Abstract
Objective:
Mixed sex cord-stromal tumors of the ovary contain combinations of granulosa cell tumor components—either adult or juvenile subtypes—and/or Sertoli-Leydig cell tumor elements. The objective of this study is to evaluate survival outcomes in recurrent mixed sex cord-stromal tumors.
Methods:
This is a retrospective cohort study of recurrent mixed ovarian sex cord-stromal tumors identified through the MD Anderson Rare Gynecologic Malignancy Registry between 2000 and 2025. Comparative cohorts with recurrent, histologically uniform adult granulosa cell tumors, juvenile granulosa cell tumors, and Sertoli-Leydig cell tumors were included. Demographic and clinical characteristics were compared using descriptive statistics. Progression-free survival after first recurrence and overall survival from first recurrence were assessed using Kaplan-Meier methods and compared using log-rank tests.
Results:
Sixteen patients with recurrent mixed ovarian sex cord-stromal tumors were identified: 6 (37.5%) with adult granulosa cell plus Sertoli-Leydig cell tumors, 4 (25%) with juvenile granulosa cell plus Sertoli-Leydig cell tumors, and 6 (37.5%) with adult plus juvenile granulosa cell tumors. When comparing adult granulosa cell tumors to adult plus juvenile granulosa cell tumors, significant differences in median progression-free survival-2 (21.2 vs 8.7 months, p = .03) and overall survival (181.9 vs 83.8 months, p = .001) were observed. No significant differences in progression-free survival-2 (p = .7) or overall survival (p = .8) were noted between juvenile granulosa cell tumors and adult plus juvenile granulosa cell tumors. Among tumors with molecular testing results, 25% (1 of 4) of adult plus juvenile granulosa cell tumors, 25% (1 of 4) of adult granulosa cell plus Sertoli-Leydig cell tumors, and 33% (1 of 3) of juvenile granulosa cell plus Sertoli-Leydig cell tumors were positive for the c.C402G FOXL2 mutation.
Conclusions:
Recurrent adult plus juvenile granulosa cell tumors may exhibit more aggressive clinical behavior than uniform adult granulosa cell tumors, aligning more closely with juvenile granulosa cell tumors in recurrence outcomes.
Keywords: Cohort Studies, Sex Cord-Stromal Tumor, Granulosa Cell Tumor, Sertoli-Leydig Tumor, Gynecology Oncology, Survival, Ovarian Neoplasm
INTRODUCTION
Sex cord-stromal tumors are rare ovarian neoplasms, accounting for approximately 7% of all ovarian tumors, and occur in both pediatric and adult populations.1,2 According to the World Health Organization, ovarian sex cord-stromal tumors are classified into 3 groups: pure stromal tumors, pure sex cord tumors, and mixed sex cord-stromal tumors.3,4 Mixed sex cord-stromal tumors contain combinations of granulosa cell tumor components—either adult or juvenile subtypes—and/or Sertoli-Leydig cell tumor elements. These tumors are uncommon and pose diagnostic challenges due to their broad morphological spectrum.5,6
Patients with mixed sex cord-stromal tumors typically present at an early stage and are treated with upfront surgery.7,8 Mixed sex cord-stromal tumors are thought to exhibit indolent behavior, with only a few reported cases of recurrence.9,10 Survival outcomes for histologically uniform sex cord-stromal tumors are well-characterized. Adult granulosa cell tumor patients have a 5-year overall survival rate above 90%11 and a 10% to 30% recurrence rate. Time to recurrence ranges from 1 to 10 years.11–14 In an analysis of 40 recurrent adult granulosa cell tumor cases, the median progression-free survival between the first and second recurrence was 25 months, and the overall survival from the first recurrence was 90 months.15 Juvenile granulosa cell tumor patients have a good prognosis with a 5-year survival rate of 97% for those with stage I disease, and advanced stages are rarely diagnosed.16,17 In cases of recurrence, however, juvenile granulosa cell tumors tend to behave more aggressively than recurrent adult granulosa cell tumors, with patients dying between 7 and 36 months after initial treatment.18 Sertoli-Leydig cell tumors are reported to have an overall good prognosis, with a 5-year survival rate between 70% and 90%. The survival rate varies depending on the degree of differentiation and tumor staging.19 Sertoli-Leydig cell tumors recur faster than other ovarian sex cord-stromal tumors. When they recur, they can be more aggressive, as noted by a median overall survival following recurrence of 48 months and a 5-year survival rate of 39% in a recent systematic review.20
Recent molecular studies have uncovered distinct genomic alterations in sex cord-stromal tumors. The c.C402G missense mutation in the FOXL2 transcription factor21 is present in ~95% of adult granulosa cell tumors,22 suggesting a pathognomonic role. DICER1 gene mutations have been linked to the development of Sertoli-Leydig cell tumors, with both germline and somatic mutations identified.23 The germline mutations are loss-of-function variants inherited in an autosomal dominant pattern, while somatic mutations are hotspot missense mutations affecting the RNase IIIb domain.24 When accounting for both germline and somatic mutations, DICER1 variants were present in over 90% of the cases,25 while in other investigations, the germline mutation was present in at least 57% of cases.26 Juvenile granulosa cell tumors do not have a pathognomonic mutation variant, but AKT1 activating somatic duplications are reported in more than 60% of the tumors.27
Despite these advances, little is known about the clinical behavior and molecular profiles of mixed sex cord-stromal tumors, particularly in the recurrent setting. Existing literature is limited to histopathological descriptions and upfront treatment strategies, with recurrence rarely described. This study aims to address the gaps in the literature by assessing the prognosis of these rare tumors after recurrence.
METHODS
Case Selection
This is a retrospective cohort study of patients with recurrent mixed sex cord-stromal tumors enrolled in the University of Texas MD Anderson Cancer Center Rare Gynecologic Malignancy Registry from January 2000 to March 2025. All patients were enrolled in an institutional review board-approved Rare Gynecologic Malignancy Registry (protocol #PA17–0586) from 2 affiliated institutions—MD Anderson Cancer Center and Lyndon B. Johnson General Hospital. Patients were included in the registry either by signing an informed consent or through a waiver if they had not been seen in the last 3 years or were deceased. The registry collects information related to demographics, diagnosis, and treatment courses. All pathology was reviewed by a gynecologic pathologist at MD Anderson Cancer Center.
Patients were included in this study analysis if they had a confirmed mixed sex cord-stromal tumor diagnosis after review by pathology at MD Anderson Cancer Center and at least 1 documented recurrence. Most of the patients included in this study had their initial surgery and diagnosis at other institutions. Pathologists were not able to confirm the percentages of each component of the mixed ovarian sex cord-stromal tumors, as the full set of pathology slides was not always transferred to our institution. Exclusion criteria from the study included: patients with mixed sex cord-stromal tumor lost to follow-up after their initial visit, and diagnosis made before January 2000. The date cutoff was used to limit the heterogeneity of the sample, due to the limited availability of taxanes as a treatment line prior to 2000. Patients with mixed sex cord-stromal tumor diagnosis but no documented recurrence were included in the data collection and reported separately in the results, but were excluded from further analysis. Comparative cohorts with recurrent, non-mixed (pure) adult granulosa cell tumors, juvenile granulosa cell tumors, and Sertoli-Leydig cell tumors were drawn from the same registry using identical exclusion criteria.
Data Collection
Study data were compiled and managed using REDCap software tools hosted at MD Anderson Cancer Center.28,29 Data collected from the secure database included demographics (age, race, ethnicity, institution), diagnosis and staging (date of diagnosis, date of surgery, staging, tumor histology), recurrence treatment modalities, and vital status.
Statistical Analysis
Demographic and clinical characteristics of patients with mixed sex cord-stromal tumors were summarized using descriptive statistics. Progression-free survival-2 was defined as the time from first recurrence to second recurrence or to death/last gynecologic oncology assessment in cases where a second recurrence was not documented. Overall survival was determined from the date of first recurrence to death or last contact. Using Rstudio v2024.12.1,30 Kaplan-Meier curves were generated to estimate progression-free survival-2 and overall survival for each mixed sex cord-stromal tumor cohort compared to its uniform histology group counterpart, from the date of first recurrence to the analysis date in March 2025. Survival differences were compared using a log-rank test, with a significance threshold set at p < .05.
In accordance with the journal’s guidelines, we will provide our data for independent analysis by a team selected by the Editorial Team for the purposes of additional data analysis or for the reproducibility of this study in other centers if such is requested.
RESULTS
A total of 50 patients with ovarian mixed sex cord-stromal tumors were identified in the rare tumor registry during the study period. Among them, 22 patients were excluded from the study: 15 due to missing follow-up data after their first visit, and 7 due to a diagnosis made before January 2000. Our cohort consisted of 28 patients: 16 patients with documented recurrent mixed sex cord-stromal tumors of the ovary and 12 with no documented recurrence at the time of final data collection (Fig. 1). The demographic and clinical characteristics for both groups are summarized in Table 1. The recurrence rate was calculated to be 57% in our cohort. The median time to first relapse in the recurrent group was 27.25 months, while patients with no recurrence were followed up for a median time of 86 months without a documented relapse. The 12 non-recurrent patients were treated with surgery alone (n = 6, 50%) or surgery plus systemic therapy (n = 6, 50%). One of the 12 patients underwent molecular testing, which was positive for DICER1, TP53, CDK4, and BRCA1. All patients with no documented recurrence were then excluded from subsequent comparative analysis with the recurrent uniform histology groups.
Figure 1.
Study flow diagram. AGCT, adult type granulosa cell tumor; JGCT, juvenile type granulosa cell tumor; MDACC, MD Anderson Cancer Center; SCST, sex cord-stromal tumor; SLCT, Sertoli-Leydig cell tumor.
Table 1.
Demographics and Clinical Characteristics of Mixed Sex Cord-Stromal Tumors with no Documented Recurrence
| Characteristic | No recurrence N = 12 (%) | Recurrence N = 16 (%) |
|---|---|---|
| Age at time of diagnosis (y) | ||
| Median (range) | 32.5 (15–71) | 35 (12–74) |
| Age at time of first recurrence (y) | ||
| Median (range) | N/A | 38 (16–81) |
| Race | ||
| White | 8 (66.66) | 15 (93.75) |
| Black/African American | 3 (25) | 0 |
| Asian/Native Hawaiian or Other Pacific Islander | 0 | 1 (6.25) |
| Other | 1 (8.33) | 0 |
| Ethnicity | ||
| Hispanic or Latino | 5 (41.66) | 3 (18.75) |
| Not Hispanic or Latino | 3 (25) | 10 (62.5) |
| Other/unknown | 4 (33.33) | 3 (18.75) |
| Final histology | ||
| Adult granulosa + Sertoli-Leydig cell tumor | 6 (50) | 6 (37.5) |
| Juvenile granulosa + Sertoli-Leydig cell tumor | 3 (25) | 4 (25) |
| Adult + juvenile granulosa cell tumor | 2 (16.66) | 6 (37.5) |
| Adult + juvenile granulosa + Sertoli-Leydig cell tumor | 1 (8.33) | 0 |
| FIGO stage at diagnosis | ||
| I | 12 (100) | 12 (75) |
| II | 0 | 4 (25) |
| III-IV | 0 | 0 |
Abbreviation: FIGO, International Federation of Gynecology and Obstetrics; N/A, not applicable.
The remaining 16 patients were included in the study analysis: 6 (37.5%) patients were diagnosed with mixed adult plus juvenile granulosa cell tumors, 4 (25%) with mixed juvenile granulosa cell plus Sertoli-Leydig cell tumors, and 6 (37.5%) with mixed adult granulosa cell plus Sertoli-Leydig cell tumors. The degree of differentiation for the Sertoli-Leydig cell tumor components was well differentiated (n = 2), intermediately differentiated (n = 4), poorly differentiated (n = 2), and unknown (n = 2). The median age at time of diagnosis for the mixed sex cord-stromal tumors cohort was 35 years. The median age at time of first recurrence was 38 years (range; 16–81), and the subsequent median follow-up time was 61.1 months. Patients with histologically uniform tumors were identified in the same registry for comparative analysis: 97 with adult granulosa cell tumors, 14 with juvenile granulosa cell tumors, and 11 with Sertoli-Leydig cell tumors. The same exclusion criteria were used. The Sertoli-Leydig cell tumors identified were well differentiated (n = 1), intermediately differentiated (n = 3), intermediately to poorly differentiated (n = 3), poorly differentiated (n = 2), and unknown (n = 2).
Table 2 summarizes the treatment modalities used to treat mixed ovarian sex cord-stromal tumors and uniform histology cohorts. There were no significant differences in treatment modalities observed in the upfront (p = .17) or at first recurrence (p = .54) when the 2 cohorts were compared. In the upfront setting, 62% of mixed tumor patients were treated with surgery combined with systemic therapy. The agents administered were platinum- and taxane-based (n = 5); bleomycin, etoposide, and cisplatin (n = 4); and letrozole (n = 1). Mixed ovarian sex cord-stromal tumor patients were treated for first recurrence with surgery alone (n = 4, 25%), surgery combined with systemic therapy (n = 11, 68.7%), and systemic therapy alone (n = 1, 6.2%). The systemic therapy agents used were platinum- and taxane-based therapy (n 8), bleomycin, etoposide, and cisplatin (n = 2), leuprolide (n = 1), tamoxifen (n = 1), and doxorubicin with ifosfamide and vincristine (n = 1). On the other hand, patients with uniform histology tumors were treated in the upfront setting with surgery alone (n = 72, 59%) and surgery plus systemic therapy (n = 50, 41%). The most common agents used were again platinum- and taxane-based (n = 26), bleomycin, etoposide, and cisplatin (n = 19), and endocrine therapy agents (n = 5). Treatment for first recurrence included surgery only (n = 22, 18%), surgery plus systemic therapy (75, 61.5%), and systemic therapy only (n = 18, 14.7%). The most common systemic therapy agents used were carboplatin and paclitaxel (n = 34), bleomycin, etoposide, and cisplatin (n = 13), and aromatase inhibitors (n = 10), as well as carboplatin and paclitaxel combined with an aromatase inhibitor (n = 10).
Table 2.
Treatment Modality and Systemic Therapy in Upfront and First Recurrence Settings
| Variable | Patient cohort | p-Valuea | |
|---|---|---|---|
| Uniform histology N = 122 (%) | Mixed histology N = 16(%) | ||
| Upfront treatment modality | .17 | ||
| Surgery alone | 72 (59) | 6 (37.5) | |
| Surgery plus systemic therapy | 50 (41) | 10 (62.5) | |
| First recurrence treatment modality | .54 | ||
| Surgery alone | 22 (18.0) | 4 (25) | |
| Surgery plus systemic therapy | 75 (61.5) | 11 (68.7) | |
| Surgery plus radiotherapy | 7 (5.7) | 0 (0) | |
| Systemic therapy | 18 (14.7) | 1 (6.25) | |
χ2test.
Figure 2 demonstrates the progression-free survival-2 and overall survival Kaplan-Meier curves for each mixed sex cord-stromal tumor and its uniform histology components. A pairwise comparison was conducted for each of the mixed sex cord-stromal tumor cohorts against their corresponding uniform histology components, and the results are summarized in Table 3. When comparing adult granulosa cell tumors to adult plus juvenile granulosa cell tumors, significant differences in median progression-free survival-2 (21.2 months for adult granulosa cell tumors vs 8.7 months for adult plus juvenile granulosa cell tumors, p = .03) and overall survival (181.9 months for adult granulosa cell tumors vs 83.8 months for adult plus juvenile granulosa cell tumors, p = .01) were observed. On the other hand, no significant differences were observed in median progression-free survival-2 (8.9 months for juvenile granulosa cell tumors vs 8.7 months for adult plus juvenile granulosa cell tumors, p = .7) and median overall survival (32.2 months for juvenile granulosa cell tumors vs 83.8 months for adult plus juvenile granulosa cell tumors, p = .8) when the juvenile granulosa cell tumor cohort was compared to adult plus juvenile granulosa cell tumors. No significant progression-free survival-2 or overall survival differences were noted in the pairwise analysis when adult granulosa cell plus Sertoli-Leydig cell tumors, as well as juvenile granulosa cell plus Sertoli-Leydig cell tumors, were compared with their corresponding uniform histology components.
Figure 2.
Kaplan Meier (KM) Progression-Free Survival2 and Overall Survival curves by group cohort. A, KM of PFS2 comparing AGCT+JGCT to AGCT only and JGCT only with log-rank test p1 value (AGCT+JGCT vs AGCT) and p2 value (AGCT+JGCT vs JGCT). B, KM of OS comparing AGCT+JGCT to AGCT only and JGCT only with log-rank test p3 value (AGCT+JGCT vs AGCT) and p4 value (AGCT+JGCT vs JGCT). C, KM of PFS2 comparing AGCT+SLCT to AGCT only and SLCT only with log rank test p5 value (AGCT+SLCT vs AGCT) and p6 value (AGCT+SLCT vs SLCT). D, KM of OS comparing AGCT+JGCT to AGCT only and SLCT only with log rank test p7 value (AGCT+SLCT vs AGCT) and p8 value (AGCT+SLCT vs SLCT). E, KM of PFS2 comparing JGCT+SLCT to JGCT only and SLCT only with log rank test p9 value (JGCT+SLCT vs JGCT) and p10 value (JGCT+SLCT vs SLCT). F, KM of OS comparing JGCT+SLCT to JGCT only and SLCT only with log rank test p11 value (JGCT+SLCT vs JGCT) and p12 value (JGCT+SLCT vs SLCT). AGCT, Adult Granulosa Cell Tumor; JGCT, Juvenile Granulosa Cell Tumor; SLCT, Sertoli-Leydig Cell Tumor; OS, Overall Survival; PFS2, Progression-Free survival 2.
Table 3.
Pairwise Comparative Analysis for Each Mixed Sex Cord-Stromal Tumor Cohort and its Corresponding Uniform Components
| Mixed histology | Uniform histology | Mixed histology progression-free survival-2 (95% CI) in mos | Uniform histology progression-free survival-2 (95% CI) in mos | p-Value | Mixed histology overall survival (95% CI) in mos | Uniform histology overall survival (95% CI) in mos | p-Value |
|---|---|---|---|---|---|---|---|
| Adult plus juvenile granulosa cell tumors | Adult granulosa cell tumor | 8.7 (3.2 to NR) | 21.2 (16.6 to 33.8) | .03 | 83.8 (11.3 to NR) | 181.9 (137.7 to NR) | .01 |
| Juvenile granulosa cell tumor | 8.7 (3.2 to NR) | 8.9 (3.8 to 43.1) | .70 | 83.8 (11.3 to NR) | 32.2 (20.3 to NR) | .80 | |
| Adult granulosa cell plus Sertoli-Leydig cell tumor | Adult granulosa cell tumor | 19.1(6.4 to NR) | 21.2 (16.6 to 33.8) | .82 | 99.7 (83.4 to NR) | 181.9 (137.7 to NR) | .31 |
| Sertoli-Leydig cell tumor | 19.1(6.4 to NR) | 9.8 (4.2 to NR) | .53 | 99.7 (83.4 to NR) | 63.3 (22.5 to NR) | .43 | |
| Juvenile granulosa cell plus Sertoli-Leydig cell tumors | Juvenile granulosa cell tumor | 12.5 (10.6 to NR) | 8.9 (3.8 to 43.1) | 1.00 | 74.0 (14.6 to NR) | 32.2 (20.3 to NR) | .62 |
| Sertoli-Leydig cell tumor | 12.5 (10.6 to NR) | 9.8 (4.2 to NR) | .55 | 74.0 (14.6 to NR) | 63.3 (22.5 to NR) | .08 |
Abbreviation: NR, not reported.
Molecular profiling was performed on 11 of the 16 mixed sex cord-stromal tumors. One of 4 (25%) tested adult plus juvenile granulosa cell tumors, one out of 4 (25%) tested adult granulosa cell plus Sertoli-Leydig cell tumors, as well as 1 out of 3 (33.3%) tested juvenile granulosa cell plus Sertoli-Leydig cell tumors were positive for the c.C402G FOXL2 mutation. One adult granulosa cell plus Sertoli-Leydig cell tumors tested positive for a DICER1 mutation. No AKT1 mutations were identified in any of the tested tumors.
DISCUSSION
Summary of Main Results
Patients with recurrent mixed adult plus juvenile granulosa cell tumors had shorter progression-free survival-2 and overall survival outcomes compared to patients with uniform adult granulosa cell tumors. In contrast, no differences in survival outcomes were observed when compared to patients with uniform juvenile granulosa cell tumors. Thus, adult plus juvenile granulosa cell tumors may behave more similarly to juvenile granulosa cell tumors in the recurrent setting, rather than the indolent behavior of pure adult granulosa cell tumors. Only 1 of the 4 tested mixed granulosa cell tumor patients was positive for the c.C402G FOXL2 mutation characteristic of adult granulosa cell tumors, suggesting a different molecular identity. No significant differences in survival outcomes were noted when adult granulosa cell plus Sertoli-Leydig cell tumors were compared to adult granulosa cell tumors only and Sertoli-Leydig cell tumors only, and when the juvenile granulosa cell plus Sertoli-Leydig cell tumors cohort was compared to the juvenile granulosa cell tumors only and Sertoli-Leydig cell tumors only cohorts. FOXL2 and DICER1 mutations were each positive in 1 of the 4 molecularly tested adult granulosa cell plus Sertoli-Leydig cell tumors. None of the tested juvenile granulosa cell plus Sertoli-Leydig cell tumor patients had a positive DICER1 mutation.
Results in the Context of Published Research
Mixed sex cord-stromal tumors of the ovary are extremely rare tumors that have variable components of granulosa cells and Sertoli-Leydig cells.8 So far, the available data on these tumors are limited to case reports and histopathological and molecular investigations. Mixed sex cord-stromal tumors are reported to have an indolent behavior, with the majority of cases presenting as stage I and treated with surgical resection with or without adjuvant chemotherapy.9,25,31 To date, only 2 cases of recurrence were noted in the literature, occurring 9 and 10 years after initial diagnosis.9,10 The disease course remains uncertain due to the low incidence of these tumors, the infrequent number of recurrences reported, and the relatively short follow-up time after upfront surgical treatment.9 In fact, the longest disease-free survival time reported is 77 months in patients with no documented recurrences.32 Other case reports have a follow-up time of around 1 to 2 years.5,7,33 The literature lacks any reports or investigations beyond first recurrence, as well as any reports on mixed adult plus juvenile granulosa cell tumors.
Prior publications have focused on the molecular identity of mixed sex cord-stromal tumors and how they compare to their histologically uniform components. In mixed ovarian sex cord-stromal tumors with a Sertoli-Leydig cell tumor and juvenile granulosa cell tumor component, DICER1 RNase IIIb hotspot mutations were identified and labeled as a driving force in the development of these cancers. This has been particularly true for patients with Sertoli-Leydig cell tumors of intermediate or poor differentiation.25,34 In contrast, these tested tumors always harbored the wild-type AKT1 gene (known for its implication in the juvenile granulosa cell tumor pathogenesis), which has led Ordulu and Young to suggest that these mixed juvenile granulosa cell plus Sertoli-Leydig cell tumors are, in reality, Sertoli-Leydig cell tumors with juvenile granulosa cell tumor-resembling follicular differentiation.35 Additionally, the characteristic FOXL2 mutation of adult granulosa cell tumors was not detected in 2 studies, each testing 6 mixed sex cord-stromal tumors with adult granulosa cell plus Sertoli-Leydig cell tumor components.6,34 Both studies suggested that in mixed sex cord-stromal tumors with adult granulosa cell tumor and Sertoli-Leydig cell tumor components, the granulosa cell tumor component has a different molecular basis than uniform adult granulosa cell tumors, despite having a similar histological appearance.
Strengths and Weaknesses
The use of a rare tumor registry facilitated the identification of a significant number of patients with extremely rare mixed sex cord-stromal tumors of the ovary. Thus, a key strength of our study is that it represents the largest investigation of survival outcomes in patients with recurrent mixed sex cord-stromal tumors at the time of our analysis. The long follow-up interval, with a median of 5 years, further enhances the credibility of our findings. Moreover, including large cohorts of uniform histology tumors strengthens the results obtained in this analysis by providing a strong comparative baseline, thereby highlighting the relevance and validity of the findings.
This study has several limitations. This is a retrospective study limited to the data available from patient medical records, which may be incomplete or inconsistent. Information related to the date of recurrences, proof of recurrences, treatment modalities, and responses was collected from physician notes and reports, which can be susceptible to inaccuracies. The percentage composition of each mixed sex cord-stromal tumor was not completed as only part of, and not the full set of slides, was transferred to MD Anderson Cancer Center. This study also spans over 25 years, during which changes in practice and advancements in patient care may have affected the recurrence outcomes following treatment of the first relapse. Additionally, incomplete molecular testing was noted in our analysis, as 31% of the patients included in the study did not complete molecular testing, which limits the ability to assess potential associations between clinical outcomes and molecular targets. While our sample size is relatively large, given the rarity of mixed sex cord-stromal tumors, it remains too small to validate the significance of our findings.
Implications for Practice and Future Research
Given the limited existing data on the clinical behavior of mixed ovarian sex cord-stromal tumors, our findings challenge the historical perception of these tumors as uniformly indolent. Additionally, in the recurrent setting, patients with mixed ovarian sex cord-stromal tumors tend to have similar, if not worse, survival outcomes than patients with histologically uniform sex cord-stromal tumors. While our sample size is too small to draw generalizable conclusions, the findings are likely to drive prognostic and clinical discussions with patients related to follow-up and tumor behavior awareness. Molecular testing should be interpreted with caution by health care providers, as these tumors do not harbor the same genetic identity as their individual components.
While our findings suggest that mixed sex cord-stromal tumors of the ovary have similar or worse survival outcomes in the recurrent setting when compared to their histologically uniform components, future studies with larger sample sizes are needed to validate the results. Further studies should explore the molecular nature of these tumors, identifying new potential mutations and assessing the efficacy of treatment modalities in the recurrence setting. Research can also be directed at establishing standardized classification criteria for these tumors based on histology and molecular testing, in order to address clinical and prognostic questions more effectively.
CONCLUSIONS
Patients with recurrent mixed adult plus juvenile granulosa cell tumors experienced significantly worse survival outcomes compared to those with uniform adult granulosa cell tumors, suggesting that the presence of a juvenile granulosa cell tumor component confers a more aggressive behavior in the recurrent setting. Adult plus juvenile granulosa cell tumors appear to have a different molecular identity than their separate components. To our knowledge, this is the first report of adult plus juvenile granulosa cell mixed sex cord-stromal tumors of the ovary, and the first investigation of survival outcomes in mixed ovarian sex cord-stromal tumors. Our findings are important for driving prognostic discussion, but research with a larger cohort is still needed to understand the clinical and molecular behavior of mixed ovarian sex cord-stromal tumors.
WHAT IS ALREADY KNOWN ON THIS TOPIC
Mixed sex cord-stromal tumors have been reported in the literature as indolent tumors with few cases of recurrences. Due to the rarity of mixed sex cord-stromal tumors, few data about prognosis and treatment outcomes are available to guide clinical decision-making.
WHAT THIS STUDY ADDS
This retrospective cohort study demonstrates that some mixed sex cord-stromal tumors may exhibit more aggressive clinical behavior than their uniform histology components. Specifically, the presence of a juvenile granulosa cell tumor component as part of a mixed sex cord-stromal tumor may be associated with worse clinical outcomes.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE, OR POLICY
These data suggest the need for a tailored prognostic approach and further molecular profiling of mixed sex cord-stromal tumors. The observation that differences in prognosis distinguish mixed sex cord-stromal tumors with a juvenile granulosa cell tumor component may inform enrollment criteria for future clinical trials.
Funding/Support
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Footnotes
Declaration of Competing Interests None declared.
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