Ovarian Granulosa Cell Tumour

Ovarian granulosa cell tumours are rare hormone-producing tumours that account for about 5% of all ovarian cancers. Most are diagnosed early and grow slowly, often causing symptoms related to high estrogen levels such as irregular bleeding or early puberty in young girls.

Table of contents

• What is an ovarian granulosa cell tumour?
• Types of granulosa cell tumours
• Causes and genetic factors
• Signs and symptoms
• Possible complications
• How the condition is diagnosed
• Treatment options
• Outlook and prognosis
• Follow-up care

What is an ovarian granulosa cell tumour?

A granulosa cell tumour (GCT) is a type of ovarian tumour that forms within the ovary, which is part of the female reproductive system. These tumours develop from granulosa cells, which are cells that normally help produce eggs and female sex hormones^[1].

Granulosa cell tumours belong to a group called sex cord-stromal tumours, which are tumours that occur in the tissues around the ovaries. GCTs are the most common type within this group, accounting for approximately 70% of all sex cord-stromal tumours and about 5% of all primary ovarian cancers^[2][1].

• Ovary
• Female reproductive system

Most granulosa cell tumours are malignant (cancerous), but they typically grow slowly. Because they often produce hormones that cause noticeable symptoms, healthcare providers usually diagnose them in early stages when treatment outcomes are generally good^[1][5].

Types of granulosa cell tumours

There are two distinct types of granulosa cell tumours based on their characteristics and the age at which they typically occur^[2][3].

Adult granulosa cell tumours

Adult granulosa cell tumours are the most common variety, accounting for about 95% of all GCT diagnoses. These typically occur in women who are in their peri-menopausal or post-menopausal years. The average age at diagnosis is 50 years old, though they can occur at any age^[1][2].

Adult type tumours are characterized by slow growth and an indolent course with a long natural history. Most patients are diagnosed at an early stage, which contributes to a relatively favorable prognosis^[6].

Juvenile granulosa cell tumours

Juvenile granulosa cell tumours constitute only about 5% of cases and occur in prepubertal girls and young women, typically those under 30 years of age^[2][1].

Juvenile GCTs can be more aggressive than adult types if diagnosed after the cancer has already spread outside the ovary. They may also be more likely to recur (come back) within a few years^[1].

Causes and genetic factors

Experts do not entirely understand what causes granulosa cell tumours. However, research has identified specific genetic changes associated with these tumours^[1].

Adult granulosa cell tumours

Using advanced DNA sequencing techniques, researchers have found that 97% of adult granulosa cell tumours contain an identical mutation in the FOXL2 gene. This is a somatic mutation, meaning it occurs in the body’s cells and is not usually transmitted to descendants^[3].

The specific mutation is c.402C>G in the sequence of FOXL2, which leads to an amino acid substitution. The FOXL2 gene typically functions to help granulosa cells develop normally, and this mutation is believed to play a role in causing granulosa cell tumours^[1][3].

Juvenile granulosa cell tumours

Juvenile granulosa cell tumours have a different genetic basis. Research shows that the enzyme AKT1 is involved in these tumours. More than 60% of juvenile granulosa cell tumours occurring in girls under 15 years of age have been found to contain duplications in a specific part of the AKT1 protein. Tumours without these duplications carried point mutations affecting highly conserved parts of the protein^[3].

Signs and symptoms

The symptoms of granulosa cell tumours are often related to the high levels of estrogen these tumours produce. Estrogen is one of the female sex hormones, and excess amounts can cause various effects depending on the patient’s age^[1][5].

In young girls

When granulosa cell tumours occur in girls who have not yet reached puberty, high estrogen levels may cause early onset of puberty^[1][3].

In adult women of reproductive age

Women of reproductive age commonly experience irregular menstrual cycles, absence of periods, or abnormal uterine bleeding^[1][5].

In postmenopausal women

Postmenopausal women typically present with bleeding after menopause, which is often the symptom that prompts them to seek medical attention^[3][5].

Other common symptoms

Regardless of age, women with granulosa cell tumours may experience^[1][5][9]:

• Increased abdomen size or bloating (a swollen belly)
• Abdominal or pelvic pain that does not go away
• A lump in the abdomen or pelvis
• Tender or sore breasts
• Constipation
• Passing urine more often than usual

Abdominal pain is usually only experienced if the tumour ruptures (bursts)^[1].

Possible complications

Without treatment, granulosa cell tumours can increase the risk of other health complications. The prolonged exposure to high estrogen levels produced by these tumours can lead to^[1][6]:

• Endometrial hyperplasia – an unusually thick lining of the uterus
• Uterine cancer (cancer of the womb)
• Breast cancer
• Infertility

Granulosa cell tumours have a high chance of late recurrence, meaning the cancer can come back even many years after successful treatment. Recurrences have been reported even after 30 years^[2][3].

How the condition is diagnosed

Healthcare providers use various tests to diagnose granulosa cell tumours^[1][5].

Imaging tests

Imaging techniques are typically the first diagnostic tools used. These may include^[1][5]:

• Ultrasound – a test that uses sound waves to create pictures of the inside of the body
• Transvaginal ultrasound – an ultrasound probe inserted into the vagina for clearer images of the ovaries
• CT scan (computed tomography) – a specialized X-ray that creates detailed cross-sectional images
• MRI (magnetic resonance imaging) – a test using magnets and radio waves to create detailed images
• Chest X-ray
• PET scan

Blood tests and tumour markers

Blood tests can help diagnose granulosa cell tumours and monitor the disease. Granulosa cell tumours often produce chemicals or hormones called tumour markers that doctors can measure in the blood^[1][5].

Important tumour markers for granulosa cell tumours include:

• Inhibin – a hormone produced by granulosa cell tumours
• CA125
• Anti-müllerian hormone (AMH)

Staging

After diagnosis, doctors use a process called staging to determine how far the cancer has spread. Granulosa cell tumours use the same staging system as other types of ovarian cancer^[1][5]:

• Stage 1 – the cancer is only in the ovary (or both ovaries)
• Stage 2 – the cancer has spread into the fallopian tube, womb, or elsewhere in the pelvis
• Stage 3 – the cancer has spread to the lymph nodes or to the tissues lining the abdomen (called the peritoneum)
• Stage 4 – the cancer has spread to another body organ some distance away, such as the lungs or liver

Stage is the most important factor in determining prognosis and treatment approach^[9].

Treatment options

Surgery

The first and primary treatment for granulosa cell tumour is surgery. The surgeon will remove as much of the tumour as possible while keeping healthy tissue intact^[1][2][10].

The type of surgery depends on several factors including the patient’s age, whether she has completed childbearing, and the stage of the tumour^[9][5]:

• For young women who wish to preserve fertility and have early-stage disease, surgery may involve removing only the affected ovary (unilateral salpingo-oophorectomy) along with appropriate surgical staging
• For postmenopausal women or those who have completed childbearing, doctors may recommend removing both ovaries (oophorectomy) and possibly the uterus (hysterectomy)

Appropriate staging with intact removal of the tumour and optimal reduction of cancerous tissue are the main goals of surgical therapy^[10].

Chemotherapy

Chemotherapy may be recommended after surgery for some patients. This additional treatment is typically considered for^[5][12]:

• Juvenile granulosa cell tumours when the cancer is stage 1C or greater
• Adult granulosa cell tumours when the cancer is stage 1C2 or greater
• Patients with advanced disease by surgical staging
• Patients with recurrent tumours

Studies show that chemotherapy has an objective response rate of about 30% and a disease control rate of 58%^[12].

Anti-hormonal therapy

Anti-hormonal therapy using medications such as GnRH analogues and aromatase inhibitors is another treatment option, particularly for recurrent disease. While the objective response rate is lower at 11%, the disease control rate is 66%^[12].

Radiation therapy

Radiation therapy has limited efficacy but may be considered for advanced-stage patients or those with pelvic recurrence. Studies show that almost half of patients treated with radiation therapy experience a clinical response^[10].

Outlook and prognosis

When healthcare providers diagnose granulosa cell tumours early, the outlook is usually good^[1]. Most patients are diagnosed at an early stage (78-91% at stage Ia), which contributes to the relatively favorable prognosis^[6].

Survival rates vary depending on the stage of disease at diagnosis^[9]:

• For early-stage disease, 10-year survival rates range from 84-95%
• The estimated 5-year overall survival is 84.6%
• The estimated 10-year overall survival is 72.5%
• Event-free survival is 76.5% at 5 years and 52.9% at 10 years

Advanced stage is the most significant poor prognostic indicator for both overall survival and event-free survival^[9].

Follow-up care

Because granulosa cell tumours have a high chance of late recurrence, lifelong follow-up is indicated^[2]. Regular monitoring is essential as recurrences can occur even decades after initial successful treatment.

Surveillance typically consists of^[10]:

• Frequent pelvic examinations
• Assessment of tumour markers (such as inhibin levels, if applicable)
• Imaging studies (such as CT scans) if physical examination or laboratory studies suggest recurrence

The life management of postoperative patients is crucial and requires multidisciplinary experts to design recurrence treatment from the perspective of patients and implement meaningful treatment measures^[6].