Granulosa Cell Tumor: Symptoms, Types, Causes and Treatment

Granulosa cell tumors (GCTs) are rare ovarian neoplasms that stand apart from other ovarian cancers due to their unique biology, hormonal activity, and often indolent course. Understanding their symptoms, subtypes, causes, and treatment is crucial for timely diagnosis and optimal management. This article provides a comprehensive, evidence-based guide to granulosa cell tumors, drawing from the latest research and clinical experience.

Symptoms of Granulosa Cell Tumor

Granulosa cell tumors can present in a surprisingly broad range of ways, often mimicking more common gynecological problems. Their symptoms are primarily related to the tumor's ovarian location and the hormones these tumors can produce, especially estrogen. Recognizing these signs is essential for early detection and improved outcomes.

Symptom	Age Group	Clinical Feature	Source
Abnormal Bleeding	Adult Women	Irregular or postmenopausal bleeding	1 2 3 4
Abdominal Distension/Pain	All Ages	Abdominal swelling, mass, or pain	1 2 4 5
Precocious Puberty	Children	Early breast development, menstruation	2 5
Endometrial Hyperplasia/Cancer	Peri/Postmenopausal	Thickened endometrium, endometrial cancer	1 3
Ovarian Torsion	Children	Acute abdomen, sudden pain	5

Table 1: Key Symptoms

Abnormal Uterine Bleeding

Abnormal genital bleeding is the most common symptom in adult women with GCTs. This can include:

• Menstrual irregularities (especially in premenopausal women)
• Postmenopausal bleeding, which is a red flag for underlying pathology
• In older women, prolonged exposure to estrogen produced by the tumor can result in endometrial hyperplasia or even endometrial cancer, making uterine bleeding a particularly concerning symptom in this group 1 2 3 4.

Abdominal Symptoms

Many patients, regardless of age, notice abdominal:

• Distension (bloating or swelling)
• Pain or discomfort, which may be gradual or acute
• Palpable mass on physical or pelvic examination

In some cases, especially in children, acute abdominal pain may indicate ovarian torsion caused by the tumor's weight or size 1 2 4 5.

Hormonal Effects in Children: Precocious Puberty

In prepubertal girls, granulosa cell tumors can cause isosexual precocious puberty due to excessive estrogen production. This might manifest as:

• Early breast development
• Pubic hair
• Vaginal bleeding

This constellation of symptoms in a young girl should prompt urgent evaluation for an ovarian tumor 2 5.

Rare Presentations

• Ovarian Torsion: Sudden, severe abdominal pain due to twisting of the ovary, sometimes with nausea or vomiting 5.
• Endometrial Pathology: In older women, the estrogenic effect can lead to thickening of the endometrium (lining of the uterus) and, less commonly, endometrial carcinoma 1 3.

Other Associations

There is a higher-than-expected incidence of breast cancer and endometrial cancer in patients with granulosa cell tumors, possibly related to chronic estrogen exposure 1 17.

Types of Granulosa Cell Tumor

Granulosa cell tumors are not a uniform group; they are classified into distinct biological types, with differences in presentation, molecular features, and prognosis. Understanding these differences is crucial for diagnosis and management.

Type	Typical Age Group	Key Molecular Marker	Source
Adult	Middle-aged/Older	FOXL2 C134W mutation	6 7 10 11 12
Juvenile	Children/Young Adults	FOXL2 wild-type	7 11 12
Testicular (rare)	Males (children/adults)	WNT/PI3K pathway dysregulation	14

Table 2: Granulosa Cell Tumor Types

Adult Granulosa Cell Tumor (AGCT)

• Epidemiology: The most common subtype, typically seen in women aged 40–69 1 6.
• Molecular hallmark: Over 95% of AGCTs carry the unique FOXL2 C134W (402C→G) mutation 6 7 10 11 12.
• Behavior: Indolent but with a significant risk of late recurrence, even decades after initial treatment 2 6 9.
• Hormonal activity: Often produce estrogen, causing symptoms like abnormal bleeding and endometrial pathology 3.

Juvenile Granulosa Cell Tumor (JGCT)

• Epidemiology: Occurs mainly in children and young women, often presenting before puberty 5 7 11 12.
• Molecular Features: Lacks the FOXL2 C134W mutation; other genetic changes are less clearly defined 7 11 12.
• Hormonal activity: Typically also estrogenic, causing precocious puberty in girls 2 5.
• Behavior: Generally more aggressive than adult type but can have a good prognosis if detected early 5.

Granulosa Cell Tumor of the Testis (Very Rare)

• Occurs in males, usually children, and is linked to dysregulation of WNT/CTNNB1 and PI3K/AKT pathways 14.
• Presents as testicular masses; may have hormonal effects 14.

Histological and Molecular Differences

• Histology: Adult types often show Call-Exner bodies, nuclear grooves, and a variety of architectural patterns 4.
• Molecular Testing: FOXL2 mutation analysis is key for distinguishing AGCT from other ovarian tumors 10 11 12.

Causes of Granulosa Cell Tumor

The development of granulosa cell tumors is a complex interplay of genetic, molecular, and possibly environmental factors. Recent research has revealed some critical molecular drivers, especially in the adult subtype.

Cause/Factor	Description	Molecular/Genetic Detail	Source
FOXL2 Mutation	Pathognomonic for adult type	c.402C→G (C134W)	6 7 10 11 12
KMT2D/MLL2 Mutation	Associated with recurrence	Truncating/inactivating	8
TERT Promoter Mutation	Linked to recurrences	More common in recurrent cases	9
Hormonal Stimulation	Chronic estrogen production	FSH/inhibin/estrogen axis	2 3 7
Oxidative Stress	Induces granulosa cell apoptosis	ROS-JNK-p53 pathway	13
WNT/PI3K/AKT Pathways	Testicular GCT, rare in ovary	Pathway dysregulation	14

Table 3: Key Causes and Molecular Features

FOXL2 Mutation – The Molecular Signature

• FOXL2 c.402C→G (C134W) Mutation: Nearly all adult-type GCTs harbor this point mutation, which is not found in juvenile GCTs or other ovarian tumors 6 7 10 11 12.
• Function: FOXL2 is a transcription factor crucial for granulosa cell development. The mutation is thought to promote tumor cell survival and proliferation 10.
• Diagnostic Role: Testing for the FOXL2 mutation is now considered essential for confirming AGCT diagnosis, especially when histology is ambiguous 10 11 12.

Other Genetic Drivers

• KMT2D/MLL2 Inactivation: More frequent in recurrent AGCTs. Loss of KMT2D function appears to drive disease recurrence and may indicate a higher-risk group 8.
• TERT Promoter Mutations: Significantly enriched in recurrent tumors, suggesting a role in tumor progression and late relapse 9.
• Cell Cycle Genes: TP53, MED12, and TET2 mutations, as well as CDKN2A/B deletions, have been identified in recurrent disease, highlighting genetic complexity 9.

Hormonal and Molecular Pathways

• Hormonal Axis: GCTs arise from sex-cord stromal (granulosa) cells, which are responsive to FSH and produce estrogen and inhibin. The hormonal environment may foster tumor growth 2 3 7.
• Oxidative Stress: Experimental models suggest that increased reactive oxygen species (ROS) and related pathways (e.g., JNK, p53) can trigger granulosa cell apoptosis, potentially playing a role in tumor biology 13.
• WNT/PI3K/AKT Dysregulation: Especially relevant in rare testicular GCTs and possibly some ovarian cases, these pathways govern cell proliferation and survival 14.

Environmental and Other Risk Factors

No strong environmental or lifestyle risk factors have been firmly linked to GCTs. A higher prevalence in women of European/American origin compared to Asian/African populations has been reported but is not fully understood 1.

Treatment of Granulosa Cell Tumor

Treatment of granulosa cell tumors is guided by the tumor type, stage, patient age, and desire for fertility. Due to the rarity of these tumors, management is often based on case series and expert consensus, but some principles are clear.

Treatment Option	Indication	Effectiveness/Outcome	Source
Surgery	First-line, all stages	Mainstay, curative in early stage	2 4 6 10 16 18
Fertility-sparing surgery	Young, early-stage patients	Unilateral salpingo-oophorectomy	2 10
Complete staging	All patients	Key for prognosis, survival	16
Chemotherapy (BEP regimens)	Advanced/recurrent	Variable, mainly palliative	2 17 18
Radiotherapy	Persistent/recurrent disease	Occasional long-term remission	2 19
Hormone Therapy	Recurrent/advanced cases	Partial/complete response in some	15
Surveillance	All patients, lifelong	Essential due to late recurrences	2 6

Table 4: Main Treatment Approaches

Surgery: The Cornerstone

• Initial Management: Surgical removal of the tumor is the primary treatment for all patients. For young women with early-stage disease, fertility-sparing surgery (removal of the affected ovary and tube) is often possible 2 4 10 16.
• Complete Surgical Staging: Includes removal of the tumor, evaluation of the abdomen, and sampling of nearby tissues. Incomplete staging is associated with worse outcomes 16.
• Postmenopausal or Advanced Disease: Total abdominal hysterectomy with bilateral salpingo-oophorectomy is recommended 2 10.

Adjuvant Therapy

• Chemotherapy: Reserved for advanced, metastatic, or recurrent disease. The BEP regimen (bleomycin, etoposide, cisplatin) is most commonly used, but its effect on long-term survival is uncertain 2 17 18.
• Radiotherapy: Can induce remission in some patients with persistent or recurrent disease, though not a standard first-line option 19.
• Hormone Therapy: Aromatase inhibitors have shown some efficacy in recurrent or advanced cases; other agents like tamoxifen are less effective 15.

Surveillance and Recurrence

• Lifelong Follow-Up: Recurrences can occur many years after initial treatment, making long-term surveillance essential 2 6.
• Tumor Markers: Anti-Müllerian Hormone (AMH) and inhibin B are useful for monitoring recurrence 10.

Prognostic Factors

• Stage at Diagnosis: The single most important determinant of long-term outcome 1 6 10 16.
• Tumor Size, Surgical Completeness, and Residual Disease: Larger tumors, incomplete resection, and residual disease are linked to higher relapse and mortality rates 16 17.
• Molecular Markers: Emerging data suggests that patients with KMT2D or TERT mutations may be at higher risk for recurrence 8 9.

Conclusion

Granulosa cell tumors of the ovary are rare, hormonally active neoplasms with unique clinical and molecular features. Awareness of their symptoms, distinct types, genetic underpinnings, and evidence-based treatment strategies is vital for clinicians and patients alike. Key points include:

• Symptoms often involve abnormal bleeding, abdominal mass or pain, and hormonal effects such as precocious puberty in children.
• Types include adult and juvenile forms, with the adult type characterized by a FOXL2 C134W mutation.
• Causes are rooted in specific genetic mutations (notably FOXL2), with additional molecular changes influencing recurrence risk.
• Treatment is centered on complete surgical removal, with adjuvant therapies reserved for advanced or recurrent cases. Lifelong surveillance is critical due to the risk of late recurrence.

Key summary:

• Most GCTs are diagnosed early and have a favorable prognosis with proper surgery.
• Molecular testing (particularly for FOXL2) is now standard for accurate diagnosis.
• Late recurrences highlight the need for prolonged follow-up.
• Individualized treatment, considering age, fertility, and molecular profile, offers the best outcomes.

By staying informed about the evolving science of granulosa cell tumors, both clinicians and patients can make empowered, evidence-based decisions.