Decoding UTROSCT heterogeneity: systematic clinicopathological evaluation combined with molecular profiling

Objectives Uterine tumors resembling ovarian sex cord tumors (UTROSCT) are rare mesenchymal neoplasms of uncertain histogenesis that are challenging to diagnose due to their morphological and immunohistochemical overlap with more conventional entities. While DNA sequencing has failed to identify recurring mutations in these tumors, RNA sequencing recently detected NCOA2/3 fusions in two small series. The objective of this study was to further describe the characteristics of two UTROSCTs. Methods We retrospectively evaluated the clinicopathological and immunohistochemical features of two UTROSCTs, and performed RNA sequencing to detect gene fusions. Results The patients were 52 and 57 years old, tumors measured 5 and 12 cm, and were confined to the myometrium. Both showed multiple histologic patterns including diffuse, cord-like, and trabecular, with rhabdoid cells focally present. One UTROSCT had significant cytologic atypia and brisk mitotic activity, but both lacked necrosis and lymphovascular invasion. Variable immunohistochemical expression for calretinin, inhibin, WT-1, ER, CD10, and pankeratin was noted. RNA sequencing detected an ESR1-NCOA3 fusion in one tumor, whereas the other had a GREB1-NCOA2 rearrangement. The former patient is alive and well five months after diagnosis, while the latter recurred two years later, and is currently alive with disease (six years after original diagnosis). Conclusions The detection of NCOA2/3 fusions in two additional UTROSCTs further supports this rearrangement as a characteristic finding in these rare tumors. Additional studies are warranted to determine its sensitivity and specificity in UTROSCTs compared to other gynecologic neoplasms.

Uterine Tumors Resembling Ovarian Sex Cord Tumors (UTROSCTs) are rare uterine mesenchymal neoplasms with uncertain biological potential. These tumors, which affect both premenopausal and postmenopausal women, usually have a benign clinical course. Nevertheless, local recurrences and distant metastases have been described. By analyzing 511 cases retrieved from individual reports and cases series, we provide here the most comprehensive overview of UTROSCT cases available in the literature, supplemented by two new cases of UTROSCTs. Case 1 was an asymptomatic 31-year-old woman who underwent a laparoscopic resection of a presumed leiomyoma. Case 2 was a 58-year-old postmenopausal woman with abnormal vaginal bleeding who underwent an outpatient hysteroscopic biopsy of a suspicious endometrial area. In both cases, immunohistochemical positivity for Calretinin and Inhibin was noted, typical for a sex cord differentiation. In both cases, total laparoscopic hysterectomy with bilateral salpingo-oophorectomy was performed. In light of the available literature, no pathognomonic clinical or imaging finding can be attributed to UTROSCT. Patients usually present with abnormal uterine bleeding or pelvic discomfort, but 20% of them are asymptomatic. In most cases, a simple hysterectomy appears to be the appropriate treatment, but for women who wish to become pregnant, uterus-preserving approaches should be discussed after excluding risk factors. Age, tumor size, lymphovascular space invasion, nuclear atypia, and cervical involvement are not reliable prognostic factors in UTROSCT. The current research suggests that aggressive cases (with extrauterine spread or recurrence) can be identified based on a distinct genetic and immunohistochemical phenotype. For instance, UTROSCTs characterized by GREB1::NCOA1-3 fusions and PD-L1 molecule expression appear to be predisposed to more aggressive behaviors and recurrence, with GREB1::NCOA2 being the most common gene fusion in recurrent tumors. Hence, redefining the criteria for UTROSCTs may allow a better selection of women suitable for fertility-sparing treatments or requiring more aggressive treatments in the future.

Clinical characteristics and outcomes of uterine tumors resembling ovarian sex-cord tumors (UTROSCT): a systematic review of literature

Introduction: Among uterine tumors resembling ovarian sex cord tumors (UTROSCTs), it has been suggested that GREB1-rearranged cases are biologically distinct from ESR1-rearranged cases and might be considered as a separate entity. Objectives: The aim of this systematic review was to assess the difference between GREB1- and ESR1-rearranged UTROSCTs with regard to several clinico-pathological parameters. Methods: Three electronic databases were searched from their inception to February 2025 for all studies assessing the presence of GREB1 and ESR1 rearrangements in UTROSCTs. Exclusion criteria comprised overlapping patient data, case reports, and reviews. Statistical analysis was performed to compare clinicopathological variables between GREB1- and ESR1-rearranged UTROSCTs. Dichotomous variables were compared by using Fisher's exact test; continuous variables were compared by using Student's t-test. A p-value < 0.05 was considered significant. Results: Six studies with 88 molecularly classified UTROSCTs were included. A total of 36 cases were GREB1-rearranged, and 52 cases were ESR1-rearranged. GREB1-rearranged UTROSCTs showed a significantly older age (p < 0.001), larger tumor size (p = 0.002), less common submucosal/polypoid growth (p = 0.005), higher mitotic index (p = 0.010), more common LVSI (p = 0.049), and higher likelihood to undergo hysterectomy (p = 0.008) compared to ESR1-rearranged cases. No significant differences were detected with regard to margins, cytological atypia, necrosis, retiform pattern, and rhabdoid cells. No significant differences were found in the immunohistochemical expression of any of the assessed markers (wide-spectrum cytokeratins, α-inhibin, calretinin, WT1, CD10, CD56, CD99, smooth muscle actin, desmin, h-caldesmon, Melan-A/MART1, SF1, or Ki67). GREB1-rearranged UTROSCTs showed significantly lower disease-free survival compared to ESR1-rearranged UTROSTCs (p = 0.049). Conclusions: In conclusion, GREB1-rearranged UTROSCTs occur at an older age, are less likely to display a submucosal/polypoid growth, and exhibit larger size, a higher mitotic index, more common lymphovascular space invasion, and lower disease-free survival compared to ESR1-rearranged UTROSCTs. Nonetheless, the similar immunophenotype suggests that they belong to the same tumor family. Further studies are necessary to confirm this point.

Clinicopathological features and molecular genetic changes in 17 cases of uterine tumor resembling ovarian sex cord tumor

Rationale:The malignant potential and the appropriate treatment of uterine tumor resembling ovarian sex-cord tumor (UTROSCT) is controversial. Although these tumors generally have benign outcomes, several reports have described recurrences, metastases, and deaths associated with this disease.Patient concerns:A 57-year-old Japanese woman (gravida 2, para 2) was referred to our hospital for the evaluation and treatment of uterine fibroids. Magnetic resonance imaging revealed a right ovarian mass and multiple fibroids in the uterine myometrium.Diagnoses:The patient was diagnosed with UTROSCT with sarcomatous features.Interventions:She initially underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy, followed by second-stage surgery comprising pelvic and para-aortic lymphadenectomy and subtotal omentectomy.Outcomes:No postoperative recurrence was observed in the patient in 36 months.Lessons:In this case, extended radical surgery prevented the development of recurrent disease in a patient with UTROSCT with sarcomatous features. These clinicopathological findings suggest that UTROSCT is associated with several risk factors, including older age, presence of necrosis, lymphovascular invasion, significant nuclear atypia, and significant mitotic activity. This lesion type should be considered malignant and treated with curative intent.

Uterine tumors resembling ovarian sex cord tumors (UTROSCT) are rare neoplasms that typically follow a benign course. However, metastasis occurs in rare cases and features associated with poor outcomes are only recently being described. These include: size >5 cm, at least moderate cytologic atypia, >3 mitosis per 10 high-powered fields, infiltrative borders, necrosis, GREB1 rearrangements, ESR1 rearrangements, and NCOA2/3 fusions. To our knowledge, prominent sclerosis has not been described in UTROSCT, nor has it been associated with an increased risk of metastasis. We present the case of a 51-yr-old woman with UTROSCT with corded/trabecular growth and sclerosis. The presence of sclerosis resulted in the misdiagnosis of her uterine tumor as leiomyoma and her lung metastasis as sclerosing epithelioid fibrosarcoma. The correct diagnosis of UTROSCT with lung metastasis was reached upon a morphologic comparison of the primary and metastatic tumors and the performance of a broad panel of immunohistochemical stains revealing the tumor to be CD99, CD56, ER, and inhibin positive and negative for rearrangements in 138 targeted genes, including genes commonly described as rearranged in endometrial stromal sarcomas, Ewing sarcoma and sclerosing epithelioid fibrosarcoma. The panel did not include GREB1 or ESR or NCOA3, but NCOA1/2 rearrangements were not detected. Our case highlights the diagnostic dilemma introduced by the presence of sclerosis in UTROSCT. We suspect prominent sclerosis may be another feature predictive of malignant potential in UTROSCT.

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 (23-65y). Only 15 patients (65%) were originally diagnosed with UTROSCTs. Mitotic figures ranged from 1 to 7/10high power fields, of primary tumors and increased from 1 to 9/10high 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) are among the rarest types of uterine tumors. Diagnosis of a UTROSCT is often challenging. Imaging techniques such as ultrasound and MRI are limited in distinguishing UTROSCTs as their appearance is usually suggestive of uterine leiomyoma or adenomyosis. Additionally, the value of a preoperative biopsy remains uncertain due to the heterogeneous composition of the tumor and the inadequacy of limited samplings. We present a rare case of UTROSCT in a 59-year-old woman and we have performed a narrative review of the literature on PubMed, Scopus, and Web of Science from 2000 to June 2024, identifying 133 cases. According to our review, at histological exam UTROSCTs are mainly composed of cells resembling ovarian sex-cord elements which are arranged in cords or trabeculae, typically with a mild cytologic atypia. The most expressed sex-cord differentiation markers include inhibin, calretinin, melan A, CD56, CD99, SF1, WT1, CD10, and FOXL2. For women who have completed their reproductive plans, a total hysterectomy with adnexectomy is an adequate treatment for tumors confined to the uterus. For younger patients who wish to preserve fertility, tumorectomy via hysteroscopy or laparoscopy is the preferred treatment option and the recurrence rates range from 5% to 30%. Treatments for recurrent disease include surgery, chemotherapy, and radiation therapy, often used in combination. Advancements in molecular profiling and immunohistochemistry will improve our ability to diagnose and manage this tumor. Such investigations will enhance prognostic stratification, facilitating more accurate predictions of biological behavior and recurrence risk.

Uterine tumor resembling ovarian sex cord tumor (UTROSCT) is a rare mesenchymal neoplasm, of uncertain biological potential, that was recently reported to exhibit recurrent gene fusions involving NCOA2-3. The purpose of this study was to, using a larger sample size, better characterize the histopathologic and molecular diversity of UTROSCT. Twenty-six cases of UTROSCT from 5 institutions were selected for further study. Fluorescence in situ hybridization for NCOA1, NCOA2, NCOA3, ESR1 and GREB1, and targeted RNA sequencing was performed on 17 and 8 UTROSCTs, respectively. Eight cases underwent massively parallel sequencing to detect single nucleotide variants (SNV), copy number variations, and structural variants using a targeted hybrid-capture based assay. NCOA1-3 rearrangement was identified in 81.8% (18/22) of cases. The most common fusion was ESR1-NCOA3, occurring in 40.9% (9/22). GREB1-NCOA1 (n=4), ESR1-NCOA2 (n=3), and GREB1-NCOA2 (n=1) rearrangements were also identified. No recurrent SNVs were identified and no tumor had SNVs in FOXL2, DICER1, STK11, or AKT1, which can be seen in ovarian sex cord-stromal tumors. Copy number variations were infrequent. Clinical follow-up was available for 11 cases with a mean follow-up interval of 94.4 (range, 1 to 319) months. Only one case had a recurrence 66 months after the initial diagnosis and this was the single case with a GREB1-NCOA2 fusion. This study reports the morphologic spectrum of UTROSCT and confirms the recently reported recurrent NCOA2-3 gene fusions, in addition to identifying novel rearrangements involving NCOA1 in these tumors.

Uterine tumor resembling ovarian sex cord tumor (UTROSCT) is a uterine mesenchymal tumor defined histologically by showing sex cord-like growth patterns, such as sheets, nests, trabeculae, cords, or tubules, with/without Sertoli-like or Leydig-like components, and immunohistochemically by exhibiting variable sex cord markers in addition to epithelial, myogenic, and sex hormone markers. Recent years have seen the emergence in UTROSCT of novel fusion genes that involve key genes in sex hormone pathways, including ESR1 and GREB1 as the 5' partner, and (co)activator oncogenes, particularly NCOA1-3, as the 3' partner. While the identification of similar fusions in the majority of cases serves as a strong argument for UTROSCT to be a distinct entity, there is no denying significant clinicopathologic heterogeneity within the disease spectrum, which might to some extent correlate with the different fusion types. The current review gives a summary of the recently identified fusions in UTROSCT, along with their possible clinicopathologic relevance. Also discussed are unsolved issues including the relationship between UTROSCT and so-called GREB1-rearranged uterine sarcoma as well as other uterine mesenchymal tumors harboring similar fusions.

Uterine tumor resembling ovarian sex-cord tumor (UTROSCT) is a rare form of uterine mesenchymal neoplasm. Although UTROSCT generally exhibits benign behavior with a favorable prognosis, this neoplasm is nevertheless classified as being of uncertain malignant potential, given its low rate of recurrence and the fact that it rarely produces metastases (e.g., in the lymph nodes, epiploic appendix, omentum, small bowel, subcutaneous tissue, lungs). Its histogenesis is also uncertain. Typically, UTROSCT occurs in peri-menopausal or menopausal women, but it can sometimes be observed in young women. Usually, this neoplasm can be found in the uterine corpus as a nodular intramural lesion, while it is less frequently submucosal, subserosal, or polypoid/intracavitary. UTROSCT can cause abnormal bleeding, pelvic pain, enlarged uterus, and mass sensation, but sometimes it is found purely by chance. This neoplasm can be considered polyphenotypic on morphological, immunohistochemical, and genetic analyses. Generally, upon microscopic examination, UTROSCT shows a predominant pattern of the cords, nests, and trabeculae typical of sex-cord tumors of the ovary, while immunohistochemically it is characterized by a coexpression of epithelial, smooth muscle, and sex-cord markers. The aim of this review is to report clinical and pathological data and genetic alterations to establish their impact on the prognosis and management of patients affected by this rare entity.

ESR1 and GREB1 fusions have recently been described in uterine tumor resembling ovarian sex cord tumor (UTROSCT). Thus far, recurrences have been documented in a subset of those harboring GREB1 fusions, but not in those with ESR1 rearrangements. Here we describe the clinicopathologic features of 3 recurrent UTROSCTs with striking rhabdoid morphology (an unusual feature of these tumors overall) and ESR1-NCOA2 fusions. The patients were 32, 37, and 54 years at initial diagnosis and first recurrence occurred at 7, 9, and 32 years. The primary tumors (available in two cases) were centered in the myometrium and showed infiltrative borders. They predominantly grew in sheets and cords, but also had a pseudopapillary appearance. Cells were uniformly epithelioid with eccentric nuclei, prominent nucleoli, abundant eosinophilic globular/glassy (rhabdoid) cytoplasm, and infrequent mitoses (≤4/10 high-power fields [HPFs]). Recurrences were morphologically identical to the primary tumors, but demonstrated brisk mitotic activity (≥16/10 HPFs). The third tumor (with only recurrences available) had multiple patterns, including diffuse, corded, trabecular, and a focal retiform growth. Rhabdoid cells were conspicuous, but only comprised ~50% of the tumor, and mitoses numbered up to 2/10 HPFs. All tumors were strongly and diffusely positive for WT1, CAM5.2, ER, and PR, but negative for inhibin. Diffuse calretinin and desmin expression, as well as focal melan-A positivity, was noted in one tumor, but was negative in the others. In all 3 tumors, INI-1 and BRG-1 were retained, and ESR1-NCOA2 fusions were detected by targeted RNA sequencing. This study is the first to highlight an association between UTROSCTs with extensive rhabdoid differentiation, ESR1-NCOA2 fusions, and aggressive behavior. UTROSCTs are considered neoplasms of uncertain malignant potential, but have a benign course in most cases. Thus, it is important to be aware of these specific features and recommend long-term follow-up due to their propensity for late recurrences.

Uterine tumors resembling ovarian sex cord tumors (UTROSCT) with rhabdoid features are uncommon mesenchymal neoplasms exhibiting diverse histological patterns, including significant rhabdoid morphology. A thorough comprehension of their clinicopathologic features is crucial for precise diagnosis and effective management. This study presents 4 cases of UTROSCT with rhabdoid features, diagnosed in patients aged 31 to 58. Varied recurrence patterns were observed, including similar recurrent lesions to the primary tumors with subsequent mortality, initial invasion and lymph node metastasis, and presence of only primary tumor. Histopathological examination revealed diverse morphological patterns, prominently featuring rhabdoid differentiation. Immunohistochemical analysis showed expression of hormone receptors, sex cord, smooth muscle, and epithelial markers, notably WT1, CD56, and CD99. Molecular analysis identified ESR1-NCOA2 fusions and ESR1 and NCOA2/3 rearrangements, indicating a potential association between these genetic alterations and extensive rhabdoid differentiation. Various treatments were administered post-recurrence, including chemotherapy and targeted therapies. However, poor clinical outcomes were observed in all cases. Despite aggressive treatments, including chemotherapy and targeted therapies, poor clinical outcomes were observed, highlighting the aggressive nature of UTROSCT with significant rhabdoid differentiation. This case series emphasizes the importance of detailed pathological reporting, comprehensive molecular testing, and thorough tumor staging in UTROSCT cases with rhabdoid features. Enhanced understanding of the clinicopathologic characteristics of UTROSCT with rhabdoid differentiation is crucial for accurate diagnosis, prognostication, and management strategies.

Unraveling the Molecular Landscape of Uterine Tumor Resembling Ovarian Sex Cord Tumor: Insights From A Clinicopathological, Morphologic, Immunohistochemical, and Molecular Analysis of 35 Cases