Self assessment case. Dr Saleem Taibjee Dorset County Hospital, Dorchester

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1 Self assessment case Dr Saleem Taibjee Dorset County Hospital, Dorchester

2 Clinical details 34-year-old man: Shave excision Skin tag / papilloma left thigh

3 The best diagnosis is: Spitz naevus Epithelioid fibrous histiocytoma Dermatofibroma Epithelioid perineurioma

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9 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

10 CD68

11 CD68

12 CD34

13 CD34

14 EMA

15 EMA

16 SMA

17 SMA

18 Claudin

19 Claudin

20 S100

21 S100

22 ALK

23 ALK

24 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

25 Epithelioid fibrous histiocytoma Uncommon lesion Predilection for proximal thigh Young to middle-aged adults

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29 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: cases of epithelioid fibrous histiocytoma with unexpected ALK immunostaining FISH and next generation sequencing

30 From: Jedrych et al 2015 VCL-ALK fusion (next generation sequencing)

31 From: Jedrych et al 2015 SQSTM1-ALK fusion

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33 From: Doyle et al 2015

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35 ALK gene rearrangement by FISH Confirmed in 13/13 of the ALK-positive cases

36 ALK oncogenesis story Anaplastic lymphoma kinase t(2;5) chromosomal translocation in anaplastic large cell lymphoma Oncogenic driver Early event in tumorigenesis

37 From: Marino-Enriquez & Dal Cin 2013

38 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)

39 Differential diagnosis Dermatofibroma Conventional fibrous histiocytoma Epithelioid perineurioma Melanocytic e.g. Spitz Cutaneous myoepithelioma

40 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

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45 Conventional dermatofibroma - lipidised cells = clue Epithelioid fibrous histiocytoma

46 ALK

47 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: /42 (64%) EMA positive Claudin-1 helpful to distinguish Melanocytic e.g. Spitz Cutaneous myoepithelioma

48 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

49 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

50 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

51 Acknowledgements Eduardo Calonje