Extra-abdominal and intra-abdominal FET::CREM fusion mesenchymal neoplasms: comparative clinicopathological study of 9 new cases further supporting a distinct potentially aggressive sarcoma and report of novel sites

With the wide use of RNA sequencing technologies, the family of FET::CREB fusion mesenchymal neoplasms has expanded rapidly to include potentially aggressive neoplasms, not fitting any well established WHO entity. Recently, a group of intra-abdominal FET ( EWSR1/FUS ) ::CREB ( CREM/ATF1 ) fused uncl...

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Published in:Virchows Archiv : an international journal of pathology Vol. 485; no. 6; pp. 1007 - 1019
Main Authors: Agaimy, Abbas, Blakely, Morgan, Breimer, Gerben E., Hölsken, Annett, Koppes, Sjors A., Meidenbauer, Norbert, Rijken, Johannes A., Schad, Arno, Simon, Adrian G., Stoehr, Robert, Bishop, Justin A., Din, Nasir Ud
Format: Journal Article
Language:English
Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.12.2024
Springer Nature B.V
Subjects:
Abdomen
Abdominal diseases
Abdominal Neoplasms - genetics
Abdominal Neoplasms - pathology
Adolescent
Adult
Aged
Biomarkers, Tumor - analysis
Biomarkers, Tumor - genetics
CD30 antigen
CD34 antigen
CD99 antigen
Chemotherapy
Child
Cyclic AMP Response Element Modulator - genetics
Cyclic AMP response element-binding protein
Desmin
Fatalities
Female
FLI-1 protein
Gene sequencing
Genotypes
Head and Neck Neoplasms - genetics
Head and Neck Neoplasms - pathology
Histiocytoma
Humans
Inhibin
Keratin
Male
Medicine
Medicine & Public Health
Mesentery
Metastases
Middle Aged
Neoplasms
Nervous system diseases
Oncogene Proteins, Fusion - genetics
Original
Original Article
Pathology
Patients
Pax8 protein
Phenotypes
RNA-Binding Protein EWS - genetics
RNA-Binding Protein FUS - genetics
Sarcoma
Sarcoma - genetics
Sarcoma - pathology
Soft Tissue Neoplasms - genetics
Soft Tissue Neoplasms - pathology
Soft tissues
Sox10 protein
Synaptophysin
Tumors
Young Adult
Constitutional symptoms
Ewing sarcoma
Profiling
Precision medicine
Next generation sequencing
Genetic landscape
ISSN:0945-6317, 1432-2307, 1432-2307
Online Access:Get full text
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Summary:With the wide use of RNA sequencing technologies, the family of FET::CREB fusion mesenchymal neoplasms has expanded rapidly to include potentially aggressive neoplasms, not fitting any well established WHO entity. Recently, a group of intra-abdominal FET ( EWSR1/FUS ) ::CREB ( CREM/ATF1 ) fused unclassified neoplasms has been reported followed by recent recognition of an analogous extra-abdominal category of unclassified neoplasms carrying EWSR1::ATF1 fusions. We describe 9 additional tumors (5 extra-abdominal and 4 abdominal) carrying an EWSR1::CREM ( n  = 8) and FUS::CREM ( n  = 1) fusion. Patients were 7 females and 2 males aged 10 to 75 years (median, 34). Extra-abdominal tumors originated in the head and neck (2 sinonasal, 1 orbital) and soft tissues (1 gluteal, 1 inguinal). Abdominal tumors involved stomach (2), mesentery (1), and kidney (1). Tumor size ranged from 3.5 to 11 cm (median, 6). Treatment was radical surgery with (5) or without (2) neo/adjuvant radio/chemotherapy. Extended follow-up of 5 patients (21–52 months; median, 24) showed an aggressive course in two (40%); one died of disseminated metastases 52 months after several intensified chemotherapy regimens, and one was alive with progressive abdominal disease at 21 months. The immunophenotype of the two subcohorts was significantly overlapping with variable expression of EMA (7 of 8), keratin AE1/AE3 (5 of 9), CD99 (4 of 7), MUC4 (2 of 8), ALK (3 of 8), synaptophysin (3 of 9), chromogranin (1 of 8), CD34 (3 of 6), CD30 (1 of 6), PAX8 (1 of 7), and inhibin (1 of 7), but no reactivity with desmin (0 of 8), S100 (0 of 8), and SOX10 (0 of 8). This series further solidifies the notion that FET::CREB fusions are not limited to the triad of angiomatoid fibrous histiocytoma, clear cell sarcoma, and malignant gastrointestinal neuroectodermal tumor, but characterize an emerging family of potentially aggressive neoplasms occurring at both intra- and extra-abdominal sites. These tumors underscore the promiscuity of the FET::CREB fusions and highlight the pivotal role of phenotype-oriented classification of these neoplasms that share the same genotype, still featuring significant biological and behavioral distinctness.
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ISSN:0945-6317
1432-2307
1432-2307
DOI:10.1007/s00428-024-03917-2