Histiocytoma, Angiomatoid Fibrous

A number sign (#) is used with this entry because angiomatoid fibrous histiocytoma has been associated with somatic fusions of several genes, including FUS (137070), ATF1 (123803), EWS (EWSR1; 133450), and CREB1 (123810).

Clinical Features

Enzinger (1979) first described 'angiomatoid' fibrous histiocytoma as a distinct variant of malignant fibrous histiocytoma that typically occurs in children and adolescents and is manifest by nodular subcutaneous growth. It tends to recur after surgical excision. Characteristic microscopic features include lobulated sheets of histiocyte-like cells intimately associated with areas of hemorrhage and cystic pseudovascular spaces, as well as a striking cuffing of inflammatory cells, mimicking a lymph node metastasis. When the classic cyst-like spaces, peripheral fibrosis, and chronic inflammatory infiltrate are not seen, the lesions may be misdiagnosed as cellular or sclerosing hemangiomas, hemangiopericytoma, hemangioendothelioma, and others (Waters et al., 2000; Antonescu et al., 2007).

Cytogenetics

FUS/ATF1 Fusion Gene

Waters et al. (2000) reported a 5.5-year-old girl who presented with a 1.3-cm firm mass in her left forearm deep to the subcutaneous tissue. Analysis of tumor tissue showed complex rearrangements between chromosomes 2, 12, 16, and 17 were noted on karyotypic study, as well as deletion in the long arm of chromosome 11. A t(12;16) site was investigated using RT-PCR. The FUS gene at 16p11.2 was found to be combined with the ATF1 gene at 12q13, generating a chimeric FUS/ATF1. Waters et al. (2000) found that FUS was interrupted at codon 175 and fused to codon 110 of ATF1, resulting in an in-frame junction with a glycine-to-valine (GGT-to-GTT) transition.

EWS/ATF1 Fusion Gene

In tumor tissue derived from a patient with angiomatoid fibrous histiocytoma, Hallor et al. (2005) identified a t(12;22)(q13;q12) translocation. RT-PCR analysis detected an EWS/ATF1 fusion gene between exons 7 and 5, respectively, that functioned as a constitutive transcriptional activator.

In tumor tissue samples from 8 unrelated patients with angiomatoid fibrous histiocytoma, Antonescu et al. (2007) identified an identical EWSR1/CREB1 fusion transcript with exon 7 of EWSR1 fused to exon 7 of CREB1. In a tumor sample from a ninth patient, they identified an EWSR1/ATF1 fusion gene linking exon 7 of EWSR1 to exon 5 of ATF1. Antonescu et al. (2007) concluded that the EWSR1/CREB1 fusion gene is the most common genetic abnormality in this tumor type.