Summary of the pathological, molecular, and radiological features of the histiocytic disorders
| Disease . | ECD . | JXG/AXG . | ALK+ histiocytosis . | RDD . | LCH . |
|---|---|---|---|---|---|
| Pathologic features | |||||
| Xanthomatous histiocytes | Yes | Yes | Variable | No | No |
| Touton giant cells | Yes (mainly dermal sites) | Yes (mainly dermal sites) | Rarely | No | No |
| Emperipolesis (intracytoplasmic inflammatory cells including plasma cells and lymphocytes) | Rare | Rare | Rare | Abundant | No |
| Nuclear features | Bland; round-to-oval; small; no grooves | Bland; round-to-oval; small; no grooves | Bland; round-to-oval; small; typically no grooves | Large round; hypochromatic | Oval; retiform irregular nuclear contours |
| Nucleoli | Inconspicuous | Inconspicuous | Inconspicuous | Variable inconspicuous to distinct | Inconspicuous |
| Cytoplasm | Classically abundant, xanthomatous but often overlap with JXG/AXG | Compact; pink; glassy; progressively xanthomatous | Abundant; eosinophilic; typically not xanthomatous | Abundant foamy, clear without xanthomatous features; frequent emperipolesis | Abundant; eosinophilic |
| Immunophenotype | |||||
| CD68 (cytoplasmic) | ++ | ++ | ++ | ++ | + (paranuclear cytoplasmic dot) |
| CD163 (surface) | ++ | ++ | ++ | ++ | — |
| CD14 (surface) | ++ | ++ | ++ | ++ | — |
| CD1a (surface) | − | − | − | − | ++ |
| CD207 (Langerin) (cytoplasmic) | − | − | − | − | ++ |
| S100 (cytoplasmic/nuclear) | −/+ (light) | −/+ (light) | −/++ (in some cases dark staining) | + | + |
| Factor XIIIa (cytoplasmic) | + | + | + | + | − |
| Fascin (cytoplasmic) | + | + | + | + | − |
| CD45 (light surface) | + | + | + | + | + |
| BRAF VE1 (cytoplasmic) | ++* | − (Positive cases should be strongly favored to be in ECD family) | − | − (Rare case reports ++) | ++* |
| ALK (cytoplasmic) | ++* | ++* | ++* | − | − |
| NTRK1(cytoplasmic) | ++* | ++* | − | − | − |
| Molecular features | |||||
| BRAF V600E | Frequent (50%) | Reported (3%) | No | Reported (3%) | Frequent (55%) |
| MAP2K1 | Common (18%) | Common (12%) | No | Common (15%) | Common (15%) |
| RAS isoforms (KRAS, NRAS) | Common (8%) | Common (10%) | No | Common (30%) | Rare (2%) |
| BRAF deletions | Rare (2%) | No | No | No | Common (6%) |
| PI3K isoforms (PIK3CA, PIK3CD) | Reported (3%) | Rare (1%) | No | No | Rare (1%) |
| ARAF | Reported (4%) | Rare (1%) | No | Reported (3%) | Rare (1%) |
| Other BRAF missense | No | No | No | No | Reported (3%) |
| RAF1 | Rare (1%) | No | No | No | No |
| MAP2K2 | Rare (1%) | No | No | No | No |
| MAP3K1 | Reported (1 case) (Amplification) | No | No | No | Reported |
| CSF1R | Rare (1%) | Common (10%) | No | Rare (1%) | Rare (1%) |
| BRAF fusions | Rare (2%) | Common (6%) | No | No | Reported (3%) |
| ALK fusions | Reported (3%) | Reported (3%) | Frequent (100%) | No | No |
| NTRK1 fusions | Rare (1%) | Common (10%) | No | No | No |
| RET fusions | No | Reported (3%) | No | No | No |
| ETV3-NCOA2 fusion | No | No | No | No | Rare (1%) |
| Disease . | ECD . | JXG/AXG . | ALK+ histiocytosis . | RDD . | LCH . |
|---|---|---|---|---|---|
| Pathologic features | |||||
| Xanthomatous histiocytes | Yes | Yes | Variable | No | No |
| Touton giant cells | Yes (mainly dermal sites) | Yes (mainly dermal sites) | Rarely | No | No |
| Emperipolesis (intracytoplasmic inflammatory cells including plasma cells and lymphocytes) | Rare | Rare | Rare | Abundant | No |
| Nuclear features | Bland; round-to-oval; small; no grooves | Bland; round-to-oval; small; no grooves | Bland; round-to-oval; small; typically no grooves | Large round; hypochromatic | Oval; retiform irregular nuclear contours |
| Nucleoli | Inconspicuous | Inconspicuous | Inconspicuous | Variable inconspicuous to distinct | Inconspicuous |
| Cytoplasm | Classically abundant, xanthomatous but often overlap with JXG/AXG | Compact; pink; glassy; progressively xanthomatous | Abundant; eosinophilic; typically not xanthomatous | Abundant foamy, clear without xanthomatous features; frequent emperipolesis | Abundant; eosinophilic |
| Immunophenotype | |||||
| CD68 (cytoplasmic) | ++ | ++ | ++ | ++ | + (paranuclear cytoplasmic dot) |
| CD163 (surface) | ++ | ++ | ++ | ++ | — |
| CD14 (surface) | ++ | ++ | ++ | ++ | — |
| CD1a (surface) | − | − | − | − | ++ |
| CD207 (Langerin) (cytoplasmic) | − | − | − | − | ++ |
| S100 (cytoplasmic/nuclear) | −/+ (light) | −/+ (light) | −/++ (in some cases dark staining) | + | + |
| Factor XIIIa (cytoplasmic) | + | + | + | + | − |
| Fascin (cytoplasmic) | + | + | + | + | − |
| CD45 (light surface) | + | + | + | + | + |
| BRAF VE1 (cytoplasmic) | ++* | − (Positive cases should be strongly favored to be in ECD family) | − | − (Rare case reports ++) | ++* |
| ALK (cytoplasmic) | ++* | ++* | ++* | − | − |
| NTRK1(cytoplasmic) | ++* | ++* | − | − | − |
| Molecular features | |||||
| BRAF V600E | Frequent (50%) | Reported (3%) | No | Reported (3%) | Frequent (55%) |
| MAP2K1 | Common (18%) | Common (12%) | No | Common (15%) | Common (15%) |
| RAS isoforms (KRAS, NRAS) | Common (8%) | Common (10%) | No | Common (30%) | Rare (2%) |
| BRAF deletions | Rare (2%) | No | No | No | Common (6%) |
| PI3K isoforms (PIK3CA, PIK3CD) | Reported (3%) | Rare (1%) | No | No | Rare (1%) |
| ARAF | Reported (4%) | Rare (1%) | No | Reported (3%) | Rare (1%) |
| Other BRAF missense | No | No | No | No | Reported (3%) |
| RAF1 | Rare (1%) | No | No | No | No |
| MAP2K2 | Rare (1%) | No | No | No | No |
| MAP3K1 | Reported (1 case) (Amplification) | No | No | No | Reported |
| CSF1R | Rare (1%) | Common (10%) | No | Rare (1%) | Rare (1%) |
| BRAF fusions | Rare (2%) | Common (6%) | No | No | Reported (3%) |
| ALK fusions | Reported (3%) | Reported (3%) | Frequent (100%) | No | No |
| NTRK1 fusions | Rare (1%) | Common (10%) | No | No | No |
| RET fusions | No | Reported (3%) | No | No | No |
| ETV3-NCOA2 fusion | No | No | No | No | Rare (1%) |
Immunophenotype key: −, negative; +, weak positive; ++, moderate to strong positive.
AXG, adult xanthogranuloma.
Moderate to strong positivity should correlate with molecular alteration; BRAF VE1, ALK and pTRK are mutually exclusive.