GRANULOSA CELL TUMORS OF THE OVARY: CLINICAL FEATURES, HISTOPATHOLOGY, AND LONG-TERM MANAGEMENT

ABSTRACT

Granulosa cell tumors (GCTs) of the ovary are rare, hormonally active neoplasms belonging to the category of sex cord-stromal tumors. Despite their rarity, GCTs are clinically significant due to their estrogen production, which often leads to early detection, and their potential for late recurrence. GCTs are classified into two subtypes: adult granulosa cell tumors (AGCTs) and juvenile granulosa cell tumors (JGCTs), with AGCTs being more common and typically presenting in middle-aged or postmenopausal women. Diagnosis relies on histopathological features, including the presence of Call-Exner bodies and characteristic "coffee bean" nuclei, alongside immunohistochemical markers such as inhibin.

Surgical treatment is the primary modality for managing GCTs, with complete resection being the goal. Factors such as tumor size, mitotic index, nuclear atypia, and lymphovascular invasion impact prognosis, with advanced-stage disease and high-risk histological features being associated with a higher likelihood of recurrence. GCTs are unique in their potential for late recurrence, which can occur decades after initial diagnosis. As such, long-term follow-up is essential, with monitoring of tumor markers like inhibin and estradiol being critical for early detection of recurrence.

Adjuvant therapy, including chemotherapy and hormonal treatments such as aromatase inhibitors, may be considered in advanced or recurrent cases, although the overall benefit remains uncertain due to the tumor's rarity and indolent nature. This review examines the histopathological features, clinical presentation, prognostic factors, and management strategies for GCTs, emphasizing the importance of long-term surveillance in light of the risk of late recurrence.

АННОТАЦИЯ

Гранулёзоклеточные опухоли (ГЗО) яичников — это редкие, гормонально активные новообразования, относящиеся к опухолям полового тяжа и стромы. Несмотря на редкость, ГЗО имеют клиническое значение из-за их способности продуцировать эстроген, что часто приводит к раннему выявлению, а также из-за их потенциальной склонности к позднему рецидиву. ГЗО делятся на два подтипа: взрослые гранулёзоклеточные опухоли (ВГЗО) и ювенильные гранулёзоклеточные опухоли (ЮГЗО), причём ВГЗО встречаются чаще и, как правило, диагностируются у женщин среднего возраста или в постменопаузе. Диагностика основывается на гистопатологических признаках, таких как наличие телец Калл-Экснера и характерных ядер с "бороздками", а также на иммуногистохимических маркерах, таких как ингибин.

Основным методом лечения ГЗО является хирургическое вмешательство, цель которого — полное удаление опухоли. Прогноз зависит от таких факторов, как размер опухоли, митотический индекс, ядерная атипия и лимфоваскулярная инвазия; при этом более высокий риск рецидива связан с поздними стадиями заболевания и неблагоприятными гистологическими признаками. ГЗО уникальны своей возможностью позднего рецидива, который может возникнуть через десятилетия после первоначального диагноза. В связи с этим крайне важно длительное наблюдение, включая мониторинг опухолевых маркеров, таких как ингибин и эстрадиол, для раннего выявления рецидива.

Адъювантная терапия, включая химиотерапию и гормональное лечение, например ингибиторами ароматазы, может применяться при продвинутых или рецидивирующих случаях, хотя польза от такого лечения остаётся не до конца определённой из-за редкости опухоли и её медленного роста. В обзоре рассматриваются гистопатологические особенности, клиническое течение, прогностические факторы и стратегии лечения ГЗО, с акцентом на важность долгосрочного наблюдения из-за риска позднего рецидива.

Keywords: granulosa cell tumor, ovarian neoplasm, sex cord-stromal tumor, Call-Exner bodies, inhibin, estrogen, recurrence, histopathology, juvenile granulosa cell tumor, adult granulosa cell tumor, prognostic factors, surgical management, adjuvant therapy, hormonal therapy, long-term follow-up.

Ключевые слова: гранулёзоклеточная опухоль, новообразование яичника, опухоль полового тяжа и стромы, тельца Калл-Экснера, ингибин, эстроген, рецидив, гистопатология, ювенильная гранулёзоклеточная опухоль, взрослая гранулёзоклеточная опухоль, прогностические факторы, хирургическое лечение, адъювантная терапия, гормональная терапия, долгосрочное наблюдение.

Granulosa cell tumors (GCTs) of the ovary represent a rare subtype of sex cord-stromal tumors, which are unique in their presentation, histopathological features, and clinical behavior. These tumors account for approximately 2-5% of all ovarian neoplasms, yet they are of significant clinical interest due to their hormone-producing nature and potential for late recurrence. GCTs can be subdivided into two main types: adult granulosa cell tumors (AGCTs) and juvenile granulosa cell tumors (JGCTs). AGCTs are more common, typically presenting in middle-aged and postmenopausal women, while JGCTs are rarer and often occur in children and adolescents. The clinical and histological characteristics of these subtypes differ, with AGCTs showing a more indolent course and JGCTs often demonstrating more aggressive behavior.

Hormonal Activity and Early Detection

One of the hallmark features of granulosa cell tumors is their ability to secrete hormones, particularly estrogen. This hormonal activity frequently leads to early detection, as patients often present with symptoms related to hyperestrogenism. In premenopausal women, this may manifest as irregular menstrual cycles, menorrhagia, or amenorrhea, while postmenopausal women typically experience abnormal uterine bleeding. In younger patients, particularly those with JGCTs, precocious puberty may occur due to excessive estrogen production. This early hormonal presentation facilitates earlier diagnosis in many cases, and as a result, the majority of granulosa cell tumors are diagnosed at an early stage [10].

Estrogen production by GCTs is not only relevant for symptomatology but also plays a role in the tumor's biology and potential for recurrence. Estrogen stimulates endometrial proliferation, which can lead to endometrial hyperplasia or even endometrial carcinoma, a known complication in patients with GCTs. Therefore, endometrial sampling is often recommended in patients with granulosa cell tumors to assess for concurrent endometrial pathology [6]. Additionally, the estrogenic effect of the tumor can be used as a marker for recurrence, with rising levels of estradiol serving as an indicator of tumor recurrence during follow-up.

Histopathological Features and Diagnosis

The diagnosis of granulosa cell tumors relies on a combination of clinical, histopathological, and immunohistochemical findings. Histologically, GCTs are characterized by their distinctive "coffee bean" nuclei, which show longitudinal nuclear grooves, and the presence of Call-Exner bodies, which are small, rosette-like structures composed of granulosa cells surrounding a central space. These features help to distinguish GCTs from other ovarian neoplasms, particularly other sex cord-stromal tumors such as thecomas and fibromas, which may share some overlapping features but lack the specific characteristics of GCTs.

Call-Exner bodies, a distinctive histological hallmark, are thought to represent small, immature Graafian follicles, often filled with eosinophilic fluid. Their presence is highly suggestive of GCTs, although they are not always present, particularly in more poorly differentiated or aggressive tumors. The absence of Call-Exner bodies has been associated with a poorer prognosis, as tumors without these structures may be more aggressive and have a higher likelihood of recurrence [9].

In addition to these histological features, immunohistochemistry plays a crucial role in the diagnosis of GCTs. Granulosa cell tumors typically express specific markers, such as inhibin, calretinin, and CD99, which help to confirm the diagnosis. Inhibin, a glycoprotein hormone produced by granulosa cells, is one of the most sensitive and specific markers for GCTs. Positive staining for inhibin is a key diagnostic tool, particularly in cases where the histological features are less clear. Other markers, such as vimentin and smooth muscle actin, may also be useful in distinguishing GCTs from other ovarian tumors [4].

Juvenile Granulosa Cell Tumors (JGCTs)

JGCTs are a rarer subtype of granulosa cell tumors, comprising less than 5% of all GCTs. They typically present in younger patients, with the majority of cases occurring in prepubescent girls or young women under the age of 30. Unlike AGCTs, JGCTs are less likely to produce estrogen-related symptoms, although they may still present with signs of precocious puberty in younger patients.

Histologically, JGCTs differ from AGCTs in several ways. They tend to exhibit greater cellular atypia, higher mitotic activity, and a more solid or trabecular growth pattern. Call-Exner bodies are less commonly seen in JGCTs, and nuclear grooves, while present, may be less prominent. These histological differences reflect the more aggressive potential of JGCTs, which tend to have a higher rate of recurrence and metastasis compared to AGCTs [7]{Citation}.

Prognostic Factors

Several prognostic factors have been identified in granulosa cell tumors, including tumor stage at diagnosis, tumor size, mitotic index, nuclear atypia, and the presence or absence of Call-Exner bodies. Among these, tumor stage is the most significant prognostic factor. The majority of GCTs are diagnosed at an early stage (Stage I), confined to the ovary, which is associated with an excellent prognosis. Patients with Stage I disease have a 5-year survival rate exceeding 90% [5]. However, even in early-stage disease, long-term follow-up is essential due to the risk of late recurrence, which can occur many years after the initial diagnosis.

Advanced-stage disease (Stages II-IV), where the tumor has spread beyond the ovary, is associated with a significantly worse prognosis. In these cases, the 5-year survival rate drops to 60-70%, and the risk of recurrence is much higher. Tumor size is another important prognostic factor, with tumors larger than 5 cm being more likely to recur [3].

The mitotic index, which measures the number of mitoses per high-power field, is another critical prognostic indicator. Tumors with a high mitotic index (>10 mitoses per 10 high-power fields) are associated with a higher risk of recurrence and a poorer overall prognosis. Similarly, the presence of nuclear atypia, which indicates more aggressive tumor behavior, is linked to a higher likelihood of recurrence[8].

Lymphovascular invasion (LVSI), which refers to the presence of tumor cells in the lymphatic or vascular spaces surrounding the tumor, is also a poor prognostic factor. Tumors with LVSI are more likely to metastasize and recur, even in cases where the tumor appears to be confined to the ovary [10].

Late Recurrence

One of the most unique and challenging aspects of granulosa cell tumors is their potential for late recurrence. While most ovarian tumors, including epithelial ovarian cancers, tend to recur within the first few years after diagnosis, GCTs are notorious for their ability to recur many years, or even decades, after the initial treatment. This delayed recurrence is thought to be related to the slow-growing nature of the tumor, as well as its tendency to remain dormant for long periods before reactivating [7; 10].

Studies have shown that the risk of recurrence persists for at least 20 years after the initial diagnosis, with some cases of recurrence reported as late as 40 years after treatment. As a result, patients with GCTs require long-term follow-up, with regular monitoring for signs of recurrence. Tumor markers such as inhibin and estradiol are useful for detecting recurrence, as rising levels of these markers can indicate tumor regrowth before clinical symptoms become apparent [6].

Surgical Management

Surgical treatment remains the cornerstone of management for granulosa cell tumors. The primary goal of surgery is to achieve complete resection of the tumor, as this is associated with the best outcomes in terms of disease control and survival. In early-stage disease (Stage I), fertility-sparing surgery may be an option for younger patients who wish to preserve their reproductive potential. This typically involves unilateral salpingo-oophorectomy (removal of one ovary and fallopian tube) with careful staging to ensure there is no evidence of tumor spread [3].

In more advanced cases, or when fertility preservation is not a concern, total hysterectomy with bilateral salpingo-oophorectomy is the preferred surgical approach. This is often combined with surgical staging, which includes peritoneal washings, omentectomy, and lymph node sampling to assess for disease spread. Complete surgical staging is crucial in determining the extent of the disease and identifying patients who may benefit from adjuvant therapy [10].

For patients with recurrent disease, secondary surgery may be considered, particularly if the recurrence is localized and surgically resectable. While the role of surgery in recurrent GCTs is less well-defined, some studies suggest that complete resection of recurrent disease can lead to prolonged survival, particularly in cases where the recurrence is detected early and is limited in size [9].

Adjuvant Therapy

The role of adjuvant therapy in the management of granulosa cell tumors remains controversial. Due to the rarity of GCTs, there are no large randomized trials to guide treatment decisions, and most recommendations are based on retrospective studies and expert opinion. In early-stage disease, particularly Stage I tumors, surgery alone is often considered sufficient, and adjuvant therapy is not typically recommended. However, in cases with high-risk features, such as large tumor size, high mitotic index, or the presence of nuclear atypia, adjuvant therapy may be considered to reduce the risk of recurrence [6].

In advanced-stage disease, or in cases of recurrent GCTs, chemotherapy is often used as adjuvant therapy. The most commonly used chemotherapy regimen is a combination of bleomycin, etoposide, and cisplatin (BEP), which has been shown to be effective in treating other types of sex cord-stromal tumors. However, the response rates in GCTs are variable, and the overall benefit of chemotherapy in these tumors is still uncertain[3].

Hormonal Therapy

Given the hormone-producing nature of granulosa cell tumors, hormonal therapy has been explored as a treatment option, particularly in cases of recurrent disease. Aromatase inhibitors, which block the production of estrogen, have been used with some success in patients with recurrent GCTs. By reducing estrogen levels, these medications may help to slow the growth of the tumor and reduce the risk of recurrence [9].

Other hormonal therapies, such as gonadotropin-releasing hormone (GnRH) agonists and progestins, have also been used in the treatment of GCTs, although the evidence for their efficacy is limited. In some cases, hormonal therapy may be used in combination with chemotherapy or as a maintenance therapy following surgery to reduce the risk of recurrence [2].

Long-Term Monitoring and Follow-Up

Due to the risk of late recurrence, long-term follow-up is essential for patients with granulosa cell tumors. Regular clinical assessments, imaging studies, and monitoring of tumor markers such as inhibin and estradiol are recommended for many years after the initial treatment. The frequency and duration of follow-up depend on the stage of the disease at diagnosis and the presence of any high-risk features. Typically, patients are followed every 3-6 months for the first few years, and then annually thereafter, although this may vary depending on individual risk factors [5].

In cases of recurrent disease, early detection is key to improving outcomes. Rising levels of inhibin or estradiol may signal recurrence before clinical symptoms become evident, allowing for earlier intervention and potentially more successful treatment. Imaging studies, such as ultrasound, CT, or MRI, are also used to monitor for recurrent disease, particularly in patients with elevated tumor markers [8].

Conclusion

Granulosa cell tumors of the ovary are rare but clinically significant neoplasms that present unique challenges in terms of diagnosis, treatment, and long-term management. Their hormone-producing nature often leads to early detection, but the potential for late recurrence necessitates prolonged follow-up. The diagnosis of GCTs is based on a combination of clinical, histopathological, and immunohistochemical findings, with specific markers such as inhibin playing a key role in confirming the diagnosis.

Surgical treatment remains the cornerstone of management, with the goal of achieving complete resection of the tumor. In early-stage disease, fertility-sparing surgery may be an option for younger patients, while more advanced cases often require more extensive surgical procedures. The role of adjuvant therapy is less clear, but chemotherapy and hormonal therapy may be used in cases with high-risk features or recurrent disease.

Given the potential for late recurrence, long-term follow-up is essential, with regular monitoring of tumor markers and imaging studies. As research continues to improve our understanding of granulosa cell tumors, new treatment strategies may emerge to further improve outcomes for patients with this rare ovarian neoplasm.

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