Devins, Kyle M

Low-grade endometrial stromal sarcomas (LG-ESS) are the second most common malignant uterine mesenchymal tumors, but in contrast to the more common leiomyosarcomas, they are often characterized by a prolonged and relatively indolent course. However, a subset of patients experience significant morbidity or die of disease, and it is difficult to predict which tumors will behave aggressively, with most published studies limited in either the number of tumors or the depth of pathologic parameters evaluated. Thus, we studied the clinicopathologic features of LG-ESS in 102 patients ranging from 21 to 74 (median: 47) years. All were treated with hysterectomy and staged according to both the FIGO 2018 system (stage IA=22, IB=36, I-not otherwise specified=5, II=16, III=13, IV=10) and the FIGO 1988 system (stage I=62, II=1, III=17, IV=22). Tumors measured 1.2-49 (median: 7) cm. Microscopically, 69 involved the endometrium while 33 were centered in the myometrium. Thirteen showed only minimal infiltration of the myometrium while the rest displayed the typical extensive myometrial permeation. The cervical stroma was involved in 18, the uterine serosa in 27, and the parametrium in 22. Conventional morphology resembling proliferative endometrial stroma was seen in 95, fibroblastic appearance in 35, smooth muscle differentiation in 23, sex cord-like differentiation in 21, stromal hyalinization in 21, and myxoid stroma in 9. Less common features included glandular differentiation resembling adenomyosis (n=5), pseudopapillary pattern (n=1), deciduoid appearance (n=2), adipocytic differentiation (n=2), multinucleated cells (n=2), and rhabdomyoblastic differentiation (n=1). Mitoses ranged from <1 to 20 per 10 high-power fields (median=3). Lymphovascular invasion and infarct-type necrosis were present in 64 and 23, respectively. Follow-up was available in all patients ranging from 16 to 358 (median: 79) months. Forty-six received adjuvant treatment as hormonal therapy (n=34), radiation (n=4), radiation and hormonal therapy (n=4), chemotherapy (n=3), or chemotherapy and radiation (n=1). Three patients had persistent unresected tumor following surgery, and an additional 34 had recurrences at intervals of 3 to 272 (median: 79) months, including 2 tumors with minimal infiltration. At last follow-up, 75 patients were alive with no evidence of disease, 14 were alive with disease, and 9 died of disease at intervals of 16 to 167 (median=70) months. Four died of unrelated causes without recurrence. Five-year recurrence-free survival (RFS) and disease-specific survival (DSS) were 80% and 94%, while 10-year RFS and DSS were 51% and 87%, respectively. On statistical analysis, cervical stromal involvement ( P =0.018) and myxoid stroma ( P <0.001) were associated with shorter recurrence-free survival. Tumors lacking a conventional component had worse disease-specific survival ( P =0.048). All other clinical and morphologic features, including stage, were not significantly associated with outcome. On multivariate analysis, only cervical stromal involvement remained an independent predictor of recurrence-free survival ( P =0.047; HR: 16.939) and no factors were independently predictive of disease-specific survival. Our findings highlight the difficulty in predicting outcomes in these tumors, likely due to slow progression and frequent treatment responses even in the recurrent setting. We confirm the potential for recurrence even in tumors initially showing minimal infiltration. Cervical stromal involvement and lack of conventional morphology are potential novel risk factors that should be further evaluated in subsequent studies.

PURPOSE Sertoli-Leydig cell tumors (SLCTs) are rare sex cord-stromal tumors, representing <0.5% of all ovarian tumors. We analyze the role of germline DICER1 status in outcomes of ovarian SLCT. METHODS Patients with SLCT were enrolled in the International Pleuropulmonary Blastoma/ DICER1 Registry and/or the International Ovarian and Testicular Stromal Tumor Registry. Medical records were systematically abstracted, and those with known germline DICER1 status were selected for analysis. RESULTS Of 162 patients with SLCT, 60% had a germline DICER1 pathogenic or likely pathogenic (P/LP) variant. The adjusted 3-year recurrence-free survival (RFS) was 87.2% (95% CI, 79.4 to 95.8) for patients with a germline DICER1 P/LP variant compared with 78.1% (95% CI, 66.4 to 91.9) for those without a germline DICER1 P/LP variant ( P = .043). The adjusted 3-year and 5-year overall survival (OS) was 93.9% (95% CI, 87.3 to 100.0) for those with a germline DICER1 P/LP variant compared with the 3-year OS of 91.3% (95% CI, 83.4 to 100.0) and the 5-year OS of 78.2% (95% CI, 63.8 to 95.9) for those without a germline DICER1 P/LP variant ( P = .021). Among patients with a germline DICER1 P/LP variant, the risk of a subsequent, nonrecurrent event was 36.2% (95% CI, 21.4 to 48.1) within 10 years. Previous/concurrent and subsequent neoplasms were rare among those without a germline DICER1 P/LP variant. CONCLUSION This cohort study of patients with SLCT demonstrated that those with germline DICER1 P/LP variants had superior RFS and OS even when adjusting for other prognostic factors. Beyond prognostic implications of a germline DICER1 P/LP variant, germline testing helps identify patients at risk of subsequent neoplasms, including metachronous SLCT.

AbstractBackgroundOvarian juvenile granulosa cell tumors (juvGCT) are rare sex cord‐stromal tumors that occur primarily in children and adolescents. This study summarizes the clinical presentation and outcomes of patients with juvGCT.MethodsPatients were enrolled in the International Ovarian and Testicular Stromal Tumor and/or International Pleuropulmonary Blastoma/DICER1 Registries. Available medical records were abstracted, and pathology was centrally reviewed. Surgical staging was classified using the 2014 International Federation of Gynecology and Obstetrics (FIGO) criteria.ResultsIn total, 70 patients with juvGCT enrolled and were diagnosed between 2001 and 2024; most patients (81%, 57 of 70) presented with FIGO stage I disease. Adjuvant chemotherapy was given in 30% (21 of 70); all regimens were platinum‐based. Three‐year event‐free survival among patients with stage IA tumors was 80.2% (95% confidence interval [CI], 62.4%–100.0%), IC1 was 87.4 (95% CI, 72.4%–100.0%), IC2‐IC3 was 63.6% (95% CI, 40.7%–99.5%), and II‐IV was 48% (95% CI, 24.6%–93.8%). Of the patients with recurrent juvGCT with known mitotic index (MI), all had MI greater than 19 mitoses per 10 high power fields (HPF) at diagnosis.ConclusionOutcomes were worse for patients with FIGO stage ≥IC2 disease and for tumors with >19 mitoses per 10 HPF. Given the prognostic significance of MI, the authors strongly recommend the assessment of MI for all juvGCTs. More information about tumor biology is critical to identify which patients may benefit from adjuvant chemotherapy and to facilitate the development of novel therapies.