Self assessment case Dr Saleem Taibjee saleemtaibjee@gmail.com Dorset County Hospital, Dorchester
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
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)
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