Angiomatoid fibrous histiocytoma occurring at distal/acral extremity sites: clinicopathological and molecular study of 26 cases highlighting frequent myxoid histology and site-dependent genotypic variation.

Angiomatoid fibrous histiocytoma (AFH) is a rare mesenchymal neoplasm of borderline malignancy (locally recurring, rarely metastasizing), most often involving the limbs, trunk, and head/neck. Rarely, AFH may involve unusual locations. Herein, we characterize the clinicopathologic features of 26 AFH of the distal extremities, including acral sites. The tumors occurred in 19 females and 7 males ranging in age from 12 to 76 years (median, 23 years). Tumors involved the upper (n = 19) and lower (n = 6) distal extremity; one affected an unspecified digital site. Twenty-two cases occurred in acral locations (hands and feet). Subsets of cases showed the following morphologic features: multinodular architecture (26/26), lymphoid cuffs (23/26), prominent stromal myxoid change (11/25), angiomatoid features (9/26), and cytologic pleomorphism (8/26). The average mitotic count was 1/10 HPF; 3 cases showed brisk mitotic activity (> 10 mitoses/10 HPF). Immunohistochemistry revealed variable expression of desmin (16/25), EMA (14/21) and ALK (5/8). Molecular testing revealed EWSR1 rearrangements in 17/18 cases (94%). Among 12 tumors with known fusion partners, the fusions partner was CREB1 in 6 cases (50%), CREM in 4 tumors (33%), ATF1 in one tumor (8%) and PBX3 (8%) in another tumor. Prominent myxoid features were noted in 75% CREM versus 33% of CREB1 versus 0% of ATF1-fused tumors. AFH occurring in distal extremity/acral locations have a predilection for females, upper extremity locations, frequent unusual (solid, non-angiomatoid and myxoid) morphology and higher frequency of CREM over ATF1 fusions. Awareness of the morphologic spectrum of these rare neoplasms is essential for correct classification.