Recurrent Uterine Tumors Resembling Ovarian Sex-cord Tumors with the Growth Regulation by Estrogen in Breast Cancer 1-Nuclear Receptor Coactivator 2 Fusion Gene: A Case Report and Literature Review

Abstract

Background: Uterine tumors resembling ovarian sex-cord tumors (UTROSCTs) are rare mesenchymal neoplasms predominantly arising in perimenopausal and postmenopausal women. UTROSCTs with growth regulation by estrogen in breast cancer 1 (GREB1)-rearrangement or GREB1-rearranged uterine tumors are exceptionally rare, with only 12 previously reported cases. Here, we report a case of UTROSCT with the GREB1-nuclear receptor coactivator 2 (NCOA2) fusion gene. Case Presentation: A 57-year-old woman presented with a 10.0 cm uterine mass. The tumor was composed of short spindle or epithelioid cells, arranged in diffused sheets, nested, and trabecular/cordlike. The tumor harbored the GREB1-NCOA2 fusion gene, as confirmed by RNA sequencing. The tumor recurred in the pelvis at 30 months after the initial diagnosis. We also compared the clinical and pathologic features of this case with those of the 12 previously published uterine GREB1-rearranged tumors. Of the combined 13 cases (present case and 12 previous cases), the mean age of patients was 64.8 years (range, 51‒74 years). Of the nine reported cases of GREB1-rearranged tumor with follow up, four cases recurred or metastasized (44.4%). Microscopically, most tumors (10/12, 83.3%) showed infiltrative growth, and two were well demarcated. Mitotic figures ranged from 0 to 14 per 10 high-power fields (2 mm2; mean: 3.6). Lymphovascular invasion and necrosis were each present in two cases (2/12, 16.7% and 2/7, 28.6%, respectively). Conclusions: This case provided further evidence that UTROSCTs with GREB1-rearrangement may have a high risk of recurrence/metastasis. Further studies are necessary to clarify the clinical features of this type of tumor, particularly the prognosis, potential treatment, and range of possible molecular events.

Uterine Tumor Resembling Ovarian Sex Cord Tumor With Aggressive Histologic Features Harboring a GREB1-NCOA2 Fusion: Case Report With a Brief Review

“…For comparison, only 3 of 22 ESR1-rearranged UTROSCTs have developed these adverse events, and it is interesting that all the 3 cases harbored ESR1-NOCA2 fusion and showed extensive rhabdoid morphology (4). These collective findings suggest that both GREB1 and ESR1 fused UTROSCTs could behave in an aggressive manner despite their general indolence, while tumors harboring GREB1 rearrangements seem to be more aggressive than those with ESR1 fusions (3,4,(11)(12)(13). However, it is also possible that the 3′ fusion genes, particularly NCOA2, could impart the possibility of recurrence of aggressive outcomes, as 7 of the 9 cases of UTROSCT with adverse outcomes contained NCOA2 as the 3′ partner gene (3,4,(11)(12)(13)18,19).…”

“…In contrast, tumors with ESR1 fusions tend to occur in premenopausal females and are predominantly composed of sex cord-like elements; they may contain foamy or lipidized cells and eosinophilic or Leydig-like cells, and are more likely to express multiple specific sex cord markers (3,4,(10)(11)(12)(13). On the basis of the current body of knowledge, it has been suggested that ESR1rearranged UTROSCTs and uterine tumors with GREB1 fusions are better to be regarded as a unifying entity despite significant heterogeneity, containing variable sex cord-like elements (3,13). With regard to the prognosis, including the current case and those have previously been called as GREB1-rearranged uterine sarcomas (11,18), there are a total of 16 cases of GREB1-fused uterine tumors/UTROSCTs have been described to date, among which 6 (4 with NCOA2, 1 with CTNNB1, and 1 with NR4A3) have experienced local recurrence or distant metastasis within a follow-up period ranging from 3 wk to 14 y (3,(11)(12)(13)18,19).…”

“…While the identification of similar molecular abnormalities in the majority of cases provides strong support that UTROSCT is a distinct entity, there is significant clinicopathologic heterogeneity within this disease spectrum (1). Genotype and phenotype correlation has suggested that GREB1-rearranged UTROSCTs may have a higher tendency to behave aggressively (3,(10)(11)(12)(13). Herein, we report a UTROSCT with aggressive histologic features harboring a GREB1-NCOA2 fusion detected by RNA sequencing and validated by fluorescence in situ hybridization (FISH) analysis, with an emphasis on the diagnostic implications.…”

An update of molecular findings in uterine tumor resembling ovarian sex cord tumor and GREB1‐rearranged uterine sarcoma with variable sex‐cord differentiation

“…The genetic fusions so far identified in UTROSCT are summarized in Table 1 3,18‐25 . The domains included in the chimeric proteins are illustrated in Figure 1.…”

“…Indeed, 6 UTROSCT with local or distant recurrence harbored GREB1 fusions (4 with NCOA2 , 1 with CTNNB1 , and 1 with NR4A3 ; see Table 1). 3,19‐21,23,25 The first case (with GREB1‐NCOA2 ) developed lung metastases, 2 and 11 years after the initial excisional surgery. Two subsequent patients with GREB1‐NCOA2 tumors underwent pelvic recurrence at 66 months and 30 months, respectively.…”