Liver metastasis of ovarian granulosa cell tumors: a case report and literature review.

Background
Ovarian granulosa cell tumors (GCTs) originate from ovarian granulosa cells and represent 70% of ovarian sex cord-stromal tumors and 2% ~ 5% of ovarian malignancies [1]. Owing to its unique hormone-producing activity, GCT often presents with endocrine-related symptoms that facilitate early detection. Reproductive-aged patients typically present with menstrual irregularities, such as menorrhagia, intermenstrual bleeding, and secondary amenorrhea, whereas postmenopausal patients commonly present with abnormal vaginal bleeding. GCT typically follows an indolent natural course. Currently, surgical resection serves as the cornerstone of GCT management, generally resulting in favorable short-term prognoses. Early-stage patients have a 5-year survival rate exceeding 90%. However, GCT has a remarkable tendency to recur, firmly establishing itself as a prototypical long-term recurrent malignancy within the domain of gynecological oncology. The recurrence rate of ovarian GCT ranges from 25 to 30%. Most recurrent cases present as local pelvic and abdominal dissemination [2]. Liver metastases from GCTs are infrequent, accounting for approximately 5% to 6% of all recurrent events, and they can be easily misdiagnosed as primary liver cancer [3]. Thus, liver metastasis is rare, and long-term clinical follow-up remains crucial for such recurrences. Herein, we report a unique case of an ovarian GCT. Fourteen years after the initial oophorectomy, the patient experienced recurrence in the form of liver metastasis. The patient was successfully treated with partial hepatectomy. In this study, we also conducted a review and analysis of literature pertaining to liver metastases from GCTs.

Case presentation
A 61-year-old female patient was admitted to the Hepatobiliary Surgery Department of our Hospital in 2018, with the chief complaint of "upper abdomen distension and regurgitation for over one year". She experienced acid regurgitation and belching on an empty stomach, without associated symptoms such as nausea, vomiting, diarrhea or melena. During an outpatient visit, abdominal computed tomography (CT) at our hospital revealed low-density lesions in the left lobe of the liver, which led to her hospitalization with the diagnosis of "liver space- occupying lesion". Fourteen years prior (2004), owing to "torsion of the ovarian granulosa cell tumor pedicle", she had undergone hysterectomy and bilateral salpingo-oophorectomy.
Abdominal contrast-enhanced dynamic CT findings: In the posterior lower segment of the right lobe of the liver, there is a cystic-solid-mixed-density focus measuring 8.1 × 5.9 cm. The boundary of the lesion is distinct, and it protrudes toward the surface of the liver and into the abdominal cavity (Fig. 1A, B).
Enhanced magnetic resonance imaging (MRI) revealed an irregular space-occupying lesion in the S5 segment of the liver. The lesion exhibited long T1 and isointense T2 abnormal signals (Fig. 1C, D). On diffusion-weighted imaging (DWI), the lesion showed a heterogeneous high signal. Nodular enhancement was observed at the periphery of the lesion in the arterial phase. In the portal venous phase, the enhanced area of the lesion expanded. However, in the delayed phase, the lesion still presented heterogeneous enhancement. The size of the lesion was approximately 8.6 × 6.3 × 9.8 cm. Multiple round lesions with long T2 signals of varying sizes were detected in the liver. No obvious enhancement was found in these lesions during the enhanced scan. The largest one had a diameter of approximately 0.8 cm.
During the liver tumor resection performed under general anesthesia in April 2018, the tumor was found to be located in the fifth and sixth segments of the liver, measuring approximately 8 × 7 × 7 cm. It protruded into the abdominal cavity and adhered to the hepatic flexure of the colon, duodenal bulb, and anterior surface of the right kidney. Upon dissection of the adhesions, the tumor was noted to have a complete capsule, without invasion of the surrounding tissues. The mass was adjacent to the gallbladder, and multiple liver cysts were also observed. Gross examination of the tumor revealed a texture resembling that of friable necrotic tissue with hemorrhagic areas. The tumor was cystic and solid, and the solid portion consisted of grayish-yellow to grayish-red, fleshy, necrotic tissue (Fig. 2A). The cut surface was fine, and the cyst wall was 0.2 cm thick. The closest margin from the tumor to the resection edge was 0.4 cm. The cut surface of the remaining liver tissue appeared grayish-red, without any obvious abnormalities. Intraoperative frozen-section pathology indicated a malignant liver tumor, with sarcoma being considered a possible diagnosis (Fig. 2B).
Postoperative paraffin pathology analysis revealed a cystic-solid tumor in the liver. This tumor was predominantly composed of short spindle cells, among which round epithelioid cells were sporadically distributed. Some cells within liver lesion (Fig. 2C) exhibited a nested growth pattern, a histopathological feature consistent with that of the patient's GCT resected 14 years earlier (Fig. 2D). The cells presented with mild pleomorphism, exhibiting occasional nuclear fissures. Additionally, some cells had nuclear grooves and pseudochrysanthemum-like structure (Call-Exner bodies) (Fig. 2E). On the basis of these observations, the hepatic lesion was suspected to be a metastatic focus originating from the patient’s adult-type ovarian GCT. Notably, there was no typical intravascular tumor thrombus or nerve invasion. The liver capsule remained intact, and the surgical resection margin was free of tumor cells. The immunohistochemical results were as follows: CEA (-), hepatocyte (-), glypican-3 (-), CK19 (-), CK7 (-), CK (AE1/AE3) (-), EMA (-), Ki-67 (1% +), β-catenin (partial +, Fig. 2F), CD99 (+, Fig. 2G), CD56 (spindle cell partial +), vimentin (+, Fig. 2H), inhibin-α (a small number of epithelioid cells +, Fig. 2I), calletinin (CR) (a small number of epithelioid cells +), and Syn (-). Considering the immunohistochemical findings, the morphological characteristics observed via Hematoxylin–Eosin (H&E) staining, and the patient’s medical history, the diagnosis was consistent with metastasis of the ovarian granulosa cell tumor.

Discussion and conclusions
Among sex cord stromal tumors, ovarian granulosa cell tumors are relatively rare low-grade malignant neoplasms and represent the most prevalent type [4]. Granulosa cell tumors can be classified into adult and juvenile types, which exhibit distinct differences in their molecular pathological characteristics and prognoses. Adult granulosa cell tumors constitute approximately 95% of all granulosa cell tumors and predominantly affect women aged 50–55 years, whereas juvenile granulosa cell tumors are distinct malignant subtype that occur almost exclusively in adolescents and young women under the age of 30.
Granular cells possess hormonal activity and are able to synthesize estradiol along with transforming growth factors, notably inhibin and anti-Mullerian hormone (AMH). Multiple studies have firmly demonstrated that in female patients with GCT, the levels of AMH and inhibin increase [5]. Moreover, there was a positive correlation between the levels of these two factors and the diameter of the tumor. These two biomarkers exhibit high sensitivity (92% vs. 93%, respectively) and specificity (81% vs. 83%, respectively), and their detection plays a crucial role in differentiating GCTs from epithelial ovarian tumors as well as predicting GCT recurrence in clinical practice. Notably, neither AMH nor inhibin was measured in the present case, which represents a limitation of this report. Recent research revealed that a missense point mutation in the FOXL2 gene (FOXL2C134W) serves as a potential initiator in the pathogenesis of GCT [6]. The co-occurrence of FOXL2C134W and SMAD4 can contribute to carcinogenesis, while a TERT-124C > T promoter mutation, which is associated with high tumor invasiveness and a poor overall survival (OS) outcome [7, 8]. These molecular markers may help predict GCT development and guide therapeutic strategies. In future research, it is recommended to conduct relevant genetic testing for patients with GCT, with particular emphasis on the FOXL2 gene.
Here, we present a case of a GCT with liver metastasis that was detected 14 years after an ovariectomy. The patient underwent successful resection of the liver tumor. Since no tumor biopsy was performed before the operation, an exact diagnosis could not be established at that time. The postoperative pathological findings indicated the presence of a GCT. H&E-stained specimens revealed that the tumor cells had nuclei with characteristic longitudinal grooves, which are representative features of GCTs. Notably, the occurrence of a GCT originating from the liver has not been previously reported. On the basis of our case and relevant observations, we concluded that a GCT in the liver is a metastatic lesion resulting from the resection of an ovarian tumor.
It is widely acknowledged that the late recurrence rate of GCTs is 25–30%. Liver metastases from GCTs are relatively uncommon, accounting for 5–6% of all GCT recurrences. Since Garcia et al. first described GCT liver metastasis in 1996, only 21 cases(including our case) of GCT treated with hepatectomy have been reported [9, 10]. The interval from initial GCT diagnosis to hepatectomy is typically prolonged, as observed in our case. It is well known that GCTs are prone to late recurrence [11]. For patients with advanced or recurrent GCTs, tumor cytoreductive surgery remains the most effective therapeutic approach. In our patient, liver metastasis occurred fourteen years after ovariectomy. Koganezawa I et al. reported the longest recurrence-free survival for GCTs, with a 30-year interval from primary tumor onset to pelvic recurrence [12]. Yu et al. reported a 27-year recurrence-free interval until liver metastasis developed [13]. Table 1 summarizes the epidemiological and clinical characteristics of ovarian GCTs with liver metastasis treated by hepatectomy. Notably, most liver metastases are diagnosed several years after the primary tumor, which is consistent with our patient’s course [20]. This finding aligns with current literature recommendations. Given that ovarian GCT is typically a low-grade malignancy, long-term follow-up is essential for most patients, who should be counseled on the disease’s indolent natural history.
Currently, there are no established standardized recommendations or clinical practice guidelines specifically for managing recurrent GCTs. Clinically, however, various therapeutic approaches, including surgical resection, chemotherapy and radiotherapy, are employed to treat recurrent GCTs [21, 22]. Previous reports have shown that surgical resection to eliminate residual lesions can improve the postoperative quality of life of patients and facilitate recurrence-free survival [11]. In our patient, liver metastasis was identified as the sole site of GCT recurrence, with no evidence of additional metastatic foci. Consequently, we performed liver tumor resection. Surgical resection is believed to achieve a disease-free state, offering the potential for long-term survival.
Postoperative adjuvant chemotherapy for GCT remains controversial. The MITO-9 study demonstrated that adjuvant chemotherapy fails to reduce recurrence rates in phase IC of granulosa cell tumors and does not alter outcomes for patients with recurrence. Current recommendations advocate for repeat surgery when feasible, with chemotherapy avoided in the absence of residual tumor [23]. In our case, the patient underwent liver tumor resection for isolated liver metastasis, the sole site of GCT recurrence. No additional adjuvant therapy was administered following this recurrence treatment. With a follow-up period exceeding 7 years after hepatectomy (2025), no evidence of recurrent liver metastasis was observed. In the latest follow-up conducted in 2024, the patient underwent contrast-enhanced CT and testing for tumor markers including AMH; no abnormalities were detected.
In summary, ovarian granulosa cell tumors are characterized by a propensity for "late recurrence", making consistent long-term follow-up particularly critical. When liver metastasis occurs, active surgical intervention (e.g., hepatectomy) should still be pursued, as this approach may offer patients an opportunity to achieve prolonged disease-free survival.