Virilizing tumors of the ovaries

Virilizing tumors (Latin virilis - masculine) are hormonal-active neoplasms that secrete male sex hormones - androgens (T, A, DHEA). Virilizing tumors of the ovaries are a rare form of pathology. N. S. Torgushin for 25 years revealed androblastomy in 0.09% of 2309 ovarian tumors.

Epidemiology

Virilizing tumors of the ovaries can be observed in any age group, but the greatest number of cases was found in patients aged 20 years.

[1], [2], [3], [4], [5]

Causes of the virilizing tumors of the ovaries

The cause and pathogenesis of hormonal-active or virilizing ovarian tumors (VOJ), as well as tumors in general, are unknown. It is generally believed that they are all formed from the remains of the male part of the gonad in the ovary. According to modern ideas, the pathogenesis of virilizing ovarian tumors is also associated with the state of the hypothalamic-pituitary system. From the data of AD Dobracheva it follows that 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 showed violations of gonadotropic regulation at the level of interaction of LH with the receptor, and GG are not necessary for maintaining the secretion of androgens by the tumor.

The role of genetic disorders is not established.

Patanatomy. Virilizing tumors of the ovaries are tumors of the stroma of the genital tract, which combine hormone-producing and hormone-dependent tumors of complex genesis. According to WHO classification (1977), they belong to the group of lipid or leukocytic cells. A granulosa cell tumor, a tecoma and an androblastoma of different degrees of differentiation can determine the development of the viril syndrome in women.

Granulocytic tumors are more common in women older than 40; they are usually one-sided and often malignant. Macroscopically represent an encapsulated node up to 10 cm in diameter on a solid, solid-cystic or cystic incision. 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 - bubbly with grooves, giving them the appearance of coffee beans. In malignant variants there are giant ugly nuclei, figures of mitosis, sometimes atypical. Tumor cells can form small structures such as rosettes with unstructured basophilic masses in the center, the so-called callus-Exner corpuscles.

In their cytoplasm, lipid inclusions are often present. The virilizing variants of granulosa cell tumors contain a distinctive teakal component, formed either by typical tekal cells forming solid structures, or by clusters of small fibroblast-like cells. In the both types of tekal cells, high activity of steroidogenesis enzymes is revealed: 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 peculiar to steroid-producing cells. In the cells of the granule cell component, enzymes of steroidogenesis, with the exception of 3β-hydroxysteroid dehydrogenase, are also detected, but their activity is incomparably lower than in the cells of the texal component.

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

Tecoma is the most common virilizing tumor of the ovary. Malignant variants are rare, on average in 4-5% of cases. Tekoma, as a rule, one-sided, without visible capsules. The diameter of tumors varies from 1 to 5 cm, rarely - up to 20-25 cm. According to their consistence they are densely elastic, their surface is smooth or finely chopped, and on the cut is ocher-yellow, often spotted. Dystrophic processes, especially in large tumors, lead to the appearance of smooth-walled cavities with serous or gelatinous contents, sometimes with an admixture of blood. In the ovary, where the Tecoma is localized, the cortical substance 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 tecomatosis.

Virilizing tecomes belong to a variety of luteinized formed by epithelioid cells, similar to the cells of theca interna folliculi. Tumor cells form fields, strands and nests; cytoplasm abundant, oxyphilic, fine-grained, contains lutein and a variety of lipids. The nuclei are relatively large, with distinct nucleoli. In tumor cells, a high activity of enzymes, which ensure the processes of biosynthesis of sex steroids, is detected, which reflects their high functional activity. There is a definite relationship between the activity of steroidogenesis enzymes and the lipid content in the cell: the more lipids, especially the esterified cholesterol, the lower the enzyme activity, and vice versa. A small part of the current with the phenomena of nuclear atypism; in them, there is rarely an increase in mitotic activity. For malignant diseases, the phenomena of nuclear and cellular polymorphism and atypism, the presence of atypical figures of mitosis and the phenomenon of destructive growth are characteristic. Relapses and metastases occur infrequently.

Androblastoma (arrenoblastoma, tubular adenoma, tumor from the sustenocytes and glandulocytes, masculinae, etc.) - occasionally observed ovarian tumors that cause the development of the viral syndrome. Arise at any age, but more often in the age of 20 to 30 years. Usually it is one-sided benign tumors, with a diameter of 1 to 10 or more cm. Microscopically distinguish highly differentiated, intermediate and low-differentiated variants.

Among the first four forms are distinguished, two of which consist of Sertoli cells: tubular adenoma (Pike adenoma) and androblastoma with accumulation of lipids, a tumor from Sertoli and Leydig cells, as well as a leidigoma. All these forms can cause virile syndrome, but more often it develops in the last 3 types. The tubular adenoma is formed by closely located monomorphic tubular or pseudotubular structures from Sertolium 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 parts of the trabecular, diffuse or cribriform structure, often with typical collaxner bodies.

The bulk of tumor cells is rich in cytoplasmic lipids. This is a tubular androblastoma with accumulation of lipids, or the so-called lipid follicle. But electron microscopically it is proved that in all these cases their Sertoli cells are formed. Viral syndrome 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 appear, obviously, from the precursors of the hilar or from the ovarian stromal cells. In the first case, they are localized as a node in the mesovarium, and in the second - in the cerebral layer of the ovary.

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

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

Lipid cell tumors of the ovaries are a collective concept that unites neoplasms of unclear or questionable histogenesis. These include tumors from the dystocia of the cortical layer of the adrenal gland, Leydig cells (from their ovarian analogues - hylus cells), as well as luteomes, stromal luteomes or, if a woman is pregnant, pregnancy luteomes. All these tumors are united into one group on the grounds that they consist of cells with morphology typical for steroid-producing cells and containing large amounts of lipochromic pigment, as well as lipids related to steroidogenesis processes (cholesterol and its ethers).

These tumors are, however, devoid of the topographical and microscopic features that are necessary for their identification. Lipidectomy tumors are mostly benign. Malignant variants are found among tumors from the dystocia of the adrenal cortex. Differentiate lipid-cell neoplasms with the adrenal glands of the adrenal cortex, ovaries, other virilizing tumors and stromal ovarian tecomatosis, accompanied by virile syndrome. Decisive in establishing the diagnosis is the pathohistological study of the removed tumor, taking into account its localization.

Neoplasms from the dystopia of adrenal tissue are rare. They are found at any age. For the most part, one-sided, can reach large sizes, they have the shape of a well-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 specimens, it looks frothy or "empty." A good proof of the origin of the tumor from the ectopic adrenal tissue is its secretion of cortisol. These tumors are often malignant.

Neoplasms from the hylus (Leidig) cells, attributed to this group, are characterized by small size, yellow in the cut, abundance of cytoplasmic lipids and sometimes Reinke crystals.

Stromal luteomes are a rare ovarian tumor. It occurs more often in women in menopause. Located in the thickness of the cortical layer; consists of luteinized cells of the interstitial tissue of the cortical layer. These tumors are usually multiple, often bilateral, often accompanied by stromal ovary tecomatosis.

If the luteinized virilizing tumor of the ovary can not be attributed to any of the listed types, it should be included in the category of non-specific lipid-cell tumors. In the ovary with the virilizing tumor, atrophic changes are noted with the death of part of the follicular apparatus and the phenomenon of compression. The second ovary is either hypotrophic or not microscopically altered. Microscopically, a pathology characteristic of stromal tecomatosis can be observed.

[6], [7], [8], [9], [10], [11], [12]

Symptoms of the virilizing tumors of the ovaries

Symptoms of virilizing ovarian tumors are determined by the level and biological activity of the androgen secreted by the tumor and does 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 a corresponding clinical picture.

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

Simultaneously with the violation of the menstrual function, there is progressive  hirsutism, then the so-called androgenic alopecia, that is, male pattern baldness. Coarsening of the voice is added quite quickly. There is a noticeable defemination - the disappearance of secondary female sexual characteristics. Diminished in size and become "flabby" mammary glands, disappear fatty deposits on the hips, the physique is approaching the male. Gynecological examination attracts attention hypertrophy and virilization of the clitoris. Mucous membranes become atrophic, with a cyanotic hue. Dimensions of the uterus are reduced, sometimes it is possible to palpate an enlarged ovary.

When the colpocytological study showed a decrease in CI to O, the predominance of parabasal and basal cells of the epithelium. Symptom "pupil" is negative.

All these signs are pronounced, they appear suddenly (the patients can accurately indicate from which month they became ill) and are rapidly progressing. In the case of mixed androgen-estrogen secretion, these symptoms may not be so pronounced.

With virilizing tumors of the ovaries, the excretion of estrogens can be decreased, normal or elevated. The level of urinary excretion of 17-CS 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 the value of this indicator. Androsterone - (9.36 ± ± 1.04) μmol / s at n = 7 and 11-oxidized 17-CS - (7.62 ± 0.93) μmol / s for n = 6. Excretion 17 = ACS 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 VOJ significantly exceeds the norm - (15.58 ± 0.92) nmol / l at a norm (1.47 ± 0.41) nmol / l. The degree of its growth and determines the severity of the virile syndrome in general. Correlation between T-level and tumor size was not revealed.

The content of HG (LH and FSH) with virilizing tumors of the ovaries, as a rule, is not disturbed. According to our data, the LH level averaged (11.53 ± 2.5) ED / L at n = 8; FSH - (8.1 ± 2.7) ED / L for n = 7. In 4 patients the prolactin level appeared to be normal (588 ± 177) MED / L, while in the remaining patients the level of prolactin was significantly elevated (3249 ± 1011) MED / l. Galactorrhea in these patients was not observed.

In all patients under 18 years old, on the chest radiographs, the bone age corresponded to the sexually mature - the growth zones were closed, which is probably due to the anabolic effect of androgens. Violations of protein, carbohydrate and mineral metabolism in patients with virilizing tumors of the ovaries have not been revealed. About a quarter of the patients had obesity.

Among the characteristics of the flow should be noted rapid progression of all the symptoms of the disease. It is not excluded the development of virilizing tumors of the ovaries during pregnancy. Some patients have signs of hypothalamic-pituitary disorders, such as obesity II (15%) and III (10%) degrees, pink striae on the hips (5%), presence of endocraniosis on the radiograph of the skull (32%), increased blood pressure, neurological microsymptomatics (10%), characteristic changes in the EEG (3%). The presence of these symptoms sometimes makes diagnosis much more difficult.

Data on the state of the adrenal glands with virilizing ovarian tumors are of interest.

Diagnostics of the virilizing tumors of the ovaries

Diagnosis and differential diagnosis of virilizing ovarian tumors. It is not difficult to suspect a virilizing tumor with a pronounced clinical picture, but it is often difficult to identify the source of hyperandrogenism. The diagnosis is based on these clinical manifestations, a significant increase in the level of T in plasma and does not present difficulties with sufficient tumor size, allowing it to freely palpate. However, virilizing tumors of the ovaries are rarely large, often their diameter is 1-2 cm, which does not allow detecting a neoplasm even with pneumopelvigraphy or laparoscopy.

In addition, the presence of bilateral virilizing tumors of the ovaries, which also makes diagnosis difficult. At the same time, the introduction of laparoscopy and ultrasound into practice greatly increased the diagnostic capabilities. However, with a very small tumor size and with changes in the adrenal gland, the topical diagnosis is also difficult. In such cases, the method of separate catheterization of the ovary and adrenal glands with blood sampling is of great value for studying the androgen level. Lympho- and phlebography can be used.

Functional test with DM and HC in virilizing ovarian tumors is poorly informative, as there is no significant decrease or increase in T level in the blood, but the presence of a tumor in the body is indicated by a high initial level of T.

Do not forget about the possibility of metastases when determining virilizing tumors of the ovaries. Obligatory is the radiographic examination of patients.

Differentiating virilizing tumors of the ovaries follows with androsteromas, glucoandrosteromas, with stromal ovary tecomatosis, with post-pubertal form of adrenal cortex dysfunction.

With androsteremia, the clinical picture is the same as with virilizing ovarian tumors, the difference is only in the source of hyperandrogenism. In addition, with these tumors, excretion in the urine of 17-CS, as a rule, and in the case of glucoandrosteremia - and 17-ACS is usually increased. The introduction of DM does not reduce their elevated levels.

Methods of topical diagnosis (retropneumoperitoneum, ultrasound, computed tomography) help to identify the adrenal tumor, while similar methods of ovarian research determine their hypoplasia.

In post-pubertal form, dysfunction of the adrenal cortex with symptoms of virilization and impaired menstrual function show increased urinary excretion of 17-CS and a high level of T in the blood, well-suppressed DM. Simultaneously, the revealed bilateral hyperplasia of the adrenal cortex and ovarian hypoplasia finally resolve the issue of diagnosis.

With pronounced stromal ovary tecomatosis, viril symptoms are often observed, including alopecia, clitoris virilization, voice coarsening, that is, the clinic is in many respects similar to the VOY clinic. However, with stromal ovary tecomatosis, as a rule, there are symptoms of hypothalamic-pituitary disorders, areas of skin hyperpigmentation, there may be disturbances in carbohydrate metabolism, the disease as a whole progresses slowly, the level of T is lower than in VOA. Under the influence of DM, the level of T is reliably reduced, and stimulation of HG causes its significant increase. The increase in the size of the ovaries is bilateral.

[13], [14], [15], [16], [17], [18]

Treatment of the virilizing tumors of the ovaries

Treatment of virilizing tumors of the ovaries is only operative. Given the available literature data on neuroendocrine disorders after removal of the ovary, even one, and the young age of the patients, many authors adhere to the sparing, organ-preserving tactics of removing the tumor with maximum preservation of healthy ovarian tissue and mandatory biopsies of the second ovary.

Uterus is preserved in all cases. As stressed by SS Selitskaya (1973), maintaining a healthy ovary is the prevention of endocrine disorders, which are the background for the development of the tumor and the occurrence of relapses. Only in patients in menopause, removal of both ovaries and supravaginal amputation of the uterus body is possible. It is mandatory to examine the entire small pelvis and the omentum to exclude metastases. RT Dtsamyan recommends more active surgical tactics: extirpation or supravaginal amputation of the uterus body with appendages, but notes that the results of treatment of patients with virilizing ovarian tumors are more dependent on the histological type than on differences in the methods of treatment.

According to the research, in all patients in reproductive age, recovery of menstrual function, disappearance of signs of defemination, hirsutism and alopecia, softening of the voice were noted. A part of women under different terms after the operation had a pregnancy, which ended with urgent labor or artificial abortion.

Relapses of the disease or late metastases we have not revealed in any case.

Following the operation, a rapid and steady decrease in the T level to normal values occurs. In our opinion, the level of T after surgery can be used as an indicator of tumor recurrence. Chemotherapy in the postoperative period is performed only in the case of distant metastases. Patients should be under dispensary supervision with obligatory control of ovarian function according to TFD. In the case of a violation of ovulation, we use therapy aimed at stimulating it, for which the entire arsenal of hormonal agents (SEGP, pure progestins, clomiphene, etc.) can be used. Restoration of ovulation as an indicator of the full function of the ovaries is considered a necessary condition for the prevention of relapse.

Forecast

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

Work ability is not violated.

[19], [20], [21], [22], [23], [24], [25]