Erdheim-Chester disease (ECD) is a rare form of non-Langerhans’ cell histiocytosis. Diagnosis of ECD is based on the identification in tissue biopsy of histiocytes, which are typically foamy and immunostain for CD68+ CD1a−. Central nervous system involvement is a major prognostic factor in ECD. Interferon alpha may be the best first-line therapy and significantly improves survival of ECD. The BRAFV600E mutation is found in more than 50% of cases. Vemurafenib has been used for a small number of patients harbouring this mutation; inhibition of BRAF activation by vemurafenib was highly beneficial in these cases of severe multisystemic and refractory ECD.
Key points
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Diagnosis of Erdheim-Chester disease (ECD) is based on the identification in tissue biopsy samples of histiocytes, which are typically foamy and immunostain for CD68+ CD1a–, whereas histiocytes in cases of Langerhans cell histiocytosis (LCH) are CD68+ CD1a+.
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Two signs highly suggestive of ECD are technetium Tc 99m bone scintigraphy showing nearly constant tracer uptake by the long bones and a hairy kidney appearance on abdominal computed tomography scan (observed in about half such cases).
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Central nervous system involvement is a key prognostic factor and an independent predictor of death in ECD.
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Interferon α (IFN-α) (or PEGylated IFN-α) may be the best first-line therapy for prolonged treatment of ECD and significantly improves survival. Tolerance of this treatment is poor in some cases.
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ECD is associated with intense systemic immune activation mainly involving IFN-α, interleukin 1 (IL-1)/IL-1 receptor antagonist, IL-6, IL-12, and monocyte chemotactic protein 1, consistent with the systemic immune Th-1-oriented disturbance associated with this disorder.
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The BRAF V600E mutation is an activating mutation of the proto-oncogene BRAF, and is found in more than 50% of cases of ECD. Vemurafenib has been used for a few patients harboring this mutation and with severe multisystemic and refractory ECD and LCH; inhibition of BRAF activation by vemurafenib was highly beneficial in these cases.
Introduction
Erdheim-Chester disease (ECD) is a rare, non-Langerhans form of histiocytosis of unknown origin. The disease was first described as the lipoid granulomatose by Jakob Erdheim’s pupil William Chester in 1930. Between then and January 2013, more than 500 cases were reported. ECD is characterized by xanthomatous or xanthogranulomatous infiltration of tissues by foamy histiocytes, lipid-laden macrophages or histiocytes, surrounded by fibrosis. The immunohistologic characteristics of histiocytes can be used to distinguish ECD from Langerhans cell histiocytosis (LCH): in ECD, cells stain positive for CD68 and negative for CD1a; staining for the S-100 protein is also negative in most cases (80%).
ECD is a true multisystemic disease, with diverse manifestations, including skeletal involvement with bone pain, exophthalmos, diabetes insipidus, xanthelasma, interstitial lung disease, bilateral adrenal enlargement, retroperitoneal fibrosis with perirenal or ureteral obstruction, renal impairment, testis infiltration, and the involvement of the central nervous system (CNS) or cardiovascular system.
The clinical course of ECD is largely dependent on the extent and distribution of the disease. It may involve only asymptomatic bone lesions or present as multisystemic, life-threatening forms with poor prognosis. This review focuses on the 53 patients published in 2011 ( Table 1 ). Our personal experience with ECD has increased rapidly since then. We have seen 95 patients with ECD at least once, and most of them were regularly assessed in our center, between 1991 and January 2013. Most of these patients live in France, although 21 come from abroad, mainly Europe, and some from Israel and South Africa. Twenty of these patients have died (21%).
| From the Literature (%) | Personal Experience (%) a | |
|---|---|---|
| Bone pain | 50 | 40 b |
| Periaortic infiltration | 60 | 66 |
| Coated aorta (sheathing of the whole thoracoabdominal aorta) | 30 | 23 b |
| Pericardial involvement | 45 | 42 |
| Exophthalmos | 27 | 25 |
| Diabetes insipidus | 27 | 25 b |
| Xanthelasmas | 19 | 28 |
| Hairy kidney aspect | ND | 68 |
| CNS involvement | 15–25 | 51 |
| Pulmonary involvement | 22 | 43 |
| Death | 60 | 26 |
a In all cases, unless mention of comparison with another series, based on the 53 patients in the series published in 2011.
b Compared with the 48 patients followed at Pitié-Salpêtrière Hospital (taken from the 53 patients from the series published in 2011 ).
Histiocytoses are heterogenous diseases and some patients present with associations of various types of histiocytoses (most often ECD and LCH but also with Rosai-Dorfman disease (RDD), another non-Langerhans form of histiocytosis, with a generally more favorable outcome). Such associations are found in about 15% of the 95 patients followed at our institution until January 2013: 11 patients had ECD and LCH, 2 had ECD and RDD, and 1 had LCH, ECD, and RDD. The frequency of these overlap forms of LCH and ECD seems to be too high to be fortuitous, and suggests a pathogenic link between the various histiocytic disorders. Clinicians should be aware of this association and should consider the possibility of ECD in patients with LCH.
Diagnostic Criteria
The diagnosis of ECD is mainly based on the characteristic histology of the disease ( Fig. 1 ): infiltration with foamy histiocytes nested among polymorphic granuloma and fibrosis or xanthogranulomatosis, with CD68-positive and CD1a-negative immunohistochemical staining. Virtually any tissue can be infiltrated by histiocytes in ECD.
There are 2 signs that are highly suggestive of ECD: tracer uptake by the long bones is observed by technetium Tc 99m bone scintigraphy ( Fig. 2 ) in almost all patients (96% of our 53 patients) ; and hairy kidney on abdominal computed tomography (CT) scan ( Fig. 3 ) (≈50% of cases). Biopsy is required to diagnose ECD, so an elegant diagnostic approach is to use ultrasound-guided biopsy of the perirenal infiltration (when present, ie, 68% of our 53 patients).
Our team has established possible diagnostic criteria for ECD:
- 1.
Characteristic histologic findings (see Fig. 1 ): infiltration by foamy histiocytes into polymorphic granuloma and fibrosis or xanthogranulomatosis with CD68-positive and CD1a-negative immunohistochemistry, typical of ECD histiocytes;
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Typical skeletal findings with (a) radiographs showing bilateral and symmetric cortical osteosclerosis of the diaphyseal and metaphyseal regions in the long bones or (b) technetium Tc 99m bone scintigraphy evidence of symmetric and abnormally strong labeling of the distal ends of the long bones of the lower limbs, and in some cases the upper limbs.
These ECD criteria were those used for our previous literature reviews in 1996, 2004, and 2011. All cases followed at our center fulfilled criterion 1 and all but 4 fulfilled criterion 2.
Thus, a few cases of true ECD lack the typical hallmark of the disease, defined by the long bone involvement; in these cases, bone scintigraphy, radiographs, magnetic resonance imaging (MRI) and positron emission tomography (PET)-CT investigations do not reveal abnormalities.
Epidemiology
The 95 patients currently followed at our center are mostly men (74% men and 26% women), consistent with our previous analysis in 2011. The mean age at diagnosis in the 2 large series published by our team was relatively stable between 2004 and 2011: 55 years ± 14 (range, 16–80 years) in the 2011 series. ECD is rarely described in children, and there have been only 8 pediatric cases reported, none of which had cardiac involvement.
The mean delay before diagnosis for the patients included in our preliminary study in 2006 was between a few months and several years (up to 25 years). However, this delay has shortened substantially because of better awareness of the disease.
Clinical Manifestations
Osseous involvement
Almost all patients with ECD present with skeletal involvement (96% of the 53 patients reported in the 2011 series), but only 50% of patients suffer bone pain, which is nevertheless the most common clinical feature of ECD (see Table 1 ). The bone pain mostly affects the legs, is often mild, and can emerge at any time. Typical skeletal findings in cases of ECD are bilateral and symmetric cortical osteosclerosis of the diaphyseal and metaphyseal regions in the long bones on radiographs or symmetric and excessive labeling of the distal ends of the long bones of the legs, and sometimes the arms, on technetium Tc 99m bone scintigraphy. Unlike LCH, the axial skeleton and the mandible are typically not affected in cases of ECD. PET using 18 F-labeled fluorodeoxyglucose (PET-CT) has recently been used rather than bone CT scans. Bone MRI may be informative in some cases, because unlike radiographs, it may reveal the epiphyseal involvement of the long bones and periostitis. It may also be useful in the rare cases of ECD for which bone CT scans reveal no anomalies.
Cardiovascular involvement
Recent case reports show how improvements in radiologic imaging techniques have increased the likelihood of detecting cardiovascular involvement. The most frequent cardiovascular manifestations are the involvement of the circumferential periaortic sheathing of the thoracic or abdominal aorta (66% of cases in our series in 2011). Serratrice and colleagues coined the term “coated aorta” for cases in which the whole aorta is sheathed (38% of cases in the series we reported in 2006). The periarterial infiltration may spread to the main aortic branches, generally with limited clinical consequences apart from renovascular hypertension (21% of our 95 patients), which can be treated by renal artery stenting.
Although myocardium and endocardium may be involved, pericardial involvement is by far the most frequent heart lesion (42% of the 53 patients) and may be complicated by a tamponade. Systematic retrospective cardiovascular screening (MRI or heart CT scan) in 2009 revealed abnormal heart imaging results in 70% of 37 patients: 49% showed abnormal infiltration of the right heart, including 30% with pseudotumoral infiltration of the right atrium, and 19% had infiltration of the auriculoventricular sulcus.
Myocardial infarctions secondary to pericoronarial infiltration have been reported in about 15 patients, leading to death in some cases. Symptomatic heart valve disease (aortic and mitral regurgitations) were reported in 17% of 53 patients studied. Valve replacement was required in 3 patients, including 1 case in our center. However, valve replacement should be carefully discussed on a case-by-case basis at a specialist center, because this intervention can be challenging technically due to the overall infiltration of the heart tunics.
Retro-orbital infiltration
One-quarter of the patients in our series developed exophthalmos, often bilateral, because of infiltration of the retro-orbital soft tissues. It is massive in rare cases, and may be refractory to conventional therapies and require surgical debulking.
Endocrine involvements
The most frequent endocrine manifestation of ECD is diabetes insipidus caused by infiltration of the pituitary gland (25% of our patients). Pituitary or hypothalamic infiltration with various other endocrine consequences, such as hyperprolactinemia, gonadotropin insufficiency, and abnormally low levels of insulinlike growth factor 1 has been reported in rare cases.
We reported 7 cases of adrenal gland enlargement in a series of 22 patients with ECD. In all cases, the diagnosis was radiologic and was confirmed by autopsy in 1 patient. One of these patients had adrenal insufficiency. These investigations indicate that adrenal infiltration is not rare in patients with ECD and may in some cases lead to adrenal insufficiency.
Cutaneomucosal involvements
Xanthelasmas, most frequently on the eyelids or in the periorbital spaces, affected 28% of our 53 patients. Although less frequent, papulonodular lesions, and infiltrations of the vulva and of the clitoris may be observed.
Urologic and nephrologic infiltrations
Approximately 30% of ECD cases present with pseudoretroperitoneal fibrosis, sometimes complicated by bilateral hydronephrosis, which may require ureteral stenting. By contrast with idiopathic retroperitoneal fibrosis, the pelvic ureters are never involved in ECD cases and the inferior vena cava is rarely affected. This fibrosis sheaths the aortic walls completely and circumferentially, whereas in cases of idiopathic retroperitoneal fibrosis, the posterior aortic wall is rarely affected.
Pulmonary involvement
We reported a retrospective study, performed in 2008, of the characteristics of 34 consecutive patients with ECD. High-resolution CT scans of the chest revealed the involvement of lung parenchyma in 53% of the cases, and of the pleura in 41%. The pulmonary lesions predominantly involve the interlobular septa. Pulmonary involvement was not found to be a major prognostic factor in ECD and this finding contrasts with those of previous small case series. A MEDLINE search identified descriptions of pulmonary involvement in 70 (22%) of the 319 patients with ECD reported before November 2008. However, this feature was often incompletely described.
CNS involvement
CNS involvement is a common feature of ECD (15%–25%), and was extensively described in the largest neurologic series, reported in 2006. This multicenter literature review analyzed 66 patients with ECD (including 6 personal cases) with neurologic involvement. The most frequent clinical manifestations were cerebellar and pyramidal syndromes (41% and 45% of cases, respectively); seizures, headaches, neuropsychiatric manifestations or cognitive impairment, sensory disturbances, cranial nerve paralysis, and asymptomatic lesions have also been reported. Neurologic involvement led to severe functional disability in almost all patients. CNS involvement is a major prognostic factor in ECD: our survival analysis in 2011 indicated that it is an independent predictor of death (hazard ratio [HR] = 2.51; 95% confidence interval [CI], 1.28–5.52; P = .006).
We reviewed brain MRI, performed up to 2009, for 33 patients with ECD followed at Pitié-Salpêtrière Hospital. The imaging results were normal for only 3 patients, and at least 2 different anatomic sites were involved in two-thirds of the patients. Lesions of the brain, meninges, facial bones and orbits are frequent in ECD and brain MRI and CT should be used systematically in all patients with ECD, even those who are asymptomatic.
Other infiltrations
Several other organs have been reported to be involved in ECD. In particular, testes, thyroid, and lymph node involvement has been revealed by autopsy. Breast infiltration has also been described in numerous case reports.
Trying to Assess Disease Activity
The clinical course of ECD has not been rigorously established, although it seems to be that of a chronic disease. The various organs and systems affected by ECD accumulate lesions that do not generally regress spontaneously. The C-reactive protein (CRP) concentration is increased in more than 80% of cases, but this has little therapeutic impact once the diagnosis is established. Disease activity is mainly evaluated by regular clinical examination and radiologic investigations (about every 6 months). No disease activity score has been established.
Our experience is that PET scanning is particularly valuable for assessing disease activity in cases of ECD. Follow-up PET scans are particularly useful for assessing CNS involvement: PET scanning can reveal early therapeutic responses of CNS lesions, even before MRI shows a decrease in their size. PET scanning can also be used to evaluate the cardiovascular system, and the heart and the entire vascular tree can be studied during a single session. We therefore recommend using PET for assessment of patients with ECD, because this single technique is informative about many of the most relevant lesions encountered in patients with ECD. Furthermore, we found PET investigations particularly valuable in our recent pilot study of use of BRAF inhibitors in patients with ECD.
First-Line Treatment of ECD is Interferon α
The treatments used up to 2005 in cases of ECD included steroids, cytotoxic agents, and double autologous hematopoietic stem cell transplantation. It was difficult to assess the efficacy of such treatments because many were used for only a few patients, in combination with other drugs, or the follow-up periods were short. Braiteh and colleagues administered interferon α (IFN-α) to 3 patients with ECD and described rapid, substantial, and long-lasting regression of retro-orbital infiltration and gradual improvement in bone lesions, pain, and diabetes insipidus. However, we found that the efficacy of IFN-α at low doses (3 MU × 3/wk) was different between the 8 patients with ECD treated and according to the site involved in the disease. Symptoms in some cases failed to respond to such low-dose IFN-α, especially in patients with severe multisystem forms of ECD (CNS and cardiovascular involvement). We therefore recommend higher doses, if possible, up to 9 MU × 3/wk, because such doses may be more effective against meningeal infiltrations, suprasellar and retrosellar masses, and pericardial and pseudoatrial infiltrations. Treatment should be long-term, and this may be problematic because of side effects, including depression and fatigue. The effectiveness of IFN-α in cases of pseudodegenerative forms of cerebellar involvement (similar to that observed in LCH) has been disappointing.
Nevertheless, the evidence overall is that IFN-α is a valuable first-line therapy for prolonged treatment of ECD. In a recent survival analysis of our series of 53 patients, we found that treatment with IFN-α or PEGylated IFN-α was a major independent predictor of survival (HR = 0.32; 95% CI, 0.14–0.70; P = .006). Our current attitude is to start treatment with PEGylated forms of IFN-α, because it is generally better tolerated than IFN-α in the long-term.
There were reports in 2010 of the efficacy of imatinib mesylate in histiocytoses, although our preliminary experience with this treatment in 6 patients with ECD was disappointing. Promising results were reported, in the same year, for recombinant human interleukin 1 (IL-1) receptor (anakinra) treatment of 2 patients with ECD; neither of these patients had cardiovascular or CNS involvement. After this report, we administered this treatment to 10 patients with ECD at our institution: overall, the efficacy was poor. Cladribin may be beneficial for treating CNS localizations of the disease refractory to IFN-α, although the outcome was not favorable among the few patients receiving this treatment at our center. The use of infliximab, with some success after 12 to 18 months of treatment, in 2 patients with ECD with cardiac involvement was reported in 2012. Even more encouraging was the demonstration in 2012 of the rapid efficacy of a BRAF inhibitor (vemurafenib) in 3 patients.
BRAF Inhibition May be an Alternative to IFN-α in Patients with ECD Carrying the BRAF V600E Mutation
The RAS-RAF-MEK-ERK pathway is a cellular signaling pathway, and is involved in diverse tumors. The BRAF V600E mutation has been identified in many human tumors. It is an activating mutation of the proto-oncogene BRAF, and results in an activation of the RAS-ERK pathway, independently of RAS activation. Inhibition of BRAF activation by vemurafenib improves the survival of patients with metastatic melanomas carrying the BRAF V600E mutation. BRAF V600E mutations were detected in patients with LCH in 2010. We therefore tested for this mutation in other types of histiocytosis. We reviewed histology findings for 127 patients with histiocytoses, and screened DNA extracted from paraffin-embedded samples for BRAF V600E mutations by pyrosequencing. The diagnoses corresponding to the samples studied were ECD, LCH, RDD, juvenile xanthogranuloma, histiocytic sarcoma, xanthoma disseminatum, interdigitating dendritic cell sarcoma, and necrobiotic xanthogranuloma (n = 46, 39, 23, 12, 3, 2, 1, and 1, respectively). BRAF status was successfully determined in 93 cases, and BRAF V600E mutations were detected in 13 of 24 (54%) ECD samples, 11 of 29 (38%) LCH samples, and none of the other histiocytoses tested. Subsequently, we reported BRAF mutations in 51% of a series of 37 patients with ECD.
Vemurafenib is a newly approved inhibitor of mutant BRAF, and has some efficacy against both melanoma and hairy-cell leukemia associated with the BRAF V600E mutation. We therefore conducted a pilot study of vemurafenib treatment of 3 patients with multisystemic and refractory ECD, and carrying the BRAF V600E mutation; 2 also had skin or lymph node LCH involvement. The patients were followed clinically, biologically (CRP values), histologically (skin biopsy), and morphologically (PET, CT, and MRI). Vemurafenib treatment led to substantial and rapid clinical and biologic improvement in all 3 cases. The tumor response was confirmed by PET, CT, or MRI after 1 month of treatment. For 1 patient, the PET response increased between months 1 and 4 of treatment. The treatment remained effective after 9 months of follow-up, although disease activity persisted in 1 patient. These findings lead us to believe that treatment with vemurafenib should be considered for patients with severe and refractory BRAF V600E histiocytoses, particularly when the disease is life-threatening.
Follow-Up
The 2 series we published before the IFN-α era showed the severity of the prognosis of ECD. In 2004, 35 (60%) of the 58 patients for whom data were available died, and the mean survival after diagnosis was 19.2 months (range, 0–120 months). However, the most recent data, those from our survival analysis in 2011, show that overall mortality after treatment with IFN-α is now only 26%, and the 5-year survival is 68%.
Pathophysiology
The pathogenesis of ECD was poorly documented, mostly because previous studies included only a few patients. Stoppacciaro and colleagues described an immunohistochemical study of 3 patients, showing that histiocyte recruitment and accumulation in the lesions is regulated by a complex network of cytokines and chemokines. Dagna and colleagues studied both spontaneous and stimulated cytokine production by mononuclear cells in biopsy fragments from a single patient; these investigators reported the production of tumor necrosis factor α after stimulation, and spontaneous secretion of IL-6 and IL-8, IL-8 being a chemoattractant for polymorphonuclear cells and monocytes. Aouba and colleagues reported evidence in 2 patients that targeting the IL-1 pathway might be beneficial. We recently assayed serum samples from 37 patients with ECD for 23 cytokines. We found substantial and systemic immune activation, mainly involving IFN-α, IL-1/IL-1 receptor antagonist, IL-6, IL-12, and monocyte chemotactic protein 1. This finding further confirms that ECD is associated with systemic immune Th-1-oriented perturbation, and provides clues for choosing better-targeted therapeutic agents.
The recent finding of BRAF V600E mutations in more than 50% of ECD cases clearly adds further complexity to the pathophysiology of this disorder: it also provides evidence of clonal proliferation (associated with the BRAF V600E mutation) and of both nonclonal accumulation of histiocytes within the affected tissues (as a consequence of systemic chemokines and proinflammatory cytokines in the circulation).
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