title: YWHAE rearrangement identified by FISH and RT-PCR in endometrial stromal sarcomas: genetic and pathological correlations.
abstract: Endometrial stromal sarcomas represent the second most common mesenchymal uterine tumor. The 2003 WHO classification distinguishes low-grade and undifferentiated endometrial stromal sarcomas with different prognoses. Endometrial stromal sarcomas are a genetically heterogeneous group of sarcomas harboring different cytogenetic anomalies. Recently, a fusion between the YWHAE and FAM22A/B genes subsequent to a t(10;17) (q22;p13) has been described in endometrial sarcomas with high-grade histology. We examined YWHAE rearrangements by FISH break-apart and RT-PCR in a series of 27 undifferentiated uterine stromal sarcoma without JAZF1 rearrangements. Immunohistochemistry (IHC) was carried out with a panel of antibodies (estrogen (ER) and progesterone (PR) receptors, CD10, Cyclin D1, β-catenin, p53, and Ki-67). We identified a subgroup of endometrial sarcomas with high-grade histology and uniform morphology harboring YWHAE rearrangements. FISH break-apart was interpretable in 20 cases (74%). Twelve cases (60%) showed <10% of tumor cells with a YWHAE rearrangement, 4 cases (20%) showed between 10 and ≤20%, and 4 (20%) >20%. RT-PCR was tested on 24/27 cases (88%) and 19 cases were interpretable (79%). Five cases (26%) showed a specific fusion transcript YWHAE-FAM22A/B sequence. The best concordance rate between FISH and RT-PCR (94%) was obtained with the threshold of 20% of cells with a YWHAE rearrangement. The YWHAE-rearranged cases showed high-grade morphology with uniform appearance, spindle or round epithelioid cells, low ER and PR, CD10 expression, and a high and diffuse positivity for Cyclin D1, p53, and nuclear β-catenin negativity. Cyclin D1 was the most sensitive marker for high-grade endometrial sarcomas with YWHAE rearrangement. All undifferentiated uterine sarcomas with pleomorphic appearances did not harbor any YWHAE rearrangements, except for one case. Overall, for endometrial sarcoma cases with high-grade morphology we recommend to test for YWHAE rearrangements by FISH break-apart, a cost- and time-efficient method, and to complete the investigation by RT-PCR in borderline cases.
authors.affiliation: Department of Pathology, Institut Bergonié, Bordeaux, France.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Croce
authors.forename: Isabelle
authors.initials: I
authors.lastname: Hostein
authors.forename: Agnes
authors.initials: A
authors.lastname: Ribeiro
authors.forename: Delphine
authors.initials: D
authors.lastname: Garbay
authors.forename: Valérie
authors.initials: V
authors.lastname: Velasco
authors.forename: Eberhardt
authors.initials: E
authors.lastname: Stoeckle
authors.forename: Frederic
authors.initials: F
authors.lastname: Guyon
authors.forename: Anne
authors.initials: A
authors.lastname: Floquet
authors.forename: Agnes
authors.initials: A
authors.lastname: Neuville
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Coindre
authors.forename: Gaëtan
authors.initials: G
authors.lastname: MacGrogan
authors.forename: Frederic
authors.initials: F
authors.lastname: Chibon
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018203:Sarcoma, Endometrial Stromal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor; D015514:Oncogene Proteins, Fusion; C482983:YWHAE protein, human