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, b-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 o10% of tumor cells with a YWHAE rearrangement, 4 cases (20%) showed between 10 and r20%, and 4 (20%) 420%. 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 YWHAErearranged 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 b-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. According to the 2003 WHO classification, endometrial stromal sarcomas are divided into low-grade and undifferentiated, depending on tumor morphology and irrespective of tumor mitotic count. Indeed, low-grade endometrial stromal sarcomas are characterized by small oval or fusiform (blue) cells appearing similar to proliferative endometrial stroma with (often extensive) myometrial permeation, frequent lymphatic invasion, and indolent clinical behavior. 3 Undifferentiated endometrial stromal sarcomas, previously described as high-grade endometrial stromal sarcomas are a group of undifferentiated tumors bearing little

Endometrial stromal tumours revisited: an update based on the 2014 WHO classification

“…Diffuse cytoplasmic/membranous c-Kit expression is consistently seen in the round cell areas 76. The distinctive morphological and immunohistochemical features of HGESS are generally good surrogate markers for the underlying rearrangement, but fluorescence in situ hybridisation and/or reverse transcriptase-PCR studies may be used in equivocal cases 70 77…”

Aggressive Behavior and Poor Prognosis of Endometrial Stromal Sarcomas With YWHAE-FAM22 Rearrangement Indicate the Clinical Importance to Recognize This Subset

“…19 Paired signals were defined as a single yellow (overlapping) signal or a red and green signal less than 2 signal diameters apart, whereas unpaired signals were those separated by greater than 2 signal diameters from an oppositely colored signal. For each case, 100 nuclei were counted, and a rearrangement was defined when the cell displayed 1 fusion, 1 green, and 1 orange signal pattern.…”

“…For each case, 100 nuclei were counted, and a rearrangement was defined when the cell displayed 1 fusion, 1 green, and 1 orange signal pattern. 19 A cutoff of 30% of tumor cell with rearrangement was established.…”

“…14,19 Reverse transcription-polymerase chain reaction (RT-PCR) did not show the specific transcript fusion YWHAE-NUTM2A/B.…”

Small biopsy pathology of mass lesions of the endometrial cavity: differential diagnostic considerations

“…Therefore, hormone receptor stains should always be performed. [32][33][34] In conclusion, the WHO classification of uterine tumours provides the reference framework within which communication between the pathologist, surgeon and oncologist takes place. It is important to be aware of the limitations imposed by small diagnostic biopsies.…”