Ovarian granulosa cell tumours are rare ovarian cancers that produce hormones and can cause unusual symptoms like irregular bleeding or early puberty in young girls. Most patients are diagnosed early and face a better outlook than those with more common types of ovarian cancer, though these tumours require lifelong monitoring due to their tendency to return years after treatment.

Epidemiology

Ovarian granulosa cell tumours represent a small fraction of all ovarian cancers, accounting for approximately 5% of primary ovarian tumours and about 70% of all sex cord-stromal tumours of the ovary^[1][2]. These tumours are considered rare, with an estimated 100 women diagnosed annually in Australia, around 3,000 cases per year in the United States, and approximately 4,000 cases in Europe^[15]. The rarity of this condition means that many healthcare providers have limited experience treating it, which can make diagnosis and management more challenging for patients.

The disease can occur at any age, but there are distinct patterns based on the type of tumour. The average age of diagnosis is around 50 years old, with most cases appearing in perimenopausal or postmenopausal women^[1][9]. In fact, the peak age at which these tumours occur is between 50 and 55 years, though patients as young as 17 and as old as 71 have been diagnosed^[3][9]. There are two distinct types of granulosa cell tumours: adult type and juvenile type. Adult type granulosa cell tumours are far more common, representing about 95% of all granulosa cell tumour diagnoses^[1][2]. Juvenile granulosa cell tumours, which make up only about 5% of cases, typically occur in girls who have not yet reached puberty or in young women under 30 years of age^[1][2].

One of the remarkable characteristics of ovarian granulosa cell tumours is that most patients are diagnosed at an early stage. Between 78% and 91% of patients are diagnosed when the cancer is still confined to the ovary, classified as stage I disease^[6][9]. This early detection is largely due to the hormone-producing nature of these tumours, which causes noticeable symptoms that prompt patients to seek medical attention sooner than they might with other types of ovarian cancer. The early-stage diagnosis contributes significantly to the generally favourable prognosis for patients with this condition.

Causes

The exact causes of ovarian granulosa cell tumours remain not entirely understood by medical experts. However, researchers have identified important genetic changes that appear to play a central role in the development of these tumours. These tumours arise from proliferating normal preovulatory granulosa cells, which are cells that normally exist in the ovary and produce sex hormones and peptides needed for the reproductive process^[2][6].

The most significant genetic discovery in understanding these tumours came in 2009, when researchers identified that approximately 97% of adult-type granulosa cell tumours contain an identical mutation in the FOXL2 gene^[3][6]. This specific mutation, known as c.402C>G, leads to an amino acid change in the resulting protein. The FOXL2 gene typically functions to help granulosa cells develop normally, so when this mutation occurs, it disrupts the normal cell development process^[1]. This mutation is what scientists call a somatic mutation, meaning it occurs in the body’s cells during a person’s lifetime rather than being inherited from parents, and therefore is not usually passed on to descendants^[3].

For juvenile granulosa cell tumours, the genetic landscape is somewhat different. Recent studies have shown that more than 60% of juvenile granulosa cell tumours occurring in girls under 15 years of age have duplications in a specific part of the AKT1 enzyme^[3]. Tumours without these duplications carried point mutations affecting highly conserved parts of the gene. These genetic changes lead to strong activation of the AKT1 pathway, which appears to drive the development of juvenile-type tumours through a different mechanism than adult-type tumours.

Risk Factors

Unlike many other cancers, ovarian granulosa cell tumours do not have well-established lifestyle or environmental risk factors that increase a person’s likelihood of developing the disease. Because the condition is so rare and appears to be driven primarily by spontaneous genetic mutations that occur within cells, researchers have not identified specific behaviours, exposures, or habits that significantly increase risk. The genetic mutations associated with these tumours, particularly the FOXL2 mutation in adult-type cases, are somatic mutations that occur randomly during a person’s lifetime rather than being inherited or caused by external factors.

Age does appear to be a demographic factor, as adult-type granulosa cell tumours most commonly occur in women who are perimenopausal or postmenopausal, typically between ages 50 and 55. However, this is more of an observation about when these tumours tend to appear rather than a modifiable risk factor. For juvenile-type tumours, young age itself is a defining characteristic, with most cases occurring before puberty or in young women under 30.

There is limited evidence linking granulosa cell tumours to family history or hereditary cancer syndromes. The mutations involved are typically not inherited, which means that having a family member with the condition does not significantly increase one’s risk. This distinguishes granulosa cell tumours from some other types of ovarian cancer, such as high-grade serous ovarian cancer, which can be associated with inherited genetic mutations like BRCA1 and BRCA2.

Symptoms

The symptoms of ovarian granulosa cell tumours are often distinctive because these tumours produce hormones, particularly estrogen, which is one of the female sex hormones. The high estrogen levels caused by these tumours lead to symptoms that differ depending on the patient’s age and reproductive status. These hormone-related symptoms are actually beneficial in a sense, as they tend to alert patients and doctors to a problem earlier than might occur with other types of ovarian tumours that don’t produce noticeable symptoms until they’ve grown quite large.

In adult women, the most common symptom is abnormal bleeding. Women who are still menstruating may experience irregular menstrual cycles, unusually heavy periods, or absence of periods altogether^[1][5]. For postmenopausal women who have not had periods for months or years, vaginal bleeding that occurs after menopause is a significant warning sign that should always be evaluated by a healthcare provider^[1][5]. This postmenopausal bleeding occurs because the excess estrogen produced by the tumour stimulates the lining of the uterus to grow and shed, even though the woman is no longer ovulating.

Many patients also notice physical changes in their abdomen. An increase in abdomen size, often described as a swollen belly or bloating, is common as the tumour grows^[1][5]. Some patients may be able to feel a lump or mass in their abdomen or pelvis. Abdominal pain is another symptom, though it typically occurs only when the tumour becomes very large or if it ruptures, which is when the tumour bursts open^[1][9]. Other related symptoms can include constipation and needing to pass urine more frequently than usual, which happen when the growing tumour presses against nearby organs like the bowel and bladder^[5].

The effects of high estrogen can extend beyond the reproductive system. Some women experience tender or sore breasts due to the hormone stimulation^[1]. In young girls who have not yet reached puberty, a granulosa cell tumour can cause early puberty, meaning the development of breasts, pubic hair, and other adult characteristics at an inappropriately young age because of the excess estrogen produced by the tumour^[1].

Prevention

Given that ovarian granulosa cell tumours appear to develop primarily due to spontaneous genetic mutations that occur randomly within cells, there are no known prevention strategies that can reduce the risk of developing this condition. Unlike some cancers that can be prevented through lifestyle modifications such as avoiding tobacco, maintaining a healthy weight, or limiting alcohol consumption, granulosa cell tumours do not have established lifestyle-related risk factors that can be modified.

There are no screening programmes specifically designed to detect granulosa cell tumours in women without symptoms. Standard ovarian cancer screening methods, such as transvaginal ultrasound or blood tests for CA125 tumour marker, are not routinely recommended for women at average risk because they have not been shown to reduce deaths from ovarian cancer in general. For granulosa cell tumours specifically, there is no evidence that routine screening would be beneficial or cost-effective given the rarity of the condition.

The most important aspect of early detection is awareness of symptoms. Women should be encouraged to see their healthcare provider promptly if they experience warning signs such as postmenopausal bleeding, persistent abdominal bloating or pain, irregular periods, or any of the other symptoms associated with these tumours. Early medical evaluation when symptoms appear allows for earlier diagnosis, which is associated with better treatment outcomes. Parents should also be aware that early puberty in young girls could be a sign of a hormone-producing tumour and should be evaluated by a doctor.

For women who have already been diagnosed and treated for a granulosa cell tumour, prevention of recurrence is an important concern. While there are no guaranteed ways to prevent recurrence, regular follow-up care is essential. This typically involves frequent pelvic examinations and blood tests to monitor tumour markers, which can help detect any return of the disease as early as possible^[10].

Pathophysiology

Understanding how ovarian granulosa cell tumours develop and affect the body requires looking at both the cellular changes that occur and the broader effects these changes have on normal bodily functions. These tumours originate from granulosa cells, which are specialized cells that normally exist in the ovary as part of the structures called follicles. In healthy ovaries, granulosa cells surround and support the developing egg, produce sex hormones including estrogen, and play essential roles in the reproductive cycle^[2].

When a granulosa cell tumour develops, these cells begin to multiply abnormally and excessively. In adult-type tumours, the driving force behind this abnormal growth is most commonly the FOXL2 gene mutation. This mutation disrupts the normal signals that control cell division and death, allowing the cells to continue dividing when they should stop. The mutated cells retain many characteristics of normal granulosa cells, including the ability to produce estrogen, but they lose the normal controls that would limit their growth and lifespan.

The tumour cells arrange themselves in characteristic patterns that pathologists can recognize under the microscope. Adult-type granulosa cell tumours often show cells arranged in structures called Call-Exner bodies, which are small circular formations that help distinguish these tumours from other types of ovarian cancer. Juvenile-type tumours have a different appearance under the microscope, with cells arranged in different patterns and often containing structures called hyaline globules.

The hormone production by these tumours has widespread effects throughout the body. The excess estrogen produced by granulosa cell tumours acts on tissues throughout the body that have estrogen receptors. In the uterus, the high estrogen levels cause the endometrium (the lining of the uterus) to become abnormally thick, a condition called endometrial hyperplasia^[1]. This thickened lining is unstable and tends to shed irregularly, causing the abnormal bleeding that is the most common symptom. If left untreated for a long time, the prolonged exposure to high estrogen levels can increase the risk of developing cancer of the uterine lining^[1].

In terms of cancer behaviour, granulosa cell tumours are usually classified as malignant, meaning they are cancerous. However, they behave quite differently from the more common epithelial ovarian cancers. Granulosa cell tumours typically grow slowly, which is one reason why many patients are diagnosed at early stages when the disease is still confined to the ovary. When these tumours do spread beyond the ovary, they tend to spread to the omentum (a fatty tissue layer in the abdomen) and the peritoneum (the lining of the abdominal cavity), with occasional spread to lymph nodes^[2].

At the molecular level, researchers have identified several signalling pathways that appear to be disrupted in these tumours. Beyond the FOXL2 mutation, studies have found mutations in the TERT promoter region in about 41% of cases, which is more common in recurrent tumours^[7]. Mutations in genes called KMT2D and TP53 have also been identified in some cases. These additional genetic changes may help explain why some tumours behave more aggressively than others and why some recur while others do not. The tumour mutational burden, which is a measure of how many mutations are present in the cancer cells, is typically low in granulosa cell tumours compared to other types of cancer^[7].