Erdheim-Chester Disease

Defnition

Erdheim-Chester disease (ECD) is a neoplastic disorder marked by hyperactivation of MAPK signaling in myeloid cells that results in xanthogranulomatous in ltration of multiple organ systems organs often by foamy (lipid-laden) histiocytes accompanied by T cells and B cells including plasma cells [25]. The diagnosis requires a multidisciplinary approach including correlative pathology (histology and molecular) and integration of key clinical and radiographicndings [25]. Pulmonary ECD is a rare disorder that is not often included in the initial differential of patients presenting with interstitial lung disease; it is generally rst suspected when changes in diffuse lung in ltrates are accompanied by long bone pain [21, 26] (Fig. 16.7).

Epidemiology

There are limited epidemiological data available for ECD, with only ~800 cases reported in the literature through 2020

[1]. Most cases of ECD are diagnosed in middle age, between the fth and seventh decades of life, although there have been reports of disease in children as young as 7 years old, and in adults up to 84 years [27]. A recent consensus statement by Goyal et al. [1] con rms the historic observation of a male preponderance of disease, with a median age of diagnosis of 46–56 years. Pediatric cases are rare, sometimes presenting as BRAFV600E positive juvenile xanthogranuloma mass lesions (JXG) in the CNS [28, 29].

Cellular and Molecular Pathogenesis

Similar to PLCH, ECD is a neoplastic disease arising from mutations in myeloid progenitor cells. The ECD cell of origin is believed to be a monocyte precursor as opposed to a dendritic cell precursor as is the case for PLCH; however, both likely have a common CD34+ bone marrow cell origins. Differences in the timing of mutation and local cytokine stimuli also play important roles in disease presentation and pathogenesis [30]. The paucity of mitotic gures within ECD lesions suggests that enhanced recruitment or cellular survival is a more likely mechanism of cellular accumula-

Fig. 16.7  Radiographic manifestations of pulmonary involvement of ECD. (a) 30 years old male smoker with ECD. Advanced destructive emphysema is present in the upper lobes. Diffuse ssural thickening (white arrow), bronchovascular thickening, and septal lines (black arrow) are present refecting histiocyte in ltration. (Case courtesy of Seth Kligerman, M.D. San Francisco, CA). (b–e) 57 years old man presenting with cellulitis and exophthalmos. (b) Frontal chest radiograph is notable for a markedly enlarged cardiac silhouette consistent with the

pericardial effusion identi ed at CT. (c) Contrast enhanced chest CT in soft tissue windows shows diffuse perivascular in ltration surrounding the great vessels (arrowheads). (d) Contrast enhanced chest CT in soft tissue windows at the level of the left atrium is notable for a large pericardial effusion (asterisk) and small right pleural effusion (white arrow). Periaortic soft tissue is also present (arrowhead). (e) At the level of the mid poles of the kidneys the perinephric halo sign can be seen with extensive retroperitoneal in ltrative soft tissue

tion than increased proliferation [27, 31]. ECD histiocytes are positive for CD68, CD163, CD14, CD4 (usually light staining), and often factor XIIIa, but not the characteristic immunohistochemical markers of Langerhans dendritic cells, S100, CD1a, and langerin [1, 4, 11, 20] (Table 16.2). There is mounting evidence of clonal derangements underlying ECD pathogenesis as more than 50% of patients have been found to have activating mutations in MEK/ERK pathways including BRAF, NRAS, KRAS, and phosphatidylinositol-­3-­kinase/protein kinase B (PIK3CA) [1, 4, 6, 21, 26, 32]. Genetic analysis of ECD lesions offers the potential for targeted treatment, such as the use of vemurafenib and other BRAF V600E inhibitors in patients who exhibit this mutation [21, 27, 32] or a MEK inhibitor such as cobimetinib or trametinib in patients found to have mutations elsewhere in the MAPK pathway. The observations that ECD and LCH pathologies are occasionally seen in the same individual suggests that they may share a common progenitor cell of origin [27].

ECD lesions exhibit a unique cytokine and chemokine signature that is consistent with Th1 polarization including

increased levels of interferon-alpha, interferon-gamma, interleukin-6, interleukin-12, tumor necrosis factor-alpha, monocyte chemotactic protein-32, occasionally interleukin- 1­ beta, and decreased levels of interleukin-4, interleukin-7, and interleukin-10 [10, 27]. Several prior therapeutic approaches have been based on immunomodulatory agents (interferon-α), anti-cytokine therapies (IL1and TNFα-­ blockers), and immunosuppressants (mTOR-inhibitors) [33].

Histopathology and Immunohistochemistry

ECD lesions characteristically demonstrate in ltration of non-LCH cells with either foamy (lipid-laden) and/or eosinophilic cytoplasm with or without multinucleate/Touton giant cells on an infammatory background of polymorphic lymphocytes and plasma cells [1, 4], and varying degrees ofbrosis (Fig. 16.8). The dendritic cells within these lesions are distinct from LCH as they lack Birbeck granules and stain for light granular CD68, CD163, CD14, and often Factor XIIIa, but not for Langerin, CD1a or S100 [1, 10, 21,

Fig. 16.8  Pathology of Erdheim Chester Disease (ECD) of the lung. (a, b) Epithelioid to foamy and xanthomatous histiocytes with occasional Touton Giant cells and a variable degree of brosis. Mixed infammation including eosinophils can be noted in pulmonary nodular foci (a, H&E, 10×, b, H&E, 40×). Another more insidious pattern in pulmonary ECD is a lymphatic distribution of plump to spindled lesional histiocytes (c, H&E 20×). The histiocytes are diffusely positive for CD163 (d, immunostain, 20×), CD68 with a nely granular cyto-

plasmic staining as opposed to darkly stained alveolar macrophages (e, immunostain 20×), and are often lightly stained for Factor 13a (f, immunostain, 20×). Unlike high-grade malignant lesions, there is a very low Ki-67 proliferation rate index in ECD (not shown). Often the clonal histiocytes will express the mutant-speci c BRAF VE1 immunostain with strong expression (2–3+) that correlates with the BRAF-­ V600E mutation (not shown)

26, 27]. As in LCH, demonstration of the mutant-speci c BRAF VE1 immunostain can serve as a surrogate for the BRAF-V600E mutation if there is strong and diffuse cytoplasmic staining in >10% of lesional histiocytes. However, a notable staining pitfall in the lung for BRAF VE1 is strong staining of normal cilia which should not be interpreted as positive staining. Similarly, the normal anterior pituitary has dark BRAF VE1 staining in wild-type cells.

Clinical Presentation

Patient presentations are protean and range from incidentalndings on imaging performed for unrelated reasons to multisystem dysfunction due to widespread histiocytic in ltration of multiple organ systems [1, 21]. Garcia-Gomez et al. described three prototypical presentations: disease con ned to the skin which follows the most indolent course, multifocal involvement with central nervous system preservation,

and systemic involvement with CNS in ltration, the most aggressive form with the worst prognosis. Bone involvement occurs in almost all (approximately 96%) of patients and bone pain typically manifests in the knees and ankles (approximately 50%) [1, 32] (Fig. 16.9). Bony involvement may be accompanied by constitutional symptoms such as fever, weakness, weight loss, night sweats, neurologic complaints, or polyuria [1, 32].

About 20–40% of those afficted with ECD may have involvement in the pulmonary system [1, 11, 20], and in many cases is not associated with respiratory symptoms. CTndings include mediastinal in ltration, pleural thickening/ effusion, reticular interstitial changes, centrilobular nodular opacities, ground glass opacities, or lung cysts. Common respiratory symptoms include chronic dry cough and dyspnea that progresses over months to years [27]. Cyanosis at the time of presentation is uncommon, however with increasing disease burden patients may develop hypoxic respiratory failure with or without hypercapnia [27]. If there