Uterine Tumor Resembling Ovarian Sex Cord Tumors: 23 Cases Indicating Molecular Heterogeneity With Variable Biological Behavior

Abstract

Uterine tumor resembling ovarian sex cord tumor (UTROSCT) is a rare mesenchymal neoplasm that mainly harbors NCOA1-3 rearrangements with partner genes ESR1 or GREB1. Here, we explored 23 UTROSCTs by targeted RNA sequencing. The association between molecular diversity and clinicopathologic features was investigated. The mean age of our cohort was 43 years (23–65 y). Only 15 patients (65%) were originally diagnosed with UTROSCTs. Mitotic figures ranged from 1 to 7/10 high power fields, of primary tumors and increased from 1 to 9/10 high power fields in recurrent tumors. Five types of gene fusions were identified in these patients, including GREB1::NCOA2 (n=7), GREB1::NCOA1 (n=5), ESR1::NCOA2 (n=3), ESR1::NCOA3 (n=7), and GTF2A1::NCOA2 (n=1). To our knowledge, our group included the largest cohort of tumors with GREB1::NCOA2 fusions. Recurrences were most common in patients with GREB1::NCOA2 fusion (57%), followed by 40% (GREB1::NCOA1), 33% (ESR1::NCOA2), and 14% (ESR1::NCOA3). The recurrent patient who harbored an ESR1::NCOA2 fusion was characterized by extensive rhabdoid features. Both of the recurrent patients who harbored GREB1::NCOA1 and ESR1::NCOA3 had the largest tumor sizes in their own gene alteration groups, and another recurrent GREB1::NCOA1 patient had extrauterine involvement. The GREB1-rearranged patients were of older age, larger tumor size, and higher stage than non-GREB1-rearranged patients (P=0.004, 0.028, and 0.016, respectively). In addition, the GREB1-rearranged tumors presented more commonly as intramural masses rather than non-GREB1-rearranged tumors presenting as polypoid/submucosal masses (P=0.021). Microscopically, nested and whorled patterns were frequently seen in GREB1-rearranged patients (P=0.006). Of note, estrogen receptor expression was weaker than progesterone receptor in all 12 GREB1-rearranged tumors, whereas the similar staining intensity of estrogen receptor and progesterone receptor was observed in all 11 non-GREB1-rearranged tumors (P<0.0001). This study demonstrated that UTROSCTs were present at a younger age in the Chinese population. The genetic heterogeneity of UTROSCTs was correlated with variable recurrence rate. Tumors with GREB1::NCOA2 fusions are more likely to recur compared with those with other genetic alterations.

Uterine Tumors Resembling Ovarian Sex Cord Tumors (UTROSCTs): A Scoping Review of 511 Cases, Including 2 New Cases

“…On the other hand, recent findings have identified recurrent fusions involving NCOA2 and NCOA3 (such as ESR1-NCOA3, ESR1-NCOA2, or GREB1-NCOA2) in UTROSCT. These genes, NCOA2 and NCOA3, are known to be involved in steroid hormone regulation, and the disruptions in their nuclear receptor coactivator domains are thought to play a crucial role in the development of UTROSCT [7,76,104,105,124,125,[131][132][133][134].…”

“…Bi et al reported that in recurrent UTROSCT cases, the GREB1::NCOA2 fusion was the most common, accounting for 57% of cases, with GREB1::NCOA1 and ESR1 fusions also detected. These GREB1-rearranged tumors were typically more advanced, larger, and occurred in older patients [132]. Lu et al reported recurrent NCOA1-3 rearrangements in 87.5% (14/16) of their series, without JAZF1, PHF1, BCOR, or YWHAE rearrangements, underscoring the diagnostic value of these rearrangements in distinguishing UTROSCT from endometrial stromal tumors [131].…”

“…GREB1 encodes for a protein driven transcriptionally by estrogenbound ER, being a crucial component of the canonical estrogen/ER signaling pathway. Binding with estrogen, ESR1 is essential for a broad range of physiological functions, but is also involved in pathologic processes, including breast cancer, endometrial cancer, or osteoporosis [76,104,105,[132][133][134]. Mutations in ESR1 ′ s ligand-binding domain have been correlated with resistance to hormone therapy in ER-positive breast cancer.…”

“…Particularly, tumors with GREB1::NCOA2 fusions are more likely to recur than those with any other genetic alteration [132]. The suggestive study by Xiong et al combined classical histomorphological, immunohistochemical, and molecular-genetic predictors, and finding a significant mitotic activity, a high expression of stromal PD-L1, and an NCOA2 gene alteration may help in identifying the subset of UTROSCT with aggressive behavior and shorter disease-free survival (DFS) [130].…”

p160 nuclear receptor coactivator family members and their role in rare fusion‑driven neoplasms (Review)

“…Expression of CD56, WT1, SF-1, and CD99 was detected in a high percentage of analyzed samples, and diffused expression of ER and PR was detected in all cases. Although there was a high molecular variability amongst samples, 5 different types of gene fusions were detected, all containing NCoA fusion partners with GREB1-NCoA2 fusions being the most common ( 102 , 103 ). A recent study found that malignant UTROSCT is more likely to have higher mitotic activity, high expression of stromal PD-L1, and a gene alteration involving NCoA2 ( 104 ).…”