Clinicopathologic and genetic characterization of angiofibroma of soft tissue: a study of 12 cases including two cases with AHRR::NCOA3 gene fusion

Abstract

Aims: Angiofibroma of soft tissue (AFST) is a benign tumour characterised by prominent arborizing blood vessels throughout the lesion. Approximately twothirds of AFST cases were reported to have AHRR:: NCOA2 fusion, and only two cases have been reported to have other gene fusions: GTF2I::NCOA2 or GAB1::ABL1. Although AFST is included in fibroblastic and myofibroblastic tumours in the World Health Organization's 2020 classification, histiocytic markers, especially CD163, have been reported to be positive in almost all examined cases, and it still remains the possibility of a fibrohistiocytic nature of the tumour. Therefore, we aimed to clarify the genetic and pathological spectrum of AFST and identify whether histiocytic marker-positive cells were true neoplastic cells. Methods and results: We evaluated 12 AFST cases, which included 10 cases with AHRR::NCOA2 and two with AHRR::NCOA3 fusions. Pathologically, nuclear palisading, which has not been reported in AFST, was detected in two cases. Furthermore, one tumour resected by additional wide resection revealed severe infiltrative growth. Immunohistochemical analysis indicated varying levels of desmin-positive cells in nine cases, whereas CD163-and CD68positive cells were diffusely distributed in all 12 cases. We also performed double immunofluorescence staining and immunofluorescence in situ hybridisation in four resected cases with >10% desmin-positive tumour cells. The results suggested that the CD163positive cells differed from desmin-positive cells with AHRR::NCOA2 fusion in all four cases. Conclusion: Our findings suggested that AHRR:: NCOA3 could be the second most frequent fusion gene, and histiocytic marker-positive cells are not genuine neoplastic cells in AFST.

Novel NCOA2/3‐rearranged low‐grade fibroblastic spindle cell tumors: A report of five cases

“…In recent years, a number of mesenchymal neoplasms have been identified, which harbor molecular rearrangements involving sometimes multiple members of the NCOAx gene family, including angiofibroma of soft tissue, a subset of spindle cell rhabdomyosarcomas, and recently described PRRX::NCOAx-rearranged fibroblastic tumors. [1][2][3][4][5][6][7] To our knowledge, only one case where an NCOA gene is partnered in a rearrangement with CCCTC-binding factor (CTCF) has been described and, as far as we know, none with CRTC1 as a partner. 8 We herein present five cases of low-grade, NCOA2/3-rearranged fibroblastic spindle cell neoplasms with CTCF or CRTC1 as 5 0 gene partners.…”

Novel EWSR1::GFI1B gene fusion in angiofibroma of soft tissue

“…8,9 Moreover, incidental cases were found to harbour GTF2I::NCOA2, AHRR: NCOA3 or GAB1::ABL1 fusions. [9][10][11] Conversely, in a recent case series of 13 fibroblastic spindle cell tumours with GAB1::ABL1 fusions, it was shown that these tumours show morphological and immunophenotypical overlap with perineurioma or hybrid schwannoma-perineurioma, often with expression of CD34, EMA, claudin 1 and GLUT1, with EMA immunohistochemical staining highlighting delicate bipolar cytoplasmic processes reminiscent of perineurioma. 5 In this study, we report novel EWSR1::GFI1B gene fusions in three soft tissue tumours with the characteristic morphological features of angiofibroma of soft tissue.…”

“…In later years it appeared that these AHRR::NCOA2 fusions were encountered in 60–80% of all angiofibromas 8,9 . Moreover, incidental cases were found to harbour GTF2I::NCOA2 , AHRR:NCOA3 or GAB1::ABL1 fusions 9–11 . Conversely, in a recent case series of 13 fibroblastic spindle cell tumours with GAB1::ABL1 fusions, it was shown that these tumours show morphological and immunophenotypical overlap with perineurioma or hybrid schwannoma–perineurioma, often with expression of CD34, EMA, claudin 1 and GLUT1, with EMA immunohistochemical staining highlighting delicate bipolar cytoplasmic processes reminiscent of perineurioma 5 …”

CYP1A1 immunohistochemistry is highly specific for angiofibroma of soft tissue among morphological mimics

“…5 This fusion is present in 60-70% of AFST, 3,6 while alternate AHRR::NCOA3 and GTF2I:: NCOA2 fusions have been identified in a minor subset of tumours. [6][7][8] The AHRR::NCOA2 fusion leads to expression of downstream targets of the aryl hydrocarbon receptor pathway, particularly CYP1A1. 5 This gene encodes a cytochrome P450 protein, which is normally expressed in mitochondria in the liver and extra-hepatic sites.…”

“…AFST harbours a recurrent translocation, t(5;8)(p15;q13), resulting in fusion of aryl hydrocarbon receptor repressor ( AHRR ) and nuclear receptor co‐activator 2 ( NCOA2 ) genes 5 . This fusion is present in 60–70% of AFST, 3,6 while alternate AHRR :: NCOA3 and GTF2I :: NCOA2 fusions have been identified in a minor subset of tumours 6–8 . The AHRR :: NCOA2 fusion leads to expression of downstream targets of the aryl hydrocarbon receptor pathway, particularly CYP1A1 5 .…”