ALK Rearrangement and Overexpression in an Unusual Cutaneous Epithelioid Tumor With a Peculiar Whorled “Perineurioma-like” Growth Pattern: Epithelioid Fibrous Histiocytoma

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To the Editor:
We report the case of a 49-year-old female patient who presented with a 1-cm cutaneous flesh-colored nodule arising on the right shoulder. Histology of the excision revealed a well-circumscribed dermal tumor composed of a relatively monotous population of polygonal cells with moderate amounts of eosinophilic cytoplasm, vesicular nuclei, and small nucleoli (Figs. 1A, B). Numerous capillaries were dispersed among the epithelioid tumor cells. Perivascular accentuation of tumor cells with a whorled growth pattern was observed (Figs. 1C, D). Immunohistochemically, the tumor cells were diffusely positive for Factor XIIIa and ALK (clone ALK1, Dako and clone D5F3, Roche) (Figs. 2A, B). Staining for epithelial membrane antigen (EMA) was positive in a patchy distribution (Fig. 2C). A retained expression of INI1 (BAF47/SMARCB1) was observed in essentially every tumor cell nucleus. The tumor cells were negative for S100, SOX10, CD34, pancytokeratin AE1/AE3, p63, GFAP, SMA, desmin, and calponin. Fluorescence in situ hybridization was performed using the Vysis LSI ALK dual-color break-apart probe (Abbott Molecular, Bergisch Gladbach, Germany) and demonstrated a balanced ALK rearrangement (split signals and a pair of fused signals) in 56% of the tumor nuclei (Fig. 2D). Altogether, the above findings let us conclude on the diagnosis of an epithelioid fibrous histiocytoma (EFH) with ALK overexpression and a molecularly confirmed ALK rearrangement. EFH (also known as “epithelioid cell histiocytoma”), first described in 1989 by Wilson Jones et al,1 has traditionally been considered as a rare morphologic subtype of benign fibrous histiocytoma (FH) (dermatofibroma) of the skin.2,3 Clinically, EFH typically presents as a solitary dermal-based nodule, most commonly on the extremities of young to middle-aged adults. Histopathologically, EFH is often exophytic with an associated epidermal collarette. Although some conventional FHs can show epithelioid features, the diagnosis of EFH has been reserved for tumors with at least 50% epithelioid morphology. EFH also differs from conventional FH in that it tends to lack lateral entrapment of collagen, and usually does not display a prominent infiltrate of foamy macrophages, multinucleate giant cells, and lymphocytes. EFH is also characterized by a relatively sharp circumscription, location in the papillary and superficial reticular dermis in most cases, and effacement of the rete ridges, which is in contrast to the typical reticular dermal location and epidermal hyperplasia of conventional FH. Given these morphologic differences between EFH and conventional FH, and recent data showing the identification of ALK fusions in EFH, EFH probably represents a distinctive entity.4,5 The diagnosis of EFH is often challenging as this entity frequently lacks the characteristic microscopical features of conventional FH. Furthermore, the epithelioid morphology of this cutaneous lesion may mimic other diverse dermal neoplasms. Differential diagnoses of EFH to consider include Spitz nevus, epithelioid sarcoma, cutaneous syncytial myoepithelioma, and epithelioid perineurioma.6,7 Similar to EFH, Spitz nevi are relatively circumscribed and contain similar epithelioid tumor cells. Most Spitz nevi have a junctional component, but some are wholly intradermal. Moreover, 10% of the Spitz nevi have also been shown to harbor ALK rearrangements,8 showing corresponding overexpression of ALK by immunohistochemistry, which could be a diagnostic pitfall if using ALK immunohistochemistry as a sole diagnostic marker to differentiate EFH from histologic mimics. However, the expression of S100 and other melanocytic markers and the absence for EMA expression in Spitz nevi readily distinguishes the 2. The high frequency of EMA expression in EFH, as in the present case, is also a potential diagnostic pitfall in the diagnosis of EFH.9 Similar to EFH, EMA expression is noted in epithelioid sarcoma, cutaneous syncytial myoepithelioma, and epithelioid perineurioma.
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