Virilizing ovarian tumors

Virilizing tumors (Latin virilis - male) are hormonally active neoplasms that secrete male sex hormones - androgens (T, A, DHEA). Virilizing ovarian tumors are a rare form of pathology. N. S. Torgushina has identified androblastomas in 0.09% of 2,309 ovarian tumors over 25 years.

Epidemiology

Virilizing ovarian tumors can occur in any age group, but the highest number of cases are found in patients aged 20 years.

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Causes virilizing ovarian tumors

The cause and pathogenesis of hormonally active or virilizing ovarian tumors (VOT), as well as tumors in general, are unknown. It is generally accepted that they all form from the remains of the male part of the gonad in the ovary. According to modern concepts, the pathogenesis of virilizing ovarian tumors is also associated with the state of the hypothalamic-pituitary system. According to A. D. Dobracheva's data, the level of gonadotropic hormones in patients with such tumors can be different: low, high and normal, and their secretion has no characteristic features. At the same time, patients have been found to have gonadotropic regulation disorders at the level of LH interaction with the receptor, and HG are not necessary to maintain androgen secretion by the tumor.

The role of genetic disorders has not been established.

Pathological anatomy. Virilizing ovarian tumors are neoplasms of the sex cord stroma that combine hormone-producing and hormone-dependent tumors of complex genesis. According to the WHO classification (1977), they belong to the lipid cell or lipoid cell group. Granulosa cell tumor, thecoma, and androblastoma of varying degrees of differentiation can cause the development of virilization syndrome in women.

Granulosa cell tumors are more common in women over 40 years of age; they are usually unilateral and often malignant. Macroscopically, they are an encapsulated node up to 10 cm in diameter on a section of a solid, solid-cystic or cystic type. These features determine their consistency. Cystic cavities are single- or multi-chambered, filled with transparent and/or hemorrhagic contents, serous or mucous. Microscopically, the tumor has a diverse structure: discomplexed, follicle-like, trabecular, alveolar, adenomatous, sarcomatoid, etc. Tumor cells are small. The nuclei are relatively large, dense, rarely vesicular with grooves, giving them the appearance of coffee beans. In malignant variants, giant ugly nuclei, mitotic figures, sometimes atypical, are found. Tumor cells can form small rosette-like structures with structureless basophilic masses in the center, the so-called Koll-Exner bodies.

Their cytoplasm often contains lipid inclusions. Virilizing variants of granulosa cell tumors contain a thecal component expressed to varying degrees, formed either by typical thecal cells forming solid structures or by clusters of small fibroblast-like cells. Thecal cells of both types show high activity of steroidogenesis enzymes: 3beta-hydroxysteroid dehydrogenase, glucose-6-phosphate dehydrogenase, NAD- and NADP-tetrazolium reductase, as well as a significant amount of lipids: cholesterol, its esters and phospholipids. They are characterized by ultrastructural features inherent in steroid-producing cells. In the cells of the granulosa cell component, steroidogenesis enzymes are also detected, with the exception of 3beta-oxysteroid dehydrogenase, but their activity is incomparably lower than in the cells of the thecal component.

Thus, the main source of androgens in virilizing granulosa cell tumors is apparently their thecal component.

Thecoma is the most common virilizing tumor of the ovary. Malignant variants are rare, on average 4-5% of cases. Thecomas are usually unilateral, without a visible capsule. The diameter of the tumors ranges from 1 to 5 cm, rarely - up to 20-25 cm. In consistency, they are densely elastic, their surface is smooth or finely tuberous, and on the section they are ocher-yellow, often spotted. Dystrophic processes, especially in large tumors, lead to the appearance of smooth-walled cavities with serous or jelly-like contents, sometimes with an admixture of blood. In the ovary where the thecoma is localized, the cortex is preserved, but in a state of pronounced atrophy, especially its interstitial tissue. The opposite ovary is hypoplastic, sometimes with focal hyperplasia of the "stroma" and / or thecomatosis.

Virilizing thecomas are a type of luteinized thecomas; they are formed by epithelioid cells similar to the cells of theca interna folliculi. Tumor cells form fields, cords, and nests; the cytoplasm is abundant, oxyphilic, fine-grained, and contains lutein and a variety of lipids. The nuclei are relatively large, with clearly distinguishable nucleoli. Tumor cells exhibit high activity of enzymes that ensure the processes of biosynthesis of sex steroids, which reflects their high functional activity. There is a certain relationship between the activity of steroidogenesis enzymes and the lipid content in the cell: the more lipids, especially esterified cholesterol, the lower the enzyme activity, and vice versa. A small proportion of thecomas have phenomena of nuclear atypism; increased mitotic activity is rarely observed in them. Malignant thecomas are characterized by nuclear and cellular polymorphism and atypism, the presence of atypical mitotic figures and destructive growth. Relapses and metastases occur infrequently.

Androblastomas (arrenoblastoma, tubular adenoma, tumor of sustentocytes and glandulocytes, masculinomas, etc.) are rarely observed ovarian tumors that cause the development of virilization syndrome. They occur at any age, but most often between the ages of 20 and 30. These are usually unilateral benign tumors, with a diameter of 1 to 10 cm or more. Microscopically, highly differentiated, intermediate, and poorly differentiated variants are distinguished.

Among the first, there are 4 forms, two of which consist of Sertoli cells: tubular adenoma (Pick adenoma) and androblastoma with lipid accumulation, Sertoli and Leydig cell tumor, and Leydigoma. All of these forms can cause virilization syndrome, but it most often develops in the last 3 types. Tubular adenoma is formed by closely spaced monomorphic tubular or pseudotubular structures of Sertoli-type cells. Pseudotubular structures, or so-called solid tubules, are elongated and resemble the seminiferous tubules of prepubertal testes. In some cases, there are also areas of trabecular, diffuse, or cribriform structure, often with typical Kohlexner bodies.

The bulk of tumor cells are rich in cytoplasmic lipids. This is tubular androblastoma with lipid accumulation, or the so-called lipid folliculoma. But electron microscopy has proven that in all these cases they are formed by Sertoli cells. Viril syndrome most often occurs in women with tumors of mixed structure - from Sertoli and Leydig cells. The ratio of tubular structures and Leydig cells varies from tumor to tumor, as does the degree of differentiation of the glandular component. Tumors only from Leydig cells apparently arise from the precursors of hilus or ovarian stromal cells. In the first case, they are localized in the form of a node in the mesovarium, and in the second - in the medulla of the ovary.

The majority of tumors are benign, although cases of metastasis of such tumors, which caused the death of patients, are described in the literature. The main source of testosterone in tumors are Leydig cells and, to a lesser extent, Sertoli cells.

Intermediate-type androblastomas differ from highly differentiated ones by the powerful development of mesenchymal-like stroma. Low-differentiated androblastomas are characterized by the predominance of the stromal component, reminiscent of sarcoma, over the epithelial component, represented by pseudotubular structures from atypical Sertoli cells. In the contralateral ovary, pronounced stromal hyperplasia is observed.

Lipid cell tumors of the ovaries are a collective term that includes neoplasms of unclear or questionable histogenesis. They include tumors from dystopias of the adrenal cortex, Leydig cells (from their ovarian analogues - hilus cells), as well as luteomas, stromal luteomas or, if the woman is pregnant, luteomas of pregnancy. All these tumors are combined into one group on the basis that they consist of cells with a morphology typical of steroid-producing cells and contain large amounts of lipochrome pigment, as well as lipids related to the processes of steroidogenesis (cholesterol and its esters).

These tumors, however, lack the topographic and microscopic features necessary for their identification. Lipid cell tumors are mostly benign. Malignant variants are found among tumors from adrenal cortex dystopia. Lipid cell neoplasms must be differentiated from androblastomas of the adrenal cortex, ovaries, other virilizing tumors, and stromal thecomatosis of the ovaries, accompanied by virilization syndrome. The pathohistological examination of the removed tumor, taking into account its localization, is decisive in establishing the diagnosis.

Neoplasms from adrenal tissue dystopia are rare. They occur at any age. Mostly unilateral, can reach large sizes, have the form of a clearly defined node of ocher-yellow color. Tumor cells form abundantly vascularized cords and columns, their cytoplasm is rich in lipids (free and bound cholesterol). On histological preparations, it looks foamy or "empty". Strong evidence of the tumor's origin from ectopic adrenal tissue is its secretion of cortisol. These tumors are often malignant.

Neoplasms from hilus (Leydig) cells, which belong to this group, are characterized by small size, yellow color on section, abundance of cytoplasmic lipids and sometimes Reinke crystals.

Stromal luteomas are a rare ovarian tumor. They are more common in postmenopausal women. They are located in the thickness of the cortex; they consist of luteinized cells of the interstitial tissue of the cortex. These tumors are usually multiple, often bilateral, and are often accompanied by stromal thecomatosis of the ovaries.

If a luteinized virilizing ovarian tumor cannot be classified as one of the above types, it should be included in the category of non-specific lipid cell tumors. The ovary with a virilizing tumor shows atrophic changes with loss of part of the follicular apparatus and compression phenomena. The other ovary is either hypotrophic or microscopically unchanged. Microscopically, pathology characteristic of stromal thecomatosis may be observed.

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Symptoms virilizing ovarian tumors

The symptoms of virilizing ovarian tumors are determined by the level and biological activity of androgens secreted by the tumor and do not depend on the morphological structure of the tumor. It is known that with the same histology, tumors can be androgen-producing and estrogen-producing and cause the corresponding clinical picture.

One of the first symptoms of virilizing ovarian tumors is a sudden cessation of menstruation - amenorrhea, less often it is preceded by a short period of irregular scanty menstruation - oligoopsomenorrhea. In the case of mixed production of androgens by the tumor, metrorrhagia (acyclic uterine bleeding) is also possible, often in the form of spotting bloody discharge.

Progressive hirsutism appears simultaneously with the menstrual dysfunction, then so-called androgenic alopecia, i.e. male-pattern baldness. The voice becomes coarser rather quickly. Defeminization becomes noticeable - the disappearance of secondary female sexual characteristics. The mammary glands decrease in size and become "flabby", fat deposits on the hips disappear, the body type approaches that of a man. During a gynecological examination, hypertrophy and virilization of the clitoris attract attention. The mucous membranes become atrophic, with a cyanotic tint. The size of the uterus decreases, sometimes it is possible to palpate an enlarged ovary.

Colpocytological examination reveals a decrease in CI to 0, and a predominance of parabasal and basal epithelial cells. The "pupil" symptom is negative.

All the listed signs are sharply expressed, appear suddenly (patients can accurately indicate from which month they fell ill) and progress rapidly. In the case of mixed androgen-estrogen secretion, the indicated symptoms may not be so pronounced.

In virilizing ovarian tumors, estrogen excretion may be decreased, normal, or increased. The level of 17-KS excretion in urine is very individual, according to our data, from 22.53 to 206.63 μmol/s, on average - (53.73±3.81) μmol/s, n=38, which significantly reduces the diagnostic value of this indicator. When determining the 17-KS fractions, androsterone was significantly increased - (9.36±1.04) μmol/s at n=7 and 11-oxidized 17-KS - (7.62±0.93) μmol/s at n=6. Excretion of 17=OCS did not differ from the norm - (12.9±1.15) μmol/s at n=37.

A more reliable indicator of the androgenic function of the ovaries is the level of T in the plasma. Its level in all patients with OVF significantly exceeds the norm - (15.58±0.92) nmol/l with the norm being (1.47±0.41) nmol/l. The degree of its growth determines the severity of the virilization syndrome as a whole. No correlation was found between the level of T and the size of the tumor.

The content of HG (LH and FSH) in virilizing ovarian tumors is usually not disturbed. According to our data, the level of LH on average was (11.53±2.5) U/l for n=8; FSH - (8.1±2.7) U/l for n=7. In 4 patients, the level of prolactin was normal - (588±177) mU/l, and in the rest it was significantly increased - (3249±1011) mU/l. Galactorrhea was not observed in these patients.

In all patients under 18 years of age, the bone age on X-ray images of the hand corresponded to sexual maturity - the growth zones were closed, which is probably due to the anabolic effect of androgens. No protein, carbohydrate and mineral metabolism disorders were found in patients with virilizing ovarian tumors. Approximately a quarter of patients were obese.

Among the features of the course, it is necessary to note the rapid progression of all symptoms of the disease. The development of virilizing ovarian tumors during pregnancy is not excluded. Some patients have signs of hypothalamic-pituitary disorders, such as obesity of II (15%) and III (10%) degrees, pink striae on the thighs (5%), the presence of endocraniosis on the X-ray of the skull (32%), increased blood pressure, neurological microsymptomatology (10%), characteristic changes in the EEG (3%). The presence of these symptoms sometimes significantly complicates diagnosis.

Of interest are data on the state of the adrenal glands in virilizing ovarian tumors.

Diagnostics virilizing ovarian tumors

Diagnostics and differential diagnostics of virilizing ovarian tumors. It is not difficult to suspect a virilizing tumor with a pronounced clinical picture, but it is often quite difficult to identify the source of hyperandrogenism. The diagnosis is based on the indicated clinical manifestations, a significant increase in the T level in the plasma and is not difficult if the tumor is large enough to be easily palpated. However, virilizing ovarian tumors are rarely large, often their diameter is 1-2 cm, which does not allow the tumor to be detected even with pneumopelvigraphy or laparoscopy.

In addition, the presence of bilateral virilizing ovarian tumors is possible, which also complicates diagnostics. At the same time, the introduction of laparoscopy and ultrasound into practice has significantly expanded diagnostic capabilities. However, with very small tumor sizes and changes in the adrenal glands, topical diagnosis is also difficult. In such cases, the method of separate catheterization of the veins of the ovaries and adrenal glands with blood sampling for androgen levels is of great value. Lymphography and phlebography can be used.

A functional test with DM and hCG in virilizing ovarian tumors is uninformative, since no reliable decrease or increase in the level of T in the blood is observed, but the presence of a tumor in the body is indicated by a high initial level of T.

When determining virilizing ovarian tumors, one should not forget about the possibility of metastases. X-ray examination of patients is mandatory.

Virilizing ovarian tumors should be differentiated from androsteromas, glucandrosteromas, stromal ovarian thecomatosis, and postpubertal adrenal cortex dysfunction.

In androsteromas, the clinical picture is the same as in virilizing ovarian tumors, the only difference being the source of hyperandrogenism. In addition, in these tumors, as a rule, the excretion of 17-KS in urine is increased, and in glucandrosteromas - also 17-OCS. The introduction of DM does not reduce their increased level.

Methods of topical diagnostics (retropneumoperitoneum, ultrasound, computed tomography) help to identify a tumor of the adrenal gland, while similar methods of examining the ovaries determine their hypoplasia.

In postpubertal adrenal cortex dysfunction with virilization symptoms and menstrual dysfunction, increased urinary excretion of 17-KS and high blood T levels are detected, which are well suppressed by DM. Simultaneously detected bilateral adrenal cortex hyperplasia and ovarian hypoplasia finally resolve the diagnosis.

In severe stromal ovarian thecomatosis, virilization symptoms are often observed, including alopecia, virilization of the clitoris, and coarsening of the voice, i.e. the clinical picture is largely similar to that of OVS. However, in stromal ovarian thecomatosis, as a rule, there are symptoms of hypothalamic-pituitary disorders, areas of skin hyperpigmentation, and carbohydrate metabolism disorders may occur. The disease generally progresses slowly, and the T level is lower than in OVS. Under the influence of DM, the T level significantly decreases, and stimulation with hCG causes a significant increase. The increase in the size of the ovaries is bilateral.

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Treatment virilizing ovarian tumors

Treatment of virilizing ovarian tumors is only surgical. Considering the data available in the literature on neuroendocrine disorders after removal of an ovary, even one, and the young age of patients, many authors adhere to a gentle, organ-preserving tactic - removal of the tumor with maximum preservation of healthy ovarian tissue and mandatory biopsy of the second ovary.

The uterus is preserved in all cases. As S. S. Selitskaya (1973) emphasizes, preservation of a healthy ovary is the prevention of endocrine disorders, which are the background for tumor development and relapses. Only in menopausal patients is it possible to remove both ovaries and perform supravaginal amputation of the uterine body. An examination of the entire pelvis and omentum is mandatory to exclude metastases. R. T. Dtsamyan recommends a more active surgical tactic: extirpation or supravaginal amputation of the uterine body with appendages, but notes that the results of treatment of patients with virilizing ovarian tumors depend more on the histological type than on differences in treatment methods.

According to research data, all patients of reproductive age showed restoration of menstrual function, disappearance of signs of defeminization, hirsutism and alopecia, and softening of the voice. Some women became pregnant at various times after the operation, ending in urgent delivery or artificial abortion.

We did not detect any recurrence of the disease or late metastases in any case.

Following the operation, there is a rapid and stable decrease in the T level to normal values. In our opinion, the T level after surgery can be used as an indicator of tumor recurrence. Chemotherapy in the postoperative period is carried out only in the case of existing distant metastases. Patients should be under dispensary observation with mandatory control of ovarian function by TFD. In case of ovulation disorders, we use therapy aimed at its stimulation, for which the entire arsenal of hormonal agents can be used (SEGP, pure progestins, clomiphene, etc.). We consider the restoration of ovulation as an indicator of full ovarian function to be a necessary condition for preventing relapse.

Forecast

The prognosis for virilizing ovarian tumors in the absence of metastases is favorable.

Working capacity is not impaired.

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