Complications of the first trimester of pregnancy: Spontaneous abortion. Trophoblast neoplasia - benign and malignant formations Disruption of trophoblast invasion

Content:

Trophoblastic disease is a rare pathology of embryo development that causes proliferative formations in the trophoblast. It is manifested by the abnormal development of the outer layer of the embryo.

Trophoblast is the material from which the outer walls of the shell of the embryo are formed.

Trophoblastic disease can lead to the following diseases:

• Benign lesions: complete and partial cystic drift.
• Transient formations: invasive cystic drift.
• Malignant tumors: chorionic carcinoma, trophoblastic epithelioma, tumor of the placental bed.

Cancer tumors are distinguished by the presence of metastases: metastatic, non-metastatic.

There are 4 stages of trophoblastic disease:

1. Placement of the tumor in the uterus without leaving it.
2. The tumor affects the broad ligament of the uterus, spreads into the vagina, but does not extend beyond the genitals.
3. The tumor is complicated by metastasis to the lungs.
4. The liver, spleen, kidneys, gastrointestinal tract, and brain are damaged.

An anomaly can be detected using computed tomography or ultrasound examination. An informative diagnostic method is a test for hCG in the patient's blood. Depending on the quality and stages of development, trophoblastic disease is treated by curettage, vacuum aspiration, chemotherapy, hysterotomy, complete removal of the uterus.

Causes

The likelihood of developing neoplasia increases with the age of the pregnant woman. The number of patients with trophoblastic disease after 40 years of age is 5 times higher than patients under 35 years of age. But even young women 25 years old have the disease.

Prerequisites for the appearance of pathological formations of the trophoblast:

• Influence of the special properties of the egg.
• Postponed viral infections.
• Weak immunity.
• Protein deficiency in the body.
• Hyaluronidase hyperactivity.
• Chromosomal abnormalities.
• Artificial and spontaneous abortion.

The chances of developing a malignant neoplasm increase in women who have suffered a benign trophoblast neoplasia. The causes of trophoblastic disease are not fully understood by medicine, which does not interfere with coping with the disease.

Signs

The most striking symptom of the appearance of neoplasms in the trophoblast is the volume of the woman's uterus inappropriate to the gestational age. The uterus may be too small or enlarged. However, in 20% of cases, its size corresponds to gynecological standards.

Another formidable symptom is the presence of luteal cysts in the ovaries - bilateral capsules capable of rapid growth. Luteal cysts can fill the entire pelvic area, causing severe pain in the lower abdomen and lower back. Even after removal of neoplasia and luteal neoplasms, cysts can develop again within the first 3 months.

Benign tumors

Bubble drift is a chorionic anomaly. Normally, it should have a villous coating. A photo of trophoblastic disease demonstrates that the pathology causes swelling of the chorionic villi:

With a cystic drift, the pathology takes the form of fluid-filled vesicles that replace the trophoblast. Depending on the area of ​​replacement, there are full and partial forms of cystic drift.

Pregnancy predictions are almost always negative. Full bladder drift in the 1st trimester leads to the death of the embryo. The partial form allows the fetus to be carried up to the 2nd trimester, however, the likelihood of premature birth increases, as a result of which the fetus also dies.

The danger of the disease lies in the ability of the vesicular villi, even when the pathological formation is removed, to enter the lungs of a woman, causing acute pulmonary failure and even death.

Residual villi can be malignant. The risk of malignancy increases with the age of a pregnant woman, an increase in the level of hCG in the blood, and the presence of a uterus inappropriate for the gestational age.

Symptoms

The main sign of skidding is intermittent spotting with a delay in the menstrual cycle (during pregnancy). You should also be wary of the symptoms that are usual for pregnant women: toxicosis, weakness, vomiting. The presence of luteal cysts in the ovaries, which can only be seen with CT and ultrasound, also speak of trophoblast pathologies.

Diagnostics and treatment

Diagnosis of benign neoplasia is carried out using ultrasound tomography. In making the diagnosis, the level of human chorionic gonadotropin that does not correspond to the gestational age also helps. The gynecologist can note the discrepancy between the size of the uterus and the timing of the development of the embryo.

Bubble drift must be removed. This is done using vacuum aspiration and curettage, as in early abortion. After that, you should make sure that all fragments are completely removed in order to avoid the remainder of the swollen chorionic villi inside.

Next, the level of hCG in the patient's blood is checked once a week for 2 months. An ultrasound scan of the pelvic organs is done every two weeks. With continued bleeding from the genital tract, an increase in the level of hCG and other signs of neoplasia, chemotherapy is resorted to.

In case of invasive cystic drift (3% of cases of benign neoplasia), an operation is performed to remove it, followed by the appointment of a course of chemotherapy.

Malignant tumors

Chorionic carcinoma is a tumor that develops from the epithelium of the outer shell of the embryo and contains elements of syncytio- and cytotrophoblast. Appears after the transferred cystic drift (50%), artificial termination of pregnancy (25%), ectopic pregnancy (5%).

Chorionic carcinoma can develop even if there is no pregnancy. Trophoblastic disease then arises from the germ cells of the female ovaries. Dislocation of neoplasia - mediastinum, lungs, brain and other functional organs.

Unlike cystic drift, chorionic carcinoma does not have villous structures. Chorionic carcinoma is a pleomorphic cytotrophoblastic formation surrounded by a rim of isolated cytoplasmic cells with significant hemorrhagic areas.

Symptoms

Chorionic carcinoma signs:

• Bloody vaginal discharge after surgery on the pelvic organs, abortion, childbirth, and cystic drift. At first, the bleeding is insignificant, but over time it increases, which is caused by damage to the blood vessels of the uterine mucosa and possible metastasis in the vagina.
• Intra-abdominal bleeding, which develops as a result of the location of chorionic carcinoma in the cavity of the fallopian tube. Bleeding is caused by deformation and destruction of the serous cover of the tube. Its occurrence can be triggered by metastases in the peritoneal organs: liver, kidneys.
• Intoxication and developing anemia as a result of significant blood loss, impaired blood clotting. There may be a fever caused by necrosis of the chorionic carcinoma nodes and their infection.
• Various symptoms depending on the location of the metastases. Cough, phlegm, chest pain, hypertension with spread of metastases to the lungs. Vomiting, headaches, paralysis, neurological symptoms with metastasis to the brain. Abdominal pain, abdominal bleeding, nausea with lesions of the gastrointestinal tract, urine with blood (hematuria) with kidney damage.

Diagnostics and treatment

In case of alarming symptoms, you should contact a medical institution. After the collected anamnesis, the doctor will prescribe:

• histological examination of the scraping of the uterus;
• check the level of human chorionic gonadotropin in the blood serum.

If there is a suspicion of metastasis to individual organs, an X-ray examination is indicated. A gynecologist can detect cyanosis of the mucous membrane of the uterus and cervix on a simple examination, and red bumps and grayish nodules seen in the vagina will indicate vaginal necrosis.

The most sensitive diagnostic method is ultrasound tomography.

Chemotherapy is the main tool in the fight against malignant tumors. The nature of chemotherapy and the extent of its impact are determined in accordance with the stage and prognostic factors.

Chemotherapy made it possible to reduce the number of surgeries to remove chorionic carcinoma. Surgery is practiced by surgeons only when uterine or intra-abdominal bleeding is diagnosed (that is, an emergency), and when neoplasia shows high resistance to chemotherapy.

Surgical intervention is advisable only for patients after 40 years of age who have already performed childbearing function. Then, in the presence of luteal cysts, the complete removal of the uterus and appendages is performed. Before extirpation, several courses of chemotherapy are prescribed to suppress the growth of tumor cells.

Following implantation embryo both in the chorion and in the endometrium, rapid and profound changes occur. Although these changes are carried out together, their significance will be easier to understand if, before considering changes in the uterus and the relationship between chorionic villi and endometrium, we study the early changes in chorionic villi.

Primordial cell masses from which chorionic villi arise, are at first only groups of proliferating cells of the trophectoderm. Some cells of trophectodermal origin, pushing out to the periphery, lose their cell boundaries and, as they say, constitute a trophoblastic syncytium, or syntrophoblast. Trophoblastic tissue rapidly spreads and forms elongated anastomosing strands, including variable spaces called trophoblastic lacunae.

In structure trophoblast at these early stages there is little resemblance to the characteristic branching villi seen in later flocks, and embryos with such an extended unformed trophoblast are usually called pre-villous.

Once embryos reach the end of the second week in their development, villi begin to form in the trophoblast. These newly formed villi initially consist exclusively of epithelium and do not contain a connective tissue backbone. They are called primitive (or primary) villi. And. Their differentiation proceeds very quickly, since even previllous cell masses begin to show two types of cells.

Outdoor cells increase, lose their intercellular boundaries and combine into a syncytium called syntrophoblast (plasmodiotrophoblast), while the cells lying deeper and making up the so-called cytotrophoblast (Langgans layer) remain smaller and retain distinct boundaries.

Developing villi remain without a mesenchymal base for a very short time. While the primary villi are formed, the vessels and mesoderm of allantois grow into the inner surface of the blastodermic vesicle wall. At the beginning of the third week after fertilization, the mesoderm enters the primary villi, and the trophoblast cells no longer fill the entire structure, but create an epithelial membrane over the skeleton of delicate connective tissue.

In the connective tissue base villi branching blood vessels soon appear. Such villi with a vascular connective tissue base are called "true" chorionic villi. By the end of the third week, the villi are ready for the absorption function. The villi retain their general structural plan unchanged throughout pregnancy, although at later stages of development their connective tissue base and blood vessels become better developed, and signs of regression appear in their epithelial membranes.

Invasion of the embryo into the endometrium

Invasive activity trophoblast continues for some time after the initial introduction into the endometrium. When the primary villi grow, they destroy the adjacent maternal tissue, possibly as a result of the action of a proteolytic enzyme produced by the cells that make up the outer layer of the trophoblast. This process increases the space occupied by the growing chorionic vesicle, and the solute of the disintegrating cells of the uterus is possibly used to nourish the embryo until a more efficient vascular exchange mechanism is formed.
Based on this assumption, the solute is commonly referred to as an embryotroph.

Later, as a result of invasion into endometrium this type of vascular exchange is created, on which the embryo depends during the rest of intrauterine life. When spreading in the mucous membrane of the uterus, the growing villi of the trophoblast come into contact with small blood vessels and destroy their walls. Although, apparently, the amoeboid cells of the trophoblast can to some extent close the opened vessels and delay the excessive outflow of blood, nevertheless the outflow of blood from the damaged vessels should continue, since the trophoblast secretes a substance that inhibits blood coagulation.

As it grows trophoblast there is also transudation of blood serum and lymph. As a result, the invaded villi end up in the destroyed areas of the endometrium, soaked in maternal blood and lymph. By this time, as mentioned above, the villi themselves are vascularized. The small vessels of the villi are in direct connection with the main intraembryonic vessels through the allantoid arteries and veins. All that remains for the heart of the embryo is to begin blood circulation, and the entire complex nutritional mechanism of the embryo will be able to take action. As already indicated when considering the early stages of the onset of the vascular system, the formation of blood circulation in human embryos occurs by the end of the third or the beginning of the fourth week after fertilization, or about two weeks after implantation.

E.K. Ailamazyan, O. I. Stepanova, S.A. Selkov, D.I. Sokolov

Research Institute of Obstetrics and Gynecology named after BEFORE. Otta SZO RAMS, St. Petersburg, Russian Federation

Cells of the mother's immune system and trophoblast cells: "constructive cooperation" to achieve a common goal

The review provides modern data on changes in the morphological and functional properties of trophoblast during pregnancy, the effect of cytokines produced by cells of the microenvironment, incl. maternal leukocytes, on the functional state of the trophoblast; the features of the interaction of the trophoblast with the cells of the mother's immune system during physiological pregnancy and during pregnancy complicated by preeclampsia are described. This work was supported by a grant from the President of the Russian Federation No. NSh-131.2012.7 and a grant from the Russian Foundation for Basic Research No. 13-04-00304A.

Key words: trophoblast, cytokines, lymphocytes, NK cells, macrophages, preeclampsia.

(Bulletin of the RAMS. 2013; 11: 12-21)

Introduction

Pregnancy is a unique example of the coexistence of tissues of different genetic origin in one organism. Blastocyst implantation is the result of intercellular interactions of trophoblast cells with the endometrium of the uterus. Fetal trophoblast cells in contact with the tissues of the mother's body differentiate into different populations of trophoblast cells, perform various functions during the development of the placenta, and are influenced by the cells of the immune system, which are present in excess in the decidua and placenta during pregnancy.

The cells of the mother's immune system play an important role in the formation of immunological tolerance in the mother-fetus system, the preparation of the endometrium for blastocyst implantation, the establishment of contact between the blastocyst and the endometrium of the uterus, the formation of the placenta and the subsequent provision of adequate functioning of the placenta and the protection of the fetus from pathogens. The study of the development of the human placenta is associated with the inaccessibility of the material, the complexity of reproducing the processes occurring in vivo, in vitro. Currently, some knowledge has been accumulated about the patterns of development of trophoblast cells and the participation of cells of the immune system in the formation of the placenta and interaction

E.K. Ailamazyan, O.I. Stepanova, S.A. Selkov, D.I. Sokolov

D.O. Ott Research Institute of Obstetrics and Gynecology North-West Branch under the Russian Academy of Medical

Sciences, St. Petersburg, Russian Federation

Cells of Immune System of Mother a ^ Trophoblast Cells: Constructive Cooperation for the Sake of Achievement of the Joint Purpose

In the present review modern data about change of morfo-functional properties of a trophoblast during pregnancy, and also about influence of the cytokines produced by cells of a microenvironment, including leucocytes of mother, on afunctional state of trophoblast is cited. Features of interaction between trophoblast and immune cells of mother are described within physiological pregnancy and within pregnancy complicated by preeclampsia. Key words: trophoblast, cytokines, lymphocytes, natural killer cells, macrophages, preeclampsia.

(Vestnik Rossiiskoi Akademii Meditsinskikh Nauk - Annals of the Russian Academy of Medical Sciences. 2013; 11: 12-21)

TOPICAL ISSUES OF OBSTETRICS AND GYNECOLOGY

with trophoblast cells. With some pathology of pregnancy, for example, preeclampsia, there is a local dysfunction of trophoblast cells and cells of the immune system, but this area of ​​knowledge is still not sufficiently studied.

Changes in the morphofunctional properties of trophoblast during pregnancy

After adhesion of the blastocyst to the endometrium, differentiation of trophoectoderm cells begins, giving rise to 2 types of trophoblast cells - syncytio- and cytotrophoblast (Fig.), Differing in morphological and functional characteristics (Table 1). The villous tree has an outer shell of syncytiotrophoblast, which protects the cytotrophoblast from direct contact with the mother's blood. The villous cytotrophoblast is considered a source of trophoblast stem cells necessary for the growth and regeneration of the trophoblast, and provides cell replenishment with invasive properties. Cytotrophoblast cells make up the bulk of the placenta formed in the first trimester of pregnancy. The syncytiotrophoblast is a single multinucleated structure that covers the fruit cells and is the first to enter the uterus. Syncytiotrophoblast

contains a large number of lysosomal granules with hydrolytic enzymes, does not have a proliferative function and grows due to cytotrophoblast cells located in the inner cavity of the blastocyst.

Syncytiotrophoblast cells perform a trophic function until the hematotrophic type of nutrition of fruit cells is established, and also perform such functions as the exchange of oxygen, nutrients between the mother's body and the fetus, excretion of metabolites, synthesis of hormones and the formation of immunological tolerance.

The main structural element of the forming placenta is the villi. The villi can be loose and attached to the decidua. The fixed villi are called anchorage (see Fig.), And the structures at the base of their connection with the endometrium are called trophoblastic columns. The spatial location of trophoblast cells determines the direction of their differentiation: in loose villi, the cytotrophoblast differentiates into syncytiotrophoblast, and in the anchoring villi, into extravillous (extravillous) cytotrophoblast with invasive properties (see Fig.). Contact with the adhesive surface also stimulates cytotrophoblast cell proliferation. Cells of extravillous cytotrophoid proliferate from the trophoblastic columns.

Intervillous

Vorsina I trimester of pregnancy

Vorsin I trimester

pregnant

Rice. A. Types of trophoblast: I - cytotrophoblast; II - syncytiotrophoblast; III - endovascular trophoblast; IV - interstitial trophoblast (according to P. Kaufmann, 2003). B. The structure of villi in the first and third trimester of pregnancy (according to M. Mori et al., 2007). Note. * - fruit capillaries, STB - syncytiotrophoblast, CTB - cytotrophoblast.

Table 1. Expression of receptors and secretion of cytokines by various subpopulations of trophoblast cells

Subpopulation of trophoblast cells Expression of receptors for cytokines Expression of adhesion molecules Secretion of cytokines

Syncytiotrophoblast VEGFR-1, IFN yR1, IFN yR2, LIFR No data IL 10, SDF-1, IL 4, CSF-1, TNF a, IL 1p, VEGF, VEGF-C

Cytotrophoblast VEGFR-1, IFNyR1, LIFR, IL 10R, IL 4R, CXCR4, IGF1R E-cadherin, a6p4 IL 10, SDF-1, IFN y, IL 1p, IL 4, IGF II, VEGF, VEGF-C

Cytotrophoblast columns IFN yR1, IFN yR2 avp6, PECAM-1, a1P1, a5b 1 and a? B1 IGF II, VEGF

Endovascular cytotrophoblast LIFR, bFGFR afc “^ 3 VCAM-1, PECAM-1 VEGF-C

Interstitial cytotrophoblast LIFR No data VEGF-C

Extravillous trophoblast CCR1 (MCP-1 receptor), VEG-FR-1, IFN yR1, LIFR, CXCR4 a5, a1P1, a5P1, “vP3 and VCAM-1 VEGF, SDF-1, TGFp2, RANTES, IGF-I, IGF- II

BULLETIN OF RAMS / 2013 / No. 11

blast, among which there are 2 types of cells: interstitial trophoblast, migrating into the stroma of the endometrium, and endovascular trophoblast, migrating along the lumen of the vessels of the uterus. The extravillous invasive trophoblast expresses high levels of matrix metalloproteinases (MMPs) 2, 3, 9 and cathepsin. The interstitial trophoblast can form separate structures - giant cells (or groups of cells) in the stroma of the endometrium of the uterus, which have an invasive phenotype and represent the last stage of differentiation of the interstitial trophoblast. The interstitial trophoblast expresses LIFR (leukemia inhibitory factor receptor), which allows it to migrate into the decidua. The endovascular trophoblast is involved in the remodeling of the spiral arteries of the uterus, replacing the endothelial lining of the vessels. This process is accompanied by expression by endovascular cytotrophoblast cells of adhesion molecules characteristic of endothelial cells (ECs) (see Table 1), replacement of vascular ECs by trophoblast cells due to Fas- and TRAIL-mediated induction of EC apoptosis, induction of Fas- and TRAIL-mediated apoptosis vascular smooth muscle cells, which promotes vasodilation of the vessels of the uterus and increased maternal blood flow to the trophoblast.

By the third trimester of pregnancy, the terminal type of trophoblast villi predominates. The cytotrophoblast layer of the villi becomes thinner (see Fig.), However, its continuity throughout the entire volume of the villi is not disrupted. Syncytiotrophoblast prevails in cell volume over cytotrophoblast, contacts with maternal blood, forming a vasculo-syncytial membrane. At the same time, cyto- and, to a lesser extent, syncytio-trophoblast cells are susceptible to apoptosis.

An important role in the adhesion and implantation of the blastocyst, the penetration of the trophoblast into the endometrium and the development of the placenta are played by adhesion molecules, integrins, cadherins, selectins. E-cadherin is expressed on epithelial and blastocyst cells and mediates cell-cell adhesion through homophilic binding. With the participation of the E-cadherin molecule, the adhesion of the blastocyst to the endometrium occurs. This molecule is a characteristic marker of cytotrophoblast cells in the placenta. The expression of E-cadherin decreases with differentiation from cytes to syncytiotrophoblasts. During differentiation from cytotrophoblast into invasive cells of extravillous trophoblast, E-cadherin also ceases to be expressed by trophoblast, which is accompanied by an increase in the expression of integrin a5 on cytotrophoblast cells and increased invasiveness of cytotrophoblast cells. Also, integrins a3, a5, P1, P35, expressed by trophoecto-dermis, are involved in the adhesion of the blastocyst. The ligands of integrins in the endometrium are the components of the extracellular matrix. Integrins aurz and aur5 are vitronectin receptors, a4P1 and a5P1 are fibronectin receptors. The integrins a3P1, a1P1, and a2P1 bind to collagen. Integrin a6P4 has an affinity for the laminin family of proteins. Depending on the stage of differentiation of trophoblast cells, their expression of integrins (see Table 1) characterizes the modification of their invasive activity due to changes in specific binding to the components of the extracellular matrix. So, as cytotrophoblast cells differentiate into an invasive extravillous cytotrophoblast on their surface, the intensity

the level of expression of integrin complexes a6P4 with a simultaneous increase in the level of expression of a1P1, a5P1. The expression of integrin a5P1 by cytotrophoblasts negatively correlates with the migratory activity of the trophoblast. The cytotrophoblast cells at the base of the column are characterized by the expression of aurb and PECAM-1. There is also information on the expression of the integrins a1P1, a5P1, and a2P1 by the cells of the column. It has been shown under in vitro conditions that the column cytotrophoblast expresses integrins a1, a5, and P1. Secretion of laminin and fibronectin by cells of cytotrophoblast columns in vitro was noted, which promotes adhesion when binding to integrins expressed by the endometrium of the uterus. The extravillous cytotrophoblast is characterized by the expression of integrin molecules aur3 and VCAM-1, which determine invasiveness.

Different populations of trophoblast cells produce cytokines (see Table 1): interleukins (IL) 1, 4, 6, 8, 10, 11, granulocyte macrophage colony-stimulating factor (GM-CSF), interferon (IFN) γ, tumor necrosis factor (TNF) a, transforming growth factor (TGF) p, vascular endothelial growth factor (VEGF), as well as SDF-1, IGF, RANTES, which carry out auto- and paracrine regulation of trophoblast invasion. In addition, trophoblast is one of the main sources of MMP-2, -3, -9 enzymes and cathepsin in the placenta, which ensure the destruction of the extracellular matrix during invasion. With the development of pregnancy, the invasiveness of the cytotrophoblast decreases. At the end of pregnancy, extravillous cytotrophoblast is characterized by decreased secretion of MMP.

Cytokines, growth factors and enzymes, secreted in the placenta by trophoblast cells, placental cells and decidua, have a para- and autocrine effect on the functional activity of the trophoblast and their interaction with cells of the microenvironment. These interactions underlie the control of placental development and the maintenance of immunological tolerance in the mother-fetus system.

Influence of cytokines on the functional state of the trophoblast

Cytokines secreted by cells of the microenvironment in the area of ​​uteroplacental contact affect the functional state of trophoblast cells (Table 2). Endometrial cells secrete cytokines HGF, bFGF, GM-CSF, IL 1p, 6, 8. During implantation, the secretion of IL 6 by the endometrium is enhanced. Decidual NK cells (dNK) produce IFN y, IL 1p, 6, 8; IP-10, MIP-1a, GM-CSF, PlGF, CSF-1, TNF a, TGF p, leukemia inhibitory factor (LIF), angiopoietins-1 and -2 (Ang-1, Ang-2), VEGF- C. Decidual macrophages secrete IFN y, IL 1, 6, 10, VEGF, PlGF, angiopoietins, MMP. Placental macrophages secrete macrophage colony stimulating factor (M-CSF), VEGF, IL 1, 6, 8, 10, MCP-1, HGF. Decidual T-lymphocytes produce CSF-1, TNF a, IFN y, TGF p1, LIF.

The implantation process largely depends on the secretion of IL 1p, which is one of the first cytokines involved in the interaction of the endometrium and blastocyst during invasion. IL 1p enhances endometrial adhesiveness by stimulating the expression of P3 integrin by these cells. Also an important cytokine at the stage of implantation, invasion and decidualization of the endometrium

TOPICAL ISSUES OF OBSTETRICS AND GYNECOLOGY

Table 2. Influence of some cytokines on the functional activity of trophoblast cells

Cytokine Cytokine source Effect of cytokine on trophoblast cell function

IL 1p Endometrium, cytotrophoblast, decidual macrophages, syncytiotrophoblast, cytotrophoblast, placental macrophages, decidual CD8 + T cells Stimulates invasion, migration

IL 6 Cytotrophoblast, endometrium, decidual macrophages, placental macrophages, decidual CD8 + T cells Stimulates migration

TNF a Macrophages, trophoblasts, decidual CD8 + T cells Decreases viability; inhibits migration

IFN y Decidual macrophages, dNK cells, decidual CD8 + T cells Inhibits migration

IL 12 Macrophages, dendritic cells, decidual CD8 + T cells Inhibits invasion, stimulates IFN production in

TGF p dNK cells, trophoblast Inhibits differentiation into syncytiotrophoblast villi and stimulates the formation of anchoring structures, inhibits migration

IL 11 Endometrium (maximum after implantation), cytotrophoblast Inhibits migration, stimulates migration

IL 10 Decidual macrophages, placental macrophages, trophoblasts, decidual CD8 + T-lymphocytes Supports viability, autocrine inhibitor of MMP-9 production, inhibits invasion

IL 4 Trophoblast, fetal endothelial cells, T-lymphocytes In combination with TNF a stimulates the production of thymic stromal lymphopoietin, which stimulates the proliferation and invasion of the trophoblast

IL 13 Cytotrophoblast and syncytiotrophoblast of the first trimester of pregnancy, activated T-lymphocytes No data

LIF Endometrium, trophoblast Stimulates proliferation and migration

HGF Endometrium Anti-apoptotic action, stimulates migration, proliferation, invasion

EGF Trophoblast, decidua Anti-apoptotic effect on cytotrophoblast cells, stimulates trophoblast cell differentiation, migration, proliferation, invasion

IGF-I, IGF-II Fibroblasts, extravillous cytotrophoblast, invasive cytotrophoblast Stimulates trophoblast cell differentiation; proliferation, migration and invasion, reduces the expression of a5P, trophoblastomas

SDF Trophoblast Supports viability, stimulates proliferation and migration

PDGF Endothelial cells, monocytes Stimulates proliferation

bFGF Trophoblast, endometrium, endothelial cells Stimulates differentiation and proliferation

PlGF Decidual macrophages, trophoblasts, endothelial cells upon activation Supports viability, proliferation

VEGF-A Decidual macrophages, placental macrophages, trophoblast, endothelial cells Stimulates proliferation, stimulates the expression of aura integrins,

VEGF-C dNK cells, trophoblast Increases resistance against NK cell cytotoxicity

GM-CSF Trophoblast, large granular endometrial lymphocytes Stimulates trophoblast cell differentiation; proliferation

M-CSF (CSF-1) Placental and decidual macrophages, syncytiotrophoblast, decidual NK cells Stimulates the differentiation of trophoblast cells into syncytiotrophoblast

MCP-1 Placental and decidual macrophages, trophoblast No data

IP-10 Endometrial stromal cells, monocytes Stimulates migration

IL 8 Endometrium, placental and decidual macrophages, endothelial cells, decidual CD8 + T cells Stimulates migration, viability, expression of integrins a1 and p5, production of MMP and invasion

is LIF. LIF is involved in the stimulation of implantation, incl. through increased secretion of prostaglandin E2, which promotes blastocyst adhesion and further decidualization. In the first trimester of pregnancy, all types of trophoblast cells express the LIF receptor. LIF itself is expressed in the endometrium. Invasions of trophoblast cells are promoted by EGF, HGF.

The maintenance of the viability of trophoblast cells is promoted by IL 10 and PlGF, IL 1p - indirectly, by stimulating the secretion of IL 8 by the endometrium, as well as by SDF, exerting an antiapoptotic effect. TNF a inhibited the growth of the primary culture of trophoblast cells, while the Jeg-3 choriocarcinoma cell culture had no effect. EGF inhibits apoptosis

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cytotrophoblast and does not affect the viability of the syncytiotrophoblast. HGF inhibits apoptosis of trophoblast cells.

The differentiation of trophoblast cells is controlled by the cytokines EGF, GM-CSF, bFGF. It was found that the factors EGF, hCG, M-CSF, GM-CSF, IGF-I stimulate the differentiation of cytotrophoblast in the direction of the villous cytotrophoblast, while TGF p promotes the formation of anchoring structures of the trophoblast. LIF promotes syncytiotrophoblast formation from cytotrophoblast.

Cytokines HGF, EGF, IL 11, LIF, SDF, IL 1p, IL 6, IP-10 (CXCL10), IL 8 have a stimulating effect on trophoblast migration. On the contrary, IFN y, TGF p, TNF a in vitro, IL 11 have an inhibitory effect on trophoblast migration. IGF-I stimulates trophoblast migration, incl. through the induction of internalization of a5P1. The proliferation of trophoblast cells is stimulated by EGF, HGF, VEGF, PlGF, LIF, GM-CSF, PDGF, bFGF, SDF.

Cytokines also control the secretory activity of trophoblast cells. IL 6 stimulates their production of MMP-2 and -9, HGF; TNF a enhances the production of collagenases by trophoblast; M-CSF also stimulates the production of MMP-9. TNF a enhances the secretion of VEGF by trophoblast, which contributes to the maintenance of the viability and functional activity of trophoblast cells in the first trimester of pregnancy. IL 1p stimulates the secretion of MMP-9 and LIF by trophoblasts. In turn, the effect of LIF on the trophoblast stimulates the secretion of tissue inhibitors of matrix metalloproteinases (TIMP) -1 and -2, which can inhibit trophoblast invasion. IFN y inhibits the production of MMP-2 by trophoblast. In vitro, it was shown that IL 12 has an inhibitory effect on the secretion of MMP-2 and -9 choriocarcinoma cells and a stimulating effect on the production of TIMP-1, but the mechanism of this effect remains unclear. TGF p may also be involved in inhibiting the proliferation and invasion of trophoblast due to the stimulation of TIMP and a decrease in the activity of MMP-9. Due to the aforementioned effect, TGF p may be one of the mediators of impaired trophoblast invasion during gestosis.

Currently, the mechanisms of switching the expression of integrins by trophoblast cells as they differentiate remain poorly understood. It was shown that the expression of a5, a1, and HLA-G is associated with the expression of IL 1p, which may indicate the participation of this cytokine in trophoblast differentiation. In trophoblast cells of the TCL-1 and Jeg-3 lines, the participation of TNF a and VEGF in an increase in the expression level of avP3 integrins by trophoblast cells was proved. It was found that VEGF stimulates avP3 aggregation activity. Integrin avP3 is usually expressed on EC, but during differentiation of extravillous cytotrophoblast of columns into endovascular trophoblast, its expression is an important mechanism in remodeling of spiral arteries, in particular, in the formation of junctions between EC of spiral uterine arteries and invasive trophoblast. It was found that LIF inhibits the expression of P4 integrin mRNA in the primary culture of trophoblast cells, which may indicate the stimulating effect of LIF on trophoblast differentiation towards invasive cytotrophoblast. With the participation of TGF p, there is an increase in the expression of integ-

nov a1, a5, ay determining its inhibitory effect on trophoblast migration.

The main producers of cytokines in the area of ​​uteroplacental contact are the cells of the immune system from both the mother and the fetus. It was found that 40% of decidua cells are represented by maternal leukocytes. Of these, up to 70% are NK cells, 20-30% are macrophages, and up to 10% are T cells. These cells control the decidualization of the endometrium and the functional activity of the trophoblast not only through the production of cytokines, but also through ligand-receptor interactions.

Interaction of trophoblast with cells of the immune system

The cells of the maternal immune system play an important role in the differentiation and invasion of trophoblast cells into the maternal endometrium. Decidual NK cells and macrophages are located along the spiral arteries of the uterus and are the main sources of cytokines in the decidual membrane of the uterus. It has been shown that, despite the ability of NK cells to secrete the cytokines IFN y, TNF a and TGF p, which inhibit trophoblast invasion, secretory factors of decidual NK cells can stimulate the migration of extravillous trophoblast, for example, due to IL 1p, 6, 8, IP- 10, LIF. Also, decidual NK cells stimulate the secretion of MMP-9 by trophoblasts and reduce the level of apoptosis of trophoblast cells. However, other molecules secreted by the trophoblast are probably involved in the control of the secretion of cytokines by NK cells (which ones are currently unclear). Thus, it was found that when NK cells of peripheral blood come into contact with trophoblast cells, the expression of intracellular TNF a by NK cells decreases, but this effect is independent of the expression of the HLA-G locus molecule. Decidual NK cells have an increased ability to secrete IFN in comparison with NK blood cells. The secretion of IFN y by NK cells and macrophages inhibits trophoblast migration, limiting its penetration into the endometrium. This effect is especially important in the third trimester of pregnancy and contributes to the inhibition of trophoblast invasion. The inhibitory effect of IFN y on trophoblast invasion into the decidua occurs due to a decrease in the activity of MMP-2 and -9.

Cytotoxic CD8 + T cells of the decidual membrane secrete IFN y, IL 1, 2, 6, 8, 10, 12 and TNF a and thus participate in the regulation of trophoblast cell invasion. In late pregnancy, IFN y and TNF a secreted by CD8 + T cells are involved in limiting trophoblast invasion. The cytotoxic effects of CD8 + T cells on fetal cells also contribute to limiting trophoblast migration and invasion.

CD4 + T-lymphocytes in the decidua perform the function of maintaining immunological tolerance during the physiological course of pregnancy. Indirectly (through dendritic cells) CD4 + T-lymphocytes can control the activity of cytotoxic CD8 + T-lymphocytes in the decidua during physiological pregnancy. The content of T-regulatory cells in the decidua is much higher than in the endometrium of non-pregnant women, and in the peripheral blood, on the contrary:

TOPICAL ISSUES OF OBSTETRICS AND GYNECOLOGY

There are more T-regulatory cells in non-pregnant women compared to pregnant women. This indicates the predominant migration of T-regulatory cells into the decidua during pregnancy. In vitro contact with trophoblast cells demonstrated specific activation of CD8 + T-regulatory cells. The CD8 + T regulatory lymphocytes activated as a result of interaction with trophoblast have the properties of increased IL 10 secretion, absence of IFN and TGF p secretion, high expression of CD28, and absence of FasL expression. In addition, they have no cytotoxic activity. Their action can be aimed at correcting the antibody-dependent immune response during pregnancy. T regulatory cells (CD4 + and CD8 +) generally play an important role in maintaining maternal tolerance towards the fetus through the secretion of IL 10 and TGF p, which reduce the cytotoxicity of CD8 + T lymphocytes and NK cells against trophoblast cells, increasing their viability ... The activity of these cells is especially high in the first trimester of pregnancy when a blastocyst is implanted into the endometrium of the uterus.

Decidual macrophages, being one of the sources of IL 10, and also due to the increased production of CCL18, CD209, IGF-1 in the first trimester of pregnancy, contribute to the formation of immunological tolerance. Placental macrophages, in addition, stimulate the growth and differentiation of the trophoblast.

The placenta is a unique example of the immunological tolerance of maternal cells to semi-allogeneic fetal tissues. The mechanisms of the implementation of immunological tolerance during physiological and pathological pregnancy remain insufficiently studied at present, although the participation of some molecules in these processes has been shown. One of the mechanisms of induction of immunological tolerance during pregnancy is the production by trophoblast of a nonclassical molecule of the HLA-G locus. As a result of alternative splicing, 4 membrane isoforms of molecules of the HLA-G locus and 3 soluble ones are formed. It was shown that the enhancement of the expression of the HLA-G locus molecule by trophoblast cells is facilitated by the effect of LIF. An important feature of the soluble forms of molecules is dimerization, since it has been shown that dimers are more active than the monomeric form of the molecule. All isoforms have the same functional purpose. The expression of HLA-G on the trophoblast is stimulated by the action of progesterone, IL 10. The receptors of the HLA-G locus molecules are expressed on NK cells, cytotoxic CD8 + T lymphocytes and CD4 + T lymphocytes, monocytes / macrophages, and dendritic cells. The HLA-G locus molecule inhibits the cytotoxic and proliferative activity of NK cells, cytotoxic CD8 + T lymphocytes, stimulates the formation of T regulatory cells, and influences the maturation and functions of antigen presenting cells. When interacting with trophoblast through molecules of the HLA-G locus, dendritic cells reduce the expression of costimulatory molecules, increase the secretion of IL 6 and 10, decrease the secretion of IL 12 and TNF a, and promote the differentiation of T-regulatory cells. On the dendritic cells themselves, the expression of molecules of the HLA-G locus is also noted, which is enhanced by the action of IL 10, the production of which is increased during physiological pregnancy by decidual macrophages. Increased expression of HLA-G locus molecules by dendritic cells promotes the formation of immunological

genetic tolerance. It has been established that the HLA-G locus molecule is able to stimulate the secretion of cytokines IFN in, G-CSF, IL 1, 6, 8 decidual NK cells and IL 1, 6, 8 and TNF in decidual macrophages, and reduce the secretion of TNF a by NK cells. Since the secretion of the aforementioned cytokines during implantation and early pregnancy determines the penetration of the trophoblast into the endometrium and the development of the placenta, macrophages and NK cells can promote trophoblast invasion in the presence of HLA-G. The soluble form of HLA-G secreted by trophoblast stimulates dNK proliferation. On T-lymphocytes, the soluble form of HLA-G has an inhibitory effect, predominantly inhibiting the activity of CD8 + cells in comparison with CD4 + cells, and thus promoting the secretion of the anti-inflammatory spectrum of cytokines.

Another mechanism for the formation of immunological tolerance towards fetal cells is the expression of the CD200 molecule by trophoblast cells. All 4 known CD200R isoforms are expressed in the placenta. Interaction of CD200 with CD200R receptors, expressed in incl. on dendritic cells, promotes the differentiation of the latter, leading to the induction of tolerance through the formation of a pool of T-regulatory cells. Also, the presence of CD200 on the trophoblast determines the predominant activation of Th2 lymphocytes, which contributes to the physiological development of pregnancy.

Molecules of the B7 family of receptors are involved in the formation of an adaptive immune response and the formation of immunological tolerance during tissue transplantation, as well as during pregnancy. In the placenta, in particular in the villous and extravillous cytotrophoblast, as well as syncytiotrophoblast, a high expression of the B7-H1 molecule (PD-L1, CD274) is observed throughout pregnancy. The expression of B7-H1 by trophoblastomas is higher in the II and III trimester of pregnancy compared to I. Expression of B7-H1 by trophoblast cells is stimulated by the cytokines EGF and IFN y. Also, stromal cells of the decidual membrane, the bulk of which are macrophages and dendritic cells, express B7-H1. The ligand B7-H1 is the PD-1 (CD279) molecule located on decidual T cells. The B7-H1 / PD-1 interaction causes a decrease in the intensity of secretion of IFN y and TNF a by T lymphocytes. Blockade of the CD274 / CD279 interaction leads to increased apoptosis, a decrease in the content of T-regulatory cells in the placenta and an increase in the number of Th ^-lymphocytes, which impairs tolerance in the mother-fetus system.

Disruption of the functional activity of trophoblast cells during preeclampsia

Until now, gestosis remains one of the most severe complications of pregnancy. Perinatal mortality in this pathology is 3-4 times higher than in healthy women. Despite the intensive study of pathological changes in the body of pregnant women accompanying the development of gestosis, it is currently not possible to identify the triggering mechanism of its development. During pregnancy complicated by preeclampsia, changes in the population composition of lymphocytes in the placenta, changes in the secretory and functional activity of placental cells and functional

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activity of trophoblast cells. At the same time, the mechanisms of intercellular interactions remain poorly understood.

Impaired angiogenesis in the placenta, insufficient development of the vasculature and impaired invasion of the trophoblast lead to insufficient oxygenation of the placenta, fetal hypoxia and its retarded development. With gestosis, a decrease in the expression of MMP-2 EC by fibroblasts of intermediate villi and in the extracellular matrix of the placenta was shown, which may be a consequence of a reduced activity of trophoblast and its insufficient invasion. Under in vitro conditions, it was noted that in the presence of peripheral blood serum obtained from pregnant women with preeclampsia, trophoblast invasion is impaired. It is believed that insufficient invasion of the trophoblast into the endometrium of the uterus may be associated with impaired expression of adhesion molecules by endovascular trophoblast during remodeling of the spiral arteries. With preeclampsia, a high expression of a6P4 trophoblast cells and a weak expression of aF are observed, which indicates a low differentiation of the cytotrophoblast. Shallow invasion of the trophoblast into the endometrium during gestosis is accompanied by increased expression of E-cadherin by the cytotrophoblast of the decidual membrane. Expression of these molecules during the physiological course of pregnancy characterizes a cytotrophoblast with low invasiveness. Significantly reduced expression and secretion of HGF by placental explants in gestosis, compared with physiological pregnancy, can also contribute to the violation of trophoblast invasion during pregnancy complicated by gestosis. In addition, in this condition, there is an increased expression in the placenta and decidua of the IGF binding protein (IGFBP-1), as well as its increased content in the serum of pregnant women. An increase in IGFBP-1 production in this pathology is one of the mechanisms for disrupting trophoblast invasion, since IGFBP-1 restricts invasion.

Increased expression of ICAM-1 on trophoblast cells during gestosis ensures migration of maternal leukocytes to the placenta. As a result, the development of gestosis is characterized by local inflammation with the participation of mononuclear cells in the placenta. There is an increased level of deposition of fibrin in the placenta with the participation of macrophages and their accumulation around the spiral arteries of the uterus. Under in vitro conditions, it has been shown that decidual macrophages have an increased secretion of TNF a and suppress trophoblast invasion. Also, TNF-a inhibits the production of trophoblasts, which is important for the formation of fetoplacental contact, chorionic gonadotropin and participates in the disruption of trophoblast syncytialization. These negative effects of macrophage activation can be "canceled" by IL 10, however, with gestosis, a decreased content of IL 10 in the serum of pregnant women and a decreased expression in the trophoblast villi were recorded.

In gestosis, decidual NK cells and lymphocytes secrete an increased amount of IL 1, 2, IFN y compared to physiological pregnancy, while decreasing the secretion of IL 5 and 10. The predominance of proinflammatory cytokines leads to the activation of placental and decidual macrophages. Increased expression of IFN y in the placenta during gestosis with reduced expression of its receptors can contribute to the disruption of the functional activity of the trophoblast. Since IFN γ is involved in the termination of excessive trophoblast invasion in the II and III trimester of pregnancy, an increase in its content in the decidua during

preeclampsia disrupts the invasion of the trophoblast into the endometrium. In addition, in the placenta, there is a decreased expression of cytokines VEGF, bFGF and increased expression of PDGF, TGFp, MMP-2. Such changes can lead to reduced activity of proliferation and migration of the trophoblast.

A decrease in the intensity of expression by trophoblasts of molecules of the HLA-G locus, accompanied by a change in the secretory activity of placental cells, may be one of the mechanisms of impaired immunological tolerance during pregnancy. Reduced expression of the FasL molecule by trophoblast cells during gestosis leads to a decrease in the level of their protection against the cytotoxic effect of CD8 + T-lymphocytes, susceptibility of trophoblast to damage by NK-cells and CD8 + T-lymphocytes of the mother, an additional decrease in the invasive ability of trophoblast and its viability. Under conditions of hypoxia in the placenta with gestosis, in violation of immunological tolerance, a decrease in the level of expression of the CD274 molecule by trophoblast can also contribute, since an inhibitory effect on its expression of a reduced oxygen content has been shown.

According to different authors, apoptosis in the placenta during gestosis increases or remains unchanged compared with physiological pregnancy, combined with a change in the expression of factors that control it. Expression in the placenta of Fas (CD95) during gestosis is reduced, and TRAIL is increased. The interaction of Fas / FasL molecules plays an important role in the remodeling of spiral arteries; therefore, the registered decrease in Fas expression in the placenta during gestosis may be one of the mechanisms of impaired remodeling of uterine arteries and insufficient invasion. Since the participation of TRAIL has been shown predominantly in the protection of placental cells from the cytotoxic action of lymphocytes, an increase in the level of its expression during gestosis can be a compensatory mechanism directed against the increased cytotoxic activity of lymphocytes and NK cells noted in this pathology.

Conclusion

The invasion of the trophoblast into the endometrium of the uterus is mediated by a wide range of molecules, including integrins, cadherins, and cell adhesion molecules. The production of cytokines by trophoblast and the expression of adhesion molecules by it vary depending on the type of trophoblast, the nature and depth of its penetration into the decidua. The regulation of the expression of integrins a5, a1, ay P3, molecules of the HLA-G locus, secretion of cytokines and MMPs, as well as the functional characteristics of trophoblast cells, is under the control of microenvironmental cells, among which the cells of the mother's immune system localized in the decidua are of the greatest importance. At the same time, trophoblast cells modulate the functions of cells of the immune system through the secretion of cytokines and the expression of surface molecules. The formation of immunological tolerance in the mother-fetus system is largely determined by the expression of nonclassical molecules of the HLA-G locus, molecules B7-H1, CD200 and FasL by trophoblast cells, suppression of the cytotoxic activity of NK cells and CD8 + T lymphocytes by trophoblast cells, production of anti-inflammatory cytokines by trophoblastomas, attraction and stimulation of differentiation of T-regulatory cells

TOPICAL ISSUES OF OBSTETRICS AND GYNECOLOGY

current. Disruption of the equilibrium interaction between the cells of the trophoblast and the cells of the mother's immune system leads to the development of pathologies of pregnancy, incl. to gestosis. Violation of the expression by trophoblast cells of integrins a6P4, a ^, E-cadherin, ICAM-1, as well as the expression of molecules of the HLA-G locus, changes in the production of cytokines by both trophoblast cells (IL 10) and the mother's immune system (TNF a, IFN y, IL 1p, 2, 10, 15) is accompanied by impaired differentiation

trophoblast cells, impaired immunological tolerance in the mother-fetus system, reduced protection of trophoblast cells from the cytotoxic action of maternal lymphocytes, and the development of a local inflammatory reaction in the uteroplacental contact zone.

This work was supported by a grant from the President of the Russian Federation No. NSh-131.2012.7 and a grant from the Russian Foundation for Basic Research No. 13-04-00304A.

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In the second trimester of pregnancy (13-20 weeks), the mass of the placenta continues to increase due to the growth of new villi. Weekly the mass of the placenta increases by 10 g. Lobules - cotyledons - begin to form. At 16 weeks of gestation, the weight of the placenta and the fetus are leveled, then the weight of the fetus begins to overtake the weight of the placenta.
With the growth of the fetus, more blood is required in the intervillous space, therefore, the number of capillaries in the placenta increases, and in each villi the capillary approaches from the center to the periphery for better exchange with the mother's blood. The capillaries of the villi pulsate rhythmically, the villi lengthen and shorten. The volume of blood in the intervillous space is 300-350 ml. But with the growth of the fetus, the placenta needs even more blood, and then the phenomenon of gestational restructuring of the uteroplacental vessels arises, providing a 12-fold increase in the volume of BMD.
The essence of gestational restructuring of the spiral arteries of the subplacental uterine zone under the influence of trophoblast cells is the disappearance of muscle cells from the vascular walls. From narrow convoluted vessels, they turn into wide vessels with a pliable wall.
Recall that as a result of the first wave of trophoblast invasion (the first 12 weeks of pregnancy), the decidual segments of the spiral arteries are replaced by the trophoblast growing in them and the developing fibrinoid. By the end of the I trimester of pregnancy, the trophoblast cells occupying the lumen of the spiral arteries leave it, which is accompanied by a significant blood flow to the intervillous space.
During the second wave of trophoblast invasion (14–20 weeks), the latter is introduced into the walls of arterial vessels located in the myometrial segment. The process of gestational restructuring of the uterine vascular system is accompanied by intensive production of E2 class prostaglandins, a decrease in total vascular resistance and, accordingly, a decrease in systemic blood pressure in the mother (on average by 10-12 mm Hg).
The transformed coiled vessels provide improved placental perfusion and, since they are devoid of smooth muscle cells, they become unable to respond to the action of vasoconstrictor factors. The entire process of gestational vascular remodeling of the spiral arteries of the uterus is completed by the end of the 20th week of pregnancy.
From 20 weeks, the active growth of immature intermediate villi begins and the type of stroma changes to a denser one. Insufficiency of the second wave of cytotrophoblast invasion disrupts the process of further formation of placental villi. A variant of chaotic and sclerosed villi develops, the branching of small villi becomes erratic, the formation of new capillaries decreases, the stromal component prevails in the placental tissue in the absence of the vascular and epithelial cover of the villi. All this increases the pathological permeability of the placental barrier.
The placenta is considered an extraembryonic organ of the fetus, although it includes the blood vessels of both the fetus and the mother, closely adjacent to one another. Of all the organs of the fetus, the placenta is most intensively supplied with blood (40% of the fetal cardiac output). Towards the end of pregnancy, it competes with the fetus for nutrients, consuming most of the glucose and oxygen delivered to the uterus. The functional unit of the placenta is cotyledone. In the mature placenta, there are about 120 of them, they are grouped into lobules visible to the naked eye. Each cotyledon is a stem villus extending from the chorionic plate and dividing into numerous branches. Stem villi, dividing, form villi of the second and third order, which in turn give rise to terminal villi, which are directly involved in the metabolism between mother and fetus. Cotyledons form around the spiral arteries that enter the decidual lining of the uterus. The center of each cotyledon contains a cavity that receives blood from the spiral artery. Initially, the blood moves vertically to the surface of the chorionic plate, then spreads in the lateral direction, penetrating between the terminal villi (at this stage, an exchange of substances between the maternal and fetal blood occurs).
In this case, the blood is depleted in oxygen and nutrients, saturated with carbon dioxide and waste products of the fetus. Then the blood enters the narrow venous channels between the cotyledons, through which it moves back to the decidua, where it enters the uterine veins and returns to the maternal bloodstream. Thus, the maternal and fetal blood flow is separated by three tissue layers: trophoblast cells, villous connective tissue, and fetal capillary endothelial cells. However, ultramicroscopic examination of the terminal villi located inside the cotyledon reveals numerous areas in which the endothelial and trophoblast cells merge, forming the thinnest vascular syncytial membrane, through which the diffusion of gases and nutrients mainly occurs.
The flow of maternal blood to the placenta increases during pregnancy from 50 ml / min in the I trimester to 600 ml / min at the time of delivery.
6.3.4.1. Violation of placentation
It is known that a violation of the first wave of trophoblast invasion into the wall of the decidual arteries leads to primary placental insufficiency, a decrease in the blood supply to the placenta and the fetus. This most often leads to spontaneous miscarriage in the 1st trimester.
Disruption of the second wave of trophoblast invasion into the walls of the myometrial spiral arteries is also accompanied by a decrease in placental perfusion.
Doppler study of BMD can determine a decrease in arterial blood flow and, in some cases, difficulty in venous outflow at 21-24 weeks of gestation, which is a direct consequence of the failure of the second wave of trophoblast invasion. It is these patients that should be attributed to the risk group for the development of placental insufficiency, fetal IUGR and late gestosis.
The causes of impaired trophoblast invasion in the second trimester of pregnancy can be maternal diseases (arterial hypertension, connective tissue diseases, diabetes mellitus, APS, infections (gestational or chronic pyelonephritis), neuroendocrine metabolic disorders (hypothalamic syndrome, obesity).
All of these diseases lead to the formation of a small placenta or a thin spread placenta. In such clinical observations, hemorrhages (heart attacks), basal hematomas or areas of ischemic necrosis of cotyledon (a consequence of vascular thrombosis) are often detected.
Clinical signs of impaired placentation are as follows:
placental insufficiency;
late miscarriage;
preeclampsia;
IUGR of the fetus.
The structure of the placenta during these periods is characterized by the complication of the villous tree, the differentiation of the villi into three types:
support villi;
intermediate immature villi;
intermediate mature villi.
At the beginning of the second trimester of pregnancy, intermediate immature villi dominate. The intermediate differentiated ones only appear and make up no more than 10-15% of the villi mass. By 24-27 weeks of gestation, intermediate mature (differentiated) villi and 5-10% of terminal (final) villi predominate. The diffuse capacity of the placenta increases, which also contributes to the growth of the fetus. The placenta provides a transplacental transition from the mother to the fetus with class G immunoglobulins, which protect the fetus from exposure to an infectious agent. When the mother's IgG level is reduced (chronic infection, the presence of a long-term illness, stress), the risk of fetal infection increases, and therefore the intravenous administration of immunoglobulin to a pregnant woman is necessary. In an acute infection, which the mother first encounters, IgM is secreted.
The second wave of cytotrophoblast invasion, the peak of which occurs at 22-24 weeks of gestational age, coincides with the need to increase the blood supply to the fetal brain, since at this time the structural construction of the higher parts of the central nervous system is completed.
During pregnancy, the placenta produces hormones that are similar in structure and action to the following hormones and biologically active substances:
hypothalamic hormones:
- gonadotropin-releasing hormone,
- corticotropin-releasing hormone,
- thyrotropin-releasing hormone,
- somastatin;
pituitary-like hormones:
- HG,
- PL,
- chorionic corticotropin,
- adrenocorticotropic hormone;
growth factors:
- IPFR (insulin-like growth factor),
- EGF (epidermal growth factor),
- FGF (fibroblast growth factor),
- TFR (transforming growth factor),
- inhibin,
- activin;
cytokines:
- IL-1,
- IL-6,
- colony-stimulating factor;
protein hormones produced in the mother's body:
- prolactin,
- relaxin,
- protein-binding insulin-like growth factor,
- IL,
- colony stimulating factor,
- progesterone-associated endometrial protein;
proteins specific to pregnancy:
-? 1 glycoprotein,
- RAPP-A.
The hormones secreted by the placenta are essential for the growth of the fetus. They affect the intensity of metabolism, tissue growth, maturation of individual organs. Insulin-like growth factors coordinate the consistent acceleration of fetal growth in the third trimester of pregnancy. If the fetus has a body weight of 1100 g at 28 weeks of gestation, then a linear increase in body weight occurs every 6 weeks. So, at 34 weeks its weight is 2200 g, at 40 weeks - 3300 g.
Fetal hyperinsulinemia, which occurs in connection with maternal diabetes mellitus, leads to macrosomia, due to excess fat deposition. With IUGR, the level of insulin in the fetus is low, which further slows down its growth.
Deficiency of thyroid hormones delays the maturation of the skeleton and brain, disrupts the formation of surfactant in the lungs of the fetus.
Cortisol is needed to increase the elasticity of the lungs and release a surfactant to allow spontaneous breathing at birth.
In the fetal liver, cortisol stimulates the formation of (J-adrenergic receptors and the deposition of glycogen, which the fetus needs to release glucose and provide energy during childbirth and in the first hours after birth.
In the intestine, cortisol stimulates the proliferation of villi, the synthesis of digestive enzymes that are necessary for the newborn when switching to enteral nutrition.

Trophoblastic disease is a group of benign and malignant neoplasms originating from placental trophoblasts. Having a different histological structure, various forms of trophoblastic disease have such common features as origin from the human placenta, a common maternal gene and the secretion of human chronic hepatitis.

Trophoblastic disease is relatively rare. So, for 1000 births there is 1 case of cystic drift, for 100,000 births or abortions - 2 cases of chorionic carcinoma.

Most often, cystic drift affects women aged 20-24 years, chorionic carcinoma develops mainly in 25-30 years. For the invasive form of cystic drift, the main peak of the disease is 40-49 years.

Trophoblastic disease. Etiopathogenesis

It is still unclear whether cystic drift, invasive cystic drift and chorionic carcinoma are the same in etiopathogenetic terms. First of all, cystic drift can be regarded as a benign tumor process only with certain restrictions, although the presence of cystic drift significantly increases the likelihood of malignant chorionic carcinoma. The differences between gallbladder drift and invasive gallbladder drift are less significant and are based mainly on histological criteria and symptoms of the absence or presence of signs of trophoblast invasion into the myometrium.

Meanwhile, the long-term preservation of CG production after removal of the cystic drift from the uterine cavity indicates that in the absence of morphological criteria for malignancy, the disease, which was originally regarded as a true cystic drift, often acquires the properties of metastatic chorionic carcinoma. Some researchers believe that in these cases there is an independent development of both cystic drift and chorionic carcinoma, and the latter was not diagnosed in a timely manner. However, one cannot exclude a tumor transformation in the trophoblast tissue, which intensively proliferates with cystic drift. Thus, all trophoblastic tumors can be considered as a single etiopathogenetic process.

Viral transformation theory trophoblast gives leading importance to viral etiology, especially during influenza epidemics.

The rapid development of chorionic carcinoma almost at the zygote stage may be the result of a mutation. The pathologically altered egg cell causes the death of the embryo and the proliferation of plasma cells and Langhans cells.

Immunological theory. It is known that pregnancy hormones (HCG, progesterone, estrogens) have an immunosuppressive effect. Accordingly, during pregnancy, atrophy of the thymus gland, hypoplasia of the germinal centers in the lymph nodes, a decrease in the number of lymphocytes circulating in the peripheral blood, the tension of cellular immunity and the reaction of blast transformation are observed.

At the same time, during pregnancy, there is a metabolic predisposition to the development of a tumor. Metabolic conditions associated with increased production of PL and cortisol, which are necessary for the energy metabolism of the mother and the fetus, create a state of immunosuppression, which is characteristic of a malignant process.

The fertilized egg and fetus are considered as transplants in relation to the mother. An immune response develops to these antigens in a woman's body, and with the predominance of an immunological reaction in relation to the proliferation of trophoblastic elements, pregnancy ends in miscarriage. If the reaction caused by the antigens of the fetus is weaker than the proliferative changes in the trophoblast, then the immunological interruption of the undeveloped pregnancy does not occur, but a cystic drift develops.

Enzymatic theory is based on an increase in the level of hyaluronidase, which destroys the vascular wall with cystic drift by 7.2 times, with chorionic carcinoma - by 15.6 times compared to the normal level.

Protein deficiency theory. A lack of protein leads to a deficiency of genes in the chromosomes of the fertilized egg.

Trophoblastic disease. Classification

In accordance with the latest International Classification of Oncological Diseases (1995), among trophoblastic neoplasms, there are:

1. Bubble drift (complete or partial).
2. Invasive cystic drift.
3. Chorionic carcinoma or chorionepithelioma.
4. Chorionic carcinoma in combination with teratoma or embryonic cancer.
5. Malignant trophoblastic teratoma.
6. Trophoblastic tumor of the placental site.

According to the clinical course:

1. Benign.
2. Malignant.

Non-metastatic;

Metastatic:

a) low risk,

b) high degree of risk.

By the pathohistological structure:

1. Bubble drift.
2. Invasive drift.
3. Chorionic carcinoma.

Trophoblastic disease. WHO International Classification 10th revision (1995)

■ О01 Bubble drift

Excluded: malignant cystic mole (D39.2)

O01.0 Bubble drift classic

Bubble drift full

O01.1 Partial and incomplete vesicular drift

O01.9 Vesiculate mole, unspecified

Trophoblastic disease NOS

Bubble drift NOS

■ D39 Neoplasms undefined or unknown nature of female genital organs

D39.2 Placenta

Destructive chorioadenoma Bubble drift:

• invasive
• malignant

Excluded: cystic drift NOS (O01.9) Cytogenetically cystic drift is divided:

1. Complete - potentially malignant, having a diploid component exclusively of parental chromosomes with a 46XX karyotype.
2. Partial - has no tendency to malignancy and has a triploid karyotype (69).

Trophoblastic disease. International classification FIGO 1992 (Singapore):

Stage I - the lesion is limited to the uterus, there are no metastases.

Stage II - there are metastases in the vagina or in the small pelvis.

Stage III - there are metastases to the lungs.

Stage IV - there are other distant metastases.

Trophoblastic disease. Risk factors

The concept of risk factors in relation to the problem of trophoblastic disease is ambiguous. Several risk categories are considered in the problem of trophoblastic disease.

1. Age:

For women over the age of 40, the risk of the disease is 5 times higher than for women between the ages of 21 and 35; there is a slight increase in risk for women younger than 20 years old.

1. A history of early spontaneous abortion.
2. Previous pregnancies:

The number of patients with trophoblastic tumors in re-pregnant women is much higher than the number of patients with primary pregnant women.

1. Geographical region:

It is more common in the countries of the East compared to Western countries.

1. The risk of developing chorionic carcinoma is about 1000 times higher after a hydatidiform mole than after a normal pregnancy.
2. The risk of developing invasive bladder drift is higher after complete bladder drift.
3. The process of metastasis depends on the duration of the latency period and the duration of the symptoms of the disease:

The longer the latency period and the longer the symptoms of the disease exist, the more the likelihood of metastases increases.

Bubble drift

Vesiculate mole is not a true tumor. and only the need to differentiate the complete cystic drift from its invasive form and chorionic carcinoma dictates its inclusion in the group of trophoblastic neoplasms.

Vesicular drift is, in some cases, a chromosomally determined, pathologically altered villous chorion with hydropic transformation of the placenta - many bubbles of various sizes filled with a clear liquid completely (complete drift) or partially (partial drift) replace the placental tissue. Histologically, the vesicles are enlarged due to a pronounced edema of the chorionic villi with the formation of cavities containing a mucus-like fluid in the central parts of some of these villi. Elements of a cystic drift can be freely located in the uterine cavity and be associated with its wall.

Partial drift has differentiable embryonic tissue (trophoblast of the usual two-row type) and edematous villi, but without trophoblastic proliferation.

The following morphological characteristics (the last two are the most important) are characteristic of complete or classic cystic drift:

• severe swelling and an increase in villi;
• the disappearance of blood vessels;
• the epithelial cover of the villi is absent or undergoes dystrophic changes;
• there are Kashchenko-Gofbauer cells (with cystic drift, they are called Khaletskaya-Neumann cells);
• proliferation of trophoblast lining villi (both layers of trophoblast mix and the sequence of layers is disrupted);
• lack of germ tissue.

Complete cystic drift is observed in the first trimester of pregnancy, and the embryos in such cases die. With partial cystic drift, pregnancy can progress to urgent delivery with a viable fetus, but more often fetal death occurs at 14-16 weeks, or premature birth occurs with fetal death in the ante- or intrapartum period.

Fragments of vesicular villi spontaneously or during the evacuation of a drift from the uterine cavity can enter the venous bed and reach the pulmonary capillaries, causing acute pulmonary hypertension, pulmonary edema, and even death of a pregnant woman. Potential regression of the villi particles after removal of the cystic drift.

The most severe outcome is the development of chorionic carcinoma from the remnants of the cystic drift in 3.8-5% of cases.

A rare variant of cystic drift is invasive cystic drift (destroying cystic drift, intravenous form of cystic drift, destroying chorionadenoma, penetrating drift). It occurs in about 5-6% of cases. Invasive drift is characterized by growths with pathological germination and extensive local invasion with pronounced trophoblastic proliferation and a well-defined villous structure.

Abnormal, sharply edematous villi migrate along the venous collectors or spread throughout the entire thickness of the myometrium, sometimes growing to the serous cover and even the thickness of the broad ligament of the uterus. Chorionic villi do not show true malignant growth, vascular walls do not grow. The absence of foci of necrosis, hemorrhage and tissue melting is also characteristic.

There is a strong belief that invasive cystic drift should always be attributed to malignant neoplasms, since it is accompanied by tissue destruction. Despite this, a number of researchers consider it a benign pathology or preblastomatous, others - a limitedly malignant form of cystic drift, since it has a stroma, affects only the uterus and does not give metastases.

Based on the degree of proliferation of the trophoblastic epithelium, its invasive properties and clinical course of the disease, cystic drift should be subdivided into the following main groups.

1. Benign cystic drift without signs of proliferation of the chorionic epithelium (simple cystic drift) is most common.
2. "Potentially malignant" cystic drift with mild anaplasia of the cells of the trophoblastic proliferating epithelium, rarely giving metastases.
3. "Potentially malignant" invasive cystic drift with pronounced proliferation and anaplasia of the chorionic epithelium.

The transition of cystic drift into chorionic carcinoma occurs only in groups II and III, although the overwhelming majority of all three groups of cystic drift are benign.

The histological form of cystic drift cannot be a criterion for predicting the outcome of the disease. It is more correct to single out several risk factors, that is, various clinical, morphological and laboratory indicators that serve as a background for the transformation of a cystic drift into a chorionic carcinoma:

• age over 40;
• discrepancy between the size of the uterus and the timing of pregnancy;
• the presence of luteal ovarian cysts;
• a persistent increase in the CG titer, which does not decrease after the evacuation of the cystic drift.

The risk of malignant transformation of cystic drift increases in those patients who have three or more of these signs. In such patients, as well as with recurrent cystic drift, the progression of the disease is observed in half of the cases, and in the presence of less than three signs - in a third.

Chorionic carcinoma

Chorionic carcinoma (syn. Chorionepithelioma) is a malignant form of trophoblastic disease arising from the chorial epithelium after cystic drift (up to 40% of cases), normal abortion (25%) and childbirth (22.5%). Described are isolated cases of the simultaneous development of chorionic carcinoma and gallbladder drift.

It is rare and is not always associated with a previous pregnancy, interrupted at various times, or a hydatidiform mole. Chorionic carcinoma, which has arisen out of connection with pregnancy, is a teratogenic tumor.

Macroscopically, the tumor is represented by a dark hemorrhagic mass with ulceration. Differs in a very soft consistency, the presence of extensive areas of decay.

The shape of the tumor node is different and is largely determined by its localization. Often there is not one tumor node, but two or more. The sizes of the nodes are different - from a few millimeters to the head of an adult. The tumor does not have a capsule, the borders of the tumor node are indistinct.

The most common localization of chorionic carcinoma is the body of the uterus (in the area of ​​implantation of the ovum), while the submucous location occurs in 83% of cases, intramural - in 5, 6%, subserous - in 7%. Often located in the interstitial section of the fallopian tubes. Chorionic carcinoma of the ovaries and fallopian tubes is rare - 1-4 %. About 17% of chorionepitheliomas are not associated with the uterus.

Chorionic carcinoma may develop from ectopic pregnancy (2.5%).

Germinating the body of the uterus, tumor masses can fill the small pelvis without clinical manifestations of compression of the surrounding tissues, blood vessels and nerve trunks, causing mild pain syndrome or its absence.

Histologically, chorionic carcinoma is characterized by the disorderly proliferation of trophoblastic tissue growing into muscles with destruction and coagulation necrosis. In the tumor itself, there is no stroma, chorionic villi and vessels. Consists of Langhans cells and syncytium elements.

Chorionic carcinoma is very rare during pregnancy. More often, the tumor manifests itself with a 4-6 month pregnancy, less often with a full-term pregnancy. Chorionic carcinoma during pregnancy usually leads to metastatic lesions of various organs.

When chorionic carcinoma occurs during pregnancy, it is difficult to recognize a neoplasm even in situations where the process has taken on a widespread form. The disease may not show any symptoms for a long time and has a poor prognosis.

The diagnosis of chorionic carcinoma by scraping causes significant difficulties, and sometimes it is not possible, since blood clots, necrotic endometrial tissue and single trophoblastic elements often predominate in micropreparations. In all cases, a study of the level of hCG is mandatory.

The greatest difficulties arise in the differential diagnosis of chorionic carcinoma, invasive cystic drift and trophoblastic tumor of the placental site, which are also characterized by active invasive processes in the uteroplacental region. In difficult cases of diagnosis, it is necessary to take into account the clinical manifestations and histological features of scrapings.

Chorionic carcinoma of the ovary in most cases occurs from the elements of the placenta and is in many ways similar to a tumor of the yolk sac. This is an example of extraembryonic differentiation of malignant embryonic cells. Most ovarian chorionic carcinomas occur in combination with other fetal cell tumors, while pure chorionic carcinomas are considered very rare.

Histologically, they are similar to the more frequent placental lesions. Their tissue consists of syncytio- and cytotrophoblast elements with pronounced signs of malignancy. Tumors actively produce hCG.

In addition to the development of chorionic carcinoma from the trophoblast, in some cases it can arise from the germ cells of the female and male reproductive gonads, located in various extragonadal places: the pineal gland, mediastinum, lungs, stomach, bladder or in the tissues of the retroperitoneal space. In these very rare cases, it is not possible to establish any connection between chorionic carcinoma and a previous pregnancy.

Chorionic carcinoma combinedwith teratoma or embryonic cancer

It arises out of connection with pregnancy (including in men) from trophoblastic primordia that are part of teratogenic tumors.

Chorionic carcinoma in the ovaries is rare, usually associated with tecalutein cysts or teratomas in non-pregnant women. Chorionic carcinomas in the testes and mediastinum in men are extremely rare.

Malignant trophoblastic teratoma diagnosed in cases where syncytio- and cytotrophoblast is part of organoid teratomas with malignant growth of trophoblastic or other tissue rudiments.

Placental site trophoblastic tumor

As a separate histogenetic form of this tumor in non-pregnant women, they began to isolate only recently. The tumor is rare.

Macroscopically, the tumor is represented by polyposis masses within the uterine cavity or endophytic growth of the myometrium in the body region, less often the cervix. In the blood serum of women, PL prevails over chorionic gonadotropin, which can serve as one of the signs of differential diagnosis of this disease with chorionic carcinoma.

The trophoblastic tumor of the placental site is characterized by intense invasion of the internal cytotrophoblast into the walls of the arteries, which are subject to fibrinoid replacement of the elastomuscular components. Hemorrhage and necrosis are uncommon. Tumor cells secrete PL, and only a small part of them show hCG. Thus, the cytotrophoblast completely repeats the typical gestational changes in the placental bed during the normal course of pregnancy.

The clinical course of the tumor is generally assessed as benign, but it is potentially metastatic and requires urgent surgical treatment - hysterectomy (cells of the trophoblastic tumor of the placental bed are insensitive to chemotherapy). The frequency of metastasis is 15%. The most common localization of metastases is the vagina, lungs, liver, abdominal cavity, and brain.

Differential diagnosis of a tumor of the placental site should be carried out with chorionic carcinoma, excessive growth of the placental bed and nodules of the placental bed. A combination of a trophoblastic tumor of the placental site and chorionic carcinoma or transitional forms is possible.

Prognosis - a favorable outcome was noted in 85% of women after hysterectomy. All fetal observations are associated with a high mitotic activity of the tumor - 3-5 mitoses per 10 cells (on average, 1-2 mitoses per 10 cells).

Clinic of trophoblastic disease

The interval between the end of pregnancy and the first manifestation of trophoblastic disease varies within fairly wide limits. The duration of the latent period, as a rule, is 6-12 months, more often - 3 months. There are cases of a very long latency period - 10-20 years.

It should be noted that there is not a single symptom that would be pathohomonic for chorionic carcinoma. More or less clear clinical symptoms are observed only if the primary node of the chorionic carcinoma is located in the uterus and communicates with its cavity.

The predominant symptom in patients with trophoblastic disease is bleeding from the genital tract of a different nature. In many cases, this symptom is simultaneously the first manifestation of the disease.

The nature of the bloody discharge:

• moderate with light intervals of varying duration;
• abundant with light intervals of varying duration;
• long-term, about the same intensity;
• varying intensity ("daub"), gradually increasing;
• sudden intense bleeding.

Bleeding requiring intervention most often does not stop after the first curettage and there is a need for repeated manipulation. The recurrence of bleeding, as well as the need to perform repeated curettage, is a characteristic moment for the history of patients with trophoblastic disease.

The time of the onset of bleeding in relation to the outcome of a previous pregnancy or to menstruation is also varied:

• directly or in the near future after childbirth, abortion or cystic drift;
• simultaneously with menstruation;
• after a different duration of the delay in menstruation;
• in the intermenstrual period;
• in menopause.

The unequal nature of bleeding and the time of their onset are explained by the different location of tumor nodes (chorionic carcinoma) in the uterine cavity.

Along with bloody discharge or in the intervals between them, many patients can observe discharge of a different nature - serous, purulent, sometimes with an unpleasant odor. It is associated with necrotization, decay and infection of tumor nodes.

Prolonged, repeated bleeding, often accompanied by significant blood loss, as well as intoxication of the body with the decay products of tumor masses, often lead to anemization patient, sometimes with a significant decrease in hemoglobin levels.

One of the signs of trophoblastic disease is discrepancy between the size of the uterus and the expected date pregnancy. More often (in more than half of the observations), the size of the uterus is greater than the expected gestational age, in 20% - corresponds to the gestational age, in 16 % - less time.

An important sign of trophoblastic disease is education luteal ovarian cysts in 50% of cases. In most patients, luteal cysts are bilateral, reach large sizes, fill the entire small pelvis. With cystic drift, luteal cysts may occur within the first 2 weeks. Their presence is an unfavorable prognostic sign.

Regression of luteal cysts is possible within 3 months after removal of the cystic drift.

Pain in the lower abdomen and lower back are explained by the presence of tumor masses in the uterine cavity, especially when the last germination of the walls of the uterus to the serous cover. In some cases, pain occurs due to the location of metastatic tumor masses in the parametrium and compression of the nerve trunks by them.

The presence of acute paroxysmal pain in the abdomen may be due to perforation of the uterus or, in some patients, torsion or perforation of luteal cysts.

Pain can also be caused by the localization of metastases of chorionic carcinoma in various organs of the abdominal cavity: pain in the chest area is a consequence of pulmonary metastases, headaches - brain metastases, etc.

Perhaps the presence of clinical symptoms associated with the process of metastasis: symptom complex of intestinal obstruction, intestinal bleeding, cough with bloody sputum, paresis, cachexia, etc.

The fundamental similarity of clinical manifestations in various trophoblastic tumors - bleeding, enlargement and softening of the uterus, the presence of luteal cysts, the ability to early metastasis - allow us to consider cystic drift and chorionic carcinoma as successive stages of a single pathological process.

Metastasis of trophoblastic tumors. The course of trophoblastic disease is characterized by early and intense metastasis, especially in chorionic carcinoma. In some cases, the disease is first diagnosed based on the detection of metastases.

The places most often affected by metastases of trophoblastic tumors, mainly chorionic carcinomas, are the lungs, vagina (vulva) and brain. Less commonly, the liver, kidneys, spleen, and small intestine are affected.

The selective frequency of damage to certain organs indicates that the predominant route of metastasis of trophoblastic tumors is hematogenous.

The group of high risk of metastasis of trophoblast tumors includes patients who have the following factors:

1. serum β-hCG level is higher than 40,000 mIU / ml;
2. the disease lasts more than 4 months;
3. there are brain metastases.

The basis for the assumption that trophoblastic tumors will be accompanied by metastasis, I are:

1. long-term symptoms of the disease;
2. long latency period;
3. large size of the uterus;
4. repeated therapeutic and diagnostic curettage of the walls of the uterine cavity.

Diagnosis of trophoblastic disease

For the diagnosis of trophoblastic disease, are of great importance taking anamnesis and gynecological examination.

Cyanosis of the vaginal mucosa and cervix is ​​noted. The uterus is unevenly enlarged, limited in mobility, contains softened nodes of various sizes. Palpation of the uterus can be painful, which is explained by the proximity or even germination of the serous cover of the uterus by tumor masses from its cavity. Metastatic foci in the vagina look like dark cherry and bleeding formations, which often lead to profuse bleeding. In some cases, luteal cysts are determined. It is possible to find infiltrates in the parametria, which is explained by the spread of the tumor to the parametric fiber and indicates a far-reaching process and the serious condition of the patient.

Gynecological examination of patients with trophoblastic disease should be performed carefully and very carefully in order to avoid sudden bleeding or intensification of existing bleeding.

Based on the data of the anamnesis and gynecological examination, one can only suspect trophoblastic disease. It is impossible to accurately determine the nature of a trophoblastic tumor, even if metastases are found in the vagina or on the cervix.

Ultrasound scanning. The informative value of the method is 90%, the specificity is 73%, and the accuracy is 85%.

Ultrasound diagnostics of cystic drift is based on the detection of numerous echo complexes in the uterine cavity with increased sensitivity of the device, reminiscent of a "snow storm", "sponge". When using the signal amplification values ​​commonly used for fetal imaging, the enlarged uterine cavity appears to be empty. This acoustic phenomenon is caused by the disorderly proliferation of the chorionic epithelium with a change in its shape, location and formation of liquid vacuoles, which turns the ovum into a groin-like conglomerate of heterogeneous ultrasonic density when examined using a gray scale.

According to the echographic image, the nodes of trophoblastic tumors can be conditionally divided into a predominantly solid structure, a mixed and predominantly vascular structure. The ultrasound image sufficiently reflects the morphological characteristics of two types of trophoblastic tumors.

With chorionic carcinoma, the node is usually of a solid structure, dilated tumor vessels are determined along the periphery, with cystic drift there are zones of increased vascularization in the thickness of the myometrium. In some cases, hypo- and anechoic zones of irregular shape with a diameter of up to 1-1.5 cm are observed within the tumor node.

With a cystic drift in the uterine cavity, more often in the area of ​​the internal pharynx, liquid formations, resembling a fetal egg, can be determined, due to the accumulation of blood or fluid poured out of the bubbles.

In some women, if there is a partial vesicular drift, it is possible to identify an image of the fetus. Ultrasound diagnosis of partial vesicular drift is difficult, especially with a small amount of degenerative changes in the chorion. With careful examination, it is possible to visualize luteal cysts, usually bilateral, multi- or unicameral, located on the side of the uterus.

The characteristic ultrasound criteria for gallbladder drift are more often found after 12 weeks of gestation. At an earlier date, the echographic signs of the disease are not specific enough.

Differential echographic diagnosis should be carried out with uterine myoma with secondary changes in the node (edema, necrosis) and non-developing pregnancy.

When comparing clinical and ultrasound data, the accuracy of the diagnosis of cystic drift approaches 100%.

Color Doppler mapping. Serves as an essential addition to conventional ultrasound. Allows you to identify tumor nodes even when, with conventional ultrasound, it is not possible to clearly visualize the contours of the pathological focus in the structure of the myometrium. Color Doppler mapping makes it possible to assess the state of the vascular bed in trophoblastic tumors of the uterus, as well as the effectiveness of the therapy, the required number of times.

Color Doppler mapping allows you to visualize blood flow in hypoechoic zones and divide them into areas of necrosis (without blood flow) and arteriovenous shunts (with blood flow). This is especially important in the subserous location of the tumor, since there is a threat of uterine rupture and intra-abdominal bleeding.

Clear visualization of the tumor focus in the thickness of the myometrium can significantly reduce unnecessary repeated diagnostic curettage of the uterus.

In trophoblastic disease, pathological tumor vessels with low pulsation index and resistance index are revealed.

During the latency period of the disease, color Doppler mapping makes it possible to identify foci of increased vascularization in the myometrium with a diameter of only 10 mm. This circumstance is invaluable for the early diagnosis of trophoblastic disease.

For trophoblastic tumors of a solid structure, an aggressive course is characteristic, during which pronounced necrotic changes in the tumor tissue rapidly occur.

If the treatment is effective, the size of the nodes progressively decreases. Their structure becomes more hyperechoic, in the future either a scar or varicose veins remains at the site of the tumor, or the tumor disappears without a trace. Most tumors of a solid and mixed structure leave behind a cicatricial change in the myometrium - with color Doppler mapping, small diameter venous vessels are found near the scar. In the future, the scar, as a rule, disappears completely. At the site of tumors of the vascular structure, areas of dilated vessels (the so-called arteriovenous malformations) are formed, which can remain in the myometrium for many years. In such cases, color Doppler mapping registers vessels with low values ​​of the pulsation index and resistance index in these areas, but the indicators in the uterine arteries are not reduced.

X-ray method.Hysterosalpingography. X-ray chorionic carcinoma is manifested by serration and filling defects with clearly defined or blurred contours, indicating the presence of a tumor in the uterine cavity or its intramuscular location with invasion into the uterine cavity.

In patients with destructive cystic drift, the contour arrangement of the contrast agent is noted. The severity of the radiological symptoms characterizing the cystic drift in terms of the size of the shadow or irregularity of the edges depends on the volume of the tumor. There are no specific radiological signs that can be used to make a differential diagnosis between benign and malignant forms of trophoblastic disease.

With hysteroscopy, it is possible to clarify the localization of the tumor and determine the extent of the lesion. In some cases, the method helps to clarify the diagnosis, especially when the histological examination of the scraping of the uterine mucosa is negative, as well as hysteroscopy is used to control during chemotherapy.

Pelvic angiography. It is indicated for patients with suspected chorionicarcinoma and an invasive form of cystic drift, as well as with a refined diagnosis, if it is necessary to prescribe chemotherapy to control its effectiveness. Angiography allows you to see intramural and submucosally located chorionicarcinoma nodes, to clarify their localization and size. The use of angiography in trophoblastic disease makes it possible to establish the existence of enlarged, dilated spiral arteries flowing into various sizes of "pools", which are arteriovenous shunts resulting from pathological intratumoral angiogenesis.

Chest X-ray. Establishes the presence and nature of metastases in the lungs, which makes it possible to judge the extent of the disease, although it does not specify the nature of the trophoblastic tumor. It is customary to perform a second chest X-ray every 3 weeks during treatment, especially if treatment is limited to chemotherapy (dynamic observation of regression or progression of metastases).

Hormonal research. Determination of the level of hCG in urine and serum. To determine the level of hCG, biological, immunological and radioimmunological methods are used.

The sensitivity of immunological testing is much higher than that of biological testing. The accuracy of the radioimmunological method is higher than that of the biological and immunological.

It is known that hCG production undergoes distinct changes during pregnancy. When pregnancy occurs, this hormone can be detected in urine as early as a week after the expected period of menstruation. Excretion of hCG reaches its maximum values ​​between the 40-80th day of pregnancy, and the peak of excretion ranges between 100,000-500,000 U / day. In the second trimester, the excretion of CG decreases to 5000-1000 U / day. Therefore, if the excretion of hCG does not decrease by a certain period, then this is the basis for suspecting the presence of trophoblastic disease, most often cystic drift.

Since α-hCG has cross-reactivity with LH, in order to avoid errors, β-hCG is determined, which is used as a marker of the disease.

The presence of pronounced necrotic changes in tumor tissue can lead to a decrease in the amount of β-hCG in the blood, which creates a false impression of an impending recovery.

Determination of placental lactogen. To determine this hormone, immunological and radioimmunological methods are used.

The level of PL in the blood of patients with trophoblastic disease is reduced. Therefore, if there is a suspicion of cystic drift, in which the level of hCG in the blood and urine remains low, the determination of PL helps to establish the diagnosis. A progressive decrease in the PL level indicates a possible transformation towards a malignant process.

Determination of estrogen. To determine E 3, simplified testing methods based on calorimetric and fluorometric methods are used. There are also radioimmunological methods for the determination of E 3 in the blood.

In patients with cystic drift, the excretion of E 3 sharply decreases within the range of 11-166 μg / day even at the 20th week of pregnancy, with chorionic carcinoma, even lower values ​​of E 3 excretion are determined.

Determination of chorionic thyrotropin. In rare cases, with trophoblastic disease, there is an excess production of chorionic thyrotropin.

Definitionα -fetoprotein. When a cystic drift occurs, the concentration of this protein decreases.

Histological examination. Histological verification is one of the main diagnostic methods that allows to establish not only the presence of trophoblastic disease, but also to clarify the nature of the tumor. However, the pathomorphological diagnosis of trophoblastic tumors presents certain difficulties.

Insufficiently thorough curettage complicates the diagnosis. The biopsy material often lacks tumor tissue or only the superficial, necrotic part of the tumor is taken, which may be due to the fact that the tumor node lies deep in the myometrium (for example, intramural and subserous nodes of chorionic carcinoma are inaccessible for examination using curettage).

When examining scrapings, the histological picture of which is similar to chorionic carcinoma, in particular in the presence of a large amount of necrotic tissue or layers of proliferating chorionic epithelium, a prerequisite is the study of a large number of sections.

With repeated curettage, which is often necessary, the histological identification of trophoblastic disease is even more difficult. In addition, there is a real danger leading to the prevalence of the tumor process.

In difficult cases of diagnosis, it is necessary to take into account the following clinical signs and histological features of scraping, which, in combination, may indicate chorionicarcinoma: uterine bleeding after childbirth, abortion in the absence of remnants of the ovum; overgrowth of the chorionic epithelium in the absence of villi, especially after 3 months of pregnancy; extensive areas of tissue decay in the scraping, especially in the presence of accumulations of chorionic epithelium; massive growths of polymorphic cytotrophoblast; a large number of mitotic figures in Langhans cells.

When examining a removed uterus or metastasis, the diagnosis is usually not in doubt.

Differential diagnosis Chorionic carcinoma should be performed with a placental polyp. With a placental polyp, bleeding usually occurs 4-6 weeks after an abortion or childbirth, which is associated with a violation of the integrity of the newly formed vessels in the polyp.

Treatment of trophoblastic disease

Chemotherapy. Since the introduction of antimetabolites into practice, chemotherapy has become the main method of treating malignant trophoblastic disease (Table 1).

Table 1. Principles for choosing a chemotherapy regimen

Note. MTS - methotrexate; FA - folic acid; Act-D - actinomycin D.

The indications for chemotherapy are as follows:

▲ Histological diagnosis of chorionic carcinoma.

▲ Presence of metastases.

▲ Stable or increasing serum (3-hCG after removal of the cystic mole.

▲ An increase in the level of β-hCG after its preliminary return to normal.

Active chemotherapy drugs against malignant trophoblastic disease are methotrexate, dactinomycin, alkylating drugs, cisplatin and 5-fluorouracil.

The choice of the treatment regimen is currently carried out taking into account the degree of risk of developing tumor resistance to chemotherapy according to the WHO scale (Table 15.2).

Table 2. WHO scale for determining the risk of developing resistance

Risk factor	0 points	1 point	2 points	4 points
Age	Up to 39	Over 39	-	-
Outcome of a previous pregnancy	Bubble drift	Abortion	Childbirth	-
Interval *, months	Less than 4	4-6	7-12	More than 12
CG level, IU / l	Less than 10 3 **	10 3 -10 4	10 4 -10 5	More than 10 5
Blood type	-	0 or A	B or AB	-
Largest tumor, including uterine tumor	Less than 3 cm	3-5 cm	More than 5cm	-
Localization of metastases	-	Spleen, kidney	Gastrointestinal tract, liver	Brain
Number of metastases	-	1-3	4-8	More than 8
Previous chemotherapy	-	-	1 preparation	2 or more cytostatics

* The interval between the end of the previous pregnancy and the start of chemotherapy.

** A low level of hCG can be with trophoblastic tumors at the placenta site.

According to the table. 2, in patients with trophoblastic disease, 3 degrees of risk of resistance development were identified: low, moderate, high. Depending on the degree of risk, treatment ranges from monochemotherapy to intensive chemotherapy regimens.

The total number of points is determined by summing the number of points for each predictor. With a total score of less than 5, the risk of developing tumor resistance is low, 5-7 points - moderate, and with a total of 8 or more points - high.

Non-metastatic trophoblastic disease. The treatment of choice is monochemotherapy with methotrexate or dactinomycin. From 80 to 90% of patients can be cured with one drug, in the rest it is necessary to conduct a secondary course.

Folic acid has been used in conjunction with methotrexate to create opportunities to increase the dose of methotrexate and reduce toxicity. Methotrexate at a dose of 1 mg / kg of body weight is prescribed intramuscularly on days 1, 3, 5 and 7, and folic acid at a dose of 5 mg / day is prescribed on days 2, 4, 6 and 8. The courses are repeated as soon as the patient recovers from the previous course.

Metastatic trophoblastic bo sickness. For low-risk trophoblastic disease, the same treatment tactics are used as for non-metastatic disease. At high risk, the most commonly used combination of methotrexate, dactinomycin and chlorambucil or cyclophosphamide.

For patients withI-II stage of the disease the following is recommended.

1. As the first line of chemotherapy: methotrexate (20 mg / m 2 intravenously once every 3 days); dactinomycin (500 mcg intravenously every other day). The courses of treatment are repeated every 2 weeks.
2. As a second line of chemotherapy in case of tumor resistance to previous treatment: cisplatin (100 mg / m 2 intravenously drip with water load and against the background of antiemetic therapy on the 1st day); etoposide (150 mg intravenously drip on days 2, 3, 4, 5, 6). The courses of treatment are repeated every 2 weeks.

For patients withIII-IV stage of the disease apply:

• cisplatin (100 mg / m 2 intravenously drip with water load and against the background of antiemetic therapy);
• methotrexate (20 mg / m 2 intravenously drip once every 3 days up to a total dose of 180-200 mg);
• dactinomycin (500 microns intravenously every other day);
• vincristine (1.5 mg intravenously once a week).

The courses are repeated every 2-3 weeks if creatinine and neutrophils are normal.

Chemotherapy continues until the level of (3-HCG in the blood serum falls to the normal level. After that another 1-3 cycles are performed. Recently, a sensitive reaction to (3-HCG) has been used, and these additional courses may not be required in patients low risk For high-risk patients, 2-6 additional cycles of chemotherapy are recommended.

Surgical treatment. Methods for evacuating vesicular drift: scraping of the walls of the uterine cavity or vacuum exsanguination, in rare cases - supravaginal amputation or extirpation of the uterus.

Hysterectomy is an important component in the treatment of trophoblastic disease.

The indications for surgery are:

1. Resistance to chemotherapy or toxicity for disease confined to the uterus.
2. Complications such as vaginal bleeding, uterine perforation, infection.
3. Elderly, many times giving birth to patients with a local process.

Radiation therapy. Patients with metastases to the liver or brain may develop hemorrhages due to tumor necrosis during chemotherapy. In such cases, remote irradiation at a dose of 20 Gy in 10-14 fractions is indicated in combination with polychemotherapy. When conducting radiation in order to prevent or reduce cerebral edema, dehydration therapy should be carried out.

Follow-up. All patients should be monitored monthly with a study of the level of hCG for at least the first year. After a year, patients with a high degree of risk should be examined twice a year for 5 years, and then annually. The β-hCG level is checked at each visit.

The optimal gestational age is at least 1 year after the last prophylactic course of chemotherapy for patients with stage I-II of the disease and 1.5 years for patients with stage III-IV. Hormonal contraception is an option for preventing unwanted and untimely pregnancy for women who have had trophoblastic disease. At the same time, the function of the ovaries, impaired as a result of the transferred disease and / or the chemotherapy being carried out, is regulated and normalized.

The drugs used for the treatment of trophoblastic disease do not affect the chromosome set of the mother and the child, which is confirmed by the results of cytogenetic studies.

Forecast. Chemotherapy can cure 100% of patients with non-metastatic disease and 70% or more of high-risk patients. Chorionic carcinoma of the ovaries does not respond well to chemotherapy, and the prognosis is almost always poor.

The presence of metastases worsens the prognosis of the disease.

The main prognosis factor is the duration of the existence of chorionic carcinoma. Moreover, its peculiarity, in contrast to many forms of gynecological cancer, is that the delay in starting treatment is always the fault of doctors and is associated with their low qualifications.