Primary pulmonary myxoid sarcoma with an unusual gene fusion between exon 7 of EWSR1 and exon 5 of CREB1

Koelsche, Christian; Tavernar, Luca; Neumann, Olaf; Eberhardt, Ralf; Winter, Hauke; Mechtersheimer, Gunhild

doi:10.1007/s00428-019-02716-4

Cited by 7 publications

(8 citation statements)

References 14 publications

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“…On the other hand, the recently described distinct tumor type, so-called ‘malignant epithelioid neoplasm with predilection for mesothelial-lined cavities’ 39 and subsequently validated by Shibayama et al 40 , most commonly harbor either fusions between EWSR1 or FUS and exon 7 of CREM . In contrast, PPMS is almost exclusively driven by EWSR1-CREB1 (mostly ex7-ex7) 41 – 48 except for a rare case with EWSR1-ATF1 49 . Some authors proposed that PPMS and AFH exist on a morphologic and molecular spectrum 43 , 49 .…”

Section: Discussionmentioning

confidence: 95%

Comprehensive genomic profiling of EWSR1/FUS::CREB translocation-associated tumors uncovers prognostically significant recurrent genetic alterations and methylation-transcriptional correlates

et al. 2022

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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. 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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Section: Discussionmentioning

confidence: 95%

Comprehensive genomic profiling of EWSR1/FUS::CREB translocation-associated tumors uncovers prognostically significant recurrent genetic alterations and methylation-transcriptional correlates

et al. 2022

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“…PPMS was coined by Thway et al , 11 and in the World Health Organization (WHO) classification of lung tumors it is included as a distinct tumor, although PPAFH and PPMS has significant overlap in clinicopathological, morphological and molecular features and is considered as a continuum spectrum in morphology and biology 37–41 Comparing the latest case report with the literature reviewing 26 PPMS cases, 42 the average tumor size of PPMS was greater than that of PPAFH (4 vs. 2.2 cm), and most PPMS cases presented as a myxoid tumor with predominant myxoid stroma, but just focal and up to 30% myxoid stroma was reported in PPAFH cases. Mild to severe atypia and focal necrosis was recorded in PPMS cases, but just mild atypia of tumor cells and no necrosis were described in PPAFH cases.…”

Section: Discussionmentioning

confidence: 99%

Distinct clinicopathological features of pulmonary primary angiomatoid fibrous histiocytoma: A report of four new cases and review of the literature

et al. 2020

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Background The aim of this study was to highlight the clinicopathological features of pulmonary primary angiomatoid fibrous histiocytoma (PPAFH) to assist with a differential diagnosis. Methods There were 10 previous reports in the literature and four new PPAFH cases reviewed in this study. Immunohistochemistry (IHC), fluorescence in situ hybridization (FISH) and DNA and RNA‐based next‐generation sequencing (NGS) was performed in the four new cases reported here. Results In the four new PPAFH cases, the ages of occurrence were in patients age from 33 to 55 years and tumor sizes were from 1.5 to 8 cm. Three of four (75.0%) tumors were located in the endobronchus. The most common morphological changes included delineated fibrous capsule (100%, 4/4), lymphoplasmacytic cuff (100%, 4/4), and dense or richly lymphoplasmatic infiltration (100%, 4/4). IHC analysis revealed that the tumor cells of four cases expressed vimentin and TLE1, ALK and CD163 or CD68 was positive in three cases, epithelial membrane antigen (EMA), desmin was positive in two cases, and SMA focal positive expression was observed in two cases. EWSR1 gene rearrangement was positive in all PPAFH cases (100%, 4/4) by FISH detections and four cases were confirmed as EWSR1‐CREB1 fusion variant by DNA and RNA based NGS. No regional lymph nodes and distal metastasis, recurrences and death of disease after surgical excision were recorded in all four cases. Conclusions PPAFH is a very unusual pulmonary primary mesenchymal tumor and the clinicopathological features are like other unusual sites counterparts, but with a smaller tumor size, related with large airway, with a tendency to exhibit benign biological behavior, with EWSR1 gene rearrangement and higher frequency of EWSR1‐CREB1 gene fusion. Key points Significant findings in the study: In comparison with “classic somatic” and nonpulmonary visceral angiomatoid fibrous histiocytoma, pulmonary primary angiomatoid fibrous histiocytoma display distinct clinicopathological features and prognosis. What this study adds The study provided the pathological differential diagnostic criteria and clinico‐pathological features for pulmonary primary angiomatoid fibrous histiocytoma.

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“…10 Most commonly, the fusion identified in PPMS occurs between exon 7 of EWSR1 and exon 7 of CREB1, though fusions involving CREB1 exons 5 and 8 have been reported. 11,12 PPMS are rare, low-grade malignancies that rarely metastasize and most commonly affect middle-aged women. 11,15 PPMS are composed of nodules of spindled to epithelioid cells with prominent reticular architecture and myxoid stroma.…”

mentioning

confidence: 99%

“…15 PPMS commonly show immunopositivity for EMA, but are negative for most other markers, including pancytokeratin, desmin, and S100. [12][13][14][15] One case of PPMS has been reported to show focal immunopositivity for CD56, chromogranin, and synaptophysin, 11 but to our knowledge, immunopositivity for ALK has not been reported in PPMS to date.…”

mentioning

confidence: 99%

“…Interestingly, EWSR1::CREB1 fusion transcripts are also found in more than 80% of primary pulmonary myxoid sarcomas (PPMS) 10 . Most commonly, the fusion identified in PPMS occurs between exon 7 of EWSR1 and exon 7 of CREB1 , though fusions involving CREB1 exons 5 and 8 have been reported 11,12 . PPMS are rare, low-grade malignancies that rarely metastasize and most commonly affect middle-aged women 11,15 .…”

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confidence: 99%

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Primary Pulmonary Myxoid Sarcoma and Thoracic Angiomatoid Fibrous Histiocytoma

Kerper,

Larsen,

Folpe

et al. 2024

American Journal of Surgical Pathology

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Primary pulmonary myxoid sarcoma (PPMS) and thoracic angiomatoid fibrous histiocytoma (AFH) are rare neoplasms with EWSR1 fusions and overlapping morphology. Both tumor types often show epithelial membrane antigen expression, but AFH characteristically co-expresses desmin. We encountered a case of PPMS with the unexpected finding of patchy, strong anaplastic lymphoma kinase (ALK) (previously reported in AFH) and synaptophysin expression. We evaluated a cohort of PPMS and thoracic AFH with systematic morphologic comparison and surveyed for aberrant expression of ALK and synaptophysin. Medical records and slides were reviewed for 16 molecularly confirmed cases of PPMS (n=5) and thoracic AFH (n=11). Each case was scored for morphologic characteristics typical of PPMS and/or AFH. ALK, synaptophysin, chromogranin, desmin, and epithelial membrane antigen immunostains were performed on cases with available tissue. AFH and PPMS cases showed similar age at presentation and long-term tumor behavior. Almost all cases of PPMS and AFH had a fibrous pseudocapsule and lymphoid rim. All PPMS had myxoid stroma and reticular growth pattern, but these features were also present in a subset of AFH. Synaptophysin expression was present in 6 of 11 AFH and 1 of 5 PPMS; all tested cases were negative for chromogranin (n=15). One case of AFH and 1 case of PPMS showed focally strong coexpression of synaptophysin and ALK. AFH and PPMS show considerable clinicopathologic overlap. When supportive, the immunohistochemical findings described may aid in diagnosis before molecular confirmation. PPMS and AFH may be morphologic variants of the same clinicopathologic entity, which can show more immunophenotypic variability than previously reported.

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Primary pulmonary myxoid sarcoma with an unusual gene fusion between exon 7 of EWSR1 and exon 5 of CREB1

Cited by 7 publications

References 14 publications

Comprehensive genomic profiling of EWSR1/FUS::CREB translocation-associated tumors uncovers prognostically significant recurrent genetic alterations and methylation-transcriptional correlates

Comprehensive genomic profiling of EWSR1/FUS::CREB translocation-associated tumors uncovers prognostically significant recurrent genetic alterations and methylation-transcriptional correlates

Distinct clinicopathological features of pulmonary primary angiomatoid fibrous histiocytoma: A report of four new cases and review of the literature

Primary Pulmonary Myxoid Sarcoma and Thoracic Angiomatoid Fibrous Histiocytoma

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