Intracranial Myxoid Mesenchymal Tumor/Myxoid Subtype Angiomatous Fibrous Histiocytoma: Diagnostic and Prognostic Challenges

Abstract

BACKGROUND AND IMPORTANCE In the setting of intracranial neoplasms, EWSR1-cAMP Response Element-Binding Protein (CREB) transcription factor family fusions have been described in myxoid mesenchymal tumors, extremely rare entities with a close histopathologic and immunologic resemblance to myxoid subtype angiomatoid fibrous histiocytomas (AFH). Controversy exists on whether these central nervous system lesions are a subtype of myxoid AFH or a completely separate entity, which entitles a distinct clinical behavior and, consequently, a different approach to management. Upon review of the literature, only 14 cases of intracranial tumors harboring an EWSR1-CREB family fusion were identified, with only 3 cases presenting in middle-aged adults, none of which reported an EWSR1-CREM fusion mutation. Significant variability in reported radiographic and histopathological characteristics, as well as in clinical outcomes, was noted. Their similarity with other soft tissue tumors, added to the scarce information on its clinical behavior, represents a great diagnostic and therapeutic challenge to the treating physician. CLINICAL PRESENTATION We present a rare case of EWSR1-CREM mutated intracranial myxoid mesenchymal tumor/myxoid subtype AFH presenting as persistent headaches in a 36-yr-old woman with radiographic evidence of rapid growth and extensive vasogenic edema, for which she underwent surgical resection. CONCLUSION This represents a unique case of EWSR1-CREM mutated intracranial myxoid mesenchymal tumor presenting in adulthood, with evidence of aggressive behavior.

A case of intracranial myxoid mesenchymal tumor with EWSR1:CREM fusion in an adult female: Extensive immunohistochemical evaluation

“…These observations coincide with previously reported cases. 4,23 Histologically, the tumor showed a prominent myxoid stroma, spindle or histiocytoid cells arranged in cord-like or reticular patterns, and sunburst-like amianthoid fibers, all of which were consistent with the reported features of IMMT. Meanwhile, the tumor also bore a partial resemblance to conventional AFH, characterized by focal lesions with solid syncytial growth of epithelioid cells and peripheral dense lymphoplasmacytic infiltration with aggregates of hemosiderin-laden macrophages.…”

“…Among the CREB family genes, including ATF1, CREB1, and CREM, CREM is the most recently discovered constituent of fusion genes associated with oncogenesis of human tumors. However, CREM fusions have subsequently been found in a variety of tumors, including IMMT/intracranial AFH-like tumor, 11,13,[17][18][19]23,28,31 myxoid variants of extracranial AFH, 9 HCCC of the upper aerodigestive tract and lung, 32 ectomesenchymal chondromyxoid tumor of the tongue, 33 CCS of the soft tissue, 9,34 a clear cell tumor resembling CCS, 35 malignant epithelioid mesothelioma-like tumor, 36 SEF/LGFMS, 37,38 and several other unclassified tumor of intracranial and extracranial sites. 9,11,[39][40][41] This diversity of phenotypes and tumor sites makes it extremely difficult to define the characteristics of tumors with CREM fusions.…”

“…In fact, previous studies have shown that these tumors frequently pose a considerable diagnostic challenge, sometimes requiring multiple histological evaluations before the final diagnosis is established. 12,15,21,23,26 In the present case, however, the tumor differed from well-established entities because the striking myxoid appearance was unusual for neoplasms in the central nervous system, and immunohistochemical results were also inconsistent with uncommon myxoid neoplasms in this region, including chordoid meningioma, being usually positive for PgR and SSTR2, myxoid solitary fibrous tumor, being positive for CD34 and STAT6, glial/neuroepithelial tumors with myxoid change, being positive for GFAP, Olig2, or synaptophysin, myoepithelial tumors, being positive for GFAP, S-100 protein, p63 or α-SMA, and extraskeletal myxoid chondrosarcoma, being usually negative for desmin. Moreover, although the coexpression of cytokeratin and desmin was reminiscent of desmoplastic small round cell tumor, this tumor could be reliably ruled out because it is characterized by distinct histological features, including nests of small round cells within desmoplastic stroma, as well as the specific EWSR1:WT1 fusion, neither of which was observed in the present tumor.…”

An integrative histopathological and epigenetic characterization of primary intracranial mesenchymal tumors, FET:CREB‐fused broadening the spectrum of tumor entities in comparison with their soft tissue counterparts

“…More than 90% of CCS tumors harbor an EWSR1:ATF1 fusion, whereas CREB1 and CREM tumors have been, respectively, rare and only exceptionally described ( 19 ). The recent literature identified a novel intracranial histomolecular entity, variably referred to as the intracranial myxoid mesenchymal tumor (IMMT) or the intracranial AFH (44 reported cases to date) ( 16 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ). In the CNS, because these tumors mostly lacked the characteristically histopathological triad of typical AFH of the soft tissue and because they often presented a myxoid stroma, the terminology “intracranial myxoid mesenchymal tumor” has been preferred by some authors ( 21 , 22 , 25 , 27 , 30 , 31 , 33 , 36 , 39 , 40 , 41 ).…”

A novel SMARCA2-CREM fusion: expanding the molecular spectrum of intracranial mesenchymal tumors beyond the FET genes

“…IMT are characterized by recurrent FET-CREB translocations, always involving the FET genes to date, mainly EWSR1 and exceptionally FUS [3][4][5][6][7][8][9][11][12][13][14][15][16][17][18][19][20][21][22][23]. SMARCA2-CREM fusion has not been previously reported in CNS or in soft tissue.…”