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Recurrent Fusions Between YAP1 and KMT2A in Morphologically Distinct Neoplasms Within the Spectrum of Low-grade Fibromyxoid Sarcoma and Sclerosing Epithelioid Fibrosarcoma

Puls, Florian ; Agaimy, Abbas ; Flucke, Uta ; Mentzel, Thomas ; Sumathi, Vaiyapuri P ; Ploegmakers, Marieke ; Stoehr, Robert ; Kindblom, Lars-Gunnar ; Hansson, Magnus and Sydow, Saskia LU , et al. (2020) In American Journal of Surgical Pathology 44(5). p.594-606
Abstract

Sclerosing epithelioid fibrosarcoma (SEF) is an aggressive soft tissue sarcoma. In the majority of cases, there is overexpression of MUC4, and most cases show EWSR1-CREB3L1 gene fusions. A subset of SEF displays composite histologic features of SEF and low-grade fibromyxoid sarcoma (LGFMS). These "hybrid" tumors are more likely to harbor the FUS-CREB3L2 fusion, which is also seen in most LGFMS. We, here, characterize a series of 8 soft tissue neoplasms with morphologic features highly overlapping with LGFMS and SEF but lacking MUC4 expression and EWSR1/FUS-CREB3L gene fusions. Seven tumors showed fusions of the YAP1 and KMT2A genes, and 1 had a fusion of PRRX1 and KMT2D; all but 1 case displayed reciprocal gene fusions. At gene... (More)

Sclerosing epithelioid fibrosarcoma (SEF) is an aggressive soft tissue sarcoma. In the majority of cases, there is overexpression of MUC4, and most cases show EWSR1-CREB3L1 gene fusions. A subset of SEF displays composite histologic features of SEF and low-grade fibromyxoid sarcoma (LGFMS). These "hybrid" tumors are more likely to harbor the FUS-CREB3L2 fusion, which is also seen in most LGFMS. We, here, characterize a series of 8 soft tissue neoplasms with morphologic features highly overlapping with LGFMS and SEF but lacking MUC4 expression and EWSR1/FUS-CREB3L gene fusions. Seven tumors showed fusions of the YAP1 and KMT2A genes, and 1 had a fusion of PRRX1 and KMT2D; all but 1 case displayed reciprocal gene fusions. At gene expression profiling, YAP1 and KMT2A/PRRX1 and KMT2D tumors were distinct from LGFMS/SEF. The patients were 4 female individuals and 4 male individuals aged 11 to 91 years. Tumors with known locations were in the lower extremity (5), trunk (2), and upper extremity (1); 3 originated in acral locations. Tumor size ranged from 2.5 to 13 cm. Proportions of SEF-like and LGFMS-like areas varied considerably among tumors. All tumors that showed infiltrative growth and mitotic figures per 10 HPFs ranged from 0 to 18. Tumor necrosis was present in 1 case. Follow-up was available for 5 patients (11 to 321 mo), 2 of whom developed local recurrences, and 1 died of metastatic disease. The clinical behavior of these soft tissue sarcomas remains to be further delineated in larger series with extended follow-up; however, our limited clinical data indicate that they are potentially aggressive.

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keywords
Adaptor Proteins, Signal Transducing/genetics, Adolescent, Adult, Aged, Aged, 80 and over, Biomarkers, Tumor/genetics, Child, Diagnosis, Differential, Disease Progression, Epithelioid Cells/pathology, Europe, Female, Fibrosarcoma/genetics, Gene Fusion, Genetic Predisposition to Disease, Histone-Lysine N-Methyltransferase/genetics, Homeodomain Proteins/genetics, Humans, In Situ Hybridization, Fluorescence, Male, Middle Aged, Myeloid-Lymphoid Leukemia Protein/genetics, Neoplasm Grading, Neoplasm Recurrence, Local, Phenotype, Predictive Value of Tests, RNA-Seq, Sclerosis, Soft Tissue Neoplasms/genetics, Transcription Factors/genetics, Treatment Outcome
in
American Journal of Surgical Pathology
volume
44
issue
5
pages
13 pages
publisher
Lippincott Williams & Wilkins
external identifiers
  • scopus:85083546099
  • pmid:31913156
ISSN
1532-0979
DOI
10.1097/PAS.0000000000001423
language
English
LU publication?
yes
additional info
F.P., A.A., U.F., T.M. contributed equally.
id
61648dc0-e67f-41b1-af91-554d156cc2cf
date added to LUP
2020-11-10 11:12:34
date last changed
2021-04-06 01:25:02
@article{61648dc0-e67f-41b1-af91-554d156cc2cf,
  abstract     = {<p>Sclerosing epithelioid fibrosarcoma (SEF) is an aggressive soft tissue sarcoma. In the majority of cases, there is overexpression of MUC4, and most cases show EWSR1-CREB3L1 gene fusions. A subset of SEF displays composite histologic features of SEF and low-grade fibromyxoid sarcoma (LGFMS). These "hybrid" tumors are more likely to harbor the FUS-CREB3L2 fusion, which is also seen in most LGFMS. We, here, characterize a series of 8 soft tissue neoplasms with morphologic features highly overlapping with LGFMS and SEF but lacking MUC4 expression and EWSR1/FUS-CREB3L gene fusions. Seven tumors showed fusions of the YAP1 and KMT2A genes, and 1 had a fusion of PRRX1 and KMT2D; all but 1 case displayed reciprocal gene fusions. At gene expression profiling, YAP1 and KMT2A/PRRX1 and KMT2D tumors were distinct from LGFMS/SEF. The patients were 4 female individuals and 4 male individuals aged 11 to 91 years. Tumors with known locations were in the lower extremity (5), trunk (2), and upper extremity (1); 3 originated in acral locations. Tumor size ranged from 2.5 to 13 cm. Proportions of SEF-like and LGFMS-like areas varied considerably among tumors. All tumors that showed infiltrative growth and mitotic figures per 10 HPFs ranged from 0 to 18. Tumor necrosis was present in 1 case. Follow-up was available for 5 patients (11 to 321 mo), 2 of whom developed local recurrences, and 1 died of metastatic disease. The clinical behavior of these soft tissue sarcomas remains to be further delineated in larger series with extended follow-up; however, our limited clinical data indicate that they are potentially aggressive.</p>},
  author       = {Puls, Florian and Agaimy, Abbas and Flucke, Uta and Mentzel, Thomas and Sumathi, Vaiyapuri P and Ploegmakers, Marieke and Stoehr, Robert and Kindblom, Lars-Gunnar and Hansson, Magnus and Sydow, Saskia and Arbajian, Elsa and Mertens, Fredrik},
  issn         = {1532-0979},
  language     = {eng},
  number       = {5},
  pages        = {594--606},
  publisher    = {Lippincott Williams & Wilkins},
  series       = {American Journal of Surgical Pathology},
  title        = {Recurrent Fusions Between YAP1 and KMT2A in Morphologically Distinct Neoplasms Within the Spectrum of Low-grade Fibromyxoid Sarcoma and Sclerosing Epithelioid Fibrosarcoma},
  url          = {http://dx.doi.org/10.1097/PAS.0000000000001423},
  doi          = {10.1097/PAS.0000000000001423},
  volume       = {44},
  year         = {2020},
}