Erdheim-Chester disease (ECD) is a rare, non-Langerhans histiocytosis of unknown aetiology, characterised by the xanthogranulomatous infiltration of different tissues by CD68+, CD1a-, S-100-foamy histiocytes.
Erdheim-Chester disease may involve virtually every organ and tissue. The clinical course depends on the extent and distribution of the lesions, ranging from asymptomatic bone involvement to multisystemic, life-threatening forms.
Diagnosis is challenging, and the overall prognosis is poor. In recent years, understanding of the pathogenic mechanisms underlying ECD inspired new therapeutic approaches with biologic agents and BRAF-inhibitors. Here we discuss the fundamentals of ECD, from its etiopathogenesis to the current treatment approach.
Although ECD is undoubtedly rare, it is arguably a largely overlooked diagnosis. Since the first description by Jakob Erdheim’s pupil William Chester in 1930, more than 500 cases were reported. In recent years, the number of new diagnoses has dramatically increased, as a result of the superior awareness of the disease among the medical community.
ECD most frequently affects males (male to female ratio: 1.5), with no relevant clinical differences between sexes. Middleaged men are most commonly affected (median age at diagnosis: 53 years). ECD is rarely encountered in the pediatric population, with only few cases reported.
Clinical Manifestations of Erdheim-Chester disease
Since histiocytes can infiltrate virtually every tissue and system, ECD has protean manifestations. The most common clinical manifestations of ECD at the time of onset are bone pain due to skeletal involvement, diabetes insipidus, and neurological and constitutional symptoms. Less common manifestations include retroperitoneal infiltration with possible ureteral obstruction, and pulmonary, cutaneous, cardiovascular, and endocrine involvement. There seem to be differences in ECD manifestations in different age groups. In particular, the incidence of cardiac and pulmonary manifestations reaches its peak in the elderly, whereas diabetes insipidus, if not present at onset, seldom develops afterwards.
Skeletal involvement is the most common clinical feature of ECD and affects virtually all patients; nevertheless, it is often clinically silent, causing medical complaints in only 50% of cases. Lower limbs are typically involved; other sites include trunk, upper limbs, and skull. Mild, persistent, and non-invalidating pain is the most common symptom.
Skeletal involvement, either clinically silent or symptomatic, is invariably revealed by appropriate radiologic investigation. Typical and almost pathognomonic findings include bilateral, symmetric cortical osteosclerosis of the diaphyseal and metaphyseal regions of the distal ends of lower and sometimes upper limbs at plain radiographs, and symmetric uptake of technetium Tc 99m by long bones of lower extremities at bone scintigraphy . Thus, evidence of typical skeletal involvement represents a cornerstone in the assessment of the diagnosis of ECD. The pattern of skeletal involvement, with sparing of the axial skeleton and of the mandible, helps differentiating ECD from LCH.
Of note, magnetic resonance imaging (MRI) shows superior sensitivity to CT for intra-axial and extraaxial lesions, and may help detecting the epiphyseal involvement of the long bones as well as periostitis. Typical MRI findings include medullary fat replacement in long bones on T1-weighted images, and uptake of gadolinium in affected areas. Still, skeletal MRI is usually unnecessary for diagnosis. Plain radiographs and bone scintigraphy should represent the techniques of choice to evaluate bone involvement and to guide the physician in the assessment of the diagnosis.
Neurological involvement is a common feature of ECD, affecting approximately half of patients, and represents an independent predictor of death. Exophthalmos secondary to retro-orbital space infiltration is the most common manifestation. It is often bilateral, rarely massive, and occasionally accompanied by compression of extra-ocular muscles and optic nerve, causing diplopia and visual impairment, respectively. Retro-orbital infiltration may prove refractory to medical therapies, and may require surgical debridement. Additional neurologic manifestations include pyramidal and cerebellar syndromes, such as gait instability or ataxia. Radiculopathy, seizure, headache, dysarthria, cranial nerves deficits and cognitive impairment have also been reported. Although patients are usually symptomatic, silent lesions have been described. Due to the high prevalence of CNS involvement, an imaging-guided diagnostic approach based on contrast-enhanced MRI and/or CT should be systematically pursued in all new ECD cases.
Endocrine manifestations in ECD may follow pituitary, hypothalamic, or adrenal infiltration. The most common endocrine manifestation is diabetes insipidus (DI), with polyuria and polydipsia. DI is the most over-looked and misdiagnosed presentation of ECD, with a median diagnostic delay of 5 years. Intriguingly, patients without DI at ECD onset seldom develop it afterwards. Rare endocrine manifestations include hyperprolactinemia, gonadotropin insufficiency, and deficiency of insulin-like growth factor. Involvement of adrenal glands causing enlargement and insufficiency is reported.
Often misdiagnosed as idiopathic retroperitoneal fibrosis (IRP), infiltration of the retroperitoneal space is a prominent manifestation of Erdheim-Chester disease, affecting approximately 30% of patients. Relevant urologic complications, such as ureteral compression with hydroureteronephrosis, may ensue . Placement of ureteral stenting is often required in cases presenting with rampant renal failure or refractory to medical treatment. Other manifestations include nephrovascular hypertension due to the compression of renal arteries, often requiring renal artery stenting, and back pain. It is critical to differentiate this manifestation from IRP, although differential diagnosis may be challenging based on imaging findings only. Involvement of the inferior vena cava and of the pelvic ureters, both uncommon in ECD, suggest a diagnosis of IRP.
Abdominal CT discloses “hairy kidneys”, a finding specific for ECD, in approximately half of patients. When feasible, ultrasound-guided biopsy of the perirenal infiltration is a useful approach for biopsy sampling.
More than 20% of ECD patients report fever, weight loss, weakness, or fatigue. Constitutional symptoms rarely represent a prominent complaint, but in some patients they persist in a relapsing-remitting fashion, accompanying new manifestations of ECD.
Pulmonary involvement is an uncommon manifestation of ECD, but is clinically relevant as it significantly worsens the prognosis. Patients usually complain of dyspnea, cough and chest discomfort, but pleural effusion and pneumothorax and may also occur.
Interstitial infiltration is typical, and may lead to lung fibrosis in the advanced stages. Chest X-rays and CT-scans reveal interstitial infiltrates and fibrosis, often with a perilymphangitic and subpleural pattern. Pulmonary function tests typically reveal a moderate restrictive pattern with normal or reduced carbon monoxide diffusion capacity (DLCO); arterial blood gases are usually normal, but may be altered by disease progression.
Cutaneous manifestations affect more than 20% of ECD patients. The most frequent manifestations are xanthelasmas (sharply demarcated, yellowish, subcutaneous deposits of fat in the periorbital spaces) and xanthomas (elsewhere on the body). Uncommon manifestations include pruritic rash and papulonodular lesions.
Cardiovascular involvement, together with pulmonary and neurological, is associated with a poor prognosis. It affects approximately 22% of patients, and its incidence seems to increase with age. Pericardial effusion is the most frequent cardiovascular manifestation of ECD. It is often asymptomatic, but may be severe and complicated by cardiac tamponade in a minority of cases. Hystiocytes may also infiltrate the heart, thus inducing the formation of pseudo-tumoral lesions that typically localize in the right atrium or in the auriculoventricular sulcus. Diastolic heart failure or restrictive cardiomyopathy may ensue. Valvular involvement with aortic and mitral insufficiency has been reported. ECD may also involve the aorta and its main branches. Circumferential infiltration of the thoracic or abdominal aorta results in a peculiar sheathing, detectable through contrast-enhanced CT scan. This radiologic finding is so distinctive that Serratrice et al. coined the term coated aorta’ to describe it unambiguously. Rarely, pericoronarial infiltration may lead to myocardial infarctions.
Diagnosis: radiologic and histologic findings
The clinical picture of ECD, albeit rare, is highly distinctive. However, some of the most common manifestations of ECD (such as skeletal, constitutional or even neurological symptoms) may lack adequate specificity to prompt a timely diagnosis. Thereby, ECD patients often endure a remarkable diagnostic delay.
Some specific imaging findings are clearly indicative of the disease:
- increased, symmetrical uptake in the distal ends of the long bones of the lower limbs, and in some cases the upper Limbs, at technetium Tc 99m bone scan;
- symmetric cortical osteosclerosis of the diaphyses and metaphyses of the long bones at plainradiographs;
- findings of ‘hairy kidneys’ and ‘coated aorta’, secondary to retroperitoneal and periaortic infiltrationrespectively, at abdominal CT-scan.
Ultimately, the diagnosis of ECD requires histological confirmation. Typical histologic findings include CD68+, CD1a-, S100- foamy histiocytes, organized into polymorphic xanthogranulomas nested among fibrosis. Conversely, histiocytes in LCH are typically CD68+, CD1a+.
Differential diagnoses include LCH, Rosai-Dor man disease, metabolic disorders (i.e. Gaucher and Niemann-Pick disease), malignancy, and sarcoidosis. ECD and LCH are found in association in a minority of patients. Given the rarity of either disease, the frequency of this association seems too high to be fortuitous, thus suggesting a pathogenic link between the two diseases. Rosai-Dorfman disease (RDD), a separate non-Langerhans form of histiocytosis, may also be present.
The pathogenesis of ECD has not been fully elucidated. Based on histopathologic findings, Erdheim-Chester disease was first hypothesized to be a Lipid storage disorder, but investigations aimed at confirming this theory were inconclusive. In the past, some authors suggested that ECD might be a clonal disease, but this observation has not been univocally confirmed. Afterwards, our group and others demonstrated the presence of a local and systemic proinflammatory cyto/chemokine network, which may be responsible for the recruitment and activation of histiocytes into ECD Lesions. These observations led to the hypothesis that cytokine blockade might be a possible therapeutic strategy for ECD, and clinical observations on small number of patients demonstrated that interLeukin (IL)-1 and tumor necrosis factor (TNF)-a blockade can be effective against ECD (51-55).
More recently, it was shown that infiltrating histiocytes from a significant proportion of ECD patients carry a mutation in the proto-oncogene BRAF. In particular, the analysis of the Largest group of ECD patients indicated that nearLy a half (19 out of 37) harbor a mutation in the genetic sequences of BRAF causing the amino acid substitution of glutamic acid for valine at position 600 of the BRAF protein (V600E). Intriguingly, the same mutation was found in up to 57% of studied specimens of Langerhans’ cell histiocytosis.
More recently, we extended these findings by showing that BRAFV600E mutation is invariabLy detectable in biopsies and in circuLating monocytes from ECD patients, and thus univocally demonstrating that ECD is a clonal disease. BRAF is a serine-threonine protein kinase that contributes to the mitogen-activated protein kinase (MAPK) transduction pathway, which regulates cell proliferation and survival. Not surprisingly, BRAFV600E is a mutational hotspot with oncogenic potential in melanomas, papillary thyroid cancers, and hairy-cell Leukemia. BRAFV600E has been associated with oncogene-induced senescence (OIS), a major protective mechanism against oncogenic events, characterized by cell- cycle arrest and the induction of pro-inflammatory molecules. Indeed, we also showed that BRAF-mutated histiocytes have markers of OIS and express senescence associated pro- inflammatory mediators. Taken altogether, these data support a central role of BRAFV600E in ECD pathogenesis, and suggest OIS as the possible link between the oncogene mutation and the observed inflammatory activation. Consistently, it has been shown that vemurafenib, a selective BRAFV600E inhibitor, exerts a dramatic efficacy in the management of ECD. Further studies are however needed to clearly establish the specific role of BRAFV600E in the pathogenesis of ECD.
Management and Therapy of Erdheim-Chester disease
Many therapeutic approaches have been explored so far, but management of ECD remains a clinical challenge requiring an integrated, multi-disciplinary approach. Early strategies included steroids, cytotoxic drugs, radiotherapy, and autologous hematopoietic stem cell transplantation, but clinical efficacy was limited and inconsistent.
Subsequently, since the first report of its efficacy in 2005, interferon-a (IFN-a) became the first-Line drug in the management of Erdheim-Chester disease. Initially, recommended dose was 3 million units three times per week. Still, the efficacy was shown to be variable pending on the site involved. In severe multisystem forms of ECD (CNS and cardiovascular involvement), recommended dose is 9 million units three times per week, continued indefinitely. Adverse effects, such as depression and fatigue, are common. PEGylated forms of IFN-a are usually more tolerated.
After the identification of a complex chemo- chine-cytokine network orchestrating the recruitment of hystiocytes into ECD Lesions, biologic agents such as the IL-1-bLocking agent anakinra were exploited with favorable results. Recently, the monoclonal antibody infliximab yielded encouraging results in two patients with cardiac involvement . The efficacy of anti-proliferative drugs imatinib and cladribine was reported , but subsequent tests on broader cohorts of patients yielded inconsistent results.
The discovery that hystiocytes from a considerable proportion of ECD patients bear the BRAFV600E mutation inspired a new therapeutic strategy. The BRAF inhibitor vemurafenib, used in the treatment of melanoma and hairy-cell leukemia, induced considerable clinical responses in a small number of patients with severe ECD. Vemurafenib currently represents a therapeutic strategy of unprecedented efficacy in the management of ECD, but severe cutaneous and hematologic adverse effects limit its use to manifestations that are either life threatening or refractory to interferon.
Follow-up and Assessment of disease activity
ECD is a chronic disease characterized by the progressive infiltration of tissues by pathologic histiocytes. Inflammatory indexes are usually elevated, but their fluctuations do not represent a reliable indicator of disease activity in our experience. Since no disease activity score has been established, a thorough radiologic screening is imperative at diagnosis and radiological re-evaluations are recommended approximately every six months, in order to adequately assess the disease.
ECD is a rare and neglected disease. Due to the raising awareness of Erdheim-Chester disease among pathologists, radiologists, and clinicians, the number of new diagnoses is continuing to increase. In recent years, some progress has been made in the understanding of ECD pathogenesis and in the development of efficacious treatment approaches. In particular, a local and systemic pro-inflammatory network and the disease-defining roles of BRAFV600E have been identified, and the efficacy of anti-inflammatory, immunomodulant, and anti-proliferative agents has been exploited in the management of the disease. A deeper comprehension of the disease and its pathogenesis is nevertheless needed to address the unmet clinical needs of ECD patients.