Table 2.

Significant morphological features of Erdheim-Chester disease according to the most commonly involved regions

Location	Typical features of histiocytic infiltrate	Typical features of stroma and reactive infiltrate	Differential diagnosis
Bone	- In mild fibrotic background; loose clusters of classical foamy or granular histiocytes with well-defined cell borders - In prominent fibrotic background; scant infiltrate including amorphous lipid-laden or granular histiocytes	- Process replaces normal bone marrow - Sclerotic changes in trabecular bone with scant inflammatory cells -Inflammatory infiltrate can be prominent in focal areas which may be problematic related to the sampling - A certain degree of fibrosis present, relatively more extensive than other regions -Storiform fibrosis can be seen	- Benign fibrous histiocytoma of bone - Osteomyelitis - Xanthogranulomatous inflammations - RDD - LCH
CNS	- Mononuclear infiltration as single cells or small clusters especially denser in perivascular areas - The typical histiocyte has indistinct cellular margins and non-lipidized, eosinophilic cytoplasm or only faintly foamy	- Reactive astrocytic proliferation, sometimes associated with prominent Rosenthal fiber formation - Absent to mild reactive inflammatory infiltrate - Focal demyelination - No fibroplasia	- Organizing infarct - Demyelinating diseases - Alexander’s disease - LCH - JXG - Granular cell astrocytoma - Regressed primary CNS lymphoma
Lung	- Characteristic subpleural, septal, perivascular interstitium and peribronchiolar localization of infiltrate - Lesional histiocytes with eosinophilic cytoplasm and distorted shape due to fibrosis	- Absent to mild reactive inflammatory infiltrate - Marked fibrosis in pleura and interlobular septa	- Drug side effect - Interstitial lung diseases in particular, usual interstitial pneumonitis - LCH - RDD
Skin	- Diffuse or interstitial/perivascular infiltration pattern can be seen - In both, typical xanthomatous features are seen; however, lesional histiocytes can be subtle in interstitial pattern - High possibility of accompanying Touton-type giant cells in diffuse infiltration pattern	- Occasionally, small focus of neutrophilic abscesses - Occasional eosinophils as isolated cells - Perivascular dense lymphoid aggregates can be seen - No change in epidermis	- Benign xanthoma - Dermatofibroma - Hypersensitivity reactions - Granulomatous mycosis fungoides - LCH - RDD - JXG
Orbit	- Nodular to diffuse sheets of lipid-laden or eosinophilic histiocytes with classical xanthomatous features - High possibility of accompanying Touton-type giant cells	- Nodular lymphoplasmacytic aggregates without germinal center formation - Moderate to marked fibrosis	- Extranodal marginal zone lymphoma - IgG4-related disease - Adult-onset asthma and periocular xanthogranuloma
Retroperitoneum	- Mostly, histiocytic infiltrate with xanthomatous quality - Sometimes, scant infiltrate including amorphous lipid-laden or granular histiocytes in prominent fibrotic background	- Reactive infiltrate with prominent plasma cells - IgG4 expression may reach the cut off value of IgG4-related disease (>40%) - Occasionally, prominent fibrosis	- IgG4-related disease - Lymphoma - Idiopathic retroperitoneal fibrosis
Cardiac structures	- Abundant histiocytic infiltrate with xanthomatous quality - Diffuse myocardial infiltration with extension to the depth of myocardium	- Prominent chronic fibro-inflammatory exudation with moderate amount of fibrosis	- Myocarditis and other inflammatory processes

Abbreviations: RDD, Rosai-Dorfman disease; CNS, central nervous system; LCH, Langerhans cell histiocytosis; JXG, juvenile xanthogranuloma- tosis; Ig, immunoglobulin; ECD, Erdheim–Chester disease.