Granulosa cell tumor is a malignant hormone—active ovarian neoplasm originating from the granular cells of the stroma of the organ. It is manifested by early puberty in girls, menometrorrhagia and acyclic bleeding in women of reproductive age, bloody vaginal discharge in postmenopause. Ultrasound of the pelvic organs, determination of the levels of inhibins and the inhibitory substance of Muller, histological examination of the biopsy are used to make the diagnosis. Combined treatment with removal of the affected appendages or hysterectomy with resection of the omentum, if necessary, radiation and polychemotherapy.
The key features of granulosa cell tumor (follicle, granulose epithelium, granulocellular or folliculoid cancer, cylinder, feminizing ovarian mesenchioma) are the early appearance of clinical symptoms in more than 65-75% of cases of the disease, low progrediency and low risk of distant metastases.
Usually neoplasia is unilateral. According to the results of observations, such tumors account for 0.6 to 7.5% of the volume of ovarian neoplasms. The adult form of pathology is most often detected in women 40-60 years old, juvenile — in girls up to 10 years old. Although neoplasias of this type are of mesenchymal origin, they are epithelial in structure, which affects the stage of their development.
The etiology of the disease has not been definitively established. Neoplastic process presumably occurs in women with a genetic defect. 97% of patients with a late (adult) form of neoplasm and 10% of patients with a juvenile variant have the same mutation in the FOXP2 gene. The connection of the early type of granulocellular neoplasia of the ovaries with a number of hereditary syndromes, which are observed with anomalies in the 12th and 22nd autosomes, was also revealed. Perhaps such a DNA disorder manifests itself during the first half of pregnancy, when ovarian tissue is formed, and the tumor growth itself begins later under the influence of provoking factors. According to experts in the field of oncogynecology, the probability of a tumor is higher if there is a history of disorders such as:
- Dishormonal states. In 25-26% of patients, menarche is noted later, in 20% — ovarian dysfunction (opso- and amenorrhea, unstable menstrual cycle, dysfunctional bleeding) caused by a violation of the hypothalamic-pituitary regulation of the secretory function of the ovaries, which is especially significant in the adult type of neoplasia.
- Endocrine pathology. Almost 40% of women with granulosa cell tumor have obesity of various degrees of severity, 12-13% have signs of hypothyroidism. In the first case, an increase in the probability of neoplasia formation may be associated with the production of estrogens by adipose tissue, in the second — with the effect of thyroid dysfunction on oocyte maturation and steroidogenesis.
- Liver diseases. In 20-22% of cases, various types of hepatic pathology are detected. Violation of the processes of inactivation of steroid sex hormones provokes dishormonal disorders due to the effect on both ovarian tissue and the central links of neuroendocrine regulation.
- Immune deficiency. Due to the failure of tissue and humoral immunity, there is no timely recognition of pathological cellular activity and stopping tumor growth. Immunosuppression is observed in severe somatic diseases, taking glucocorticoids and some other drugs.
- Inflammatory processes in the pelvis. Chronic oophoritis and salpingoophoritis are characterized by ischemia and tissue destruction, increased blood supply, and active cellular repair processes. Such disorders can activate neoplastic processes in dysembriogenetically altered ovarian tissues.
The source of tumor growth in granulocellular neoplasia of the ovaries are granulose cells that originate from the stroma of the genital cord and surround the oocyte. Under the influence of not yet established provoking factors, uncontrolled cell division begins with the formation of a volumetric neoplasm. Apparently, the starting points in the development of juvenile and adult types of tumors differ.
Neoplasia is characterized by slow growth and late metastasis. Since it is hormonally active, the level of estrogens in the blood of patients gradually increases, less often progesterone and androgens. The effect of sex hormones on sensitive organs and tissues forms a typical clinical picture of the disease.
Oncologists distinguish two main types of granulosa cell tumor, which, with the same morphological substrate, have different time of occurrence, rate of development and degree of malignancy of the neoplastic process. The isolation of stages I-IV of the disease corresponds to the general principles of determining the stages in oncology. The key criterion for systematization is the time factor, taking into account which the diagnosis is made:
- Juvenile tumors. Such neoplasms make up no more than 5% of granulocellular tumors, have a follicular or diffuse structure, differ in a more favorable course and prognosis. They are usually detected in somatically healthy girls and adolescents, less often in women of reproductive age no older than 30 years without concomitant pathology. The main reason for the formation of such neoplasms is presumably gene mutations and dysembriogenesis.
- Adult neoplasms. They are diagnosed mainly in peri- and postmenopausal women with endocrine or somatic diseases. They are represented by two histological forms — macrofollicular with a large cavity filled with mucinous, serous or hemorrhagic contents, and luteinized with a diffuse arrangement of cell groups. Most likely, they occur due to pituitary dysfunction and related hormonal imbalance.
The clinical symptoms depend on the form of the disease, but in any case, the leading manifestations of granulose epithelium are symptoms associated with increased secretion of sex hormones and sometimes supplemented by other signs. A prolonged asymptomatic course of the tumor process is possible.
In the juvenile variant of neoplasia, more than 2/3 of patients have premature puberty or disorders of the ovarian-menstrual cycle. In girls, the mammary glands increase, hair appears in the armpits and on the pubis, bloody discharge from the vagina is observed. In women of childbearing age with granulocellular cancer, menstruation becomes abundant, their cyclicity is disrupted, mucus with an admixture of blood is released from the vagina between menstruations.
The adult version of granulocellular neoplasia is characterized by the so-called estrogen rejuvenation. In 84-85% of cases, the monthly cycle is disrupted: menstruating women have acyclic menometrorrhagia, postmenopausal patients have bloody vaginal discharge. The mammary glands become painful and rude. When androgens are secreted by the tumor, signs of virilization are possible — the growth of rod hairs above the upper lip, on the chin, body, coarsening of the voice.
Sometimes with neoplasms of large sizes or ascites, an increase in the abdomen is noted. In the later stages of the disease, pain in the abdominal cavity appears, radiating to the sacrum, coccyx, back, rectum or groin. The involvement of surrounding organs in the process is evidenced by flatulence, constipation, urination disorders.
Every tenth woman with granulocellular neoplasms of the ovaries has a rupture of the tumor capsule with the appearance of hemoperitoneum and intense pain characteristic of an acute abdomen. In a quarter of cases, feminizing ovarian mesenchioma leads to the development of ascites. Long-term consequences of neoplasia are metastasis to the mesentery of the small and large intestine, relapse after radical treatment. Extremely rarely, granulose epithelioma metastasizes hematogenously to the liver, spleen, and adrenal glands.
Hyperestrogenism, characteristic of granulosa cell tumor, provokes associated dysplastic processes and neogenesis in the mammary glands (mastopathy and other types of tumors), the growth of uterine fibroids, the occurrence of highly differentiated endometrial cancer (observed in almost 10% of sick women).
If a granulosa cell tumor is suspected, studies are prescribed to identify a volumetric neoplasm, evaluate its hormonal activity and influence on surrounding organs. There are a number of laboratory markers that are highly specific for this disease. Usually, the survey plan includes methods such as:
- Gynecological examination. With bimanual palpation, a dense elastic formation is determined in the area of the right or left appendages. In postmenopausal patients with granulose epithelioma, there are no visual signs of atrophy of the mucous membrane of the vulva and vagina, characteristic of the involution of the genitals.
- Ultrasound of the pelvic organs. Solid, single- or multi-chamber formations with a diameter of up to 100 mm or more with moderate or high vascularization and frequent inclusion of hemorrhagic components are detected in the ovarian tissues. To obtain more accurate data, sonography is supplemented with CT and MRI, if necessary.
- Determination of the level of inhibins. A highly sensitive diagnostic method, the importance of which is especially great in postmenopause. In primary follicular cancer, the concentration of inhibin A was increased in 65-77% of patients, inhibin B — in 89-100%. With relapse, the content of serum inhibins A and B increased in 58% and 85% of patients.
- Determination of the Muller inhibitory substance (MIS). It is a specific marker for the diagnosis of GKO in childbearing age, including monitoring after organ-preserving surgical interventions. The content of MIS produced by granular ovarian cells increases in 70-80% of patients.
- Histology of the biopsy. Morphological examination allows you to choose the optimal medical tactics. The histologist determines the type of tumor, the degree of its differentiation and nuclear atypia, mitotic activity, the presence of necrotic changes, vascular invasion and tumor embolism.
As additional methods, the determination of estradiol, progesterone, androgens, and FSH levels is used. Hysteroscopy reveals signs of endometrial hyperplasia. Differential diagnosis is carried out with ovarian tecomatosis, Stein-Leventhal syndrome, androsteroma, tumor-like formation of chylus cells.
At the onset of the folliculoma, symptoms of an acute abdomen that arose against the background of an asymptomatic course exclude ectopic pregnancy, rupture of an ovarian cyst, other acute gynecological and surgical pathology. Oncogynecologist, endocrinologist, and surgeon are involved in the diagnosis.
Medical tactics depend on the stage of the process and the type of neoplasm. Surgical treatment is recommended, supplemented with radiation and chemotherapy if necessary. When choosing the volume of surgery, the patient’s age, her reproductive plans and the extent of the spread of the tumor process are taken into account. Depending on the type of tumor, the following patient management schemes are recommended:
- With age—related neoplasia, supravaginal amputation or hysterectomy with fallopian tubes and ovaries. Taking into account the possible contact metastasis, resection of the large omentum is also performed. Patients with stages II-IV of the disease are intraoperatively treated with radiation therapy, and after surgery with an anti-relapse goal, at least 4 courses of polychemotherapy with platinum preparations are prescribed.
- In juvenile—type tumors – in the early stages of the neoplastic process, an organ-preserving operation is shown with the removal of appendages on the side of the lesion without resection of the omentum. In stages II-IV, the volume of intervention is determined by the localization of metastatic foci, however, pangisterectomy is performed only when the uterus and appendages are affected on the opposite side. Chemotherapy is prescribed when signs of progression of the process are detected.
Patients with metastatic or recurrent nodes are operated on repeatedly. The slow growth of the neoplasm increases the effectiveness of such interventions. In some cases, removal of solitary metastasis or recurrent tumor is sufficient to achieve long-term remission. The decision on the appointment of chemotherapy drugs and radiation therapy for each relapse is made individually.
Prognosis and prevention
Since in 89-90% of cases the disease is diagnosed at an early stage, its prognosis is more favorable than in other types of malignant ovarian tumors. Aggressive development of neoplasia is noted only in 5% of patients. Juvenile forms of the tumor are more favorable, adults differ in a torpid course with a late occurrence of relapses and metastases. The risk of rapid progression is increased with late diagnosis, moderate and severe atypia of the nuclei, the presence of vascular invasion, necrosis, tumor emboli, intermediate and low differentiation.
Primary preventive measures due to the ambiguity of the etiology have not been developed. Secondary prevention is aimed at early detection of the tumor (regular examination by a gynecologist, ultrasound screening). Tertiary prevention allows you to prevent the recurrence of the disease after treatment. The operated women are recommended to monitor tumor markers (inhibins, MIS), with organ—preserving interventions – 2-3-year follow-up and comprehensive examination up to diagnostic laparoscopy before possible pregnancy.