Clinical, laboratory, imaging, and anatomopathological findings are reported, highlighting the pertinent features of this case. Next-generation sequencing (NGS) using a custom panel for overgrowth syndromes (Custom Panel Enrichment and Nextera Flex Enrichment—Illumina) was conducted on peripheral blood with a technical sensitivity of 10%–15%. Sanger sequencing was used for validation. In addition, multiplex ligation-dependent probe amplification (MLPA) for PTEN gene was performed to detect PTEN copy number variants.

A systematic review was conducted using PubMed to identify previously published case reports and case series on jGCT in childhood. The search was carried out using the following query string in December 2024: ((granulosa cell tumor) OR (sex-cord stromal tumor)) AND ((pediatric)) OR (childhood)). Filter for case reports was applied (n = 141). Each article was reviewed for relevance, resulting in a final selection of 46 articles. The following exclusion criteria were applied to the search results: (a) pathology report of non-granulosa cell tumors of the ovary (n = 66, including n = 7 adult GCT, n = 20 sex-cord stromal tumors not otherwise specified or other subtypes, n = 39 Sertoli–Leydig cell tumors), (b) non-availability of article full text (n = 6, all published between 1960 and 1993), (c) language barriers (n = 2 in Danish and n = 1 in German), and (d) topic incoherent with the research query (n = 18). Clinical cases of pediatric ovarian tumors with mixed histopathological features, but including granulosa cell tumors, were compiled (n = 4). Additionally, one article describing extraovarian jGCT was separately described. The references of the included articles were reviewed, and additional relevant articles on ovarian jGCT were integrated. The final list comprised 65 articles, summarized in Supplementary Tables S4, S5, encompassing a total of 94 cases of jGCT in patients aged <18 years.

Ovarian jGCTs frequently secrete functionally active hormones, leading to endocrine-related clinical manifestations (Table 2). By systematically reviewing published literature, we identified precocious thelarche as the most frequently reported presenting sign among patients aged <8 years, with breast budding being the referral reason in 75.4% of the girls aged 8 years or younger. Additional signs of estrogenization in this subgroup included vaginal bleeding (31.6%) and estrogenized external genitalia (17.5%). Moreover, 35.1% of prepubertal girls exhibited signs of heterosexual precocious puberty: pubarche was described in 29.8% of prepubertal girls, clitoromegaly in 8.8%, and axillarche in 5.3%. Remarkably, three cases were diagnosed with jGCT during the neonatal period due to ambiguous genitalia resulting from antenatal testosterone exposure (19, 20, 52).

On the other hand, out of 27 post-pubertal patients, menstrual irregularities or secondary amenorrhea was reported in 40.7% of patients at diagnosis. In one remarkable case, ovarian jGCT was identified following an episode of heavy vaginal bleeding, which required uterine curettage for endometrial hyperplasia (17).

A comprehensive endocrine assessment is essential for the management of jGCT patients and should focus on (a) establishing an accurate differential diagnosis at onset (Figure 3) and (b) monitoring for the potential recurrence of signs of precocious puberty through clinical and biochemical follow-up (Figure 4).

Precocious puberty in girls is defined as the premature development of secondary sexual features before the age of 8 years (53). Central precocious puberty (CPP) is idiopathic in over 95% of female patients and represents the most common epidemiological condition (54, 55). CPP is also defined as “GnRH-dependent”, as it is the result of the premature activation of the hypothalamic–pituitary–gonadal axis, leading to early gonadotropin secretions and, accordingly, secondary ovarian stimulation (56, 57). Conversely, peripheral precocious puberty (PPP) is a rarer “GnRH-independent” cause of sexual precocity (8). It is the result of the precocious secretion of sex hormones by a peripheral ectopic source, often indicating an underlying malignancy (8). Differentiating between PPP and CPP is crucial, as management strategies differ significantly. Clinically, CPP is always isosexual, whereas PPP may present with either isosexual or heterosexual pubertal signs.

In this setting, hormonal tests play a central diagnostic role. The co-occurrence of elevated preoperative estradiol levels and suppressed LH and FSH prompts the diagnosis of PPP (58–61). Moreover, in patients with clinically detectable signs of virilization, elevated testosterone levels are generally detected (19, 59, 62). When a dynamic assessment is performed, a flat response of LH and FSH following the administration of gonadotropin-releasing hormone (GnRH stimulation test) corroborates the clinical suspicion of PPP.

When an adnexal mass is identified, second-level tests should include anti-Müllerian hormone (AMH) and inhibin A/B dosage. When assessed before surgery, inhibin A/B and AMH were constantly elevated in the previously published cases of jGCT (58, 61–64).

In addition, an unusual case of jGCT presented with acanthosis nigricans and hyperinsulinism, which resulted from peripheral insulin resistance driven by tumor-induced hyperandrogenemia and mimicking HAIR-AN syndrome (hyperandrogenism, insulin resistance, and acanthosis nigricans syndrome). The laboratory tests and clinical signs normalized following unilateral salpingo-oophorectomy (62).

Complementing clinical and laboratory assessments, radiological imaging plays a pivotal role in the diagnostic workup of girls with precocious puberty. Abdominal US is crucial in the initial evaluation of any girl presenting with PPP to detect pelvic or abdominal masses. Notably, jGCT can also arise in extraovarian sites, as exemplified by a case of adrenal gland localization (65). However, in patients with PPP, hypothalamic exposure to sex steroids may trigger the premature activation of the GnRH–gonadotropin–gonadal axis, finally leading to CPP as a consequence of the precocious GnRH-independent secretion of sexual hormones (12, 13, 56). Therefore, in selected cases of CPP, especially those with rapid progression or occurring at a younger age, abdominal US may be warranted to rule out underlying ovarian or adrenal pathology. Pelvic US plays a crucial role as a supplementary examination in the diagnostic workup of precocious puberty in girls, enabling the evaluation of estrogenization of the internal genitalia (66–68). Finally, preoperative MRI and histopathological examination are necessary for definitive diagnosis and staging of jGCT (Figure 3).

A dedicated endocrine follow-up after treatment for jGCT is highly recommended (Table 3, Figure 4). Firstly, endocrine follow-up is meant to confirm the clinical and biochemical regression of PPP in pre-pubertal girls and to monitor the recovery of regular menstrual activity in post-pubertal girls experiencing primary amenorrhea/oligomenorrhea upon diagnosis. Secondly, physical examination and hormonal assessment is essential to timely detect signs consistent with disease recurrence or with the onset of CPP secondary to exposure to a sex-steroid-secreting tumor. Finally, hormone replacement therapy (HRT) may be required in selected cases (Figure 4).

Tumor excision with unilateral salpingo-oophorectomy in localized disease leads to progressive regression of PPP signs in prepubertal patients. Telarche, signs of estrogenization and, if present, virilization often require several months to achieve complete remission. Consistently, growth velocity shows a progressive decrease over time upon auxological monitoring.

The detection of precocious or rapidly progressing pubertal development in a previously treated prepubertal girl should raise suspicion for recurrence of jGCT or the onset of CPP secondary to sex steroid exposure. Accordingly, periodic hormonal tests during follow-up are recommended. Estradiol and testosterone may serve as tumor markers in jGCT when elevated preoperatively. However, a potential complication for prepubertal patients with jGCT is the development of CPP secondary to exposure to sex-steroid-secreting tumors (12, 13, 56). Priming of the hypothalamic–pituitary–gonadal axis by sex-steroid-secreting tumors has been described in two cases of jGCT and previously reported in several cases of congenital adrenal hyperplasia, adrenal tumors, germ cell tumors, McCune–Albright syndrome, and exposure to endocrine disruptors (12, 13, 54, 69–71) (Table 3). When clinical and biochemical signs consistent with pubertal re-flare are detected following jGCT treatment, a complete hormonal assessment is warranted, including baseline endocrine tests (FSH, LH, estradiol, and testosterone), GnRH stimulation test (if required), and abdominal US, which is mandatory to rule out jGCT recurrence. In addition, for patients with a biochemical profile suggestive of CPP, cranial MRI is recommended to exclude coexisting central neoplasms (56, 72).

Finally, clinical and biochemical follow-up by endocrinologists is essential to treat patients requiring HRT, either to induce pubertal progression in prepubertal girls or to manage the resulting hypoestrogenic state in post-pubertal girls. Ovarian jGCT may be hormone-dependent, and sex steroids serve as tumor markers postoperatively (73) so that HRT should be avoided immediately after surgery (74). In post-pubertal cases, the risk of cancer recurrence must be carefully balanced against the adverse effects of prolonged hypoestrogenism (74). Fertility-sparing surgery is mandatory in the management of jGCT in childhood even in cases of bilateral ovarian involvement; however, contralateral oophorectomy is indicated for patients with contralateral ovarian relapse or metachronous contralateral jGCT (5, 75). In these selected cases, long-term endocrinological follow-up should be planned for HRT. Some patients may require HRT after unilateral salpingo-oophorectomy if further treatments, particularly radiotherapy, were needed (76) (Table 3). Pediatric patients undergoing pubertal induction typically receive progressively increasing doses of estrogens over the first 2 to 3 years. Progestin is added in non-hysterectomized patients only once adequate uterine estrogenization and development have been achieved in order to mimic physiological pubertal development and induce menstruation (77, 78). The timing and regimen of HRT should be individualized, considering the patient’s age, clinical needs, any associated comorbidities, and the patient’s request for contraception (77, 78).

Gynecologists or pediatric surgeons may be involved in the management of jGCT depending on the patient’s age and center-specific expertise. They play a crucial role in assessment at presentation, in follow-up, and in surgical procedure, which is essential for definitive diagnosis and pathological staging.

Gynecologists or pediatric surgeons are often the first specialists consulted in pediatric jGCT, either in elective or urgent/emergency settings (Figure 3). In addition, gynecologic US represents the first-line imaging modality for both diagnosis and follow-up, given its feasibility, non-invasiveness, and cost-effectiveness.

In our review, some of the most reported symptoms at presentation were associated with mass effect in the pelvis or abdomen. Among the 94 patients included, 18.1% reported abdominal pain or discomfort at diagnosis, while 15.9% presented abdominal distension and 8.5% with constipation, anorexia, or sub-occlusive symptoms. Notably, the prevalence of mass-effect-related symptoms was higher among post-pubertal patients, with 66.7% experiencing at least one abdominal symptom at diagnosis. Additionally, Meigs syndrome was described in 2.1% presenting with increasing abdominal girth at onset, while 8.5% showed ascites secondary to tumor capsule rupture or malignant peritoneal involvement (Table 2).

In our review, 5.3% of patients with jGCT needed urgent surgery for acute abdomen at presentation to tumor rupture (2, 79) (Table 2).

In the diagnostic workup of pediatric jGCT, gynecologists are involved to (a) evaluate internal genitalia estrogenization in prepubertal patients and (b) characterize the adnexal mass. Gynecologic US includes measuring the ovarian size, uterine size, uterine body-to-cervix ratio, and endometrial thickness (Figure 3) (66–68). Two pattern recognitions of GCT have been identified on gynecologic US: “pattern 1”, characterized by a solid mass with a heterogeneous echogenicity, and “pattern 2”, defined as a multilocular solid lesion with numerous small locules and a cystic component of mixed or low-level echogenicity, giving the mass a typical “Swiss cheese” appearance (80). Postoperative monitoring relies on pelvic/abdominal US to detect recurrences and assess pubertal regression by evaluating internal genitalia parameters in prepubertal patients (Figure 4) (66). On US, recurrent GCTs may exhibit two typical patterns: a small solid tumor and a tumor with vascularized echogenic ground-glass-like content (81). Finally, two girls were diagnosed prenatally in the setting of obstetric monitoring and presented at birth with virilization and ambiguous genitalia secondary to prenatal exposure to testosterone (19, 20).

The surgical management of jGCTs depends on the extent of the disease and the clinical context at the time of surgery—whether elective or emergency. The decision-making process should be individualized, considering the burden of disease and fertility preservation goals. Since jGCTs primarily affect children, adolescents, and young adults, fertility-sparing surgery is generally preferred, aiming to balance oncologic radicality with the preservation of ovarian function (10).

The treatment of choice for early-stage jGCT is unilateral salpingo-oophorectomy, but oophorectomy can be considered in tumors confined to the ovary, as recommended by the EXPeRT/PARTNER groups and FIGO Cancer Report 2021 (7, 10, 11, 82). The surgical procedure must be completed by staging, which includes inspection of the contralateral ovary, the peritoneal cavity, and the lymph nodes, with biopsy of any suspicious lesions or lymph nodes (5). Biopsies of the contralateral ovary are not routinely recommended, and lymph node biopsies can be omitted in FIGO I disease (7, 11, 82). This approach is supported by retrospective studies on patients with jGCT, which have demonstrated its safety in early-stage disease. In fact, jGCT confined to the ovary is associated with an excellent prognosis, with survival rates exceeding 90% following surgery alone (1, 10, 82). In contrast, tumorectomy is not generally recommended since ovarian-sparing mass excision has been associated with a higher risk of recurrence due to potential microscopic residual disease (7, 10, 11, 64, 82, 83). In some cases, jGCT with a cystic macroscopic appearance may initially be managed with elective ovarian cystectomy. However, the surgical plan for these patients can be completed after the anatomopathological diagnosis of jGCT (11, 61, 64, 84, 85). Additionally, laparoscopic restaging surgery is a feasible option for patients with incomplete staging at the initial surgery (86).

Recurrence after non-radical surgery and relapsed disease remain significant concerns (82). Salvage surgery may be indicated in cases of localized relapse when complete resection is feasible (2, 83, 86–88). However, in advanced-stage disease, surgical management aims for maximal cytoreduction when possible, but systemic chemotherapy is necessary (84). For locally advanced and disseminated disease, debulking surgery is not indicated, except in the context of palliative care (5). However, surgical specimens are essential for anatomopathological examination and are critical to guide chemotherapy treatment decisions (5). Moreover, obtaining anatomopathological specimens through surgery may also be crucial in cases of relapsed disease. Especially in syndromic patients, obtaining surgical specimens is essential to distinguish between tumor relapse and a second malignancy, which is crucial to define the appropriate treatment plan (14, 85, 89).

Remarkably, up to 10% of patients with jGCT may develop a contralateral metachronous ovarian tumor (84). In our review, 4.3% of patients with jGCT developed a contralateral ovarian tumor at a median follow-up of 2.3 years (range: 0.12–7 years) (19, 90–92). In cases of contralateral metachronous tumors with different histology, ovarian-sparing surgery is the preferred approach, when feasible. Accordingly, it was performed in two patients who developed a contralateral mucinous and serous cystadenoma (91, 92). However, in cases of contralateral metachronous jGCT, a second oophorectomy becomes a necessary therapeutic option (19, 90) (Table 3).

The possibility of contralateral ovarian secondary tumors requiring contralateral oophorectomy underscores the importance of addressing fertility preservation in jGCT patients. Although several fertility preservation techniques are available for cancer patients, in the context of ovarian cancer, oocyte and embryo cryopreservation appear to be the only viable options and can be proposed only for post-pubertal patients (93). In fact, while ovarian tissue cryopreservation has been extensively studied, the risk of reintroducing malignant cells upon reimplantation remains an unresolved concern in ovarian cancer patients, and no data are currently available on its safety in this population (93–95).

The oncologist plays a crucial role in disease staging, defining the treatment plan—particularly for advanced-stage and relapsed disease—and ensuring long-term follow-up for patients with jGCT.

As previously described, complete pathological staging is essential for prognosis assessment and treatment planning (5, 82, 96). Most jGCTs, especially sex-steroid-secreting tumors, are diagnosed at early stages. In our review, 71.2% of the 66 patients with jGCT—for whom disease stage was specified—presented with FIGO/WHO I disease (Supplementary Table S3). Localized disease can be treated with surgery alone, with excellent survival rates exceeding 90% when complete resection is achieved (1, 10, 82). Coherently, 95.7% of 47 FIGO/WHO I patients in our review were reported alive at the last follow-up (Supplementary Figure S1). Disease stage at diagnosis and the absence of residual disease after surgery represent two of the most relevant prognostic factors for jGCT (82).

In 2014, the FIGO Oncology Committee revised the FIGO/WHO staging system for ovarian cancers. A key update in this classification was the subdivision of stage IC, distinguishing the timing and cause of capsule rupture as intraoperative (IC1), preoperative (IC2), or associated with positive cytology in ascitic or peritoneal washing samples (IC3) (97). While avoiding intraoperative capsule rupture (IC1) is desirable, its independent impact on prognosis remains uncertain, making the need for adjuvant chemotherapy in these cases questionable (5). Conversely, the finding of malignant cells in ascitic or peritoneal cytology (FIGO/WHO IC3) prompts the use of adjuvant chemotherapy (5). For spontaneous tumor rupture (FIGO/WHO IC2), the EXPeRT/PARTNER groups recommend adjuvant chemotherapy as well (5). However, in our retrospective review, three out of five FIGO/WHO IC2 patients did not receive adjuvant chemotherapy and were alive at follow-up with a range of 3–8 years, making indication for chemotherapy in this stage a questionable option (2, 71, 96) (Supplementary Table S3).

In cases of advanced-stage disease (FIGO/WHO stages II–IV), surgery alone is unlikely to achieve complete resection, and chemotherapy is necessary. Thus, 78.9% of 19 patients with FIGO/WHO stage II–IV disease received adjuvant chemotherapy (Supplementary Table S3). In selected cases with a biopsy-confirmed diagnosis, neoadjuvant chemotherapy may be considered prior to surgery (5).

Regarding overall survival, 92.7% of 69 patients with available outcome and follow-up data were reported to be alive, with a mean follow-up time of 4.8 years (range: 0.2–18 years). When focusing exclusively on patients with advanced-stage disease, 81.2% of 16 patients with complete follow-up data were alive at a mean follow-up of 4.4 years (range: 0.6–14 years) (Supplementary Figure S1). The mortality rate observed in advanced-stage patients in this review appears lower than previously reported based on recently published data from patients enrolled in the International Ovarian and Testicular Stromal Tumor and/or International Pleuropulmonary Blastoma/DICER1 Registries (98). However, it is noteworthy that four patients (25.0%) with FIGO/WHO stage II–IV disease had a follow-up duration of less than 1.5 years. Given that the mean time to relapse in our review was 1.4 years (range: 0.12–8 years), this indicates that 25.0% of advanced-stage patients remained within the high-risk window for relapse at their last follow-up. Furthermore, among all patients with reported follow-up durations, 24.6% of 69 patients had a follow-up time of less than 1.5 years, representing a substantial proportion of patients whose short follow-up may have limited the possibility for recurrences to be observed.

Due to the rarity of jGCT, no prospectively generated treatment guidelines exist for advanced-stage disease. To standardize treatment regimens, the EXPeRT/PARTNER groups issued consensus recommendations in 2021 for the diagnosis and therapy of OSCSTs in children and adolescents, recommending cisplatin-based chemotherapy regimens, either PEB or PEI (7). Data on adults have demonstrated no superiority of either of these two regimens (75). Thus, the toxicity profile should be taken into consideration when defining treatment planning. PEB is less myelotoxic but carries a risk of pulmonary toxicity due to bleomycin, while PEI, in addition to being more myelotoxic, is associated with gonadotoxicity (75, 99). The recommendation is to administer four cycles of chemotherapy, with escalation to six cycles in cases of metastatic disease (5).

Relapse in jGCT remains a major concern for pediatric oncologists due to poor survival outcomes. In our review, 17.0% of the 94 patients included experienced one or more disease relapses, and 43.7% of these later ultimately died of disease. Relapse sites included the ipsilateral ovarian bed or abdomen/pelvis (n = 8), lymph nodes (n = 4), bone and bone marrow (n = 2), liver (n = 2), lungs (n = 1), omentum (n = 1), and peri-splenic region (n = 1).

Treatment for relapse involves a combination of chemotherapy and cytoreductive surgery (84). Several chemotherapy regimens, including PEB/PEI and VAC/VI (vincristine, dactinomycin, and cyclophosphamide alternating with vincristine and irinotecan), have been used at relapse, while paclitaxel, bevacizumab, gemcitabine, and thalidomide are typically considered as salvage therapy (84). For progressive disease, where prognosis remains extremely poor, additional treatment options have been explored, including radiotherapy (100), hyperthermic intraperitoneal chemotherapy with cisplatin in combination with cytoreductive surgery (85), and high-dose chemotherapy followed by autologous bone marrow transplantation (5, 76, 100). In addition, given the functional hormonal nature of granulosa cell tumors and their expression of sex steroid receptors, there is a rationale for a hormone-based approach. Limited data on adult patients support the use of hormone therapy with aromatase inhibitors as a viable treatment option for advanced-stage or recurrent GCT (75, 101).

jGCTs are characterized by slow growth and a tendency for late recurrence. In our review, 16 patients experienced disease relapse with a mean time to recurrence of 1.4 years (range: 0.12–8 years). The recommended surveillance for disease recurrence includes physical examination with endocrine assessment, monitoring of tumor markers if elevated preoperatively (AMH, inhibin A/B, estradiol, and/or testosterone), and pelvic/abdominal US. Notably, up to 10% of patients diagnosed with jGCT may develop a metachronous contralateral ovarian tumor over a wide follow-up period, ranging from weeks to 7 years, underlining the need for long-term follow-up for these patients (5, 19, 90–92). Follow-up evaluations should be conducted every 3 months during the first 3 years after diagnosis and may be spaced out thereafter (Figure 4) (5).

Previous molecular studies on large cohorts of pediatric cancers suggested that 10% of children diagnosed with cancer carry a predisposing germline variant (102–104). In addition, patients with cancer-predisposing syndromes (CPSs) present an increased lifetime risk to develop cancers and are known to be prone to treatment-induced second malignancies (105, 106). In this perspective, increasing awareness of CPSs is of utmost importance to refer families for genetic counseling (Figure 4) and to establish a surveillance plan for early tumor detection in affected patients when indicated (Figure 3).

Notably, both the DICER1 patient (85) and the LFS/PHTS patient (88) included in our review faced a tumor-related death. Prospective observational studies on cancer surveillance in LFS have demonstrated that a combination of clinical, biochemical, and radiologic follow-up can improve long-term survival. These findings highlight the importance of raising awareness of CPSs and prospectively evaluating surveillance protocols for affected patients (119, 120). Additionally, as previously described, early-stage jGCT is associated with better prognosis and overall survival (1, 10). These findings support the rationale to establish a structured cancer surveillance plan for patients diagnosed with other CPSs. In this context, the International DICER1 Symposium has established consensus-based surveillance recommendations for DICER1-associated tumors (14, 15), followed by the more recent recommendations provided by the Host Genome Working Group (HGWG) of the SIOPE and the Clinical Guideline Working Group of the CanGene (114). Similarly, the National Comprehensive Cancer Network (NCCN) has issued guidelines for thyroid cancer monitoring in children and cancer risk surveillance in adults with PHTS, while the PHTS Guideline Development Group and the European Reference Network GENTURIS introduced updated surveillance recommendations in 2020 (121, 122). However, prospective studies evaluating the efficacy of surveillance plans in improving overall survival for patients with DICER1 syndrome and PHTS are still lacking and would be essential to develop evidence-based protocols (114). Similarly, while there is clear evidence of malignant transformation of enchondromas in OD and MS, as well as a known predisposition to glioma development, there are no evidences supporting that a cancer surveillance plan could improve the survival rates for these patients, especially considering that the tissue distribution and load of the IDH variant may vary significantly among affected individuals, which is likely to influence the risk of malignancy (123, 124).

While early tumor detection may be proven beneficial, a major challenge in improving survival outcomes for patients with CPSs is their high risk of developing treatment-induced second malignancies (105, 106). Therefore, identifying targeted therapies tailored to specific genetic mutations would be crucial in reducing the risk of secondary cancers in these patients. In this perspective, precision medicine treatment may ultimately prove meaningful in improving long-term survival rates for individuals affected with CPSs.