless, periarterial fibrosis of the thoracic or abdominal aorta is notably present in 56% to 85% of patients with ECD, with sheathing of the entire thoraco-abdominal aorta (ie, “coated aorta”) in 23% to 30%.
      • Estrada-Veras J.I.
      • O'Brien K.J.
      • Boyd L.C.
      • et al.
      The clinical spectrum of Erdheim-Chester disease: an observational cohort study.
      • Brun A.L.
      • Touitou-Gottenberg D.
      • Haroche J.
      • et al.
      Erdheim-Chester disease: CT findings of thoracic involvement.
      • 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.
      • Villatoro-Villar M.
      • Bold M.S.
      • Warrington K.J.
      • et al.
      Arterial involvement in Erdheim-Chester disease: a retrospective cohort study.
      The periarterial fibrosis is the result of histiocytic infiltration into the adventitia.
      • 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.
      • Vaideeswar P.
      • Vaz W.F.
      Erdheim-Chester disease with extensive coronary arterial involvement.
      • Loeffler A.G.
      • Memoli V.A.
      Myocardial involvement in Erdheim-Chester disease.
      Although the characteristics and distribution of arterial lesions can vary, circumferential thickening is most commonly described. The perivascular tropism in ECD is not limited to the aorta. Indeed, periarterial thickening has been reported in up to 60% of supra-aortic trunk branches.
      • Brun A.L.
      • Touitou-Gottenberg D.
      • Haroche J.
      • et al.
      Erdheim-Chester disease: CT findings of thoracic involvement.
      In addition, periarterial fibrosis of the visceral arteries has also been described in the superior mesenteric, celiac, and renal arteries.
      • 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.
      • Villatoro-Villar M.
      • Bold M.S.
      • Warrington K.J.
      • et al.
      Arterial involvement in Erdheim-Chester disease: a retrospective cohort study.
      Although involvement of the main aortic branch vessels generally has limited clinical consequence, mesenteric vessel disease has led to bowel ischemia in a minority of patients.
      • Haroche J.
      • Arnaud L.
      • Cohen-Aubart F.
      • et al.
      Erdheim-Chester disease.
      • Estrada-Veras J.I.
      • O'Brien K.J.
      • Boyd L.C.
      • et al.
      The clinical spectrum of Erdheim-Chester disease: an observational cohort study.
      Renal artery stenosis from either isolated renal artery fibrosis or extension from periadventitial thickening of the abdominal aorta can result in resistant hypertension, which improves with endovascular stenting.
      • Estrada-Veras J.I.
      • O'Brien K.J.
      • Boyd L.C.
      • et al.
      The clinical spectrum of Erdheim-Chester disease: an observational cohort study.
      • 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.
      Periarterial thickening of the coronary arteries has been reported in as many as 55% of patients with ECD evaluated with thoracic CT angiography
      • Brun A.L.
      • Touitou-Gottenberg D.
      • Haroche J.
      • et al.
      Erdheim-Chester disease: CT findings of thoracic involvement.
      ; however, clinically significant stenosis requiring intervention or resulting in myocardial infarction seems uncommon.
      • Brun A.L.
      • Touitou-Gottenberg D.
      • Haroche J.
      • et al.
      Erdheim-Chester disease: CT findings of thoracic involvement.
      • Gianfreda D.
      • Palumbo A.A.
      • Rossi E.
      • et al.
      Cardiac involvement in Erdheim-Chester disease: an MRI study.
      • Vaideeswar P.
      • Vaz W.F.
      Erdheim-Chester disease with extensive coronary arterial involvement.
      • Shah M.V.
      • Go R.S.
      Erdheim-Chester disease.
      Direct lesional infiltration of arterial structures is not a characteristic observed in LCH, although envelopment of regional arterial structures due to tumoral expansion has been reported.
      • Chen C.Y.
      • Wu M.H.
      • Huang S.F.
      • Chen S.J.
      • Lu M.Y.
      Langerhans' cell histiocytosis presenting with a para-aortic lesion and heart failure.
      Arterial infiltration in extranodal RDD is considered exceptionally rare. Nevertheless, reports of extranodal RDD involving the carotid sheath and pulmonary artery have been described.
      • Walters D.M.
      • Dunnington G.H.
      • Dustin S.M.
      • et al.
      Rosai-Dorfman disease presenting as a pulmonary artery mass.
      • Rehman T.
      • deBoisblanc B.P.
      • Kantrow S.P.
      Extranodal Rosai-Dorfman disease involving the pulmonary artery.
      • Lee L.
      • Glastonbury C.M.
      • Lin D.
      Rosai-Dorfman disease presenting as an isolated extranodal mass of the carotid sheath: a case report.

      Retroperitoneum, Including Kidneys

      Histiocytic infiltration of the retroperitoneal space is frequently observed in ECD. By CT, this is seen as a diffuse bilateral infiltrative perinephric soft tissue thickening with a stellate pattern, the so-called hairy kidney, which is highly suggestive of ECD and present in 50% to 68% of patients.
      • Haroche J.
      • Arnaud L.
      • Amoura Z.
      Erdheim-Chester disease.
      • Dion E.
      • Graef C.
      • Haroche J.
      • et al.
      Imaging of thoracoabdominal involvement in Erdheim-Chester disease.
      Most retroperitoneal infiltrates are asymptomatic. However, extension of the mass either to the renal sinus or involving the middle to distal ureters may lead to hydronephrosis, ultimately requiring ureteral stenting.
      • Haroche J.
      • Arnaud L.
      • Amoura Z.
      Erdheim-Chester disease.
      • Dion E.
      • Graef C.
      • Haroche J.
      • et al.
      Imaging of thoracoabdominal involvement in Erdheim-Chester disease.
      • Mazor R.D.
      • Manevich-Mazor M.
      • Shoenfeld Y.
      Erdheim-Chester disease: a comprehensive review of the literature.
      Perinephric infiltrates may further extend into the adrenal fossa, resulting in faint nodularity to bulky masses, present in up to 32% of patients.
      • Dion E.
      • Graef C.
      • Haroche J.
      • et al.
      Imaging of thoracoabdominal involvement in Erdheim-Chester disease.
      • Haroche J.
      • Amoura Z.
      • Touraine P.
      • et al.
      Bilateral adrenal infiltration in Erdheim-Chester disease. Report of seven cases and literature review.
      Perinephric involvement of LCH is unusual in adults and has not been reported. Destructive interstitial nephritis
      • Materne C.
      • Porubsky S.
      • Gerth J.
      • Grone H.J.
      • Wolf G.
      Histiocytosis X and renal insufficiency.
      and membranous nephropathy have been associated with lesional tissue infiltration from LCH and require renal biopsy to confirm.
      • Rachima C.M.
      • Cohen E.
      • Iaina N.L.
      • Tobar A.
      • Garty M.
      A case of Langerhans'-cell histiocytosis with membranous nephropathy.
      Perinephric infiltrate similar to ECD has been described in RDD but is much less common. The more common features observed with renal involvement of extranodal RDD include renal hilar masses, subcapsular hypodense infiltration, or renal cortical hypodense nodules.
      • Brown W.E.
      • Coakley F.V.
      • Heaney M.
      Renal involvement by Rosai-Dorfman disease: CT findings.
      • Tabata H.
      • Hisasue S.
      • Tsukamoto T.
      Extranodal Rosai-Dorfman disease of the kidney and bone.
      Massive retroperitoneal adenopathy resulting in envelopment of the kidneys or ureters can lead to postrenal obstruction.
      • Foucar E.
      • Rosai J.
      • Dorfman R.
      Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): review of the entity.
      Although postobstructive uropathy is the most common cause of renal insufficiency in patients with histiocytic neoplasms, renal parenchymal disease must also be considered if proteinuria or hematuria is present, or if renal function fails to improve with ureteral stenting.

      Reticuloendothelial and Hematopoietic System

      The involvement of the reticuloendothelial system varies widely by the end organ involved as well as the disease. Liver and spleen involvement is uncommon in all three histiocytic disorders. In contrast, LN involvement occurs quite frequently in RDD but is quite uncommon in ECD and LCH.
      • Estrada-Veras J.I.
      • O'Brien K.J.
      • Boyd L.C.
      • et al.
      The clinical spectrum of Erdheim-Chester disease: an observational cohort study.
      • Arico M.
      • Girschikofsky M.
      • Genereau T.
      • et al.
      Langerhans cell histiocytosis in adults: report from the International Registry of the Histiocyte Society.

      Clinicopathological features, treatment approaches, and outcomes in Rosai-Dorfman disease. Haematologica. 2019 Apr 19. pii: haematol.2019.219626. https://doi.org/10.3324/haematol.2019.219626.

      In a retrospective review of 45 patients with ECD, 11% each had liver and spleen involvement.
      • Shah M.V.
      • Call T.G.
      • Hook C.C.
      • et al.
      Clinical presentation, diagnosis, treatment, and outcome of patients with Erdheim-Chester disease: the Mayo Clinic experience.
      Langerhans cell histiocytosis involvement of the liver or spleen is uncommon (10%-15% each), and the prognosis is similar to that of those with pulmonary LCH.
      • Arico M.
      • Girschikofsky M.
      • Genereau T.
      • et al.
      Langerhans cell histiocytosis in adults: report from the International Registry of the Histiocyte Society.
      In RDD, 27 of 157 patients (17%) studied had liver abnormalities, with the most common manifestation being hepatomegaly.
      • Foucar E.
      • Rosai J.
      • Dorfman R.
      Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): review of the entity.
      Of these, 4 patients had biopsy-proven involvement of the liver with RDD. Similarly, 15% of patients had spleen involvement clinically manifested as mild splenomegaly.
      • Foucar E.
      • Rosai J.
      • Dorfman R.
      Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): review of the entity.
      The presentation of liver involvement varies widely from incidental finding to jaundice, hepatomegaly, cyst- or mass-like lesions, ascites, or edema.
      Involvement of the LNs in ECD is reported but quite uncommon.
      • Cavalli G.
      • Guglielmi B.
      • Berti A.
      • Campochiaro C.
      • Sabbadini M.G.
      • Dagna L.
      The multifaceted clinical presentations and manifestations of Erdheim-Chester disease: comprehensive review of the literature and of 10 new cases.
      • Sheu S.-Y.
      • Wenzel R.R.
      • Kersting C.
      • Merten R.
      • Otterbach F.
      • Schmid K.W.
      Erdheim-Chester disease: case report with multisystemic manifestations including testes, thyroid, and lymph nodes, and a review of literature.
      On review of patients with ECD seen at Mayo Clinic, 4% of patients presented with lymphadenopathy, 1 of which had a biopsy-proven disease (unpublished data). Langerhans cell histiocytosis involving the LN alone is rare and may be observed or require localized therapies.
      • Lo W.C.
      • Chen C.C.
      • Tsai C.C.
      • Cheng P.W.
      Isolated adult Langerhans' cell histiocytosis in cervical lymph nodes: should it be treated?.
      Involvement of the LNs as a part of multisystem LCH is seen in approximately 5% to 10% of patients and is thought to represent a higher risk of disease.
      • Girschikofsky M.
      • Arico M.
      • Castillo D.
      • et al.
      Management of adult patients with Langerhans cell histiocytosis: recommendations from an expert panel on behalf of Euro-Histio-Net.
      • Arico M.
      • Girschikofsky M.
      • Genereau T.
      • et al.
      Langerhans cell histiocytosis in adults: report from the International Registry of the Histiocyte Society.
      In contrast, lymphadenopathy is notably common in RDD and is referred to as sinus histiocytosis with massive lymphadenopathy. Although historically considered to be the most common manifestation, lymphadenopathy was seen in only one-third of our patients.

      Clinicopathological features, treatment approaches, and outcomes in Rosai-Dorfman disease. Haematologica. 2019 Apr 19. pii: haematol.2019.219626. https://doi.org/10.3324/haematol.2019.219626.

      One of the frequent clinical presentations is painless lymphadenopathy involving cervical, axillary, or abdominal regions accompanied by B symptoms, but a few patients may have painful or tender LNs.
      • Foucar E.
      • Rosai J.
      • Dorfman R.
      Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): review of the entity.
      On PET-CT, LNs harboring RDD tend to have the most uptake centrally, with a photopenic halo.
      • Karunanithi S.
      • Singh H.
      • Sharma P.
      • Naswa N.
      • Kumar R.
      18F-FDG PET/CT imaging features of Rosai Dorfman disease: a rare cause of massive generalized lymphadenopathy.
      There are few data on bone marrow involvement in adults with histiocytic neoplasms. Bone marrow biopsy is not routinely performed in histiocytic neoplasms and is usually only undertaken to evaluate patients with abnormalities in peripheral cell counts, such as monocytosis, unexplained anemia, or thrombocytosis. In a recent report, patients with ECD or mixed LCH/ECD had a high prevalence of concomitant myeloid neoplasms (10%), specifically myeloproliferative neoplasm, myelodysplastic syndrome, or mixed myelodysplastic/myeloproliferative overlap syndrome, including chronic myelomonocytic leukemia.
      • Papo M.
      • Diamond E.L.
      • Cohen-Aubart F.
      • et al.
      High prevalence of myeloid neoplasms in adults with non-Langerhans cell histiocytosis.
      In our experience, the prevalence of myeloid neoplasms is lower in patients with ECD (4%), although still higher than would be expected in the general population.

      Goyal G, Call TG, Hook CC, Go RS, Rech KL. Increased prevalence of myeloid neoplasms in patients with Erdheim-Chester disease. Paper presented at: Annual International ECD Medical Symposium; October 26, 2017; New York, NY.

      Approximately 30% of patients who underwent a bone marrow biopsy for abnormal peripheral blood counts were found to have ECD involvement in the marrow. Langerhans cell histiocytosis involving the bone marrow in adults had been reported, although its exact frequency is unclear.
      • Kim H.K.
      • Park C.J.
      • Jang S.
      • et al.
      Bone marrow involvement of Langerhans cell histiocytosis: immunohistochemical evaluation of bone marrow for CD1a, Langerin, and S100 expression.
      In RDD, this percentage was low as well (6%).

      Clinicopathological features, treatment approaches, and outcomes in Rosai-Dorfman disease. Haematologica. 2019 Apr 19. pii: haematol.2019.219626. https://doi.org/10.3324/haematol.2019.219626.

      We recommend a bone marrow evaluation in patients with unexplained peripheral blood cell abnormalities, especially monocytosis, thrombocytosis, or anemia.

      Histopathologic Features and Tissue Diagnosis

      Pathologic diagnosis and classification of histiocytic neoplasms is challenging owing to the rarity of the diseases and the relatively nonspecific histologic findings. Furthermore, the neoplastic cells in ECD, LCH, and RDD are often sparsely distributed in the affected organ and are surrounded by varying degrees of fibrosis and inflammatory cells. Alerting the pathologist to the clinical suspicion of a histiocytic neoplasm is often crucial to its recognition. The diagnosis may require multiple biopsies, and targeting of anatomical sites with the greatest diagnostic yield is important. Although bone lesions are often the first identified site of disease, analysis of bone specimens is often limited by crush artifact and the decalcification process. Critical ancillary studies, including immunohistochemical (IHC) analysis and genetic testing for BRAF V600E, often give false-negative results on decalcified tissues. Hence, if a bone biopsy is performed, it is important to take additional cores to be processed without decalcification or pursuing decalcification using an EDTA-based method to enable molecular analysis.
      Erdheim-Chester disease is characterized by collections of foamy histiocytes and rare Touton giant cells in a background of fibrosis.
      • Emile J.F.
      • Abla O.
      • Fraitag S.
      • et al.
      Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages.
      • Ozkaya N.
      • Rosenblum M.K.
      • Durham B.H.
      • et al.
      The histopathology of Erdheim-Chester disease: a comprehensive review of a molecularly characterized cohort.
      • Rush W.L.
      • Andriko J.A.
      • Galateau-Salle F.
      • et al.
      Pulmonary pathology of Erdheim-Chester disease.
      Lymphoplasmacytic infiltrates may be present but are generally sparse. The histiocytes in ECD show similarly positive IHC markers as that of reactive histiocytes, except for those in which BRAF V600E mutation can be demonstrated (Table 1).
      • Go H.
      • Jeon Y.K.
      • Huh J.
      • et al.
      Frequent detection of BRAF(V600E) mutations in histiocytic and dendritic cell neoplasms.
      In our experience, classic histopathologic features of foamy histiocytes are not always present in the lesional tissue and instead may demonstrate nonspecific inflammation and fibrosis. In such cases, a diagnosis of ECD is often established using characteristic clinical or radiographic features or the presence of MAPK/ERK and phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathway mutations.
      Lesions of LCH are typically more cellular than those of ECD, and the neoplastic cells often show more overt cytologic atypia. Compared with reactive Langerhans cells, the cells of LCH may have nuclei that are slightly enlarged, with delicate nuclear grooves and less condensed chromatin.
      • Girschikofsky M.
      • Arico M.
      • Castillo D.
      • et al.
      Management of adult patients with Langerhans cell histiocytosis: recommendations from an expert panel on behalf of Euro-Histio-Net.
      Intermixed eosinophils are commonly present and often numerous. Fibrosis may be present, usually minimal in soft tissues but more pronounced in bone lesions. Langerhans cell histiocytosis involves LNs in a distinct sinus pattern, which distinguishes it from the paracortical distribution of reactive Langerhans cells seen in lymphadenopathy due to inflammatory skin conditions.
      • Ravindran A.
      • Goyal G.
      • Failing J.J.
      • Go R.S.
      • Rech K.L.
      Florid dermatopathic lymphadenopathy: a morphological mimic of Langerhans cell histiocytosis.
      By IHC analysis, LCH shows a phenotype consistent with Langerhans cell differentiation, with expression of S100, CD1a, and Langerin. BRAF V600E mutation may also be demonstrated by IHC analysis.
      • Roden A.C.
      • Hu X.
      • Kip S.
      • et al.
      BRAF V600E expression in Langerhans cell histiocytosis: clinical and immunohistochemical study on 25 pulmonary and 54 extrapulmonary cases.
      Compared with ECD and LCH, RDD infiltrates often show a more inflammatory background with numerous plasma cells and may also include lymphoid follicle formation and neutrophilic infiltrates.
      • Abla O.
      • Jacobsen E.
      • Picarsic J.
      • et al.
      Consensus recommendations for the diagnosis and clinical management of Rosai-Dorfman-Destombes disease.
      The nuclei of the histiocytes are enlarged, with open chromatin and distinct centrally placed nucleoli. These histiocytes display emperipolesis, with engulfment of intact inflammatory cells within their cytoplasm. Fibrosis may be prominent, particularly in meningeal or paraspinal lesions. When involving LNs, the cells markedly distend the sinuses. The phenotype includes histiocytic markers, and there is also expression of S100.
      • Abla O.
      • Jacobsen E.
      • Picarsic J.
      • et al.
      Consensus recommendations for the diagnosis and clinical management of Rosai-Dorfman-Destombes disease.
      When a histiocytic neoplasm is suspected, immunohistochemical stains may be useful in the diagnosis and classification. The recommended panel includes CD163 or CD68, S100, CD1a, Langerin, and factor XIIIa.
      • Emile J.F.
      • Abla O.
      • Fraitag S.
      • et al.
      Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages.
      Additional stains may be useful to exclude other entities, including systemic IgG4-related disease (IgG, IgG4), low-grade B-cell lymphoma (CD20, light chains), infection, fat necrosis, and idiopathic retroperitoneal fibrosis. In addition, for ECD and LCH, IHC analysis of paraffin sections using the BRAF V600E–mutant specific antibody has high specificity, although more sensitive testing, such as pyrosequencing or digital droplet polymerase chain reaction, may be more helpful in cases with equivocal or negative IHC testing.
      • Roden A.C.
      • Hu X.
      • Kip S.
      • et al.
      BRAF V600E expression in Langerhans cell histiocytosis: clinical and immunohistochemical study on 25 pulmonary and 54 extrapulmonary cases.
      • Melloul S.
      • Helias-Rodzewicz Z.
      • Cohen-Aubart F.
      • et al.
      Highly sensitive methods are required to detect mutations in histiocytoses.
      The expected phenotypic profiles are outlined in Table 1.

      When to Suspect Histiocytic Neoplasms

      The varied clinical manifestations of histiocytic neoplasms make it challenging to ascertain a set of pathognomonic features. Most patients present with nonspecific signs and symptoms to their primary care providers and at times are referred to various subspecialists based on their symptoms. Unless these patients have abnormalities in the peripheral blood cell counts, which rarely occur in histiocytic neoplasms, they are not referred to hematology before diagnosis. In other scenarios, the histopathologic review of tissue specimens is suspicious for, but not classic for, a particular histiocytic neoplasm. This leads to a delay in diagnosis and institution of treatment in a substantial proportion of patients.
      The earliest clinical cues that should raise suspicion for ECD and LCH are central DI and bony pain in the absence of other etiologies.
      • Estrada-Veras J.I.
      • O'Brien K.J.
      • Boyd L.C.
      • et al.
      The clinical spectrum of Erdheim-Chester disease: an observational cohort study.
      • Arico M.
      • Girschikofsky M.
      • Genereau T.
      • et al.
      Langerhans cell histiocytosis in adults: report from the International Registry of the Histiocyte Society.
      Of patients with apparently idiopathic central DI, up to 5% to 10% may be due to LCH or ECD.
      • Pivonello R.
      • De Bellis A.
      • Faggiano A.
      • et al.
      Central diabetes insipidus and autoimmunity: relationship between the occurrence of antibodies to arginine vasopressin-secreting cells and clinical, immunological, and radiological features in a large cohort of patients with central diabetes insipidus of known and unknown etiology.
      However, “classic” instances are less common, and often a combination of clinical, radiologic, and histopathologic features is needed in light of one another to establish a diagnosis. This is especially true for ECD, where the histopathologic findings are often nondiagnostic due to abundant fibrosis and inflammatory infiltrate. The pathognomonic radiographic finding of ECD is metadiaphyseal osteosclerosis around the knees, and it can be elicited on vertex-to-toes (full-body) PET-CT or technetium-99m bone scintigraphy, although we prefer the former due to the ability to simultaneously evaluate for other organ involvement.
      • Estrada-Veras J.I.
      • O'Brien K.J.
      • Boyd L.C.
      • et al.
      The clinical spectrum of Erdheim-Chester disease: an observational cohort study.
      Other findings suggestive of ECD are infiltrative perinephric soft tissue thickening (“hairy kidneys”) and smooth soft tissue thickening of the aortic adventitia (“coated aorta”).
      • Estrada-Veras J.I.
      • O'Brien K.J.
      • Boyd L.C.
      • et al.
      The clinical spectrum of Erdheim-Chester disease: an observational cohort study.
      In LCH, aggressive cortically based lytic bone lesions can be suggestive of the diagnosis. In cases with pulmonary involvement, the characteristic feature is upper lobe–predominant nodular cystic lesions seen in a smoker. Although RDD was historically described as massive neck lymphadenopathy, in our experience it presents with nonmassively enlarged (1-2 cm) LNs or subcutaneous lesions in adults.

      Clinicopathological features, treatment approaches, and outcomes in Rosai-Dorfman disease. Haematologica. 2019 Apr 19. pii: haematol.2019.219626. https://doi.org/10.3324/haematol.2019.219626.

      Rosai-Dorfman disease can also be associated with autoimmune disorders such as systemic lupus erythematosus and malignancies such as lymphoma, which can serve as additional clues to aid in its diagnosis.
      • Ambati S.
      • Chamyan G.
      • Restrepo R.
      • et al.
      Rosai-Dorfman disease following bone marrow transplantation for pre-B cell acute lymphoblastic leukemia.
      • Kaur P.P.
      • Birbe R.C.
      • DeHoratius R.J.
      Rosai-Dorfman disease in a patient with systemic lupus erythematosus.
      Key features suggestive of histiocytic neoplasms and prompting further evaluation are listed in Table 2.
      Table 2Features Suspicious for Histiocytic Neoplasms
      Major features
       1. Metadiaphyseal osteosclerosis of the femur, tibia, or fibula
       2. Idiopathic central diabetes insipidus
       3. Atypical histiocytic infiltrate (CD68/CD163+) on tissue biopsy
      Other features (combined with any major feature)
       1. Dense retroperitoneal soft tissue proliferation “hairy kidney”
       2. Medium to large vessel soft tissue “coating”
       3. Upper lobe–predominant nodular cystic lung lesions in a smoker
       4. Punched-out lytic osseous lesions, often involving flat bones (skull, sternum, ribs, pelvis)

      Initial Evaluation and Diagnostic Tests

      All patients with suspected histiocytic neoplasms warrant baseline peripheral blood and imaging studies, which can aid in diagnosis and help ascertain the extent of disease (Figure 4). All of these neoplasms are FDG PET avid, which is our modality of choice to evaluate organ involvement. Because these may involve the lower extremities, we recommend the full-body (vertex-to-toes) PET-CT protocol instead of the conventional skull base–to-thigh protocol. Sometimes a focused evaluation using CT, MRI, or both may be necessary depending on patient symptoms. In addition, we recommend pursuing brain MRI due to high rates of CNS, dural, and orbital involvement, which may be asymptomatic, especially in patients with ECD and LCH. In patients with RDD, head MRI may be considered, especially for better evaluation of sinus and orbital disease compared with PET-CT. In patients with suspected ECD, cardiac MRI is recommended for capturing lesions that would otherwise be missed. In addition, we recommend comprehensive evaluation for endocrinopathies because imaging studies are not sensitive enough. Abnormalities in peripheral blood counts may also suggest the presence of a concomitant myeloid malignancy, which warrants a bone marrow biopsy.
      Due to the challenges associated with histopathologic diagnosis of these neoplasms, we also recommend histopathologic reevaluation of ambiguous cases at centers with expertise in these neoplasms, especially those with atypical histiocytic infiltrates in the appropriate clinical context. Note that instances of mixed histiocytosis occur as well, with features of overlap between ECD and either LCH or RDD. The cases with mixed ECD/LCH are found to have a higher frequency of BRAF V600E mutations in the LCH (69%) and ECD (82%) lesions compared with that reported for either entity alone (50%-60%).
      • Hervier B.
      • Haroche J.
      • Arnaud L.
      • et al.
      Association of both Langerhans cell histiocytosis and Erdheim-Chester disease linked to the BRAFV600E mutation.
      Erdheim-Chester disease may also co-occur with RDD, which mostly occurs in males, is almost always extranodal, frequently involves the testes, and most commonly is driven by MAP2K1 mutation.
      • Razanamahery J.
      • Diamond E.L.
      • Cohen-Aubart F.
      • et al.
      Erdheim-Chester Disease with concomitant Rosai-Dorfman like lesions: a distinct entity mainly driven by MAP2K1.
      In addition, the presence of a BRAF V600 mutation in the tissue specimen nearly rules out RDD. Hence, in patients with nonclassic phenotypes or unclear histopathologic features, we recommend pursuing molecular profiling using target capture next-generation sequencing for MAPK/ERK and PI3K/AKT pathway gene mutations because the presence of such mutations can help in establishing the diagnosis of a histiocytic neoplasm regardless of the specific histology. Furthermore, the presence of these mutations also aids in subsequent treatment using targeted agents.
      • Diamond E.L.
      • Subbiah V.
      • Lockhart A.C.
      • et al.
      Vemurafenib for BRAF V600-mutant Erdheim-Chester disease and Langerhans cell histiocytosis: analysis of data from the Histology-Independent, Phase 2, Open-label VE-BASKET Study.
      • Jacobsen E.
      • Shanmugam V.
      • Jagannathan J.
      Rosai-Dorfman disease with activating KRAS mutation - response to cobimetinib.
      • Cohen Aubart F.
      • Emile J.F.
      • Maksud P.
      • et al.
      Efficacy of the MEK inhibitor cobimetinib for wild-type BRAF Erdheim-Chester disease.

      Conclusion

      In summary, these guidelines are based on review of existing literature and our own experience. Hence, they are likely subject to change as new data emerge. We hope that the comprehensive clinical phenotype descriptions, in conjunction with the evaluation and workup guidelines, help in raising awareness of these disorders and lead to correct and early diagnosis. Because we now have targeted therapies for these histiocytic neoplasms on the horizon, an accurate and expedited diagnosis of these rare neoplasms will hopefully allow for more timely treatment with better outcomes.

      Acknowledgments

      This manuscript is dedicated to Kathy Brewer, founder of the ECD Global Alliance (http://erdheim-chester.org), and patients with histiocytic disorders all over the world as they are our major inspiration for this work. We thank Donna DeSmet, Division of Biomedical and Scientific Visualization, Mayo Clinic, for her assistance in creation of the color illustrations.

      Supplemental Online Material

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