Management challenges of ovarian adult-type granulosa cell tumors at a tertiary facility in resource-limited setting: A case series of three patients and review of the current literature

Abstract

Introduction and importance

Adult-type granulosa cell tumors (AGCTs) are rare, low-grade malignant ovarian sex-cord stromal tumors, accounting for approximately 5 % of all ovarian tumors. These tumors are characterized by their potential for late recurrence and complex management, which presents significant challenges, particularly in resource-limited settings where access to advanced diagnostic tools and treatment options is restricted. This study highlights a series of rare AGCT cases diagnosed in premenopausal and postmenopausal women in Northern Tanzania. Given the global rarity of AGCTs and the limited literature on the condition, especially in this region, this study aims to address a critical knowledge gap.

Case series

This report presents a series of three patients diagnosed with ovarian adult-type granulosa cell tumors (AGCTs) based on histological findings. The series underscores the variability in clinical presentations and highlights the significance of individualized treatment approaches in managing these rare tumors.

Clinical discussion

Managing AGCTs in resource-limited settings requires balancing optimal care with available resources. Surgery remains the cornerstone of treatment; however, the lack of advanced diagnostic tools and limited access to adjuvant therapies necessitate a focus on achieving the best possible surgical outcomes and prioritizing rigorous clinical follow-up. This report explores the rarity of AGCTs, reviews existing literature on similar cases, and examines the numerous challenges associated with their management in such settings.

Conclusion

Adult granulosa cell tumors are rare, low-grade malignant neoplasms of the ovarian sex-cord stromal origin. These tumors are notable for their potential to recur even years after initial treatment. Consequently, regular follow-up with clinical examinations and tumor marker assessments is recommended. While chemotherapy can provide palliative benefits and manage recurrence, surgery remains the cornerstone of treatment, as illustrated in our case report.

Highlights

• •Granulosa cell tumor (GCT) of the ovary is a rare indolent malignant neoplasm, often diagnosed at early stages.
• •GCT should be considered in the differential diagnosis of solid / cystic and hemorrhagic ovarian mass in postmenopausal patients.
• •Complete tumor removal is essential, as any remaining disease is associated with a worse prognosis.

1. Introduction

Granulosa cell tumor (GCT) of the ovary is a rare subtype of ovarian neoplasm originating from the sex-cord stromal component of the ovary. These tumors typically present as large, complex ovarian masses. Although uncommon, GCTs are the most frequent type of sex-cord stromal tumors, with an incidence of 0.6–0.8 per 100,000, accounting for 2–5 % of all ovarian neoplasms [1]. There are two distinct forms of GCT: the adult and juvenile types. The juvenile form, comprising only 5 % of cases, is predominantly seen in prepubertal patients and generally carries a favorable prognosis, though its clinical course may become more aggressive in advanced stages [2]. Adult granulosa cell tumors (AGCTs), on the other hand, are most commonly diagnosed in perimenopausal women, typically between the ages of 50 and 54, although they can occur across the adult lifespan.

As estrogen-secreting tumors, the initial symptoms of granulosa cell tumors (GCTs) often depend on the patient's menopausal status. While their size can vary significantly, a pelvic mass is typically detected during examination. GCTs usually present as large, unilateral masses with a characteristic tan-yellow coloration due to steroid production [1]. They frequently exhibit both solid and cystic components.

Diagnostic evaluation for these tumors, as with other pelvic masses, commonly involves pelvic ultrasound. Treatment is tailored to the patient's menopausal status; in postmenopausal women, the standard approach is total abdominal hysterectomy with bilateral salpingo-oophorectomy. Due to the high risk of late recurrence, lifelong follow-up is recommended [2]. This article has been reported in line with the PROCESS criteria [17].

The prognosis for patients with sex cord stromal tumors is generally favorable, as these tumors are often detected and diagnosed early, allowing for timely and effective treatment. In this report, we present a rare case series of three women from Northern Tanzania who were diagnosed with adult granulosa cell tumors based on histological and immunohistochemical analysis.

2. Case report 1

A 59-year-old woman, 15 years postmenopausal, presented to our outpatient clinic with a 6-month history of abdominal distension accompanied by vaginal bleeding, loss of appetite, nausea, early satiety, recurrent heartburn, and weight loss. On examination, her vital signs were stable. A computed tomography (CT) scan revealed a large, multi-septated intra-abdominal cystic lesion with enhancing walls, measuring 19 × 20 × 12 cm, displacing adjacent structures. Laboratory investigations showed a significantly elevated CA-125 level of 174 U/mL (normal range: 0–35 U/mL), while all other laboratory parameters were within normal limits.

The patient underwent an exploratory laparotomy, during which a total abdominal hysterectomy and bilateral salpingo-oophorectomy were performed. A large right ovarian mass with both solid and cystic components, measuring 20 × 17 × 18 cm, was successfully removed (Fig. 1), and hemostasis was achieved. Postoperative recovery was uneventful.

Fig. 1.

a large mass of the right ovary with solid and cystic components measuring 20 × 17 × 18 cm was removed during surgery.

Histopathological examination revealed a sex cord-stromal tumor characterized by a diffuse proliferation of small, bland cuboidal to polygonal cells with scant cytoplasm and pale, uniform angulated nuclei (coffee bean appearance) (Fig. 2A–B). The patient was discharged on the 4th postoperative day and has been followed up every three months. Nine months of regular follow-up evaluations have shown no evidence of tumor recurrence.

Fig. 2.

Histopathology of adult granulosa cell tumor composed of diffuse proliferation of small, bland, cuboidal to polygonal cells with scant cytoplasm and pale, uniform angulated and nuclei, H&E staining at 40× original magnification (A, B); a mixed growth pattern of diffuse and insular or microfollicular growth patterns; H & E staining at 40× original magnification (C); focal of areas of atypical cells with enlarged hyperchromatic bizarre, some mitoses, suggestive of degenerative change and not associated with adverse outcome (D); overexpression of the tumor cells with inhibin IHC at 20× original magnification (E), and (F) diffuse cytoplasmic staining of the tumor cells with calretinin, IHC at 40× original magnification.

3. Case report 2

A 26-year-old woman presented to the gynecology outpatient clinic with a 6-month history of progressively worsening vaginal bleeding, accompanied by abdominal distension, palpitations, headaches, and generalized body weakness. On examination, she appeared pale but afebrile, with a blood pressure of 110/66 mmHg, pulse rate of 116 bpm, respiratory rate of 20 bpm, SpO2 of 99 % on room air, and a random blood glucose (RBG) level of 5 mmol/L. Bilateral lower limb pitting edema was also noted.

An abdominal CT scan (Fig. 3) revealed a large, predominantly cystic mass with enhancing papillary projections arising from the right adnexa, measuring 16 × 9 cm at its maximum axial diameter. The mass extended into the right upper abdominal quadrant, causing a mass effect on adjacent structures, and mild ascites was present. Routine laboratory investigations showed anemia with a hemoglobin level of 7.8 g/dL, and the patient was transfused with two units of whole blood before surgery. Tumor marker analysis showed an elevated CA-125 level of 56 U/mL (reference range: 0–35 U/mL) and normal CEA levels at 2.358 ng/mL (reference range: 0–5.093 ng/mL).

Fig. 3.

Abdominal CT scan (A axial view and B coronal view) revealed a huge predominantly cystic mass with enhancing papillary projections is seen arising from the right adnexa measuring 16 cm × 9 cm in maximum axial diameter.

The patient underwent a right salpingo-oophorectomy, and her postoperative recovery was uneventful. Histopathological examination revealed a tumor with mixed diffuse and microfollicular (insular) growth patterns, consistent with an adult granulosa cell tumor, as observed on H&E staining at 40× magnification (Fig. 2C).

She was discharged on the 3rd postoperative day and scheduled for follow-up every three months. She was counseled about the risk of occurrence, future fertility, and avoiding pregnancy for at least 1 year following surgery. At six months post-treatment, the patient remains stable, asymptomatic, and without evidence of recurrence or metastasis.

4. Case report 3

A 68-year-old woman, 13 years postmenopausal, presented with a 6-month history of gradually worsening abdominal distension, accompanied by loss of appetite, nausea, early satiety, recurrent heartburn, a sensation of incomplete rectal emptying, increased urinary frequency and urgency, weight loss, and, more recently, difficulty breathing, particularly while lying supine or during ambulation.

Her medical history included hypertension and diabetes, managed for 20 years, and ischemic stroke diagnosed two years ago, for which she was on regular medications. On examination, she appeared non-pale and afebrile, with a blood pressure of 155/86 mmHg, a pulse rate of 96 bpm, a respiratory rate of 22 bpm, SpO2 of 96 % on room air, and a random blood glucose (RBG) level of 8 mmol/L. Bilateral lower limb pitting edema was also noted. Laboratory tests showed hemoglobin of 13.2 g/dL, elevated CA-125 at 123 U/mL (reference range: 0–35 U/mL), and normal CEA at 1 ng/mL (reference range: 0–5.093 ng/mL). Renal and liver function tests were within normal limits.

Imaging studies revealed gross cardiomegaly on chest X-ray. Electrocardiography showed features of hypertensive heart disease, including left ventricular hypertrophy, left atrial enlargement, and left axis deviation, while the electrocardiogram confirmed normal sinus rhythm. A CT scan (Fig. 4) showed a large heterogeneous mass arising from the right adnexa, measuring 11 × 13 × 17 cm, abutting the anterior uterine wall, with associated free peritoneal fluid and mild right pleural effusion. The findings were suggestive of a right ovarian fibroma with a differential diagnosis of fibrothecoma.

Fig. 4.

A CT scan (Axial view) revealed a large heterogeneous mass arising from the right adnexa measuring 11 × 13 × 17 cm in size abutting to the anterior wall of the uterus.

A CT-guided core needle biopsy was performed. Histopathological analysis identified a diffuse tumor comprising small, uniform oval to round cells with granulosa-like features. Focal areas showed atypical cells with hyperchromatic, bizarre nuclei and occasional mitoses, indicative of degenerative changes without adverse prognostic implications (Fig. 2D). Immunohistochemistry confirmed the diagnosis of adult granulosa cell tumor, with tumor cells overexpressing inhibin (Fig. 2E) and exhibiting diffuse cytoplasmic staining for calretinin (Fig. 2F).

The case was reviewed by a multidisciplinary tumor board comprising gynecologists, oncologists, and pathologists. The consensus was to pursue surgical debulking followed by neoadjuvant chemotherapy with carboplatin and paclitaxel. However, due to her comorbidities, the patient was deemed unfit for surgery. Neoadjuvant chemotherapy was planned but not initiated due to financial constraints.

Currently, the patient remains at home, attempting to secure funds for treatment. Follow-up is conducted through regular phone consultations to minimize costs, as she has not returned for in-office visits.

5. Discussion

This study presents a series of rare adult granulosa cell tumors (AGCT) diagnosed in both premenopausal and postmenopausal women in Northern Tanzania. Due to the rarity of AGCTs globally, and particularly in this region, there is limited literature available on the subject. In this report, we explore the infrequency of this condition, review relevant literature on similar cases, and address the various challenges encountered in the management of AGCT.

Granulosa cells are somatic cells found in the ovarian sex cords, playing a key role in the maturation of developing oocytes. Granulosa cell tumors (GCT) account for approximately 5 % of malignant ovarian tumors [3]. GCTs can be classified into adult granulosa cell tumors (AGCT) and juvenile granulosa cell tumors (JGCT), based on clinical presentation and histological features. AGCT is more common than JGCT, representing about 95 % of all GCTs [3]. Most adult GCTs are diagnosed in postmenopausal women, with a peak incidence between the ages of 50 and 55 [4]. However, in our case series, the patients were aged 59, 26, and 68 years. In premenopausal women, AGCTs often present with irregular bleeding, amenorrhea, and, less frequently, infertility. In postmenopausal women, the most common symptoms are abnormal uterine bleeding and the presence of a unilateral ovarian mass [5].

Specific tumor markers play a crucial role in the early diagnosis and postoperative monitoring of ovarian adult granulosa cell tumors (AGCT), potentially enhancing patient survival rates [4]. In resource-limited settings, markers such as CEA, CA-125, 17β-estradiol (E2), anti-Müllerian hormone (AMH), follicle regulatory protein (FRP), and serum inhibin can be particularly valuable for early detection and follow-up [4].

Radiological imaging of GCTs often reveals distinctive features, especially on MRI, such as a sponge-like appearance with intermediate signal intensity areas or hemorrhagic foci with high signal intensity [6]. Alternatively, GCTs may present as predominantly cystic masses with solid components or solid masses with variable cystic areas. Estrogenic activity associated with these tumors can result in uterine enlargement or endometrial thickening [6]. Consistent with our cases, imaging findings revealed multi-septated cystic lesions accompanied by endometrial thickening.

The definitive diagnosis of GCT relies on histopathological examination of tissue obtained during surgery. Given the non-specific clinical presentation and investigation findings associated with GCTs, a high index of clinical suspicion is essential for accurate diagnosis [7].

The characteristic histological features of AGCTs are Call-Exner bodies. Call-Exner bodies are glandular structures that resemble ovarian follicles, and “coffee-bean” nuclei, which have a low mitotic rate. One important diagnostic marker for GCTs is a positive stain for the ovarian glycoprotein a-inhibin by immunohistochemistry [8]. These tumors on IHC are nonspecifically positive for CD99, CAM 5.2, AE1/AE3, CD10, S100, WT-1, smooth muscle actin and desmin. They are negative for CK7 and EMA [9]. Research has demonstrated that cellular atypia, a high mitotic index (4–10 mitoses per 10 HPF) and the lack of Call-Exner bodies are noteworthy indicators for early recurrence of the disease [10].

Due to the rarity of AGCT, evidence-based management options are limited. Currently, there are no established international guidelines for its treatment, and the International Federation of Gynecology and Obstetrics (FIGO) staging system is commonly used in practice. There are numerous recognized medical treatments for GCT. Examples include platinum-based chemotherapies in combinations with bleomycin, cisplatin, etoposide, vinblastine, actinomycin-D, 5-fluorouracil, doxorubicin and cyclophosphamide. Other studies advise the use of carboplatin and taxanes like paclitaxel either in combination with platinum or as a single agent [11]. Radiotherapy has also been suggested for patients with residual disease, disease recurrence and terminal diagnoses, the response rates have differed significantly. The efficacy of radiation in GCT is not well defined. There are no prospective trials showing the benefit with radiation [11]. Surgical intervention remains the main course of action for treatment of AGCT with hysterectomy coupled with bilateral salpingo-oophorectomy and debulking for either recurrent or advanced disease. Staging can be performed via biopsies, infracolic omentectomy and peritoneal washings [12]. It is typically not advised to remove lymph nodes surgically, specifically pelvic and para-aortic lymphadenectomy. Only large or suspicious looking nodes should be removed [12]. Most patients with ovarian AGCT are diagnosed at stage IA, where the tumors are typically confined to the ovary and have not metastasized [16], as our patients were all in stage IA.

In patients who are young a fertility sparing approach is preferable. If diagnosis is made when the disease is in its early stages a unilateral salpingo-oophorectomy can be performed with conservative approach. However, studies suggest that there is little difference in survival rates between radical and conservative therapies, with 5-year and 10-year disease-specific survival rates of 97 % and 94 %, respectively [13].

In order to exclude related endometrial pathology or metastatic disease it is recommended that a meticulous staging technique in conjunction with endometrial biopsy is performed. AGCT tend to have late recurrence and relapse of the disease is often diffuse in nature, with the pelvis being the most common location. Retroperitoneal metastases, abdominal disease, and peritoneal disease can also occur [14]. Such patients require optimal debulking which may include multivisceral surgeries. These patients are at high risk of postoperative complications [14].

The identification and subsequent treatment of patients who are more likely to relapse is not straightforward and poses a challenge for AGCT patients and their clinicians. Furthermore, there are currently no defined criteria for how these individuals should be treated and monitored in the event of a relapse. [15] Regular follow-up intervals range from two to five years, or as advised, longer than five years by National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO) [15]. Expansion of the current literature with case reports such as our own will be instrumental in developing surveillance guidelines and informing management decisions in the future.

6. Conclusion

Adult granulosa cell tumors are rare sex cord stromal ovarian low grade malignant neoplasms. Recurrence is known to occur even years following a therapeutic intervention. Therefore, it is advised to have clinical examination and tumor markers as part of follow-up. Chemotherapies can aid with palliation and recurrence, but surgery is the primary treatment as is demonstrated in our case report. Stage is universally accepted as an important prognostic Variable. Further research is required for improved targeted management of the disease, and follow-up is crucial for long-term patient treatment and care.

Consent

Written informed consent was obtained from the patient to publish this case report and accompanying images. On request, a copy of the written consent is available for review by the Editor in-Chief of this journal.

Ethical approval

This case series report is exempt from ethical approval in our institute.

Guarantor

Dr. John Lugata.

Funding

This work did not receive any fund from any source.

CRediT authorship contribution statement

John Lugata: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Data curation, Writing – original draft, Writing – review & editing. Laetitia Makower: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Data curation, Writing – original draft, Writing – review & editing. Ashley Rapheal: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Data curation, Writing – original draft, Writing – review & editing. Eusebious Maro: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Data curation, Supervision, Writing – original draft, Writing – review & editing. Alex Mremi: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Data curation, Supervision, Writing – original draft, Writing – review & editing. Bariki Mchome: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Data curation, Supervision, Writing – original draft, Writing – review & editing.

Declaration of competing interest

All authors have declared that no competing interests exist.