KEY IMMUNOHISTOCHEMICAL MARKERS AND THERAPEUTIC TARGETS IN GRANULOSA CELL TUMORS: DIAGNOSTIC AND PROGNOSTIC IMPLICATIONS

ABSTRACT

Ovarian granulosa cell tumors (GCTs) are rare neoplasms characterized by unique biological behavior and clinical presentation. Immunohistochemical markers have become indispensable in diagnosing and managing these tumors. This review synthesizes recent findings on key immunohistochemical markers such as inhibin, FOXL2, Ki-67, and estrogen receptor-α (ERα), as well as markers related to the tumor microenvironment, immune evasion, and metabolic pathways. The role of these markers in predicting recurrence, prognosis, and potential therapeutic targets is discussed, highlighting the importance of a multimodal approach in GCT management. The review also underscores the need for further validation of these markers in larger cohorts to refine their clinical utility.

АННОТАЦИЯ

Опухоли гранулезных клеток яичника (GCT) — это редкие новообразования, характеризующиеся уникальным биологическим поведением и клиническими проявлениями. Иммуногистохимические маркеры стали незаменимыми в диагностике и лечении этих опухолей. В данном обзоре обобщены последние данные о ключевых иммуногистохимических маркерах, таких как ингибин, FOXL2, Ki-67 и эстрогеновый рецептор-α (ERα), а также маркерах, связанных с опухолевым микроокружением, иммунным уклонением и метаболическими путями. Рассматривается роль этих маркеров в прогнозировании рецидивов, прогнозе заболевания и потенциальных терапевтических мишенях, подчеркивая важность многопрофильного подхода к управлению GCT. В обзоре также подчеркивается необходимость дальнейшей валидации этих маркеров на более крупных выборках для уточнения их клинической значимости.

Keywords: granulosa cell tumors, immunohistochemical markers, FOXL2, inhibin, Ki-67, estrogen receptor-α, tumor microenvironment, immune evasion, metabolic pathways.

Ключевые слова: опухоли гранулезных клеток, иммуногистохимические маркеры, FOXL2, ингибин, Ki-67, эстрогеновый рецептор-α, опухолевое микроокружение, иммунное уклонение, метаболические пути.

Introduction

Granulosa cell tumors (GCTs) of the ovary are rare neoplasms, accounting for approximately 2-5% of all ovarian malignancies. Despite their rarity, GCTs present unique challenges in diagnosis and management due to their distinct histological, molecular, and clinical features. Adult granulosa cell tumors (AGCTs) represent the majority of GCT cases, while juvenile granulosa cell tumors (JGCTs) are far less common. The diagnosis of GCTs is heavily reliant on immunohistochemistry, which helps distinguish GCTs from other ovarian neoplasms and provides insights into tumor behavior, potential therapeutic targets, and prognostic indicators. This review synthesizes the latest research on immunohistochemical markers in GCTs, focusing on their diagnostic, prognostic, and therapeutic implications.

Key Immunohistochemical Markers and Therapeutic Targets in Granulosa Cell Tumors: Diagnostic and Prognostic Implications

Inhibin is one of the most well-established immunohistochemical markers for GCTs, particularly in adult cases. A study by Yaacoub et al. reported that inhibin was present in 77.2% of AGCT cases, making it a crucial marker for diagnosis. Inhibin expression helps distinguish GCTs from other ovarian neoplasms, which is particularly useful in cases where the histopathological features are ambiguous [10]. Additionally, high tumor size and mitotic index, which are associated with poor prognosis, were prevalent in 36.9% and 20% of cases, respectively.

FOXL2 c.C402G (p.Cys134Trp) mutation is nearly ubiquitous in AGCTs, with recent studies confirming its presence in almost all cases [1, 5]. This mutation is a pivotal driver of GCT pathogenesis, as it is involved in the transcriptional activation of oncogenes via the TGF-β signaling pathway. Its presence not only aids in the diagnosis of AGCTs but also serves as a potential therapeutic target. Inhibition of the TGF-β pathway using agents like TP-6379 has shown promise in preclinical models, particularly in FOXL2-mutated GCTs [1].

The Ki-67 index is a marker of cellular proliferation and is frequently used to predict recurrence in AGCTs. According to Liu et al., a Ki-67 index greater than 15% is an independent risk factor for recurrence, making it a valuable prognostic marker. Its co-localization with other markers like PPARγ further highlights its role in tumor growth and progression [6, 7].

Estrogen receptor-α (ERα) expression serves as another independent predictor of recurrence in AGCTs. Liu et al. reported that an ERα score greater than 0.25 was associated with a higher risk of recurrence in stage I AGCTs [7]. The combination of ERα and Ki-67 indices provides a robust predictive model for assessing the likelihood of relapse, particularly in early-stage disease.

Tumor-associated macrophages (TAMs) are a significant component of the tumor microenvironment and play a crucial role in tumor progression, including invasion, migration, and angiogenesis. The pro-tumoral functions of TAMs are well established, with these cells contributing to various stages of tumor development [12]. TAMs are highly plastic cells, often characterized by the expression of markers like CD163 and CD68 on their plasma membranes [4]. In GCTs, TAMs have been shown to promote tumor survival by suppressing T-cell proliferation and inducing regulatory T cells through the production of immunosuppressive cytokines such as IL-10, TGFβ, and prostaglandins [4].

Recent studies have highlighted the critical role of TAMs in recurrent GCTs. Hilliard & Juncker-Jensen demonstrated a 113% increase in TAM density in recurrent tumors compared to primary tumors [3]. This increase in TAMs, specifically M2-type macrophages, is closely associated with angiogenic vessels, suggesting that TAMs contribute to tumor progression and recurrence. The recruitment of TAMs is generally driven by tumor-derived attractants like monocyte chemotactic protein-1 (MCP-1) [9].

Interestingly, TAMs can be reprogrammed from a tumor-promoting to a tumor-suppressing phenotype, which opens up new therapeutic strategies aimed at modifying the tumor microenvironment. Targeting TAMs to promote their cytotoxicity in tumors is a promising approach, and ongoing research is exploring the potential for TAM repolarization as a therapeutic intervention [4].

IDO1 and SPP1 (osteopontin) are significantly upregulated in recurrent GCTs, with IDO1 showing a 14-fold increase [3]. IDO1 plays a key role in immune tolerance, while SPP1 is involved in TAM recruitment and angiogenesis. These markers highlight potential therapeutic targets for recurrent GCTs, emphasizing the need for further investigation into immune-modulating therapies.

CD24 and CD47 are immune evasion markers that are upregulated in GCTs, contributing to tumorigenesis. Cheng et al. demonstrated that inhibition of CD47 with the inhibitor RRX-001 effectively suppressed GCT growth in vivo, indicating its potential as a therapeutic target [2]. These findings shed light on the role of immune evasion in GCT pathogenesis and open up new avenues for treatment.

Preoperative serum follicle-stimulating hormone (FSH) levels are significantly lower in GCTs compared to other ovarian tumors, making it a highly sensitive and specific marker for differential diagnosis. Matsuoka et al. reported that a cutoff level of 2.0 IU/L had a sensitivity of 100% and a specificity of 98% for distinguishing GCTs from other ovarian neoplasms [8]. While not an immunohistochemical marker, serum FSH levels are an invaluable tool for preoperative diagnosis.

PPARγ is overexpressed in GCTs and is associated with lipid metabolism. Yu et al. highlighted the role of PPARγ in driving tumor proliferation, particularly when co-localized with Ki-67 [11]. Inhibition of PPARγ signaling has been shown to reduce GCT proliferation, suggesting its potential as a therapeutic target. The involvement of PPARγ in lipid metabolism pathways further underscores the metabolic abnormalities present in GCTs.

The identification of key immunohistochemical markers in GCTs not only aids in diagnosis but also offers insights into potential therapeutic targets. For example, FOXL2-mutant AGCTs have shown sensitivity to TGF-β inhibition, opening up new therapeutic options for these tumors [1]. Similarly, targeting immune evasion mechanisms, such as CD24/CD47 and IDO1, could offer novel strategies for treating recurrent GCTs. The tumor microenvironment, particularly the role of TAMs and angiogenesis, also presents potential avenues for therapeutic intervention.

Discussion

The role of immunohistochemical markers in the diagnosis, prognosis, and management of ovarian granulosa cell tumors is undeniable. Markers such as inhibin, FOXL2, Ki-67, and ERα provide critical diagnostic and prognostic information, while markers related to the tumor microenvironment and immune evasion highlight potential therapeutic targets. Understanding the molecular and cellular mechanisms driving GCT progression and recurrence is essential for developing targeted therapies that can improve patient outcomes.

However, the clinical utility of these markers must be validated in larger cohorts to ensure their accuracy and reliability. The rarity of GCTs presents a significant challenge in conducting large-scale studies, but the growing body of research offers hope for more personalized and effective treatments. Additionally, the role of the tumor microenvironment in recurrence emphasizes the need for a holistic approach to GCT management, incorporating both tumor-intrinsic and extrinsic factors.

Conclusion

Immunohistochemical markers play a crucial role in the diagnosis and management of ovarian granulosa cell tumors. Markers such as inhibin, FOXL2, Ki-67, and ERα provide valuable insights into tumor behavior and recurrence risk, while emerging markers like IDO1, SPP1, and CD47 offer potential therapeutic targets. The tumor microenvironment, particularly the role of TAMs and immune evasion, is increasingly recognized as a key factor in GCT progression and recurrence. Future research should focus on validating these markers in larger cohorts and exploring the therapeutic potential of targeting the tumor microenvironment and immune evasion mechanisms.

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