Skeletal involvement is extremely frequent (96 % of the 53 patients included in a 2011 series), but only 39 % of patients suffer bone pain, which is, nevertheless, the most common clinical feature of ECD [13]. It is usually mild, may start at any time during the course of the disease and mostly affects the legs. X-ray evidence of bilateral, symmetric cortical osteosclerosis of the diaphyseal and metaphyseal regions of the long bones is an idiosyncratic feature of ECD, and abnormally strong, symmetric labeling of the distal ends of the long bones of the legs, and sometimes the arms, is also often revealed by ⁹⁹Tc bone scintigraphy (Fig. 12.3) [6, 7]. The axial skeleton and the mandible are often involved in LCH, but not in cases of ECD. In recent years, positron emission tomography (PET) with ¹⁸F-labeled fluorodeoxyglucose (PET-CT) has gradually been replacing bone CT scans [19, 20]. MRI of the long bones can be informative in some cases, because it may reveal epiphyseal involvement of the long bones and periostitis not detected on X-ray [21]. MRI may also be valuable in the rare cases of ECD showing no abnormalities on bone CT scans.

Progresses in radiological imaging has facilitated the detection of cardiovascular involvement. The most frequent cardiovascular sign is the circumferential periaortic sheathing of the thoracic or abdominal aorta (55 and 57 % of cases, respectively) [4, 7]. Serratrice et al. described cases in which the whole aorta was sheathed, showing a “coated aorta” appearance, and this has become one of the iconic features of ECD (43 % of cases) [13, 22]. Periarterial infiltration may extend to the main aortic branches. Its clinical consequences are usually not severe, apart from renovascular hypertension due to renal artery involvement (16 % of cases), a complication that can be treated by renal artery stenting [7].

With respect to heart involvement, pericardial lesions are the most frequent (30 %) (Fig. 12.3), sometimes with tamponade, but myocardial and endocardial infiltrations may also be observed [7, 23]. Abnormal heart imaging was detected by cardiac MRI in 70 % of the 37 patients undergoing systematic retrospective cardiovascular screening (MRI and/or heart CT scan) in a study published in 2009: Abnormal infiltration of the right heart was found in 49 %, including “pseudotumoral” infiltration of the right atrium in 30 %, and infiltration of the auriculoventricular sulcus in 19 % [24].

More than 20 patients with myocardial infarction secondary to pericoronary infiltration have been reported, with this condition leading to death in some cases [7, 25, 26]. In one series of 53 patients, 17 % had symptomatic heart valve disease (aortic and mitral regurgitations) [4], although valve replacement was required very rarely [7, 27]. This operation is technically difficult, due to the extensive infiltration of the heart tunicae, and should therefore be performed only in appropriately selected cases, at specialized centers.

Twenty-five percent of ECD patients develop exophthalmos, which is often bilateral and due to infiltration of the retro-orbital soft tissues (Fig. 12.3) [28, 29]. This infiltration may be massive in a small number of cases, rendering it refractory to conventional therapy, such that surgical debulking is required.

Diabetes insipidus, due to pituitary gland infiltration, is the most frequent endocrine manifestation of ECD (26 % of patients). Rare cases of pituitary or hypothalamic infiltration with other endocrine consequences have been reported, including hyperprolactinemia, gonadotropin insufficiency, and abnormally low levels of IGF-1 [30, 31].

We performed a single-center observational study between October 2007 and May 2013 with systematic endocrine evaluation in 64 consecutive ECD patients [32]; 36 of the studied patients also had follow-up assessments. Diabetes insipidus was found in 33.3 % of patients, frequently inaugural of ECD. Anterior pituitary dysfunction was found in 91.3 % of patients with full anterior pituitary evaluation, including somatotropic deficiency (78.6 %), hyperprolactinemia (44.1 %), gonadotropic deficiency (22.2 %), thyrotropic deficiency (9.5 %), and corticotropic deficiency (3.1 %). Thirty-five patients (54.7 %) had two anterior pituitary dysfunctional axes, rising to 69.6 % (16/23) when only considering patients with complete evaluation. Two patients had pan-hypopituitarism. Infiltration of pituitary and stalk was found on MRI in 24.4 % of cases. Testicular insufficiency was found in 53.1% of patients, with sonographic testicular infiltration in 29 % of men, mostly bilateral. Imaging signs of adrenal infiltration were found in 39.1 % of patients, and one case of adrenal insufficiency was observed. No patient was free of endocrine hormonal or morphological involvement. Endocrine dysfunctions were most often permanent, and new deficits appeared during follow-up. Therefore, endocrine involvement is very frequent in ECD and should carefully be evaluated at diagnosis and during follow-up.

Xanthelasmas, generally involving the eyelids or periorbital spaces, affected 25 % of our patients (Fig. 12.3). Papulonodular lesions [33] and infiltrations of the vulva and clitoris may also be observed, but they are less frequent [1]. In a recent study, we described the clinical, pathological, and molecular features of the cutaneous manifestations of 40 patients with ECD identified from a cohort of 123 patients [34]. Clinical and pathological cutaneous features were analyzed and BRAF ^V600E mutation was determined. The most frequent ECD cutaneous manifestations were xanthelasma-like lesions (XLLs), which occurred in 31 (25 %) patients. Other ECD cutaneous lesions were patchy or papulonodular lesions. Mixed forms of ECD and cutaneous LCH presented with crusty papules in some patients. Compared with classic xanthelasma palpebrarum, ECD XLL pathology more frequently involved the reticular dermis, displayed more multinucleated or Touton cells, and showed less extensive fibrosis. The BRAF ^V600E mutation was more frequently detected in patients with cutaneous involvement than in those without (76 % vs. 52 %; P = .005) and constantly found in 10 XLLs. XLLs are the most frequent cutaneous ECD manifestations and might be targeted both for pathology and determination of the BRAF mutational status.

About one third of ECD cases present with “pseudoretroperitoneal fibrosis,” in some cases complicated by bilateral hydronephrosis, which may require ureteral stenting (Fig. 12.3) [35]. This situation was observed in 25 % of the cases in our series. Involvement of the pelvic ureters has never been described, and the inferior vena cava is rarely affected in ECD. The “fibrosis” observed in ECD patients sheaths the walls of the aorta completely and circumferentially, whereas the posterior aortic wall is rarely affected in the idiopathic form of retroperitoneal fibrosis [7].

In 2008, we performed a retrospective analysis of lung involvement in 34 consecutive patients with ECD [36]. High-resolution thoracic CT scans demonstrated involvement of the lung parenchyma in 53 % of cases, and of the pleura in 41 % [37]. The lesions mostly affected the interlobular septa. Lung involvement was not a significant prognostic factor for ECD in this series, contrasting with previous findings emerged from studies on smaller number of patients. A MEDLINE search identified reports of lung involvement in 70 (22 %) of the 319 ECD cases published before November 2008, but most of the descriptions were incomplete.

CNS involvement is common in ECD patients (15–25%) [13] and was described in detail in a French neurological series [38]: this multicenter literature review was carried out in 2006 and analyzed 66 ECD patients (including six personal cases) with neurological involvement. Cerebellar and pyramidal syndromes were the most frequent neurological signs (41 and 45 % of cases, respectively), and the other features described included seizures, headaches, neuropsychiatric signs or cognitive impairment, sensory disturbances, cranial nerve paralysis, and asymptomatic lesions. Neurological involvement led to severe functional disability in almost all patients. CNS involvement is a major prognostic factor in ECD, as survival analysis has identified this factor as an independent predictor of death (hazard ratio = 2.51; 95 % confidence interval, 1.28–5.52; P = 0.006) [4]. The most damaging (and difficult to treat) neurological condition is the pseudodegenerative involvement of the cerebellum, which is present in 17 % of our patients. The overall frequency of CNS involvement is 40 %.

We reviewed brain MRI findings for 33 ECD patients followed at Pitié-Salpêtrière Hospital until 2009. Only three patients had normal imaging results [39], and two or more different anatomic sites were affected in most patients. Lesions of the brain, meninges, facial bones, and orbits are frequent in ECD patients (Fig. 12.3). MRI and CT should therefore be carried out systematically, to investigate the brain, in all ECD patients, even those without symptoms.

Before 2005, the standard treatments for ECD included steroids, cytotoxic agents [44], and double autologous hematopoietic stem-cell transplantation [45, 46]. The efficacy of these treatments was difficult to establish, because had been administered to only small numbers of patients, or in combination with other drugs. The follow-up periods were also short. Braiteh et al. reported rapid, marked, and persistent regression of retro-orbital infiltration and a progressive improvement of bone lesions, pain, and diabetes insipidus in three ECD patients given IFNα [47]. However, in eight patients with ECD treated with low-dose IFNα (3 MU X 3/week), we found that the efficacy differed according to the involved sites [16]. In some cases, the symptoms failed to respond to such low doses of IFNα; this was particularly true in patients with severe multisystem forms of ECD (CNS and cardiovascular involvement in particular). We therefore recommend higher doses, up to 9 MU X 3/week if tolerated, because such doses may be more effective against meningeal infiltrations, sub- and retrosellar masses, and pericardial and pseudoatrial infiltrations. IFNα is necessarily a long-term treatment, but it may lead to adverse effects, including depression and fatigue. IFNα treatment has also given disappointing results in cases of pseudodegenerative cerebellar involvement (similar to that observed in LCH).

Nevertheless, IFNα appears to be the best choice for the initial treatment of ECD. Survival analysis on a series of 53 patients indicated that treatment with IFNα and/or PEGylated IFNα was a major independent predictor of survival (HR = 0.32; 95 % CI, 0.14–0.70; P =0.006) [4]. We generally begin treatment with PEGylated forms of IFNα because such forms are better tolerated than IFNα in the long term.

Imatinib mesylate was reported to be effective in cases of histiocytosis in 2010 [48]. However, a small trial with this treatment in six ECD patients yielded disappointing results [49]. The treatment of two ECD patients (with neither cardiovascular nor CNS involvement) with recombinant human interleukin-1 receptor (anakinra) was described, and this treatment appeared to be promising [50]. In a larger experience with 12 cases treated with anakinra, the drug efficacy was poor overall, particularly for the severe forms of the disease (cardiovascular and CNS involvement) [51]. Other groups have shown this treatment to be effective only for mild forms of the disease (mostly bone pain). Cladribin may be useful for treating CNS involvement at sites not responsive to IFNα [44]. Infliximab treatment was shown to be beneficial after 12–18 months, in two ECD patients with cardiac involvement [52]. Recently, sirolimus combined with prednisone was reported in an open-label trial of ten consecutive patients: most patients achieved disease stabilization or objective responses; one died due to disease progression and one due to small-cell lung cancer. Overall, this therapy was well tolerated [53].

The etiology of ECD has been a matter of debate for many years; in particular, it was unclear whether the disease could be considered primarily inflammatory or neoplastic. The RAS-RAF-MEK-ERK pathway is a key cellular signaling pathway that has been found implicated in diverse tumors [54, 55]. Many human tumors carry the BRAF ^V600E mutation [56], causing activation of the RAS-ERK pathway independently of RAS activation. The inhibition of BRAF activation by vemurafenib improves the survival of patients with metastatic BRAF ^V600E–positive melanomas [57]. In 2010, recurrent somatic activating mutations of the BRAF ^V600E type were found in 57 % of archived LCH lesions [58]. Targeted pyrosequencing of paraffin-embedded samples from 127 patients with histiocytoses identified mutually exclusive BRAF ^V600E mutations in 54 % of ECD samples and 38 % of LCH samples, but none of the other non-LCH samples [59]. The frequency of BRAF ^V600E mutations in ECD is currently considered to range between 57 and 75 % of the cases, depending on the techniques used [60].

Vemurafenib inhibits the mutant BRAF protein and displays some efficacy against both BRAF ^V600E-associated melanoma and hairy-cell leukemia [61]. In 2012, we conducted a pilot study of vemurafenib treatment for three patients with multisystemic and refractory ECD who carried the BRAF ^V600E mutation [54]. Two of the patients also had skin or lymph node LCH. Vemurafenib treatment led to rapid, substantial clinical and biological improvement in all three cases, as shown by clinical, biological (CRP values), histological (skin biopsy), and imaging (PET, CT, and MRI) findings during follow-up. The tumor response assessed by PET, CT, and/or MRI was detected as early as one month after the beginning of treatment. For one patient, serial PET assessments of the response to treatment showed continuous improvement during the first four months of treatment.