Angiomatoid fibrous histiocytoma originally described
Angiomatoid fibrous histiocytoma (originally described as angiomatoid malignant fibrous histiocytoma) is a soft tissue tumor of intermediate biologic potential. AFH typically arises within extremity deep dermis and subcutis in children and young adults,157, 158, 159 but can arise in older adults and in a variety of sites, including the head and neck and trunk, and more rarely other soft tissue sites or in viscera,14, 160, 161, 162, 163, 164, 165, 166, 167, 168 and is sometimes associated with systemic symptoms. Most AFHs behave in a relatively indolent manner, although local recurrence occurs in up to 15%. Metastases are rare, occurring in between approximately 2% and 5%, sometimes after multiple recurrences, and most frequently to regional nodes and exceptionally to the lungs.170, 171
AFH are circumscribed, lobulated neoplasms that are often surrounded by a thick, frequently incomplete, fibrous pseudocapsule. Most also have a surrounding, although variably dense lymphoplasmacytic infiltrate or cuff of B and T cells, often with germinal centers. There is a wide spectrum of morphology, with the only constant finding being sheets or short fascicles of ovoid, spindled, or epithelioid cells with bland, vesicular nuclei and moderate amounts of eosinophilic cytoplasm (Figs. 7 and 8). Mitoses are usually rare, although there may be atypical forms, and small numbers of tumors exhibit focal or more marked pleomorphism, but none of these features has been associated with a worse clinical outcome.157, 172, 173, 174, 175, 176, 177, 178 Multifocal hemorrhage with blood-filled cysts lined by lesional cells is typical. Rarer findings include the presence of rhabdomyoblast-like or clear cells or reticulated cellular patterns in myxoid stroma.14, 163, 179 Extension of AFH into the deep fascia or muscle has been described to show correlation with local recurrence and distant metastasis. Desmin is variably positive in about 50% (and potential origin of AFH from fibroblastic reticulum cells has been postulated, with a subset of these cells expressing desmin), and smooth muscle epinastine (SMA) and h-caldesmon may sometimes be expressed, but myogenin and MyoD1 are consistently negative. AFH can also express EMA, CD99, and CD68.159, 169
Most AFH harbor EWSR1 (rather than FUS) rearrangements, and AFH has 3 characteristic translocations: t(2;22)(q33;q12) generating EWSR1-CREB1 fusion,15, 16 t(12;22)(q13;q12) with EWSR1-ATF,13, 15, 164, 182 and t(12;16)(q13;p11) with FUS-ATF1. FUS encodes a multifunctional RNA binding protein component of the heterogeneous nuclear ribonucleoprotein complex. EWSR1 and FUS can both act as 5′ partners for ATF1, and FUS can act as an alternative to EWSR1 in other sarcomas36, 65, 72 and acute myeloid leukemia. The most common fusion is EWSR1-CREB1,15, 16 whereas EWSR1-ATF1 has been described more frequently in AFH occurring within viscera; however, individual fusions have not been related to specific anatomic sites, and the type of fusion is not related to behavior. Multiple copies of the EWSR1-CREB1 fusion gene have been described in AFH with pleomorphism. Performing RT-PCR for specific fusion transcripts and FISH using break-apart probes in conjunction is recommended, because the presence of EWSR1 rearrangement alone may not reliably differentiate AFH from other EWSR1-rearranged neoplasms.
Tumors with other CREB family transcription factor fusions
Summary The EWSR1 gene is notable for its ability to rearrange with a wide variety of fusion partners to generate an array of distinct, mostly mesenchymal tumors that show a variety of morphologic features and clinical behaviors. It is evident that the finding of an EWSR1 gene rearrangement in isolation by FISH is nonspecific, and although the use of RT-PCR in conjunction may identify specific fusion transcripts, even this may not be a diagnostic finding. Both of these routine ancillary molecular techniques need interpretation in correlation with the clinical picture and histologic and immunohistochemical findings. The reasons for the propensity of EWSR1 to partner with many different genes leading to oncogenesis remain to be clarified, as do the mechanisms by which such histologically and clinically diverse neoplasms are generated. Further insight into the secondary genetic and epigenetic factors and the downstream pathways involved in each tumor type will ultimately help to direct targeted approaches to therapy. It is also likely that further novel EWSR1-rearranged neoplasms will be detected with the incorporation of more sophisticated sequencing techniques into the routine diagnostic setting.