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A morphologic and molecular reappraisal of myoepithelial tumors of soft tissue, bone, and viscera with EWSR1 and FUS gene rearrangements.

ABSTRACT: Myoepithelial tumors (MET) represent a clinicopathologically heterogeneous group of tumors, ranging from benign to highly aggressive lesions. Although MET arising in soft tissue, bone, or viscera share morphologic and immunophenotypic overlap with their salivary gland and cutaneous counterparts, there is still controversy regarding their genetic relationship. Half of MET of soft tissue and bone harbor EWSR1 or FUS related fusions, while MET arising in the salivary gland and skin often show PLAG1 and HMGA2 gene rearrangements. Regardless of the site of origin, the gold standard in diagnosing a MET relies on demonstrating its "myoepithelial immunophenotype" of positivity for EMA/CK and S100 protein or GFAP. However, the morphologic spectrum of MET in soft tissue and bone is quite broad and the above immunoprofile is nonspecific, being shared by other pathogenetically unrelated neoplasms. Moreover, rare MET lack a diagnostic immunoprofile but shows instead the characteristic gene fusions. In this study, we analyzed a large cohort of 66 MET with EWSR1 and FUS gene rearrangements spanning various clinical presentations, to better define their morphologic spectrum and establish relevant pathologic-molecular correlations. Genetic analysis was carried out by FISH for EWSR1/FUS rearrangements and potential partners, and/or by targeted RNA sequencing. Then, 82% showed EWSR1 rearrangement, while 18% had FUS abnormalities. EWSR1-POU5F1 occurred with predilection in malignant MET in children and young adults and these tumors had nested epithelioid morphology and clear cytoplasm. In contrast, EWSR1/FUS-PBX1/3 fusions were associated with benign and sclerotic spindle cell morphology. Tumors with EWSR1-KLF17 showed chordoma-like morphology. Our results demonstrate striking morphologic-molecular correlations in MET of bone, soft tissue and viscera, which might have implications in their clinical behavior.

SUBMITTER: Suurmeijer AJH

PROVIDER: S-EPMC7170037 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Epithelioid hemangioma (EH) is a unique benign vasoformative tumor composed of epithelioid endothelial cells. Although a small subset of EHs with atypical features harbor ZFP36-FOSB fusions, no additional genetic abnormalities have been found to date in the remaining cases. On the basis of a novel FOS-LMNA gene fusion identified by RNA sequencing in an index case of a skeletal EH with typical morphology, we sought to investigate the prevalence of FOS rearrangement in a large cohort of EHs. Thus 57 additional EH cases lacking FOSB rearrangements were studied for FOS gene abnormalities by fluorescence in situ hybridization, and results were correlated with morphologic appearance and clinical presentation. The EHs were subclassified as typical (n=25), cellular (n=21), and angiolymphoid hyperplasia with eosinophilia (ALHE) (n=12) variants. The ALHE was defined as an EH with a vascular "blow-out" pattern associated with a variable degree of inflammation. There were 17 (29%) cases bearing FOS gene rearrangements among 58 cases tested, including 12 male and 5 female patients, with a mean age of 42 years. Most FOS-rearranged EHs occurred in the bone (10) and soft tissue (6), whereas only 1 case was cutaneous. The predominant anatomic site was the extremity (12), followed by trunk (3), head and neck (1), and penis (1). The incidence of FOS rearrangement was significantly higher in bone (59%, P=0.006) and lower in head and neck (5%, P=0.009). Twelve of the FOS-rearranged cases were cellular EH (P=0.001) associated with moderate mitotic activity (2 to 5/10 HPF) and milder inflammatory background. All 12 ALHE cases lacked FOS gene abnormalities, suggesting different pathogenesis. In conclusion, FOS rearrangement was present in a third of EHs across different locations and histologic variants; however, it was more prevalent in cellular EH and intraosseous lesions, compared with those in skin, soft tissue, and head and neck. This genetic abnormality can be useful in challenging cases, to distinguish cellular EHs from malignant epithelioid vascular tumors. These results also suggest that dysregulation of the FOS family of transcription factors through chromosomal translocation is as a key event in the tumorigenesis of EH except for the ALHE variant.

Project description:An increasing number of epithelioid vascular lesions, in particular tumors from the benign and low-grade end of the spectrum, have been characterized by recurrent gene fusions. As a result, the detection of these molecular markers have improved the classification of diagnostically challenging cases. However, despite the significant progress, there are occasional lesions that do not fit in known histologic or molecular groups. Herein, we present five such unclassified epithelioid vascular lesions, which occurred in the bone and showed a distinct morphology composed of alternating vasoformative and solid growth and mild to moderate nuclear pleomorphism. The variegated morphologic appearance resembled that of composite hemangioendothelioma, being distinct from both epithelioid hemangioma and epithelioid hemangioendothelioma, and consistently showed cytologic atypia. Due to their unusual morphologic appearance and negative molecular work-up, targeted transcriptome sequencing was performed in two cases showing the presence of NFATC2 fusions with either EWSR1 or FUS genes. Three additional bone tumors with EWSR1 gene rearrangements were identified by FISH screening of a large cohort of 45 fusion-negative epithelioid vascular neoplasms, one fused to NFATC2 while two others to NFATC1. There were three females and two males, with a wide age range at presentation, mean of 44 years. The lesions occurred in the pelvis, maxillary sinus, and humerus. Two patients presented with polyostotic disease, both located in the pelvic bones. Two patients had available follow-up, one developed two local recurrences in the humerus over a 15-year period, while the other showed no recurrence 4 years subsequent to an en-bloc resection. Tumors were positive for CD31 and ERG, while negative for EMA, CK, synaptophysin, and chromogranin. FISH confirmed this abnormality in all cases, none of them being associated with gene amplifications. Further studies are needed to establish the pathogenetic relationship of this rare molecular subset with other epithelioid vascular tumors and to determine its clinical behavior.

Project description:To elucidate the mechanisms underlying the divergent clinicopathologic spectrum of EWSR1/FUS::CREB translocation-associated tumors, we performed a comprehensive genomic analysis of fusion transcript variants, recurrent genetic alterations (mutations, copy number alterations), gene expression, and methylation profiles across a large cohort of tumor types. The distribution of the EWSR1/FUS fusion partners-ATF1, CREB1, and CREM-and exon involvement was significantly different across different tumor types. Our targeted sequencing showed that secondary genetic events are associated with tumor type rather than fusion type. Of the 39 cases that underwent targeted NGS testing, 18 (46%) had secondary OncoKB mutations or copy number alterations (29 secondary genetic events in total), of which 15 (52%) were recurrent. Secondary recurrent, but mutually exclusive, TERT promoter and CDKN2A mutations were identified only in clear cell sarcoma (CCS) and associated with worse overall survival. CDKN2A/B homozygous deletions were recurrent in angiomatoid fibrous histiocytoma (AFH) and restricted to metastatic cases. mRNA upregulation of MITF, CDH19, PARVB, and PFKP was found in CCS, compared to AFH, and correlated with a hypomethylated profile. In contrast, S100A4 and XAF1 were differentially upregulated and hypomethylated in AFH but not CCS. Unsupervised clustering of methylation profiles revealed that CREB family translocation-associated tumors form neighboring but tight, distinct clusters. A sarcoma methylation classifier was able to accurately match 100% of CCS cases to the correct methylation class; however, it was suboptimal when applied to other histologies. In conclusion, our comprehensive genomic profiling of EWSR1/FUS::CREB translocation-associated tumors uncovered mostly histotype, rather than fusion-type associated correlations in transcript variants, prognostically significant secondary genetic alterations, and gene expression and methylation patterns.

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A morphologic and molecular reappraisal of myoepithelial tumors of soft tissue, bone, and viscera with EWSR1 and FUS gene rearrangements.

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