EWSR1‐CREM fusion in pulmonary mesenchymal neoplasm showing distinctive clear cell morphology

Abstract

EWSR1‐CREM gene fusions were recently discovered in several mesenchymal and epithelial tumors, including myxoid mesenchymal tumors of the central nervous system, rare cases of soft tissue clear cell sarcoma and angiomatoid fibrous histiocytoma, and hyalinizing clear cell carcinoma, which implicates the potential phenotypic diversities of tumors harboring an EWSR1‐CREM fusion. We herein present an exceedingly indolent pulmonary mesenchymal tumor showing distinctive clinicopathological features. This tumor histologically displayed a small nest and alveolar pattern consisting of monomorphic clear cells intermingled with dilated anastomosing vasculature. Immunophenotypically, tumor cells were positive for vimentin and focally positive for synaptophysin, but negative for many immunohistochemical panels including keratins, EMA, desmin, mesothelial markers, melanotic markers, smooth muscle actin, inhibin and S‐100 protein. Interestingly, RNA sequencing identified an in‐frame EWSR1‐CREM fusion, which was confirmed by subsequent real‐time/reverse transcription polymerase chain reaction and fluorescence in situ hybridization assay. Clinical follow‐up showed no evidence of recurrence and metastasis. Our pathological findings further expand the phenotypic spectrum of tumors associated with EWSR1‐CREM fusions, implying the emergence of a possible novel tumor entity.

Intra-abdominal EWSR1/FUS-CREM-rearranged malignant epithelioid neoplasms: two cases of an emerging aggressive entity with emphasis on misleading immunophenotype

“…Loss of SDHB in this case remained unexplained and represents a further confusing factor with neuroendocrine neoplasms. Finally, aberrant or equivocal TFE3 expression noted in Case 2 and in a previous case [7] may suggest a TFE3-rearranged neoplasm. This is particularly important in renal cases as rare Xp11-translocation RCC may harbor EWSR1-TFE3 fusions and be indistinguishable from EWSR1/FUS-CREM neoplasms by FISH alone [13].…”

“…Most cases expressed keratin and EMA [2,5,6]. ALK was positive in one (intra-abdominal [2]), synaptophysin in two (chest wall and lung [2,7]), and MUC4 in two (chest wall and gastric [2,6]) previous cases. We add the expression of ALK, MUC4, and synaptophysin in one case each and report novel chromogranin-A expression in one.…”

“…Seven tumors harbored EWSR1-CREM and five FUS-CREM fusions [2,5,6]. Very few examples occurred at extra-abdominal soft tissue (chest wall) or visceral (lung) sites [2,7]. These neoplasms possess a definite malignant potential with propensity for peritoneal recurrences and nodal and distant metastasis [2,5,6].…”

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

“…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. At least intracranially, however, the majority of tumors appear to exhibit the phenotype of IMMT/AFH-like tumors, with similar frequencies of mucin-rich and mucin-poor cases.…”

Detection of EWSR1 fusions in CCOC by targeted RNA-seq

“…5,14,17 EWSR1-CREM translocations are commonly found in mesenchymal tumors, including intracranial myxoid mesenchymal tumor, pulmonary mesenchymal neoplasms, and others. [18][19][20] The goal of this study is to show that targeted RNAseq is a feasible method to detect fusion transcripts in FFPE CCOC samples.…”