Fig. 16.10  Radiographic manifestations of ocular ECD involvement. (a) 57 years old man presents with cellulitis and exophthalmos. Contrast enhanced orbit CT shows bilateral retrobulbar soft tissue masses. (b, c)

Axial T1 MRI with contrast con rms enhancing retrobulbar masses (arrows), and dural masses (arrowheads)

crine presentation is central diabetes insipidus [4, 32], followed by de cits in growth hormone [4], gonadotropins, thyrotropin [4], and rarely corticotropin [4, 32].

The heart is the most common extraskeletal site of ECD in ltration, which is rare in other non-Langerhans cell histiocytic diseases, and almost never occurs in Langerhans cell histiocytosis [4]. The histiocytes of ECD can in ltrate any cardiac layer, including the pericardium (up to 40%) [4]. Pericardial involvement can result in pericardial effusion [4, 26], although cardiac tamponade is rare [4]. There is a predilection for in ltration of the right atrium, which can present as a “pseudo-tumor” on cardiac imaging [1, 4, 10, 21], and can extend into the atrioventricular sulcus causing conduction blocks [4], and even direct valvular in ltration by histiocytes [10, 21, 27]. Vascular involvement can include periarterial in ltration [26, 27] and brosis [27] has been described to involve the coronary arteries in up to 55% (although the need for stent placement is uncommon), aorta, brachiocephalic trunk, subclavian arteries, pulmonary trunk, carotid arteries, celiac trunk, superior mesenteric trunk, and renal arteries [1, 4, 6]. Periarterial in ltration can lead to dire consequences if stenosis results in cerebral, myocardial, and/or mesenteric ischemia, and renovascular hypertension [27]. Additional clinical complications can include congestive heart failure, thromboembolic disease, and valvular dysfunction [27].

Retroperitoneal and kidney involvement is common [10, 21, 27, 32], with a higher frequency in males [21]. Histiocytes may in ltrate perinephric soft tissues leading to a “hairy kidney” appearance on imaging. Extension to the renal sinus, and the midand distal ureters can cause hydronephrosis necessitating stenting [4]. Mesenteric in ltration and brosis have also been described [32].

Other extra-pulmonary and extra-skeletal manifestations of ECD include skin nodules and soft tissue masses [21, 32], which increase in incidence with age [21]. ECD involve-

ment in the reticuloendothelial and hematopoietic systems is rare [4].

Investigation/Diagnosis

The diagnosis of ECD can be extremely challenging, often requiring a multidisciplinary approach that includes the integration of clinical, radiographic, pathologic, and genetic data. There are no speci c laboratory ndings that are diagnostic or speci c for ECD, but there are several that can offer insight into the extent or activity of the disease. Infammatory markers such as erythrocyte sedimentation rate (ESR), c-reactive protein (CRP), lactate dehydrogenase (LDH) [10], and alkaline phosphatase (ALP) may be elevated [27]. Hypothalamic-pituitary axis involvement may be detected by elevations of prolactin, or decreased levels of luteinizing hormone, follicle-stimulating hormone, adrenocorticotropic hormone, growth hormone, or thyroid stimulating hormone. Central diabetes insipidus can result in hypernatremia, and the diagnosis can be revealed by a doubling of urine osmolality after desmopressin administration or increased serum osmolality after water deprivation in a patient with polyuria [27]. Elevations in blood urea nitrogen and creatinine may point toward renal involvement [27].

Chest Studies

Imaging studies can offer aid in the initial diagnosis and provide important information for monitoring disease progression­ or treatment response. CXR may demonstrate prominent interstitial markings resembling Kerley B lines, due to lymphangitic involvement [20] (Fig. 16.7).

Computed tomography (CT) allows for the identi cation of lung, pleural, aortic, and skeletal lesions [26]. High-­

resolution computed tomography (HRCT) is the gold standard for the identi cation of pulmonary manifestations of ECD. The changes seen on HRCT are due to histiocytic in l- tration that typically manifests in a lymphangitic distribution involving the visceral pleura, interlobular septa, and bronchovascular bundles [27]. Other common ndings include centrilobular nodular opacities, thin-walled cysts, ground-­ glass opaci cation, pleural effusion, and mediastinal involvement [1, 4, 11, 34]. Gallego et al. [11] described a common pattern of pleural thickening due to histiocytic in ltration of the right paravertebral basal area of the retrocrural space which creates a pseudotumor-like structure(Fig. 16.7).

When the lungs are involved, pulmonary function testing (PFT) should be completed. Findings may be normal early in the disease ranging to advanced obstructive or restrictive disease with reduced DLCO in more severely affected patients [4].

Cardiovascular Imaging

CT evaluation may also demonstrate an irregular appearance of the aortic intima, called “coated aorta,” related to brous encasement of the aorta by histiocytic in ltration of the adventitia, a pattern that is pathognomonic of ECD [10, 21, 27]. Echocardiography can be used to assess degrees of cardiac involvement [27].

CNS Imaging

Magnetic resonance imaging is the modality of choice for CNS imaging and may demonstrate masses in the pituitary stalk, cerebellum, and brainstem, as well as retro-orbital masses with and without meningeal involvement [27] (Fig. 16.10).

Bone Radiography

Plain lms demonstrating bilateral symmetric cortical osteosclerosis of the metadiaphyseal regions of long bones with sparing of the epiphyses is pathognomonic of ECD and seen in 96% of patients [1, 4, 10, 20]. The most commonly affected bones are the femur, tibia, and bula, and less frequently affected are the ulna, radius, and humerus [27] (Fig. 16.9). The axial skeleton is typically spared [27].

99mTc Bone scintigraphy can be used as a screening test for bony involvement including the identi cation of pathognomonic features of parallel, symmetric uptake in long bones of both extremities [4, 21, 26] (Fig. 16.9).

Positron emission tomography/computed tomography (PET-CT) offers good sensitivity for the detection of bone lesions and can detect subtle vertebral lesions and aid in targeting for biopsy [4, 26]. PET-CT can also detect visceral and vascular in ltration as ECD lesions exhibit increased radiotracer uptake [26].

Other Imaging Findings and Considerations

Contrast-enhanced CT may show lymphadenopathy and diffuse bilateral in ltration of the perinephric soft tissue leading to thickening in a stellate pattern, often described as having a “hairy kidney” appearance [1, 4, 6, 10]. Combinations of imaging studies have important roles at the time of diagnosis, and as part of monitoring for disease progression and/or response to treatment. Mazor et al. [27] have outlined a strategy for imaging at the time of initial presentation and over time. Initial evaluation including plain lms of the skeleton and whole-body bone scintigraphy may reveal pathognomonic symmetric osteosclerosis of the metadiaphyses of long bones. A whole-body PET-CT [1, 27] allows assessment of the extent of skeletal and extra-skeletal involvement, and identi cation of an optimal site for biopsy [1, 27]. Mazor et al. [1, 27] reported that PET-CT offers variable sensitivity, but excellent speci city for ECD lesions. A baseline MRI is the optimal study to evaluate patients for CNS involvement [1, 10, 26, 27], and baseline head CT aids investigation of skull and sinus involvement as well as guides biopsy site selection [1, 27]. HRCT screening is indicated at diagnosis and for patients who develop pulmonary symptoms [1, 27].

The gold standard for diagnosis of ECD is correlative tissue biopsy integrated with the clinical/radiographic ndings [1, 4, 21]. Histological demonstration of xanthogranulomatous family histiocytic in ltration with appropriate staining in the right clinical/radiographic setting is diagnostic [1, 21, 26, 27]. In patients with pulmonary manifestations, extra-­ pulmonary sites of involvement may be lower risk targets for biopsy [4, 11].

Disease Monitoring

Progression of the disease can be followed over time with serial PET-CT, annual low-dose CT of the chest, abdomen, and pelvis, and contrast CT of the chest if the patient develops symptoms concerning cardiac or mediastinal in ltration. Echocardiography should be obtained if cardiac involvement is suspected [27]. Lu et al. suggest serial MRI of the CNS and spine over time [21]. Pulmonary function tests are useful for following pulmonary disease progression.

Pathology

As shown in Fig. 16.8, pathologic evaluation of lung tissues reveals histiocytes with an abundance of pale, eosinophilic cytoplasm and bland appearing nuclei that in ltrate the pleura and lead to pleural thickening [20]. Histiocytic in l- tration of the lung parenchyma in a peri-lymphatic distribution leads to thickening of the interlobular septa and bronchovascular bundles, often sparing the alveoli. The histological ndings correlate with CT ndings that often include ground glass opacities and interstitial changes in a lymphatic distribution [20].

Management/Treatment

Treatment recommendations are summarized in Fig. 16.11. The FDA has approved vemurafenib, a BRAF V600 inhibitor, and given cobimetinib, a MEK-inhibitor Breakthrough Therapy Designation for the treatment of ECD [1, 24] Current treatment recommendations for other agents are drawn from case reports, case-series, small open-label trials

and retrospective studies [27]. In patients who are asymptomatic with indolent non-vital single organ disease, treatment may not be necessary for the short term, and adopting a “watch and wait” strategy with serial imaging may be reasonable [1, 10]. In patients who are symptomatic or progress with the disease that threatens to compromise major organs systems, (especially with pulmonary and CNS involvement), treatment should be initiated [1, 10].

The most thoroughly studied therapy for ECD is interferon-alpha (IFN-α) [10, 21, 26, 27, 32]. IFN-α has been reported to improve survival in multivariate retrospective studies [10, 32] but is often poorly tolerated [10, 21, 27, 32]. There is wide variability in reported dose ranges applied (from one million units three times weekly [10] to more than 18 million units total weekly [27]), with no consensus regarding the optimal regimen. Pegylated IFN-α has been reported to provide equal ef cacy, better tolerance, and more convenient dosing with weekly once administration [10, 27]. Gianfreda et al. report an untreated mortality rate in ECD of 60%, which was reduced to 26% with administration of IFN-­ α. Although the mechanism of action is not entirely clear, IFN-α is thought to promote immune-mediated clearance of

histiocytes and inhibit the terminal differentiation of immature histiocytes [27]. It is interesting to note that IFN-α levels are elevated in patients with untreated ECD [10, 32]. IFN-α results in durable regression of bone lesions and retro-orbital lesions, and reduction in pain and manifestations of diabetes insipidus [10, 27]. IFN-α does not appear to be effective for cardiac or central nervous system ECD lesions [10, 27, 32], and has a minor impact on pulmonary lesions [27]. There are currently no means to predict who will or will not respond to IFN-α therapy. Adverse effects of IFN-α include often intolerable fatigue (perhaps the most limiting adverse effect) [10], myalgia, pruritus, thrombocytopenia, and asthenia [27]. IFN-α should be used with caution in patients with a history of psychiatric disease as it can exacerbate these conditions [10], especially depression [10, 27]. As treatment is prolonged, often spanning more than 20 months, tolerance to treatment becomes a major limiting factor [27].

In patients who progress despite therapy, or cannot tolerate therapy with IFN-α, there are many other candidate therapies available. Many of these second-line therapies target key nodes in the pathogenic pathway outlined earlier.

Vemurafenib, a BRAF V600E inhibitor, has been shown to have ef cacy in LCH and PLCH patients with this mutation [1, 21, 27, 32], and is an appropriate, FDA-approved consideration in the approximately 50% of ECD [10, 21, 27, 32] patients who harbor this mutation. Vemurafenib crosses the blood-brain barrier [21] suggesting potential ef cacy for ECD CNS lesions. There have been reports of dramatic responses within a few weeks of initiation of vemurafenib [10, 21, 27], and the drug is usually well tolerated; the most common adverse effects in the literature include skin rash, fatigue, and diarrhea [10] which do not usually limit use. A recent phase II trial demonstrated a 62% response rate, with rapid and durable clinical responses in multiple disease sites with reversal of critical disease burden in some patients [1]. It was also noted during this phase II trial that about 2/3 of patients who discontinued vemurafenib relapsed within 6 months [1]. Additional risks that have since been identi ed include an increased risk of secondary neoplasia, sarcoidosis, and pancreatitis [1]. Goyal et al. [1] have suggested a management strategy that includes screening for BRAF mutations at the time of initial pathology review. In the BRAF V600E mutation-positive patients rst-line therapy with vemurafenib should be offered [1]. If ECD is con rmed and no BRAF V600 mutation is found, a MEK inhibitor (targeting a downstream effector that will block signaling by other (undetected) activating mutations in the MAPK pathway) or therapy with IFN-α are reasonable next steps [1, 10, 24]. Furthermore, in patients who progress despite these therapies, or who cannot tolerate the drugs, a trial of second-­ line therapy with anakinra, imatinib, or cladribine is recommended [1, 6, 10].

Other mutations that have been identi ed in ECD include PIK3CA (approximately 13%) and NRAS mutations (approximately 4%), which cause activation of the mammalian target of rapamycin (mTOR) pathways [32]. mTOR inhibitors represent another attractive therapeutic option [32], offering anti-proliferative, anti-infammatory, and anti-­ senescence properties [1, 32]. Gianfreda et al. performed an open-label trial utilizing the mTOR inhibitor, sirolimus, in combination with prednisone in patients with ECD who were not candidates for IFN-α therapy and did not express the BRAF V600E mutation. They reported a signi cant response with regression of peri-renal and peri-ureteral lesions, as well as improvement in pericarditis [32]. There were varied responses in CNS lesions and marginal or absent responses at other sites of disease [32]. They concluded that therapy with sirolimus and prednisone led to stabilization or improvement of disease and was generally well tolerated in patients with ECD [32].

The recombinant human interleukin-1 receptor (IL-1R) antagonist, anakinra [21, 27, 32] has been used in patients with ECD. Inhibition of the IL-1R blocks aberrant MAP kinase activation in histiocytes [10]. Munoz et al. [10] postulated that IL-1R antagonism may also downregulate the expression of IL-1 alpha receptors on the membranes of monocytes and the IL1 beta receptors of in ltrating histiocytes. Treatment with anikinra has been reported to reduce fever and bone pain, improve skin lesions, and result in weight gain. The drug is generally well tolerated [10, 27] with the most common adverse effect reported to be local skin reactions at the site of injection, and reactivation of previous infections, such as tuberculosis. Given the favorable safety pro le, Munoz et al. [10] suggest that anikinra may be an appropriate therapy in elderly patients or patients with comorbidities.

Cladribine, also called chlorodeoxyadenosine, is an antineoplastic purine analog [32], often used for the treatment of LCH and PLCH, that represents another alternative for ECD therapy, although less data are available [10, 27]. Cladribine is toxic to monocytes [10] and has been reported to lead to partial regression of CNS lesions [27]. Adverse effects of bone marrow suppression and neurologic toxicity are dose-­ dependent [27].

The anti-tumor necrosis factor alpha (TNF-α) mononuclear antibody, infiximab, has been used to treat ECD [10, 21, 27]. TNF-α has been shown to play a role in regulating the recruitment of histiocytes [10]. Infiximab therapy has been reported to improve cardiac function and cause resolution of pericardial effusions [10] in ECD. The anti-IL-6 medication, tocilizumab, has also been utilized for the treatment of ECD [27].

Imatinib is a tyrosine kinase inhibitor that selectively targets cKIT, BCR-ABL, and platelet-derived growth factor