What is Granulosa Theca Cell Tumors of the Ovary?
Granulosa theca cell cancers are a type of ovarian tumor that are made up of a mix of different cells, namely granulosa cells, theca cells, and fibroblasts. Granulosa cells, found in certain parts of the ovary involved in producing sex hormones, play a major role in the development of egg cells and ovulation. These cells can also cause a type of ovarian tumors known as granulosa cell tumors (GCT), which make up around 5% of all ovarian tumors and 70% of a specific category of ovarian tumors known as sex cord-stromal tumors.
There are two main types of GCT, known as adult and juvenile, which are distinguished by different characteristics and features. The adult type is the most common kind, and generally affects women who are about to or have already gone through menopause. On the other hand, the juvenile type makes up only 5% of cases and typically occurs in young girls who haven’t gone through puberty yet, or in young women.
Theca cells are found in another part of the ovary and play a critical role in fertility by producing a certain substance that is needed for the creation of the hormone estrogen in the ovaries. Tumors that are composed of theca cells, known as thecomas, make up less than 7% of sex cord-stromal tumors and are usually not harmful and have a very good chance of recovery. However, malignant or cancerous thecomas are rare and often also contain granulosa cells. This article primarily focuses on GCTs.
One way that GCTs stand out from other ovarian cancers is that they are often found in the early stages, can occur in young women, and normally show symptoms such as a bloated stomach, pain, or infrequently with signs related to abnormalities in hormone levels. If they spread beyond the ovary, they usually spread to the omentum and peritoneum (parts of the abdomen), and occasionally can spread through the blood to the lungs, liver, or brain. It’s a rare occurrence for them to spread to the lymph nodes. These tumors are typically treated with surgery alone and usually have a good chance of recovery. One thing to be aware of, however, is that GCTs tend to progress in a slow, continuous manner and are prone to come back late, which can happen in up to 25% of cases even after having successful surgery.
What Causes Granulosa Theca Cell Tumors of the Ovary?
Granulosa theca cell tumors, a type of tumor that forms in the ovary, have been found to have changes in chromosomes 12 and 22 and deletions in chromosome 6. Specifically, an extra copy of chromosome 12 (trisomy) and a missing copy of chromosome 22 (monosomy) are common. In young people with these tumors, changes in chromosomes 12 and 6 are often seen. However, in adults, over 95% of these tumors have a mutation, or change, in a gene called FOXL2. Recent research has found that this change in the FOXL2 gene is the main cause of the adult form of the disease.
The BRCA1 and BRCA2 genes, which can increase the risk of breast and ovarian cancers when they have certain mutations, do not seem to increase the risk of granulosa theca cell tumors. However, some studies have found a link between a family history of breast or ovarian cancer and an increased risk of these tumors. Other factors that have been linked with these tumors include being of a non-white race and being overweight. On the other hand, women who have had children (parity) or who have used oral contraceptives may have a decreased risk.
There are some health conditions that have been linked to an increased risk of granulosa theca cell tumors. These include Peutz-Jeghers syndrome and Potter syndrome, which are both rare genetic disorders. In children, these tumors have been associated with Ollier disease (a condition that causes benign bone growths) and Maffucci syndrome (a rare disorder that causes benign growths in cartilage). Similarly, certain medications, such as hormone drugs designed to act like estrogen, fertility hormones, and clomiphene citrate (a drug used to treat female infertility), have also been linked to these tumors. That being said, there is still some disagreement among researchers as to whether infertility itself or the medications used to treat it increase the risk.
Risk Factors and Frequency for Granulosa Theca Cell Tumors of the Ovary
Sex cord-stromal tumors are a type of cancer that is present in about 0.2 in every 100,000 women according to the SEER (Surveillance, Epidemiology, and End Results) database. Every year, the United States reports between 1,500 to 2,000 new cases of these tumors. The rate of another type of ovarian cancer, granulosa theca cell cancer, is between 0.58 to 1.6 in 100,000 women across the world every year. The average age of women diagnosed with granulosa theca cell cancer is 50, which is 10 years younger than the average age of women diagnosed with epithelial ovarian cancer.
Around 57% of the diagnosed women are in the age group of 30 to 60 years old, while only 12% are below 30 years. There is also data showing that black women have a higher incidence of getting this type of cancer compared to white women.
- Sex cord-stromal tumors affect 0.2 in every 100,000 women.
- 1,500 to 2,000 new cases are reported in the United States each year.
- A type of ovarian cancer, granulosa theca cell cancer affects 0.58 to 1.6 in every 100,000 women annually worldwide.
- The average age at diagnosis for granulosa theca cell cancer is 50 years, younger than the average age for epithelial ovarian cancer diagnosis.
- About 57% of diagnosed women are between 30 to 60 years old; only 12% are younger than 30.
- This type of cancer is more common in black women than white women.
Furthermore, juvenile GCT, another type of cancer, has an average diagnosis age of 20 years with a range from 8 to 45 years. More than 50% of the patients are diagnosed before the age of 20, and 45.5% of patients before they start menstruating. It is interesting to note that the rate of juvenile GCT is relatively similar across countries, including Japan, Sweden, and the West Indies.
Signs and Symptoms of Granulosa Theca Cell Tumors of the Ovary
Granulosa theca cell tumors can occur in anyone, from children to elderly individuals, but they are most commonly found in women aged 45 to 55 who have gone through menopause. Symptoms might be vague and include abdominal discomfort, a bloated belly, and a noticeable lump usually on one side of the lower belly area.
Interestingly, around 70% of these tumors produce hormones. This can lead to a condition known as hyperestrogenism, seen as various symptoms based on a person’s age and menstrual status. Older women may experience bleeding even after menopause. On the other hand, younger women who still have their periods may face heavy or irregular bleeding, absence of menstruation, and might witness enlargement or tenderness in breasts. Certain rare instances of these tumors in young women aged 15 to 35 can lead to an increase in masculine features like excess body hair, an enlarged clitoris, deepening of voice, and/or stopping of menstrual periods due to secretion of male hormones. These tumors could also lead to infertility by producing high levels of a hormone called inhibin that inhibits the secretion of the follicle-stimulating hormone, which plays a crucial part in fertility. Although very rare, these tumors might show up during pregnancy too.
Complications can occur, such as rupture of the tumor, which happens in about 10% of cases, twisting of the tumor, or internal bleeding within the tumor. These can contribute to a severe abdominal condition accompanied by low blood pressure. Some people with thecoma, a type of these tumors, might experience Meigs-like syndrome, characterized by build-up of fluid in the abdomen and chest cavity.
Testing for Granulosa Theca Cell Tumors of the Ovary
When a doctor is trying to diagnose a Granulosa Cell Tumor (GCT), they have to keep in mind that this condition can often cause an adnexal mass (a growth in the area near your uterus) and hormonal imbalances, specifically an excess of estrogen or androgen. To help get an accurate diagnosis, a medical professional will often perform lab tests to check your hormone levels (like testosterone if there’s too much androgen, or estradiol if there’s too much estrogen) and look for specific proteins related to the tumor, such as inhibin A and B. Out of the two, inhibin B is the one that gives a more accurate result. Pairing this with a test for antimullerian hormone levels can be particularly helpful in detecting if the disease has come back after treatment.
To check whether the potential tumor has spread, doctors utilize techniques like a pelvic ultrasound or a contrast-enhanced CT scan, which is a type of X-ray that helps see more details in your body. Depending on the results of these images, healthcare practitioners often see different kinds of tumors: solid masses with signs of bleeding or scarring, a form of cyst with multiple chambers, or a purely cystic tumor. What makes GCTs different from epithelial ovarian tumors, another type of ovarian cancer, is that GCTs are often found just in the ovary when diagnosed and lack certain structures called papillary projections within the cyst. Plus, the chances of this type of cancer spreading to the perineum, the area between the anus and genitals, are low, and GCTs rarely occur in both ovaries.
Additionally, due to the increased estrogen levels caused by the tumor, it’s common to see an enlarged uterus and a thickened endometrium, which is the lining of the uterus. A doctor may take a sample of this tissue to test for endometrial hyperplasia, a condition where the endometrium becomes too thick, which occurs in between 25% to 50% of GCT patients. Furthermore, an additional 5% to 10% of these patients could also have endometrial carcinoma, a type of cancer in the endometrium. For those who have thecoma, a subtype of GCT, 20% to 25% of people could have carcinoma, and another 15% could have a precursor lesion, which is the initial stage of disease development.
Fluid buildup or ascites in the abdomen is rarely seen with GCTs. However, in all patients with a suspected adnexal mass, surgery may be performed to remove the mass and to get a clear diagnosis if the ultrasound suggests that it may be cancerous, there is a risk related to the mass (like if it twists), or if the mass is causing symptoms.
Treatment Options for Granulosa Theca Cell Tumors of the Ovary
Treatment for a certain condition often depends on the patient’s age and the progression of the disease. For many, surgery by itself can be an ample initial treatment. However, more advanced stages of the disease or cases where the disease has come back might necessitate further treatments. These could include chemotherapy, which uses drugs to kill cancer cells; radiotherapy, which uses high-energy particles or waves to destroy or damage cancer cells; and biologic therapy, which helps your immune system fight cancer. Such additional treatments could potentially enhance survival rates or extend the period of time patients remain disease-free before a potential recurrence, if any.
Once the treatment is over, patients should continue to regularly meet with their medical team to check for any instances of the disease coming back. During these visits, patients may need to provide an updated medical history, undergo a pelvic examination, and possibly undertake tests for tumor markers, which are substances produced by cancer cells. If any findings raise doubts during these checkups, further exams, such as a CT scan, which creates cross-sectional images of the body, may be performed. These measures are important to ensure the disease has not made a comeback.
What else can Granulosa Theca Cell Tumors of the Ovary be?
If a person shows up with an unexpected growth in the adnexal region (near the uterus), it’s crucial to rule out a variety of causes. The growth could be due to pelvic growths from the stomach or urinary organs, growths in the retroperitoneum (the area at the back of the abdomen), or cysts.
If a person has an adnexal growth and unusual uterine bleeding, other conditions could be the cause. These include harmless conditions such as uterine fibroids and polyps, as well as more serious causes like uterine cancer with ovary spread, or ovarian cancer that has spread to the endometrium, or they might have both endometrial and ovarian cancer at the same time.
Polycystic ovary syndrome and adrenal tumors should also be ruled out when a person presents with a pelvic mass and hormone irregularities.
Surgical Treatment of Granulosa Theca Cell Tumors of the Ovary
In the early stages of certain diseases, surgery can often be a solution. One example of this is in the treatment of ovarian tumors. A surgical procedure called unilateral salpingo-oophorectomy – which means removal of one ovary and fallopian tube – is often enough for children and women who have not gone through menopause. This approach works because only 2% of these cases have tumors on both ovaries.
If during surgery it appears that the patient may have a type of tumor known as a granulosa cell tumor (GCT), additional steps are taken. These might include examining the other ovary and taking a small tissue sample if it looks enlarged. The surgeons may also collect fluid from the abdominal cavity (peritoneal washing), remove a part of the fatty tissue connecting the stomach to the other organs, called the omentum (infracolic omentectomy), and carefully examine the lining of the abdomen and the lymph nodes located behind the abdomen (retroperitoneal nodes). If they see any area that looks suspicious, they take a sample for further examination (biopsy).
If the disease has spread in the abdomen, the surgeons try their best to remove all visible tumors (full cytoreduction), as these kinds of slow-growing tumors do not respond well to chemotherapy.
For women in their childbearing years who still wish to have children, doctors may leave the uterus (womb) but will perform a procedure known as dilatation and curettage to check for the possibility of co-existing endometrial adenocarcinoma, a type of cancer of the uterus. However, the removal of lymph nodes in the pelvic or abdominal regions is not usually required, especially in early-stage diseases. Even if they appear enlarged or suspicious, they are only removed to evaluate the extent of the disease.
Studies have shown that a surgery preserving fertility, including removal of one ovary and fallopian tube, removal of the omentum, and stripping off the lining of the pelvic cavity, is safe and does not affect future pregnancies in women with certain stages of the disease. Moreover, becoming pregnant does not seem to negatively affect the progression of the disease.
What to expect with Granulosa Theca Cell Tumors of the Ovary
The stage of a disease is the most important factor in predicting the outcome of that disease. This is especially true when a tumor rapture occurs, signaling a worse outcome. Large size of the tumor (greater than 15 cm) and bilaterality (the tumor being present on both sides) are factors that indicate a worse prognosis. However, the size of the tumor isn’t as crucial when you consider the stage of the disease. Mitotic activity (the process of cell division) or nuclear atypia (abnormalities in the cell’s nucleus) are not linked to the way the disease progresses.
There are also specific genetic factors that can affect the prognosis. Patients with a homozygous FOXL2 mutation (a specific gene mutation occurring on both pairs of chromosomes), higher levels of FOXL2 mRNA expression (which relates to how genes are expressed), and chromosomal imbalance (disproportionate amount of chromosomes) might experience early relapse and worse outcomes. Moreover, higher levels of SMAD3 expression (another genetic factor) are a new predictor of recurrence specifically in early-stage disease.
Possible Complications When Diagnosed with Granulosa Theca Cell Tumors of the Ovary
In about 10% to 15% of cases, situations can get complex due to twisting of the ovary or rupture of the tumor, especially in large, thin-walled cysts and internal bleeding within the tumor. These complications can lead to the sudden onset of severe abdominal pain, which might be accompanied by blood accumulating in the abdomen and a sudden drop in blood pressure. The large size of these tumors also increases the risk of the ovary twisting.
Certain ovarian cancers, especially granulosa theca cell cancers, can lead to infertility. They can increase inhibin levels, which in turn lowers FSH (follicle-stimulating hormone) levels. They can also cause endometrial carcinoma, a type of cancer that occurs when there is too much estrogen stimulation of the endometrium and not enough counteracting progesterone.
Common complications associated with ovarian cysts or tumors:
- Ovarian torsion or twisting of the ovary
- Tumor rupture
- Internal bleeding within the tumor
- Severe abdominal pain
- Blood accumulation in the abdomen
- Dropping blood pressure
- Infertility
- Lowered FSH levels
- Endometrial carcinoma
Recovery from Granulosa Theca Cell Tumors of the Ovary
Doctors should check for symptoms, conduct a physical examination, and test for certain blood tumor markers every 2 to 4 months for the first 2 years, and then every 6 months afterwards. Unless there are symptoms indicating the tumor has returned, regular imaging studies, like X-rays or MRI scans, are not recommended as part of check-ups after surgery. Granulosa cell tumors (GCT) often come back late, and unfortunately, in 80% of cases where the tumor has returned, it is fatal. The best way to handle recurring disease is not clearly defined due to limited high-quality data. However, if the disease comes back and is able to be surgically removed, several medical reports have shown that a combination of a surgery to remove the tumor followed by a chemotherapy treatment that uses platinum can increase a patient’s chances of survival.
Preventing Granulosa Theca Cell Tumors of the Ovary
Currently, there are no known methods to prevent granulosa theca cell tumors, a type of ovarian cancer. Before surgery, doctors will discuss the possible outcomes of the procedure, such as whether the tumor is benign (non-cancerous), malignant (cancerous), or uncertain. They’ll also talk about options for preserving the ability to have children, which is recorded in the patient’s medical history.
If the patient wants to maintain their fertility, the doctor will explain that there could be a need for additional surgeries if the tumor turns out to be malignant. This is necessary to ensure all cancerous cells are removed.
Patients need to understand that they will have to continue checking in with their doctor even after treatment is done, as these tumors can come back after many years, sometimes as many as 30 years after the patient was declared cancer-free.
