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Clinical details
• 34-year-old man: Shave excision
“Skin tag / papilloma left thigh”
The best diagnosis is:
• Spitz naevus
• Epithelioid fibrous histiocytoma
• Dermatofibroma
• Epithelioid perineurioma
Microscopic features - summary
• Exophytic / polypoid lesion
• Overlying hyperkeratosis, acanthosis with hypergranulosis
• Dermis: distinctive histiocyte-like epithelioid cells
– Pink cytoplasm, vesicular nucleus and single nucleolus. Some nuclear
inclusions.
– Occasional binucleate and multinucleated cells
– Mild cytological atypia only, low mitotic activity
• Perivascular accentuation with whorled growth pattern
• Background of richly vascular stroma, superficial thin-walled
ectatic vessels and hyalinised dermal collagen
CD68
CD68
CD34
CD34
EMA
EMA
SMA
SMA
Claudin
Claudin
S100
S100
ALK
ALK
Immunohistochemistry summary
• Patchy positive staining for EMA and CD68
• Diffuse positive staining with ALK
• Negative staining for S100, Melan-A, claudin-1,
microphthalmia transcription factor, CD34, CD31
and desmin
Epithelioid fibrous histiocytoma
• Uncommon lesion
• Predilection for proximal thigh
• Young to middle-aged adults
ALK in epithelioid fibrous histiocytoma
• Jedrych J, et al
Epithelioid cell histiocytoma of the skin with clonal ALK
gene rearrangement resulting in VCL–ALK and SQSTM1–
ALK gene fusions. Br J Dermatol 2015;172:1427-9
• 2 cases of epithelioid fibrous histiocytoma with
unexpected ALK immunostaining
– FISH and next generation sequencing
From: Jedrych et al 2015
VCL-ALK fusion (next generation sequencing)
From: Jedrych et al 2015
SQSTM1-ALK fusion
From: Doyle et al 2015
• ALK gene rearrangement by FISH
– Confirmed in 13/13 of the ALK-positive cases
ALK oncogenesis story
• Anaplastic lymphoma kinase
– t(2;5) chromosomal translocation in anaplastic large cell lymphoma
• Oncogenic driver
– Early event in tumorigenesis
From: Marino-Enriquez & Dal Cin 2013
• Identical ALK fusions
– Renal cell carcinoma in sickle cell trait (VCL-ALK)
– Some diffuse large B-cell lymphoma (SQSTM1-ALK)
From: Marino-Enriquez & Dal Cin 2013
Differential diagnosis
• Dermatofibroma
– Conventional fibrous histiocytoma
• Epithelioid perineurioma
• Melanocytic e.g. Spitz
• Cutaneous myoepithelioma
Differential diagnosis
• Dermatofibroma
– Conventional fibrous histiocytoma
– Different cytology: more multinucleated cells,
lipidisation, admixed inflammatory cells
– ALK-1 negative
– Protein kinase C gene fusions
• Epithelioid perineurioma
• Melanocytic e.g. Spitz
• Cutaneous myoepithelioma
Conventional dermatofibroma
- lipidised cells = clue
Epithelioid fibrous histiocytoma
ALK
Differential diagnosis
• Dermatofibroma
– Conventional fibrous histiocytoma
• Epithelioid perineurioma
– Pitfall: epithelioid fibrous histiocytoma may be
EMA positive
• Doyle LA, Fletcher CD. J Cutan Pathol 2011;38:697-703
• 27/42 (64%) EMA positive
– Claudin-1 helpful to distinguish
• Melanocytic e.g. Spitz
• Cutaneous myoepithelioma
Differential diagnosis
• Dermatofibroma
– Conventional fibrous histiocytoma
• Epithelioid perineurioma
• Melanocytic e.g. Spitz
– Positive for melanocytic markers
– ALK can be positive i.e. Spitz can show
fusions involving kinases such as ALK
• Cutaneous myoepithelioma
Differential diagnosis
• Epithelioid perineurioma
• Dermatofibroma
– Conventional fibrous histiocytoma
• Melanocytic e.g. Spitz
• Cutaneous myoepithelioma
– Don’t see binucleate/multinucleate cells
– EMA positive
– +/- S100, GFAP, SMA, p63
– ALK negative
– EWSR1 rearrangement
Summary
• Epithelioid fibrous histiocytoma is a distinct neoplasm with recognisable clinical and histological features
• ALK gene rearrangement indicates biologically distinct and not in same spectrum as conventional fibrous histiocytoma
• ALK positivity also helps to distinguish from other differentials such as perineurioma and myoepithelioma
Acknowledgements
• Eduardo Calonje
