RREB1‐MKL2 fusion in a spindle cell sinonasal sarcoma: biphenotypic sinonasal sarcoma or ectomesenchymal chondromyxoid tumor in an unusual site?

Abstract

Biphenotypic sinonasal sarcoma (BSNS) is a rare, low grade spindle cell sarcoma, recently recognized in the WHO classification of head and neck tumors, which is characterized by a dual myogenic and neural differentiation and recurrent gene fusions, often involving PAX3‐MAML3, and less commonly PAX3 fusions with other partners such as NCOA1, NCOA2, or WWTR1. Yet, in about 4% of tumors no gene rearrangements are identified. Herein, we describe a RREB1‐MKL2 fusion in a BSNS lesion occurring in a 73‐year‐old female patient with a right maxillo‐ethmoidal angle lesion. The polypoid, moderately cellular tumor with infiltrative submucosal growth was composed of fascicles of relatively bland spindle cells embedded in a loose collagenous matrix. The tumor cells showed moderate amounts of eosinophilic cytoplasm with indistinct borders and uniform, pale, ovoid to slender nuclei. The slowly proliferating neoplastic cells co‐expressed smooth muscle actin and S100, and showed focal nuclear positivity for ß‐catenin, while lacking staining for cytokeratins, desmin, myogenin, caldesmon, glial fibrillary acid protein, and SOX‐10. Molecular analysis by targeted RNA‐based next‐generation sequencing identified an in‐frame fusion between exon 8 of RREB1 and exon 11 of MKL2, a genetic event that was reported to be a molecular hallmark of ectomesenchymal chondromyxoid tumor. Gene rearrangements in both genes were independently verified by fluorescence in situ hybridization (FISH). To evaluate its recurrent potential an additional group of 15 fusion negative BSNS were tested for abnormalities in RREB1 and MKL2 genes by FISH, but no additional positive cases were identified.

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

“…Of interest, our Case 5 showed histological features potentially overlapping with BSS with rhabdomyoblastic differentiation 35–38 . Moreover, two tumors with identical RREB1::MRTFB fusion were reported previously as BSS 13,16 . However, there is no proof that these tumors represent genuine BSS as their immunophenotype is highly heterogeneous and may overlap with more than one entity including BSS.…”

“…These extra‐glossal tumors showed variable resemblance to glossal EMCMTs but were dominated by variant histology including hypercellular nodules arranged into sheets and fascicles and hypocellular areas arranged into cords, reticular pattern, or haphazardly within a hyalinized stroma. Cellular storiform proliferation of bland spindle cells with perivascular hyalinization and occasional nuclear pseudoinclusions as well as myxoid areas containing round to polygonal cells and scattered binucleated cells were observed as well 13–16 . Overall, RREB1::MRTFB ‐rearranged neoplasms seem to fall into two morphological subcategories: tumors with lobulated, chondroid or myxochondroid epithelioid phenotype (seen in three cases) and tumors with more undifferentiated hypercellular spindle cell morphology (seen in seven cases; Table 2).…”

“…To date, very few cases of extra‐glossal EMCMT have been reported 10–16 . However, only five genuine extra‐glossal EMCMTs have been verified by molecular testing (Tables 1 and 2).…”

“…However, only five genuine extra‐glossal EMCMTs have been verified by molecular testing (Tables 1 and 2). These tumors originated predominantly in females (4:1) at a mean age of 53 years (range, 25–73) and involved exclusively head and neck (three cases; parapharyngeal, sinonasal, and mandibular 13,15,16 ) and mediastinal (two cases 14 ) sites. Including our cases, a total of 10 molecularly verified extra‐glossal RREB1::MRTFB ‐rearranged neoplasms have been documented.…”

“…8,9 While the majority of tumors originate on the anterior dorsum of the tongue, few cases deviated from this and originated from the posterior part or other lateral borders of the tongue instead. 1,8 Extraglossal examples of EMCMT are exceedingly rare [10][11][12][13][14][15][16] and only five of them have been confirmed by genotyping (Table 1 [13][14][15][16] ). We herein describe five new tumors carrying this gene fusion including the first two cases originating from extracranial/extrathoracic soft tissue sites.…”