PRRX‐NCOA1/2 rearrangement characterizes a distinctive fibroblastic neoplasm

Abstract

Fibroblastic/myofibroblastic neoplasms represent a broad, and occasionally diagnostically challenging, category of soft tissue neoplasms. A subset of these tumors defy conventional classification. However, with the advent of next‐generation sequencing, the identification of disease‐defining molecular alterations is gradually improving their subclassification. Following identification of two index cases of a distinctive fibroblastic neoplasm with a fusion gene involving PRRX1 and NCOA1, we performed a retrospective review to further characterize this entity. We identified two additional cases, including one with a fusion between PRRX1 and NCOA2. The average patient age was 38 years, and three patients were female. Two tumors occurred on the neck, and the others involved the groin and thigh. Tumors were centered in the subcutis and ranged from 2.3 to 14.0 cm (average 5.8 cm). Morphologically, they were predominantly hypocellular, with focal hypercellularity. They were composed of monomorphic spindle‐stellate cells with a vague fascicular pattern. The nuclei were bland with only rare mitotic activity, and occasional multinucleation. The intervening stroma was typically abundant and ranged from myxoid to collagenous, with frequent rope‐like collagen bundles. Three of the cases had a prominent vasculature ranging from numerous small curvilinear vessels to ectatic and branching staghorn‐like vessels. Immunohistochemistry was negative for desmin, smooth muscle actin, S100, CD34, keratin, and epithelial membrane antigen. Each of the patients was treated by simple excision and none of the tumors were associated with local recurrence or metastasis. Based on their unique morphological and molecular attributes, we believe this represents a novel fibroblastic tumor for which we have tentatively proposed the name “PRRX‐NCOAx‐rearranged fibroblastic tumor.”

Recurrent MEIS1-NCOA2/1 fusions in a subset of low-grade spindle cell sarcomas frequently involving the genitourinary and gynecologic tracts

“…The breakpoint of MEIS1 exon 7 fused to NCOA1 exon 13 is the same as one of the common fusion variants of MEIS1-NCOA2 fusions, and both preserve the C-terminal transcription activation domains of NCOA proteins in the deduced chimeric MEIS1-NCOA protein. Similar interchangeable role of NCOA1 and NCOA2 fusions has also been observed in other tumors, such as biphenotypic sinonasal sarcoma (PAX3-NCOA1/2) [7,8], PRRX-NCOA1/2 rearranged fibroblastic neoplasm [9], and uterine tumor resembling ovarian sex cord tumor (GREB1-NCOA1/ 2) [10].…”

“…NCOA2 gene encodes a nuclear hormone receptor transcriptional coactivator. Gene fusions involving NCOA2 with other partner genes have been identified in several distinct groups of mesenchymal tumors, including mesenchymal chondrosarcoma (HEY1-NCOA2) [4], soft tissue angiofibroma (AHRR-NCOA2) [5], congenital/infantile spindle cell RMS (VGLL2-NCOA2, SRF-NCOA2, TEAD1-NCOA2) [6], biphenotypic sinonasal sarcoma (PAX3-NCOA1/2) [7,8], PRRX-NCOA1/2 rearranged fibroblastic neoplasm [9], and uterine tumor resembling ovarian sex cord tumor (ESR1-NCOA2/3, GREB1-NCOA1/2) [10]. Our uterine case did not show sexcord-like differentiation as seen in uterine tumor resembling ovarian sex cord tumor.…”

Ependymoma‐like tumor with mesenchymal differentiation harboring C11orf95‐NCOA1/2 or ‐RELA fusion: A hitherto unclassified tumor related to ependymoma

“…In this study, we identified C11orf95-NCOA1/2 in three ELTMDs. Fusion genes involving NCOA1/2 have been recurrently identified in several types of soft tissue tumors and acute leukemia (33,34). In the CNS, the case of ST anaplastic ependymoma presenting clear cell morphology with C11orf95-NCOA1 was reported (5).…”

‘I Can’t Keep Up!’: an update on advances in soft tissue pathology occurring after the publication of the 2020 World Health Organization classification of soft tissue and bone tumours

“…Arguably, the classification of fibroblastic tumours has undergone the most significant changes over the past decade, with the rise and fall of solitary fibrous tumour and fibrosarcoma, respectively, 6 and the recognition of new morphologically and genetically distinctive entities, including angiofibroma of soft tissue, 7 superficial CD34‐positive fibroblastic tumour, 8 and EWSR1 :: SMAD3 fibroblastic tumour 9 . Very recently, two other distinctive subsets of fibroblastic tumour have been identified, characterised by rearrangements involving KMT2A 10–12 and PRRX :: NCOA1 / 2 fusions, 13 respectively.…”