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.

Bioptical Laboratory Ltd Plzen Czech Republic

Comprehensive Cancer Center Erlangen EMN Erlangen Germany

Department of Laboratory Medicine and Pathology Mayo Clinic Rochester MN USA

Department of Pathology and Laboratory Medicine Henry Ford Health System Detroit MI USA

Department of Pathology and Laboratory Medicine Mount Sinai Hospital and Laboratory Medicine and Pathobiology University of Toronto Toronto Canada

Department of Pathology and Laboratory Medicine University of Miami Miller School of Medicine Miami FL USA

Department of Pathology Faculty of Medicine in Plzen Charles University Plzen Czech Republic

Department of Pathology John Hopkins University Baltimore MD USA

Department of Pathology Memorial Sloan Kettering Cancer Center New York NY USA

Department of Pathology University of Michigan Ann Arbor MI USA

Institute of Pathology Friedrich Alexander University Erlangen Nürnberg Erlangen Krankenhausstraße 8 10 91054 Germany

See more in PubMed

Enzinger FM (1979) Angiomatoid malignant fibrous histiocytoma: a distinct fibrohistiocytic tumor of children and young adults simulating a vascular neoplasm. Cancer 44:2147–2157 PubMed

Costa MJ, Weiss SW (1990) Angiomatoid malignant fibrous histiocytoma. A follow-up study of 108 cases with evaluation of possible histologic predictors of outcome. Am J Surg Pathol 14:1126–32 PubMed

Chen G, Folpe AL, Colby TV, Sittampalam K, Patey M, Chen MG, Chan JK (2011) Angiomatoid fibrous histiocytoma: unusual sites and unusual morphology. Mod Pathol 24:1560–1570 PubMed

Kerper AL, Larsen BT, Folpe AL, Roden AC, Torres-Mora J, Lo YC, Aubry MC, Boland JM (2024) Primary pulmonary myxoid sarcoma and thoracic angiomatoid fibrous histiocytoma: two sides of the same coin? Am J Surg Pathol 48:562–569 PubMed

Akiyama M, Yamaoka M, Mikami-Terao Y, Yokoi K, Inoue T, Hiramatsu T, Ashizuka S, Yoshizawa J, Katagi H, Ikegami M, Ida H, Nakazawa A, Okita H, Matsumoto K (2015) Paraneoplastic syndrome of angiomatoid fibrous histiocytoma may be caused by EWSR1-CREB1 fusion-induced excessive interleukin-6 production. J Pediatr Hematol Oncol 37:554–559 PubMed

Thway K, Fisher C (2019) Mesenchymal tumors with EWSR1 gene rearrangements. Surg Pathol Clin 12:165–190 PubMed

Yoshida A, Wakai S, Ryo E, Miyata K, Miyazawa M, Yoshida KI, Motoi T, Ogawa C, Iwata S, Kobayashi E, Watanabe SI, Kawai A, Mori T (2019) Expanding the phenotypic spectrum of mesenchymal tumors harboring the EWSR1-CREM fusion. Am J Surg Pathol 43:1622–1630 PubMed

Dermawan JK, Vanoli F, Herviou L, Sung YS, Zhang L, Singer S, Tap WD, Benayed R, Bale TA, Benhamida JK, Dickson BC, Antonescu CR (2022) Comprehensive genomic profiling of EWSR1/FUS::CREB translocation-associated tumors uncovers prognostically significant recurrent genetic alterations and methylation-transcriptional correlates. Mod Pathol 35:1055–1065 PubMed PMC

Wang WL, Mayordomo E, Zhang W, Hernandez VS, Tuvin D, Garcia L, Lev DC, Lazar AJ, López-Terrada D (2009) Detection and characterization of EWSR1/ATF1 and EWSR1/CREB1 chimeric transcripts in clear cell sarcoma (melanoma of soft parts). Mod Pathol 22:1201–1209 PubMed

Stockman DL, Miettinen M, Suster S, Spagnolo D, Dominguez-Malagon H, Hornick JL, Adsay V, Chou PM, Amanuel B, Vantuinen P, Zambrano EV (2012) Malignant gastrointestinal neuroectodermal tumor: clinicopathologic, immunohistochemical, ultrastructural, and molecular analysis of 16 cases with a reappraisal of clear cell sarcoma-like tumors of the gastrointestinal tract. Am J Surg Pathol 36:857–868 PubMed PMC

Waters BL, Panagopoulos I, Allen EF (2000) Genetic characterization of angiomatoid fibrous histiocytoma identifies fusion of the FUS and ATF-1 genes induced by a chromosomal translocation involving bands 12q13 and 16p11. Cancer Genet Cytogenet 121:109–116 PubMed

Antonescu CR, Dal Cin P, Nafa K, Teot LA, Surti U, Fletcher CD, Ladanyi M (2007) EWSR1-CREB1 is the predominant gene fusion in angiomatoid fibrous histiocytoma. Genes Chromosomes Cancer 46:1051–1060 PubMed

Rossi S, Szuhai K, Ijszenga M, Tanke HJ, Zanatta L, Sciot R, Fletcher CD, Dei Tos AP, Hogendoorn PC (2007) EWSR1-CREB1 and EWSR1-ATF1 fusion genes in angiomatoid fibrous histiocytoma. Clin Cancer Res 13:7322–7328 PubMed

Thway K, Nicholson AG, Lawson K, Gonzalez D, Rice A, Balzer B, Swansbury J, Min T, Thompson L, Adu-Poku K, Campbell A, Fisher C (2011) Primary pulmonary myxoid sarcoma with EWSR1-CREB1 fusion: a new tumor entity. Am J Surg Pathol 35:1722–1732 PubMed

Argani P, Harvey I, Nielsen GP, Takano A, Suurmeijer AJH, Voltaggio L, Zhang L, Sung YS, Stenzinger A, Mechtersheimer G, Dickson BC, Antonescu CR (2020) EWSR1/FUS-CREB fusions define a distinctive malignant epithelioid neoplasm with predilection for mesothelial-lined cavities. Mod Pathol 33:2233–2243 PubMed PMC

Kao YC, Sung YS, Zhang L, Chen CL, Vaiyapuri S, Rosenblum MK, Antonescu CR (2017) PubMed PMC

Schaefer IM, Fletcher CD (2014) Myxoid variant of so-called angiomatoid “malignant fibrous histiocytoma”: clinicopathologic characterization in a series of 21 cases. Am J Surg Pathol 38(6):816–823 PubMed

Wangsiricharoen S, Gjeorgjievski SG, Bahrami A, Torres-Mora J, Zou YS, Michal M, Charville GW, Gross JM (2023) Non-cutaneous syncytial myoepitheliomas are identical to cutaneous counterparts: a clinicopathologic study of 24 tumors occurring at diverse locations. Virchows Arch 483:665–675 PubMed

Gandhi JS, Schneider T, Thangaiah JJ, Lauer SR, Gjeorgjievski SG, Baumhoer D, Folpe AL, Bahrami A (2024) Myoepithelial tumors of bone with EWSR1::PBX3 fusion: a spectrum from benign to malignant. Mod Pathol 37(7):100514 PubMed

Kao YC, Lan J, Tai HC, Li CF, Liu KW, Tsai JW, Fang FM, Yu SC, Huang HY (2014) Angiomatoid fibrous histiocytoma: clinicopathological and molecular characterisation with emphasis on variant histomorphology. J Clin Pathol 67:210–215 PubMed

Thway K, Strauss DC, Wren D, Fisher C (2016) “Pure” spindle cell variant of angiomatoid fibrous histiocytoma, lacking classic histologic features. Pathol Res Pract 212:1081–1084 PubMed

Tornóczky T, Bogner B, Krausz T, Ottóffy G, Szuhai K (2012) Angiomatoid fibrous histiocytoma: pleomorphic variant associated with multiplication of EWSR1-CREB1 fusion gene. Pathol Oncol Res 18:545–548 PubMed

Moura RD, Wang X, Lonzo ML, Erickson-Johnson MR, García JJ, Oliveira AM (2011) Reticular angiomatoid “malignant” fibrous histiocytoma–a case report with cytogenetics and molecular genetic analyses. Hum Pathol 42:1359–1363 PubMed

Mangham DC, Williams A, Lalam RK, Brundler MA, Leahy MG, Cool WP (2010) Angiomatoid fibrous histiocytoma of bone: a calcifying sclerosing variant mimicking osteosarcoma. Am J Surg Pathol 34:279–285 PubMed

Dermawan JK, Azzato EM, Goldblum JR, Rubin BP, Billings SD, Ko JS (2021) Superficial ALK-rearranged myxoid spindle cell neoplasm: a cutaneous soft tissue tumor with distinctive morphology and immunophenotypic profile. Mod Pathol 34:1710–1718 PubMed