RREB1::MRTFB fusion‐positive extra‐glossal mesenchymal neoplasms: A series of five cases expanding their anatomic distribution and highlighting significant morphological and phenotypic diversity

Abstract

The RREB1::MRTFB (former RREB1::MKL2) fusion characterizes ectomesenchymal chondromyxoid tumors (EMCMT) of the tongue. Only five molecularly confirmed extraglossal EMCMT cases have been reported recently; all occurring at head and neck or mediastinal sites. We herein describe five new cases including the first two extracranial/extrathoracic cases. The tumors occurred in three male and two female patients with an age ranging from 18 to 61 years (median, 28). Three tumors were located in the head and neck (jaw, parapharyngeal space, and nasopharyngeal wall) and two in the soft tissue (inguinal and presacral). The tumor size ranged from 3.3 to 20 cm (median, 7).Treatment was surgical without adjuvant treatment in all cases. Two cases were disease-free at 5 and 17 months; other cases were lost to follow-up. Histologically, the soft tissue cases shared a predominant fibromyxoid appearance, but with variable cytoarchitectural pattern (cellular perineurioma-like whorls and storiform pattern in one case and large polygonal granular cells embedded within a chondromyxoid stroma in the other). Two tumors (inguinal and parapharyngeal) showed spindled to ovoid and round cells with a moderately to highly cellular nondescript pattern. One sinonasal tumor closely mimicked nasal chondromesenchymal hamartoma (NCMH). Mitotic activity was low (0-5 mitoses/10 hpfs). Immunohistochemical findings were heterogeneous with variable expression of S100 (2/5), EMA (2/3), CD34 (1/4), desmin (1/4), and GFAP (1/3). Targeted RNA sequencing revealed the same RREB1::MRTFB fusion in all cases, with exon 8 of RREB1 being fused to exon 11 of MRTFB. This study expands the topographic spectrum of RREB1::MRTFB fusion-positive mesenchymal neoplasms, highlighting a significant morphological and phenotypic diversity. Overall, RREB1::MRTFBrearranged neoplasms seem to fall into two subcategories: tumors with lobulated, chondroid, or myxochondroid epithelioid morphology (Cases 2 and 3) and those with more

GAB1::ABL1 fusions define a distinctive soft tissue neoplasm, with variable perineurial differentiation, and a predilection for children and young adults

“…In a third study, one cellular neoplasm with perineurioma‐like whorling and variable expression of EMA, claudin‐1, and CD34 revealed an RREB1::MRTFB fusion 30 . These recent observations raise the possibility that a perineurioma‐like phenotype might represent a non‐lineage specific immunophenotype resulting from dysregulation of the pathways downstream of the fusion product; hence, it is unclear here—or with the report of claudin‐1 expression in low‐grade fibromyxoid sarcoma 28 —whether this immunophenotype is truly indicative of a perineural differentiation, or merely a downstream event (analogous to melanocytic differentiation in clear cell sarcoma, desmin expression in desmoplastic small round cell tumor and other heterologous lineages observed in diverse genetically distinct fusion‐driven entities).…”

Biphenotypic sinonasal sarcoma with PAX3::MAML3 fusion transforming into high-grade rhabdomyosarcoma: report of an emerging rare phenomenon

“…3 In some sections, this typical BSNS morphology sharply transitioned to a highgrade sarcoma with rhabdoid features, very high mitotic activity, and areas of necrosis (A, B). There was only patchy positivity with PAX7 (D), whereas the expression of desmin (C), MyoD1 (E), and myogenin (F) was diffused in these parts neck mesenchymal tumors [10][11][12]. During development, PAX3 determines the cell fate of melanocytic, neuronal, and skeletal muscle differentiation and regulates normal myogenesis and postnatal muscular regeneration [5,6,13], while MAML3 has been shown to function as a potent transactivator of PAX3 response elements [6].…”

“…Very rarely, other fusions partners may be involved, including RREB::MRTFB ( MKL2 ) [ 3 – 6 , 9 – 11 ]. However, the nosological classification of the latter as BSNS is somewhat controversial as identical gene fusions have been described in other head and neck mesenchymal tumors [ 10 – 12 ]. During development, PAX3 determines the cell fate of melanocytic, neuronal, and skeletal muscle differentiation and regulates normal myogenesis and postnatal muscular regeneration [ 5 , 6 , 13 ], while MAML3 has been shown to function as a potent transactivator of PAX3 response elements [ 6 ].…”

TRAF7-mutated Fibromyxoid Spindle Cell Tumors Are Associated With an Aggressive Clinical Course and Harbor an Undifferentiated Sarcoma Methylation Signature

“…However, VGLL3 rearrangements have been shown in hybrid schwannoma-perineuriomas 37. In a recent report of RREB1::MRTFB fusion-positive extraglossal mesenchymal neoplasms, at least 1 case showed a perineurioma-like morphology with spindled cells arranged in whorls and storiform pattern 38. Other benign peripheral nerve sheath tumors, such as neurofibromas may enter the differential diagnosis, but would be express neuroectodermal markers such as S100 and SOX10.…”

“…37 In a recent report of RREB1::MRTFB fusion-positive extraglossal mesenchymal neoplasms, at least 1 case showed a perineuriomalike morphology with spindled cells arranged in whorls and storiform pattern. 38 Other benign peripheral nerve sheath tumors, such as neurofibromas may enter the differential diagnosis, but would be express neuroectodermal markers such as S100 and SOX10. Finally, the emerging family of kinase fusion-positive mesenchymal neoplasms involving NTRK, ROS1, RET, BRAF, and RAF1 may show features seen in the cases in this study.…”