Granulosa Cell Tumor

Presentation of granulosa cell tumors depends on the age of the patient and her menstrual status. Symptoms are generally related to estrogen production, particularly since 70% of all tumors secrete estrogen. Some patients, nonetheless, may present with primary symptoms that are more strongly related to the growth of the tumor in the abdomen and pelvis.
Abdominal symptoms can be caused by either increase in girth or the development of ascites. Patients will generally complain of abdominal discomfort as well as pain, constipation, urinary frequency and dysuria due to pressure over the bladder. On physical exam, an abdominal mass can be palpated in the majority of patients and around 10% will show evidence of ascites.

Granulosa cell tumors can also present acutely, although this is not very common. Acute presentations are caused by complications that involve the tumor such as cystic rupture, adnexal torsion or bleeding within the peritoneal cavity or the tumor itself. Patients exhibit acute abdominal and pelvic pain that can accompany dizziness, pain in the shoulders, nausea and vomiting.

Hyperestrogenic symptoms are categorized depending on whether the patient is prepubertal, premenopausal or postmenopausal. Prepubertal girls develop secondary sex characteristics very early in 70 to 80% of cases. They may exhibit vaginal bleeding and secretions, development of pubic hair, enlargement of the breasts and the clitoris and linear growth. In a small portion of patients, the tumor may secrete large amounts of testosterone that lead to the development of male characteristics. Surgical removal of the tumor helps in resolving symptoms.

Premenopausal women can present with irregularities in the menstrual cycle in the form of increased menstrual bleeding (menorrhagia), irregular periods (oligomenorrhea) and secondary amenorrhea. They may also complain of increased abdominal girth and pelvic and abdominal symptoms resulting from tumor growth.

Dysfunctional uterine bleeding is the most common endocrine manifestation in postmenopausal women and develops subsequent to increased endometrial proliferation due to the effects of estrogen. Postmenopausal women are thus at an increased risk of endometrial hyperplasia and adenocarcinoma. Occasionally, postmenopausal women may develop virilization symptoms due to increased testosterone and androstenedione secretion. These generally consist of enlargement of the clitoris, changes in the voice, hirsutism and acne.

The most common sign on physical exam is the presence of a mass in the pelvis, usually evident on pelvic and rectal examinations. Pelvic examination is recommended in all cases to detect pelvic and abdominal masses, tenderness and nodular formations in the posterior cul-de-sac. A rectal exam is followed by taking stool samples for additional testing that may be useful in narrowing the differential diagnosis. On the other hand, patients with an acute presentation should undergo an examination with the speculum, in addition to a wet preparation and culture for sexually transmitted diseases such as those caused by Chlamydia and Neisseria gonorrhoeae. If pelvic inflammatory disease or cervicitis are strongly suspected, a gram stain may also be of additional value.

Workup for patients with granulosa cell tumors is broad and should generally begin with a pregnancy test in all women of reproductive age, especially those who present with abdominal and pelvic symptoms. This is followed by tumor marker assessment as well as imaging studies [8] [9].

Hormonal and tumor marker assessment should include beta-human chorionic gonadotropin (bhCG), lactate dehydrogenase (LDH), cancer antigen 125 (CA125), alpha-fetoprotein (AFP), inhibin and antimüllerian hormone (AMH). CA125 is usually not useful in menstruating women and may be elevated in a number of other disorders such as appendicitis, endometriosis, uterine leiomyoma, pancreatitis and inflammatory bowel disease. Nonetheless, a value of CA125 greater than 60 U/ml in postmenopausal women has positive predictive value, indicating a high likelihood of the presence of a tumor.

Imaging studies are possibly the most important modalities used in the workup. Ultrasonography is employed initially, particularly transvaginal ultrasound. It can identify adnexal masses as well as its cystic and solid constituents. It can also detect septations and excrescences within the tumor. The risk of malignancy increases in the presence of bilateral, solid, cystic or complex masses.

A chest X-ray can be useful in detecting any lung metastasis while metastasis to the peritoneum and different organs is best identified with computed tomography or magnetic resonance imaging. Imaging of the abdomen and pelvis should be initially used for monitoring any recurrences that are suspected on the physical exam.

A mammography should be performed in every woman older than 40 who did not have a mammography in the past year. This can help in detecting malignancies in women at high risk, particularly those with estrogen-producing tumors.

Tumors may be solid, cystic or contain a mixture of both features. The majority nonetheless are multicystic and show evidence of hemorrhage on cut section. Most granuloma cell tumors are multilocular, although those that tend to produce more androgens are usually unilocular. Tumor tissue is generally composed of both theca and granulosa cells. Tumors with both types of cells are referred to as granulosa-theca cell tumors. Young and Scully have suggested that at least 25% of the cells have to be either granulosa or theca cells for the term granulosa-theca cell tumors to be used [10].

Surgery is the cornerstone of treatment for granulosa cell tumors. It is also critical for histopathological diagnosis and staging of the disease [10]. Before performing surgical procedures, the patient should undergo a series of preoperative tests for accurate evaluation of his/her status. This can further motivate the counseling of the patients in regards to their disease. Surgery aims for a complete removal of the tumor. Staging is performed after bilateral para-aortic and ipsilateral lymph nodes are sampled in addition to biopsies of the peritoneum and contralateral ovary in case it appears abnormal, washings of the pelvis and partial omentectomy. Once biopsy of the contralateral ovary was used far more commonly but is nowadays not frequently performed because approximately only 2% of all granulosa cell tumors are bilateral and because it might lead to adhesion formations and subsequent problems with pain and fertility. Lymphadenectomy is currently not necessarily recommended, despite the fact that positive data exist, especially in sex cord stromal tumors. Patients for whom pregnancy is not a concern can undergo a bilateral salpingo-oophorectomy in combination with total abdominal hysterectomy, performed in addition to staging.

Patients should be closely monitored after surgery with periodic pelvic exams and measurements of tumor markers. Any suspicious findings should prompt the physician to perform imaging studies, most commonly with computed tomography, to detect any recurrence of the tumor. Recurrent tumors or advanced clinical stages require, in addition to surgery, chemotherapy, radiotherapy or a combination of the two.

Radiotherapy still has limited usage in early, stage I disease. It is most commonly employed for patients in advanced stages and those suffering from recurrent tumors. Approximately 50% of patients with recurrent tumors respond to therapy with radiation, justifying its use in this patient population.

Other treatment options for granulosa cell tumors include chemotherapy and hormonal treatment with aromatase inhibitors and analogues of GnRH. These modalities are generally employed as adjuvant treatments.

Granulosa cell tumors are generally considered benign tumors and have an excellent prognosis. 10-year survival rate can approach 96% for tumors diagnosed in Stage I. Around 90% of all granulosa cell neoplasms are diagnosed in Stage I. In contrast, 5 and 10-year survival rates for advanced stages range from 33 to 44%. Adult and juvenile granulosa cell tumors don't differ substantially in their survival rates with a value of 90 and 97%, respectively. An approximate 10-year survival rate for the adult type is 76%. Epithelial ovarian cancer has a far worse prognosis with 5-year survival rates that do not exceed 50%. This is due to the fact that only 25% of all patients with epithelial tumors are diagnosed in Stage I.

Both adult and juvenile granulosa cell tumors have a tendency for recurrence, although adult type tumors tend to recur later. Overall recurrence for granulosa cell tumors has been reported to be around 43% for stages I to III granulosa cell tumors, although other studies report rates ranging from 9 to 39% [6]. Recurrence of adult granulosa cell tumors usually takes place within a mean of 5 years after initial treatment. The course of the illness after recurrence tends to be protracted and 10-year survival rate approaches 60%. A mean survival after recurrence is 5 years. On the other hand, juvenile granulosa cell tumors recur earlier than the adult type and the disease frequently leads to death.

New research has lead to the development of models that can help estimate prognosis and predict survival. These depend on the stage of the tumor upon diagnosis, body mass index, tumor diameter and mitotic index [7].

The etiological mechanisms underlying granulosa cell tumors are still unknown. It is thought that a number of factors are responsible for the condition, including chromosomal and endocrine abnormalities.

Ovarian cancer is the most common cause of death resulting from malignancies affecting the female reproductive system in the United States. In this country, sex cord-stromal tumors represent 8% of all malignant ovarian cancers, affecting approximately 2000 individuals every year.

Studies have not reported any differential prevalence or incidence based on race or ethnic group. The disease naturally occurs much more commonly among females, although it can potentially occur in male testicular tissue. Adult granulosa cell tumors comprise 95% of all cases and most patients are postmenopausal women with a median age of 52 years. On the other hand, juvenile granulosa cell tumors comprise only 5% of all cases and affect people younger than 30.

The pathophysiological mechanisms underlying granulosa cell tumors have not been uncovered, although theories have been proposed. The first theory suggests that the tumor derives from the genital ridge, part of the developing mesenchyme in reproductive organs. The second theory postulates that the precursor cells of a neoplastic tissue are present in the coelomic and mesonephric epithelium. This theory is further supported by case reports of granulosa cell tumors that occurred outside the ovaries.

The underlying biomolecular mechanisms involve mutations in the FOXL2 gene [4]. A missense point mutation in the gene was discovered after sequencing of the whole transcriptome of four samples of adult granulosa cell tumors. This was further confirmed in a sample of 89 adult granulosa cell tumors. Furthermore, the mutation was not involved in other types of ovarian tumors arising from the epithelium, suggesting some specificity, which can be targeted in the future with new therapies [5].

Granulosa cell tumors are in general benign neoplasms, with only a few subtypes showing malignant and aggressive potential. The tumor grows locally in the pelvis and abdomen but in the case of malignant change can metastasize to anywhere in the body.

There are no measures that can help prevent granulosa cell tumors.

Granulosa cell tumors are tumors derived from granulosa cells. The underlying etiological mechanisms are still unknown. The disease can be categorized into a juvenile type that affects most commonly patients younger than 30 and an adult type with a median patient age of 52 years. Patients present with a range of symptoms that are most commonly related to a hyperestrogenic state, although abdominal and pelvic symptoms caused by excessive growth and pressure can also occur. Abdominal and pelvic symptoms include an increase in abdominal girth, abdominal discomfort, constipation, urinary frequency, and dysuria. Hyperestrogenic symptoms will vary depending on the age of the patient and her menstrual state. It is important to note that postmenopausal women can present with dysfunctional uterine bleeding associated with an increased risk of uterine malignancy. An acute presentation is also possible and is due to complications such as bleeding in the tumor or the peritoneal cavity, adnexal torsion or cystic rupture. Imaging is particularly important in the workup, especially transvaginal ultrasound which aids greatly in detecting masses and assessing their solid and cystic constituents, in addition to the presence of septations or excrescences. The latter can be important markers for malignancy. Surgery is the cornerstone of treatment, although radiotherapy and chemotherapy can be used in complicated cases. Prognosis is generally favorable because the majority of cases are benign [1] [2] [3].

Granulosa cell tumors are tumors that arise from a type of cells located in the reproductive system called granulosa cells. They are categorized into an adult and a juvenile type. The underlying pathological mechanisms are still poorly understood, but it is thought that the tumors arise from a combination of genetic and environmental factors. Patients usually present with an increase in abdominal size, abdominal discomfort, constipation, urinary frequency and pain on urination. They may also complain of manifestations related to secondary sexual characteristics and menstrual cycle such as acne, an increase in body hair or abnormal vaginal bleeding. Workup includes an ultrasound to detect the pelvic mass and X-ray, MRI or CT to identify metastases or monitor for any recurrences. Patients are treated with surgery, although chemotherapy and radiotherapy can also be used in complicated cases of malignant granulosa cell tumors. Prognosis is generally good because the majority of these tumors are benign.

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