Growth and spread of primary breast cancer. Perivascular spaces are dilated - what is it? Causes and treatment Typing of sarcomas according to the degree of cell differentiation

I. Absolute criterion– the influence of the tumor on the functioning of the organism as a whole (this feature is reflected in the definition of benign and malignant tumors).

II. Relative criteria:

1. Tumor growth pattern(benign tumors usually grow expansively; malignant tumors, as a rule, grow invasively). Some benign tumors grow invasively (eg, fibromatosis), and some malignant tumors grow expansively (eg, some mature intracranial tumors). If the slow invasive growth of a mature benign tumor causes destruction of adjacent normal tissue, then such a tumor is called benign tumor with locally destructive growth(eg, ameloblastoma).

2. Metastasis(benign tumors, as a rule, do not metastasize; malignant tumors, as a rule, do metastasize). Some benign tumors can metastasize (uterine leiomyoma sometimes metastasizes to the lungs, pigmented nevi - to regional lymph nodes), while some malignant tumors do not metastasize (such tumors are called malignant tumors with locally destructive growth eg basal cell carcinoma of the skin).

3. Tumor maturity(benign tumors are usually mature; malignant tumors are usually immature). However, some benign tumors are immature, for example, juvenile nevus (formerly called juvenile melanoma) is formed by immature pigment cells with signs of pronounced cellular atypia. A number of malignant tumors, on the contrary, have a mature structure (thus, all mature tumors in the cranial cavity, reaching a certain size, become malignant).

ETIOLOGY OF MALIGNANT TUMORS

The common cause of malignant growth is insufficiency of the antiblastoma resistance system(antitumor defense system), the main elements of which are DNA repair enzymes, antioncogenes (for example, p53) and NK cells (natural killer cells). The insufficiency of the anti-blastoma resistance system is caused by intense carcinogenic exposure, immunodeficiency states, deficiency of DNA repair enzymes and the function of antioncogenes, as well as scar tissue compaction (“cancer in the scar”).

Intense carcinogenic effects. There are traumatic, thermal, radiation, chemical and viral variants of carcinogenesis.

1. traumatic carcinogenesis– development of a malignant tumor at the site of injury (for example, chronic injury to the red border of the lips can lead to the development of cancer).

2. thermal carcinogenesis– development of a malignant tumor in places of prolonged dosed exposure to high temperature (in places of burns, for example, cancer of the oral mucosa and esophagus in lovers of hot food).

3. radiation carcinogenesis– development of an immature malignant tumor when exposed to ionizing or non-ionizing radiation in a carcinogenic dose. The main natural carcinogen for people of the Caucasian and Mongoloid races is solar ultraviolet radiation, so the habit of sunbathing in the sun contributes to the development of malignant skin tumors.

4. chemical carcinogenesis– development of immature malignant tumors under the influence of chemical carcinogens (carcinogenic substances). From exogenous chemical carcinogens, the main role is played by carcinogens from tobacco smoke, which are the main cause of the development of lung cancer and laryngeal cancer. Among endogenous chemical carcinogens, estrogenic hormones (high levels of which lead to the development of breast, ovarian, and endometrial cancer) and carcinogenic cholesterol metabolites, formed in the colon under the influence of microorganisms and contributing to the development of colon cancer, are important.

5. viral carcinogenesis– induction of malignant tumors by viruses (oncogenic viruses). Only those viruses that directly cause malignancy of a cell by introducing oncogenes (viral oncogenes) into its genome are called oncogenic. Some viruses contribute to the development of malignant tumors indirectly, causing the background pathological process (for example, hepatitis B, C, D viruses, while not oncogenic, contribute to the development of liver cancer, causing cirrhosis). The most important human tumor viruses are simplex virus(herpes simplex virus) Type II from the Herpesviridae family (causes cervical cancer, penile cancer and possibly a number of other tumors); herpes virus type VIII (leads to the development of Kaposi's sarcoma); human papilloma virus from the family Papovaviridae (causes cervical cancer and skin cancer); Epstein-Barr virus from the Herpesviridae family (causes malignant tumors mainly in countries with hot climates - Burkitt's lymphoma/leukemia, most common in Africa, nasopharyngeal cancer in Southeast Asia and possibly other tumors).

Oncogenic RNA viruses are called oncornaviruses. Two viruses from the Retroviridae family are oncogenic for humans: HTLV-I and HTLV-II. The abbreviation HTLV stands for human (H) T-lymphotropic (TL) virus (V). HTLV-I causes T-cell leukemia and adult T-cell lymphoma (adult T-cell leukaemia/lymphoma); HTLV-II – hairy cell leukemia.

"Cancer in the rumen." In humans, the most common forms of “cancer in the rumen” are cancer developing in trophic skin ulcers, peripheral lung cancer, cancer from chronic gastric and duodenal ulcers, primary liver cancer against the background of cirrhosis.

PATHOGENESIS, MORPHOGENESIS AND PATHWAYS

EVOLUTION OF MALIGNANT TUMORS

There are four main stages of development of immature malignant tumors: the stages of malignancy, pre-invasive tumor, invasion and metastasis.

1. Stage of malignancy– transformation of a normal cell into a malignant one (at the first stage, the initiation stage, a somatic mutation occurs, as a result of which oncogenes appear in the genome of malignant cells; at the second stage, the promotion stage, the proliferation of initiated cells begins). Oncogenes (onc) are any genes that directly cause the transformation of a normal cell into a malignant one or contribute to this transformation. Oncogenes, depending on their origin, are divided into two groups: cellular oncogenes (c-onc) and viral oncogenes (v-onc). Cellular oncogenes are formed from normal cell genes, called proto-oncogenes. A typical example of a cellular oncogene is the p53 protein gene - the normal (“wild”) p53 gene plays the role of one of the active antioncogenes; its mutation leads to the formation of an oncogene (the “mutant” p53 gene). The products of oncogene expression are called oncoproteins (oncoproteins).

2. Stage of pre-invasive tumor– the state of an immature malignant tumor before the onset of invasion (in the case of cancer, the term carcinoma in situ was used for this stage).

3. Infestation stage– invasive growth of a malignant tumor.

4. Stage of metastasis.

Morphogenesis of malignant tumors. 1. Tumor development de novo (“leap-like” evolution), without previous visible pretumor changes. 2. Staged carcinogenesis - the development of a tumor at the site of pre-tumor changes (in the case of cancer, the term is used to designate pre-tumor changes precancer).

There are two forms of precancer: 1. obligate precancer– precancer, which sooner or later necessarily transforms into cancer (for example, skin changes in xeroderma pigmentosum), 2. optional precancer– precancer, which does not necessarily transform into cancer (for example, leukoplakia).

Paths of evolution of malignant tumors. 1. Tumor progression– strengthening of its malignant potential over time. 2. Tumor regression(rare phenomenon) – spontaneous (without treatment) disappearance of the tumor.
epithelial tumors

Among epithelial tumors, a distinction is made between mature (usually benign) and immature (malignant). Mature epithelial tumors include primarily adenoma And papilloma, immature epithelial tumors are referred to by the general term carcinoma (cancer). The Russian term “cancer” is not successful, because it is used to refer to both all malignant tumors (in the international nomenclature the term is used for this purpose cancer), and malignant epithelial neoplasms (carcinomas).

Adenoma– a mature tumor developing from the glandular epithelium or from the single-layer columnar epithelium of the mucous membranes (nasal cavity, trachea, bronchi, stomach, intestines, endometrium). There are three special clinical and morphological variants of adenomas: adenomatous polyp, cystadenoma (cystadenoma) and fibroadenoma. Adenomatous polyp called an adenoma that develops from single-layer columnar epithelium of the mucous membranes. Adenomatous polyps should be distinguished from hyperplastic polyps, which are not tumors, but can transform into adenomatous polyps. Cystadenoma– adenoma with the presence of cysts (cavities). In this case, the cyst may precede the development of an adenoma ( primary cyst) or arise in the tissue of an already formed tumor ( secondary cyst). Cysts are filled with fluid, mucus, clotted blood, or mushy or dense masses. Cystadenomas are most common in the ovaries. An adenoma with pronounced stroma is called fibroadenoma. A typical location for fibroadenomas is the mammary glands.

Papilloma– a mature tumor developing from integumentary tissues lined with stratified squamous epithelium or urothelium (transitional epithelium), as well as in the excretory ducts of the glands. Squamous papillomas are formed on the skin and mucous membranes covered with stratified squamous epithelium (oral cavity, pharynx, esophagus, vocal folds of the larynx, vagina, vaginal portion of the cervix). Transitional cell papillomas localized in the urinary tract, primarily in the bladder.

Carcinoma (cancer, carcinoma)– immature malignant epithelial tumor. There are two main morphological forms of cancer: intraepithelial (non-invasive) and invasive (infiltrating) cancer. Intraepithelial cancer, also called carcinoma in situ(“in situ”), characterized by the absence of invasive growth; all malignant cells are concentrated in the thickness of the epithelial layer. Currently, the term “carcinoma in situ” is rarely used in practical oncopathology, because this condition is difficult or impossible to distinguish from pronounced precancerous (dysplastic) changes in the epithelium. Therefore, epithelial dysplasia and carcinoma in situ are combined under the general term intraepithelial neoplasia indicating the degree of its severity (I – mild, II – moderate, III – severe).

From the point of view of histogenesis, there are numerous variants of carcinoma, the most common of which are basal cell, squamous cell (epidermoid), transitional cell (urothelial) carcinoma, adenocarcinoma and undifferentiated (anaplastic) carcinoma.

1. Basal cell carcinoma– carcinoma, the cells of which resemble the basal cells of stratified squamous epithelium. Most often, basal cell carcinoma occurs in open areas of the skin and is a malignant tumor with locally destructive growth.

2. Squamous cell carcinoma– cancer, the cells of which differentiate in the direction of multilayered squamous epithelium. The tumor is most often localized in the lung, larynx, esophagus, tissues of the oral cavity, skin, and cervix. Squamous cell carcinoma of the lung usually develops from foci of squamous epithelial metaplasia, the formation of which is typical of chronic bronchitis of smokers. There are two main types of squamous cell carcinoma: well- and poorly differentiated squamous cell carcinoma. The most characteristic histological sign of well-differentiated squamous cell carcinoma is the formation of keratinization foci (“cancer pearls”) in the layers of tumor cells.

3. Transitional cell carcinoma– carcinoma, the cells of which differentiate towards the transitional epithelium (urothelium). Currently, this tumor is called urothelial carcinoma. In the vast majority of cases, transitional cell carcinoma develops in the mucous membrane of the urinary tract, primarily the bladder.

4. Adenocarcinoma– a form of cancer with signs of glandular differentiation of the cells that form it (literally, the term “adenocarcinoma” is translated as “glandular cancer”). The tumor often develops in the stomach, intestines, endometrium, and various endocrine and exocrine glands. Typical of adenocarcinoma are glandular, tubular (tubular carcinoma) and papillary (papillary carcinoma) structures. There are highly, moderately and poorly differentiated adenocarcinomas. Special variants of adenocarcinoma include mucous adenocarcinoma and signet ring cell carcinoma. Mucous adenocarcinoma(mucosal carcinoma) is characterized by the formation of large amounts of extracellular mucus in the tumor tissue. Signet ring cell carcinoma formed by round cells, the cytoplasm of which contains mucus, which deforms and pushes the nucleus to the periphery, which gives the cell a resemblance to a ring.

5. Undifferentiated cancer characterized by the absence of signs of tissue-specific differentiation during routine histological examination of the tumor. The use of special methods (immunohistochemical and electron microscopic) makes it possible to detect these signs. Undifferentiated cancer can develop in almost any organ and is a highly malignant neoplasm. Tumor cells can be located in the form of trabeculae (trabecular carcinoma) or sheets (solid carcinoma). The size of undifferentiated cancer cells varies significantly (large cell carcinoma, giant cell carcinoma). A peculiar variant of undifferentiated cancer is small cell carcinoma, especially characteristic of the lung.

Of the organ-specific forms of cancer, the most common are renal cell And hepatocellular carcinomas.

Depending on the severity of the stroma, two types of cancer are distinguished: medullary And fibrous (skirr). Medullary carcinoma is a cancer with scanty stroma, fibrous carcinoma is a cancer with a pronounced stroma. The tissue of medullary carcinoma is usually gray-pink, soft or elastic, and resembles the substance of the brain (Latin medulla - brain). Fibrous cancer is characterized by the density of tumor tissue due to the abundance of collagen fibers in the stroma. Medullary cancer is more common in the thyroid and breast glands; fibrous - in the mammary gland and stomach. If the term “medullary carcinoma” is used to designate independent oncological forms, then the term “fibrous cancer” is not used for this purpose in modern oncopathology.
TUMORS OF SOFT TISSUE AND BONES

(MESENCHYMAL TUMORS)

Soft tissue tumors include tumors of fibrous (fibrous), adipose, muscle tissue, blood vessels, serous and synovial membranes, as well as structures of the peripheral nervous system. Tumors of the peripheral nervous system will be discussed in the next topic. Soft tissue tumors (with the exception of neurogenic neoplasms) and specific bone tumors in oncomorphology are often combined with the concept mesenchymal tumors. Multiple mesenchymal tumors can be a manifestation of hereditary tumor syndromes - tuberous sclerosis(Pringle-Bourneville disease), Gardner's syndrome and others.

I. TUMORS OF FIBROUS TISSUE

Tumors of fibrous (fibrous connective) tissue include a variety of lesions, many of which are probably not true neoplasms, but reactive tumor-like growths of tissue. Tumors and tumor-like lesions are divided into mature and immature. Mature fibrous lesions are mainly characterized by a benign course, while immature ones are malignant neoplasms.

TO mature fibrous tissue tumors include fibroids And fibromatoses, immature fibrous tumors are called fibrosarcomas. Fibroma usually grows expansively and has clear boundaries; fibromatosis is characterized by the absence of clear boundaries of the lesion due to invasive (infiltrating) growth. Highlight superficial And deep fibromatosis. Superficial fibromatosis includes fibromatosis of the palm ( Dupuytren's contracture), soles ( Ledderhose disease), neck (usually manifested as congenital torticollis), penis ( Peyronier's disease), gums, less often in other localizations. Deep fibromatosis has a more aggressive and, in some cases, malignant course. Deep fibromatosis includes desmoid tumors (desmoids) and congenital fibromatosis (fibromatosis of young children).

Fibroids and related lesions. Fibroma– a tumor formed by mature fibrous connective tissue. There are more than ten morphological variants of fibromas (elastofibroma, myofibroma, dense fibroma, soft fibroma, calcified aponeurotic fibroma, etc.), but, as a rule, their clinical course does not differ significantly. The exception is angiofibroma of the nasopharynx, usually occurring in boys in the second decade of life. This tumor is characterized by local aggressiveness (locally destructive growth) and often recurs after removal. In addition to soft tissues, fibroids can form in bones(desmoplastic bone fibroma, odontogenic fibroma).

In addition to fibromas, benign fibrous proliferative lesions include hypertrophic scar, keloid, nodular fasciitis, proliferative fasciitis, proliferative myositis, and inflammatory myofibroblastic tumor. An excessively enlarged scar is called hypertrophic scar. A scar of cartilaginous density due to hyalinosis of the fibrous tissue that forms it is called keloid . Nodular fasciitis is a nodule that rapidly increases in size (about 1 cm per week), located in the subcutaneous tissue, skeletal muscles or associated with their fascia; the lesion rarely exceeds 3 cm in diameter and usually has clear boundaries. After removal it rarely recurs. Proliferative fasciitis called a similar lesion, in the tissue of which large fibroblasts resembling neurons are detected. The same process in skeletal muscles is called proliferative myositis . Inflammatory myofibroblastic tumor– pronounced proliferation of fibroblasts and myofibroblasts with the presence of inflammatory infiltration of the lesion. The process is usually localized in soft tissues and internal organs in children and young people. The tumor is usually benign, but can recur after removal, and occasionally transforms into sarcoma.

Deep fibromatosis. Desmoid tumors (desmoids) – deep fibromatoses, characterized by pronounced proliferation of active fibroblasts. Distinguish abdominal(in the thickness of the anterior abdominal wall), intra-abdominal(in the abdominal organs, primarily in the mesentery of the small intestine) and extra-abdominal(when the process is localized outside the abdominal wall and abdominal organs) variants of desmoid tumors. Multiple lesions of internal organs with fibromatosis of young children often end in the death of the child.

Fibrosarcoma– one of the most rare human malignant tumors. There are two clinical and morphological variants of fibrosarcoma: fibrosarcoma of young children (congenital and up to 5 years of age) and fibrosarcoma of adults. Fibrosarcoma in young children has a relatively favorable course, with a 5-year survival rate reaching 85%.

II. FIBROHISTIOCYTIC TUMORS

Fibrohistiocytic tumors are tumors of fibrous tissue with a large number of macrophages (histiocytes). There are three groups of fibrohistiocytic neoplasms: benign, borderline and malignant. Borderline tumors include frequently recurrent lesions with locally destructive growth, but rarely metastasizing, i.e. not having all the signs of malignant neoplasms. Malignant fibrohistiocytic neoplasms are referred to by the general term malignant fibrous histiocytoma.

TO benign fibrohistiocytic tumors include benign fibrous histiocytoma, xanthoma, juvenile xanthogranuloma and reticulohistiocytoma. Benign fibrous histiocytoma is a small node without clear boundaries. Benign fibrous histiocytoma of the skin is called dermatofibroma. Once removed, these lesions rarely recur. Deeply located tumors and neoplasms with high cellularity recur somewhat more often. Xanthoma is a nodule or node, less often a spot, yellow in color (from Latin xanthos - yellow). Xanthomas are often combined with elevated levels of lipids in the blood plasma (hyperlipoproteinemia). Sometimes hyperlipidemia is accompanied by the appearance of multiple small xanthomas on the skin (xanthomas as elements of a rash); such xanthomas are called eruptive. Xanthomas form in the skin and in the tissue of various organs. Xanthomas on the eyelids are called xanthelasma .

A tumor similar to a xanthoma, but with the presence of foam cells of various sizes and shapes, is called xanthogranuloma. Xanthogranuloma is rare in adults; it is mainly found in childhood ( juvenile xanthogranuloma), even in newborns. A special clinical and morphological variant of xanthogranuloma is retroperitoneal (retroperitoneal) Oberling xanthogranuloma. Oberling's xanthogranuloma more common in adults, it represents a peculiar form of retroperitoneal fibrosis. Reticulohistiocytoma– a benign fibrohistiocytic tumor, which often accompanies various forms of arthritis, is combined with autoimmune diseases, and is sometimes a paraneoplastic process, reflecting the presence of a malignant tumor of internal organs in the body.

Borderline fibrohistiocytic neoplasms. Borderline fibrohistiocytic lesions include dermatofibrosarcoma protuberans, atypical fibroxanthoma, giant cell fibroblastoma, and plexiform fibrohistiocytic tumor.

Dermatofibrosarcoma protuberans It is a rather large (several centimeters in diameter) node that rises above the surface of the skin. Tumor growth is slow; the node does not have clear boundaries; often the tumor grows into the subcutaneous fat. In rare cases, the tumor tissue is dark brown or black due to the presence of melanin-containing cells ( Bednar pigmented dermatofibrosarcoma protuberans). Bednar's tumor resembles malignant melanoma in appearance. In approximately half of cases, dermatofibrosarcoma protuberans recurs after removal, so treatment should be carried out by wide excision of the tumor. Metastases rarely form.

Atypical fibroxanthoma usually occurs in older people and is localized in the skin of exposed areas of the body. The tumor, as a rule, is a small nodule with ulceration of the surface and clear boundaries. Typically, the course of the tumor is benign, but occasionally relapses, metastases form, and transformation into malignant fibrous histiocytoma is noted. Giant cell fibroblastoma occurs mainly in children of the first decade of life in the skin and subcutaneous fat of the back and lower extremities. The tumor does not metastasize and is not characterized by locally destructive growth, but often recurs after removal. Plexiform fibrohistiocytic tumor found in children and young people in the skin and subcutaneous tissue of the extremities. After removal, the tumor often recurs; in rare cases, metastases form in regional lymph nodes.

Malignant fibrous histiocytoma- the most common sarcoma. The tumor is localized in various organs, especially in the deep tissues of the extremities and in the retroperitoneal space. Externally, it appears as a node/nodes without clear boundaries with necrosis and hemorrhages. There are five tumor variants: pleomorphic and giant cell variants are high-grade tumors, myxoid and inflammatory are intermediate, and angiomatoid variant is low-grade. Angiomatoid malignant fibrous histiocytoma is sometimes considered in the group of borderline fibrohistiocytic tumors called angiomatoid fibrous histiocytoma. The clinical picture is characterized by the development of anemia, prolonged fever and loss of body weight. This tumor most often occurs in children and young people; it rarely metastasizes, but often recurs after removal.

III. TUMORS OF FAT AND MUSCLE TISSUE

Tumors of adipose tissue. There are tumors of white and brown adipose tissue. A mature tumor of white adipose tissue is designated by the term lipoma, brown – hibernoma. Immature malignant tumors of adipose tissue are called liposarcoma .

Lipomas usually appear as soft, yellow nodules formed by lobules of adipose tissue. In addition to solitary (single) lipomas, there are multiple tumors. There are several morphological variants of lipomas (regular, spindle cell, pleomorphic and atypical), but clinically they all have the same benign course. Often, a benign tumor, along with adipose tissue, includes other tissues: numerous blood vessels (angiolipoma), vessels and bundles of smooth muscle cells (angiomyolipoma), red bone marrow (myelolipoma). Angiomyolipoma most often occurs in the kidneys, myelolipoma - in the adrenal glands and retroperitoneal tissue. In addition, intramuscular lipoma, lipoblastoma and lipomatosis are distinguished. Intramuscular lipoma localized in the thickness of skeletal muscles, characterized by slow invasive growth and, as a result, the absence of clear boundaries. A large tumor causes muscle atrophy. After removal, intramuscular lipoma often recurs. Lipoblastoma, formed by maturing fat cells, occurs mainly in children, usually in the first years of life. Diffuse lipomatosis are called foci of proliferation of adipose tissue that do not have clear boundaries (with the exception of intramuscular localization of the process). In some cases, the cause of diffuse lipomatosis is an increase in the concentration of glucocorticoids in the body (steroid lipomatosis). When the lesion is localized in the pararectal or paravesical tissue, colonic obstruction or urinary retention may occur. Multiple lipomas are also referred to as lipomatosis. The most well-known lipomatoses are Dercum's lipomatosis And Madelung's lipomatosis. Dercum's lipomatosis is characterized by the presence of painful lipomas mainly on the extremities. With Madelung lipomatosis, lipomas are localized in the neck, sometimes enveloping it in a ring, causing compression of blood vessels, nerves, respiratory tract and pharynx. Hibernoma most often located in the scapular and interscapular areas. Liposarcoma characterized by significant diversity. Well-differentiated and myxoid liposarcoma are low-grade tumors. An exception is liposarcoma of retroperitoneal localization, the prognosis of which is always less favorable. Round cell, pleomorphic and dedifferentiated liposarcoma are characterized by a highly malignant course.

Tumors of muscle tissue are divided into tumors of smooth and striated muscle tissue. Mature tumors of smooth muscles - leiomyomas, striated muscle tissue - rhabdomyomas. Immature malignant tumors of smooth muscle are called leiomyosarcoma, striated muscle tissue - rhabdomyosarcoma.

Most often leiomyomas develop in the uterus under the influence of estrogenic hormones that enhance the proliferative activity of myometrial smooth muscle cells. In addition, leiomyomas develop from vascular leiomyocytes, piliar muscles of the skin, as well as the walls of hollow organs, primarily the gastrointestinal tract. Sometimes uterine leiomyomas metastasize to the lungs ( metastatic leiomyoma), however they remain a benign process. Occasionally, tumor tissue grows into the lumen of the veins of the uterus, pelvis, and even into the inferior vena cava ( intravenous leiomyomatosis). The prognosis of intravenous leiomyomatosis remains favorable, despite incomplete surgical removal of the tumor; bilateral oophorectomy virtually eliminates the possibility of relapse. In women of reproductive age, the so-called disseminated peritoneal leiomyomatosis, in which multiple small leiomyomas (implantation metastases) are formed on the peritoneum, externally resembling metastases of a malignant tumor. This condition is usually associated with pregnancy, the presence of an estrogen-producing granulosa cell tumor of the ovary, or the use of oral contraceptives. Typically, disseminated peritoneal leiomyomatosis is an unexpected finding during cesarean section. In most cases, the lesions spontaneously regress.

Some smooth muscle tumors also contain other tissues: angiomyolipoma (typical of the kidneys), angiomyoma, lymphangiomyomatosis. Leiomyosarcoma most often develops in the uterus with malignancy of long-existing leiomyomas, usually large in size. In this case, areas of a softer consistency, foci of necrosis and hemorrhages appear in the tumor node. Rhabdomyosarcomas have significant diversity. They mainly develop in childhood. Spindle cell and embryonal rhabdomyosarcomas are low-grade tumors; alveolar and pleomorphic rhabdomyosarcomas are highly malignant neoplasms. A peculiar variant of embryonal rhabdomyosarcoma is botryoid(from Greek bothrios – bunch of grapes) rhabdomyosarcoma, developing in children of the first years of life in the mucous membranes of various organs, most often the vagina, and protruding above their surface (“bothrioid polyp”). Alveolar and pleomorphic rhabdomyosarcomas typically form in skeletal muscle.

IV. TUMORS OF BLOOD AND LYMPHATIC VESSELS

Vascular tumors are divided into endothelial tumors (developing from endothelial cells of blood and lymphatic vessels) and perivascular (arising from other types of cellular elements of the vessel wall and perivascular tissue directly adjacent to the vessel).

Endothelial tumors of blood vessels. Mature tumors of blood vessels are called hemangiomas, immature malignant tumors are designated by the term angiosarcoma (hemangiosarcoma, malignant hemangioendothelioma). A special variant of blood vessel tumors is Kaposi's sarcoma. A special group of borderline endothelial tumors consists of hemangioendotheliomas, which cannot be unambiguously classified as either benign or malignant neoplasms.

There are capillary, cavernous, intramuscular, venous, arteriovenous and epithelioid (histiocytoid) hemangiomas. A peculiar variant of hemangiomas is pyogenic granuloma (hemangioma of granulation-tissue type). Capillary hemangiomas are formed by capillary vessels; they are divided into two types: juvenile (children) and adult. Juvenile capillary hemangioma(vascular nevus) is a nodule or spot, mostly red in color, develops in 0.5% of newborns, usually forms after several weeks or months and is usually localized on the skin of the face or neck. Often these hemangiomas are multiple. After some time they spontaneously regress. Adult capillary hemangioma occurs already in adolescents, but the frequency of their development increases with age. They are localized primarily on the skin of the trunk and limbs, as well as in the internal organs. Cavernous hemangiomas formed by vessels with a sharply expanded lumen. They are located both on the skin and in internal organs (primarily in the liver and spleen). Spontaneously, cavernous hemangiomas usually do not regress; with rapid growth, destruction of the tissue surrounding the tumor may occur. Intramuscular hemangioma– capillary or cavernous hemangioma, located deep in the skeletal muscle. Venous hemangiomas formed by a focal accumulation of venous type vessels, arteriovenous hemangiomas consist of venous, capillary and arterial vessels. Epithelioid hemangioma(angiolymphoid hyperplasia with eosinophilia) is characterized by the proliferation of capillaries in the skin with large endothelial cells resembling histiocytes. The capillaries are surrounded by accumulations of lymphocytes, macrophages and eosinophilic granulocytes, and lymphoid follicles are often found. Most often the tumor is located on the scalp. Pyogenic granuloma is the growth of granulation tissue at the site of injury in the form of a nodule on the skin or mucous membranes. More often it is localized on the mucous membrane of the oral cavity, primarily on the gums. The formation of pyogenic granulomas during pregnancy is characteristic ( granuloma gravidarum), such tumors regress after childbirth or termination of pregnancy.

Depending on the number of hemangiomas, solitary and multiple hemangiomas are distinguished. Multiple hemangiomas are also referred to as hemangiomatosis. Hemangiomatoses include progressive cutaneous Darier hemangiomatosis, Kasabach-Merritt syndrome, Maffucci syndrome, and Haferkamp syndrome. Progressive hemangiomatosis of the skin Daria characterized by the presence of skin hemangiomas increasing in size and number, which can be complicated by consumption thrombocytopenia and disseminated intravascular coagulation syndrome. Kasabach–Merritt syndrome– giant skin hemangiomas with the development of consumption thrombocytopenia and disseminated intravascular coagulation syndrome. Maffucci syndrome- option Ollier's disease(enchondromatosis of bones, mainly fingers and toes) in combination with multiple capillary and cavernous hemangiomas of the soft tissues of the fingers. Haferkamp syndrome– generalized hemangiomatosis of bones. The disease progresses rapidly, ending in death. Invasive growth of intraosseous hemangiomas leads to bone deformation, their destruction (pathological fractures), and displacement of myeloid tissue from the spongy substance with the development of hypoplastic anemia.

Systemic hemangiomatoses. Diseases in which hemangiomas are localized in various organs (skin, internal organs, brain, eyes, bones) are called systemic hemangiomatosis. These include Hippel–Lindau and Sturge–Weber–Krabbe syndromes. Hippel–Lindau syndrome(retinocerebrovisceral angiomatosis) is characterized by the presence of hemangiomas in the retina, in the internal organs (liver, spleen) and in the central nervous system (usually in the cerebellum with corresponding neurological symptoms). Sturge–Weber–Krabbe syndrome– a combination, as a rule, of unilateral hemangiomas of the facial skin in the area of ​​innervation of the I or II branches of the trigeminal nerve, hemangiomas of the choroid (resulting in the development of glaucoma or retinal detachment) and hemangiomas of the brain, which is manifested by the development of convulsive syndrome and hemiparesis/hemiplegia on the opposite side tumors on the side of the body.

There are two main options hemangioendothelioma– epithelioid (histiocytoid) and spindle cell. Epithelioid hemangioendothelioma when localized in the lungs, it usually leads to severe complications and death. When the tumor is located in other internal organs and soft tissues, fatal complications rarely develop. Spindle cell hemangioendothelioma often recurs after removal, but does not metastasize. Angiosarcoma refers to tumors of high malignancy. The etiological role of arsenic compounds, vinyl chloride and insolation in the development of angiosarcoma has been established. Mostly adults and elderly people are affected. Macroscopically, angiosarcoma, as a rule, is a red nodule without clear boundaries. Kaposi's sarcoma– a tumor of poorly differentiated vascular cells (angioblasts), developing against the background of severe immunodeficiency under the influence of herpes virus type 8 (HHV-8). There are three main clinical and epidemiological variants of Kaposi's sarcoma: senile, epidemic and iatrogenic. Senile Kaposi's sarcoma, as the name suggests, develops in old age and is a low-grade tumor (the average duration of the disease is 10–15 years). Epidemic (with HIV infection) and iatrogenic (due to drug immunosuppression) variants are characterized by a high degree of malignancy. Typically, Kaposi's sarcoma appears as a brownish-red, soft plaque on the skin of the legs or feet.

Endothelial tumors of lymphatic vessels. Mature tumors of blood vessels are called lymphangiomas, immature malignant tumors are called lymphangiosarcoma. Lymphangiomas most often formed by ordinary capillary (capillary lymphangioma) or sharply dilated (cavernous lymphangioma) lymphatic vessels. Lymphangiosarcoma occurs predominantly in women. It is mainly formed against the background of prolonged lymphostasis. Lymphangiosarcoma in women who have undergone radical mastectomy for breast cancer ( Stewart–Treves syndrome), usually develops 10 years after surgery.

Perivascular tumors. Perivascular tumors include glomus tumor (and its variants glomangioma and glomangiomyoma) and hemangiopericytoma. There are benign and malignant glomus tumors, as well as benign and malignant hemangiopericytomas. Benign variants of perivascular neoplasms are more common. Benign glomus tumor, as a rule, is localized in the soft tissues of the fingers under the nail plate and is a bluish-red nodule with a diameter usually less than 1 cm. The tumor is painful, especially with hypothermia. After removal it often recurs. Benign hemangiopericytoma most often localized in the retroperitoneal space, pelvic organs and thigh tissues, it has clear boundaries. In some cases, the tumor leads to the development of hypoglycemia.

V. TUMORS OF THE SEROUS AND SYNOVIAL MEMBRANES

Tumors of the serous integument. Various benign and malignant tumors arise from the serous membranes. Benign neoplasms include solitary fibrous tumor of the pleura and peritoneum(localized fibrous mesothelioma), well-differentiated papillary mesothelioma, multicystic mesothelioma And adenomatoid tumor. Malignant neoplasms of the serous integument are malignant solitary fibrous tumor of the pleura and peritoneum, so-called diffuse mesothelioma, and epithelial, spindle cell(sarcomatoid) and biphasic malignant mesothelioma. It has been established that asbestos may be the cause of the development of malignant pleural mesothelioma.

Tumors of the synovial membranes of joints. Currently, tumors of the synovial membranes include only two neoplasms: benign And malignant tenosynovial giant cell tumor. Previously this group included "synovial" sarcoma["synovial" sarcoma], however, histogenetically it does not belong to synovial tumors, despite the fact that it is often located near the joints. “Synovial” sarcoma is less malignant in patients under 15 years of age, in the case of localization in the distal extremities and with a node size of up to 5 cm in diameter.

VI. BONE TUMORS

There are four main groups of bone tumors: bone tumors, cartilage tumors, giant cell tumors, and bone marrow tumors. In addition, bone and cartilage tumors can sometimes develop primarily in soft tissues and internal organs.

Bone-forming tumors. Mature benign bone-forming neoplasms of bone include osteoma, osteoid osteoma, and benign osteoblastoma. Immature malignant bone-forming tumors are aggressive osteoblastoma (malignant osteoblastoma) and osteosarcoma (osteogenic sarcoma).

Osteoma– a slow-growing tumor, mainly arising in the bones of the skull. Osteoid osteoma(osteoid osteoma) is located in the compact bone tissue of the superficial (cortical) layer of the bone. The proximity of the tumor to the periosteum causes the development of severe pain. The tumor develops mainly in adolescents and young people in the diaphysis of long tubular bones; it is characterized by its small size (usually less than 1 cm in diameter), extremely slow growth, clear boundaries and, as a rule, a pronounced zone of reactive bone formation. Benign osteoblastoma, similar in microscopic structure to osteoid osteoma, but is localized in the deep parts of the bone, in cancellous bone tissue. The tumor size usually exceeds 1 cm in diameter, and reactive bone formation is insignificant. As a rule, there is no severe pain characteristic of osteoid osteoma. Aggressive osteoblastoma characterized by frequent relapses after surgical treatment, but does not metastasize.

Osteosarcoma– the most common primary malignant bone tumor. It mainly develops in the second decade of life in males. In old age, osteosarcoma usually forms against the background Paget's disease of bone. Most often, osteosarcoma is localized in the metaphyses of long tubular bones. Osteosarcoma is divided into two main clinical and morphological variants: central(medullary) and surface(peripheral). As a rule, central osteosarcoma is a high-grade tumor, while peripheral osteosarcoma is low-grade. Superficial osteosarcoma adheres tightly to the surface of the bone or surrounds it in the form of a sleeve, without causing significant destruction of the cortical layer. Tumors typically develop in the diaphysis of long bones. Radiologically, in most cases, the tumor reveals radial linear opacities, as well as distal and proximal osteophytes (“Codman triangles”), formed due to reactive bone formation during periosteal detachment along the periphery of the tumor. There are two main types of superficial osteosarcoma: parosteal (juxtacortical) and periosteal. Parosteal osteosarcoma formed predominantly by tumor bone tissue, periosteal osteosarcoma mainly consists of tumor cartilage.

Cartilaginous tumors. Mature benign cartilaginous bone tumors are chondroma, osteochondroma, benign chondroblastoma, and chondromyxoid fibroma. Immature malignant tumor of cartilage tissue is designated by the term chondrosarcoma .

Chondroma represented by mature hyaline cartilage. Depending on the location in the bone, there are two types of chondromas: enchondromas, centrally located, and periosteal chondromas located in the peripheral parts of the bone. More common are enchondromas, which can be solitary (single) or multiple. Multiple enchondromas are referred to as enchondromatosis bones. Among enchondromatoses, the main ones are Ollier's disease and its variant Maffucci syndrome. Ollier's disease manifested by the formation of enchondromas in the bones of the hands and feet. Enchondromas cause curvature of the bones that continues as long as bone growth occurs, which can result in the hands and feet turning into knotty conglomerates. The presence of soft tissue hemangiomas in Ollier disease is called Maffucci syndrome. Solitary enchondromas, unlike multiple ones, rarely transform into chondrosarcoma.

Osteochondroma(osteocartilaginous exostosis) is a bone growth on the outer surface of the bone covered with a layer of cartilage (“cartilaginous cap”). Osteochondromas can be solitary or multiple, usually located in the area of ​​the metaphyses of long tubular bones and are found mainly in children (the growth of osteochondromas usually stops by the time the skeleton matures). As with chondromas, solitary osteochondromas, unlike multiple ones, rarely undergo malignancy. Benign chondroblastoma almost always located in the epiphyses of long tubular bones, usually in people under the age of 20, it is painful, often significant, sometimes recurs after removal and extremely rarely transforms into chondrosarcoma. Chondromyxoid fibroma its clinical features are similar to chondroblastoma, however, the histological picture of the tumor can simulate differentiated chondrosarcoma. On X-ray examination, the tumor appears as an intraosseous node with clear boundaries and a thin rim of hypermineralized bone tissue.

Chondrosarcoma. In contrast to chondromas, most of which are found in the peripheral parts of the extremities, chondrosarcoma occurs mainly in the pelvic bones, ribs, humerus and femur. Chondrosarcoma is formed predominantly or completely by immature cartilage tissue without the formation of tumor bone. There are four main types of chondrosarcoma: conventional, juxtacortical (periosteal), mesenchymal and dedifferentiated. There are highly and low differentiated options ordinary chondrosarcoma. The tumor is located in the central parts of the bone (central chondrosarcoma), destroys the surrounding bone tissue, and has no clear boundaries, which can be detected by X-ray examination. Juxtacortical chondrosarcoma(low-grade tumor) is an analogue of periosteal osteosarcoma, but without signs of tumor osteogenesis. Mesenchymal and dedifferentiated chondrosarcomas are highly malignant neoplasms. Dedifferentiated chondrosarcoma- one of the most malignant human tumors, more aggressive than osteosarcoma, usually develops in elderly people. The 5-year survival rate for this tumor is 10–15%.

Giant cell tumor of bone (osteoclastoma) is an aggressive but rarely metastatic tumor. In addition to mononuclear tumor cells, it contains multinucleated cells similar to osteoclasts (hence the name tumor). As a rule, the tumor develops mainly at the age of 20–40 years in the epiphyses of long tubular bones. Giant cell tumor is an osteolytic neoplasm; Having arisen in the epiphysis, near the articular cartilage, it subsequently spreads and covers the entire epiphysis and adjacent parts of the metaphysis. After removal, giant cell tumors often recur and sometimes metastasize to the lungs.

"Bone marrow" tumors. The so-called bone marrow tumors include tumors from poorly differentiated mesenchymal cells. These neoplasms are tumors of a high degree of malignancy. The main one is Ewing's sarcoma, usually occurring between the ages of 5 and 15 years, usually in the diaphysis and metaphysis of long bones. On X-ray examination, the tumor generally appears osteolytic, but bone destruction is often associated with foci of osteogenesis. Periosteal bone formation with a characteristic x-ray picture of “onion scales” is often encountered. Ewing's sarcoma early metastasizes to other bones, lungs and liver. In addition, it often develops primarily in several bones (multicentric tumor growth). Rarely, Ewing's sarcoma develops in soft tissues and internal organs ( extraosseous Ewing's sarcoma).
TUMORS OF THE NERVOUS SYSTEM, BRAIN MEMBRANES,

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Perivascular tumors of dogs belong to the group of soft tissue sarcomas and the therapeutic (or rather, surgical) approach to them is no different from other sarcomas of this group. In principle, this would be enough to live and not worry, but I can’t wait to dig a little deeper. ;)

(charming picture from retinalphysician.com)

The vascular wall in its thinnest segment, the capillary bed, consists of three main components: the endothelial cell, the basement membrane and the pericyte. As the caliber of the vessel increases, pericytes are replaced by myopericytes in arterioles and venules, then into smooth muscle cells of large vessels. Pericytes express vimentin and SMA, myopericytes add desmin and calponin to their arsenal, and smooth muscle cells - smoothelin and h-CD.

Perivascular tumors can occur in principle anywhere there are vessels with walls, but in dogs they are particularly likely to occur in areas where the capillary bed is subject to high pressure loads, particularly in the distal limbs.

Cytologically, for quite a long time it was customary to call all perivascular tumors hemangiopericytomas (proof), but studies by Avallone et al showed that cytology, although quite specific for diagnosing perivascular tumors as a group, does not provide any information about a specific type. And histologically, with confirmation by IHC, it was shown that in this group (with an absolutely similar cytological picture), in addition to hemangiopericytomas, myopericytomas, angioleiomyosarcoma and smooth muscle myomas are represented, and the latter are much more common in hemangiopericytomas themselves.

So, my dear cytologists, it is more correct to write in conclusion about a perivascular tumor, and not about hemangiopericytoma. Yes, yes, I was also a sinner...

Cytologically they have a very characteristic appearance. Firstly, unlike many SMTs, they produce a highly cellular specimen; they often even end up in needle biopsies in the form of large clusters, if the circumstances are successful for the cytologist - even together with capillaries, around which very specific vortices are formed. Anisocytosis and anisokaryosis are not too pronounced, which correlates with low biological aggressiveness. A fairly noticeable feature is the almost perfectly round shape of the nucleus, with other signs of a “spindle cell” tumor.

The matrix produced by perivascular tumors is very scarce and fibrillar. Sometimes they may not produce it at all. Multiple point vacuoles are sometimes observed in the cytoplasm of cells.

Perhaps the most striking feature of perivascular tumors is the formation of multinucleated cells. At the same time, the nuclei try to be located as far as possible from each other. When there are two of them, the cell begins to resemble the head of an insect, and when there are many of them, together with the cytoplasmic processes, the cell looks like a crown with large precious stones in the teeth, as a result of which such formations are called crown cells.

Why should we, as practitioners, even distinguish perivascular tumors from the galaxy of other SMTs? First of all, due to the fact that, other things being equal, perivascular tumors behave less aggressively. Thus, distant metastases were detected, according to the same Avallone group, in 2% of cases (compared to an average of 20% for all - this is 10 times less common!). The Kuntz grade of differentiation used in the diagnosis of STS is equally applicable to perivascular tumors, but few of them will receive grade 2, let alone 3. In addition, the histological grade of differentiation correlates well with the likelihood of distant metastasis, but not with local invasiveness and likelihood of relapse. Therefore, as for all SMTs, the histological assessment of the radicality of the removal becomes almost more important.

It is interesting that perivascular tumors in the distal parts of the extremities exhibit an expansive growth pattern, and if the boundaries are clear upon first removal, then the likelihood of recurrence is very low. In all other localizations, the prognosis depends on the nature of the spread and the presence/absence of muscle infiltration. With infiltrative growth and the presence of invasion into the perimysium, the probability of local recurrence is very high, and this only variant of perivascular sarcomas has been seen to grow distant metastases. Non-acral tumors (i.e., not on the distal extremities) often have microsatellite nodules in the surrounding tissue, therefore requiring responsible management of boundaries.

Autonomous tumor growth is characterized by a lack of control over the proliferation and differentiation of cells of the tumor-bearing organism. Tumor invasion occurs in three phases and is ensured by certain genetic rearrangements.

The first phase of tumor invasion is characterized by weakening of contacts between cells. In the second phase, the tumor cell secretes proteolytic enzymes and their activators, which ensure the degradation of the extracellular matrix, thereby clearing the way for invasion.

The metastasis stage is the final stage of tumor morphogenesis, which is associated with the spread of tumor cells from the primary tumor to other organs through the lymphatic, blood vessels, perineural, and implantation, which was the basis for identifying the types of metastasis.

Autonomous tumor growth

Autonomous tumor growth is characterized by a lack of control over cell proliferation and differentiation by the tumor-bearing organism. This does not mean that tumor cells are in some kind of proliferative chaos. In fact, tumor cells switch to autocrine or paracrine mechanism for regulating its growth.

During autocrine stimulation of growth, the tumor cell itself produces growth factors or oncoproteins-analogues of growth factors, as well as receptors or oncoproteins-analogues of growth factor receptors. This happens, for example, in small cell lung cancer, the cells of which produce the growth hormone bombesin and at the same time receptors for it. Paracrine stimulation also occurs, since bombesin can also interact with neighboring cells.

A striking example of paracrine tumor stimulation is the production of insulin-like growth factor 2 by fibroblasts in the lung cancer stroma. The growth factor interacts with receptors on cancer cells and stimulates their proliferation. Autonomous tumor growth is expressed in the loss of contact inhibition and immortalization (acquisition of immortality) of tumor cells, which can be explained by the transition of cells to autocrine and paracrine ways of regulating their growth.

The autonomy of the tumor is relative in nature, since the tumor tissue constantly receives from the body various nutrients, oxygen, hormones, and cytokines brought through the bloodstream. In addition, it is influenced by the immune system and the surrounding non-tumor tissue.

Thus, tumor autonomy should be understood not as the complete independence of tumor cells from the body, but as the acquisition by tumor cells of the ability to self-govern.

In malignant tumors, autonomous growth is significantly expressed, and they grow rapidly, invading adjacent normal tissues. In benign tumors it is extremely weakly expressed. Some of them are amenable to regulatory influences and grow slowly, without growing into neighboring tissues.

Tumor progression

Tumor progression theory developed by L. Foulds in 1969 based on experimental oncology data. According to the theory of tumor progression, there is a constant staged progressive growth of the tumor with its passage through a number of qualitatively different stages. Autonomy is manifested not only in growth, but also in all other signs of the tumor, as the author of the theory himself believed.

It is difficult to agree with the latter point of view, since the malignancy of a tumor always has a material basis in the form of active synthesis of certain oncoproteins, growth factors, and their receptors. This circumstance leaves an imprint on the manifestations of morphological atypia of the tumor and is used in predicting the life of cancer patients.

The tumor is constantly changing: progression occurs, usually towards increasing its malignancy, which is manifested by invasive growth and the development of metastases.

Stage invasive tumor characterized by the occurrence of infiltrating growth. A developed vascular network and stroma appear in the tumor, expressed to varying degrees. There are no boundaries with adjacent non-tumor tissue due to the growth of tumor cells into it. Tumor invasion occurs in three phases and is ensured by certain genetic rearrangements.

First phase of tumor invasion characterized by a weakening of contacts between cells, as evidenced by a decrease in the number of intercellular contacts, a decrease in the concentration of some adhesion molecules from the CD44 family and others, and, conversely, an increase in the expression of others that ensure the mobility of tumor cells and their contact with the extracellular matrix.

The concentration of calcium ions on the cell surface decreases, which leads to an increase in the negative charge of tumor cells. The expression of integrin receptors increases, ensuring cell attachment to the components of the extracellular matrix - laminin, fibronectin, collagens.

In the second phase the tumor cell secretes proteolytic enzymes and their activators, which ensure the degradation of the extracellular matrix, thereby clearing the way for invasion.

At the same time, the degradation products of fibronectin and laminin are chemoattractants for tumor cells that migrate to the degradation zone during third phase invasion, and then the process repeats again.

Stage of metastasis- the final stage of tumor morphogenesis, accompanied by certain geno- and phenotypic rearrangements of the tumor. The process of metastasis is associated with the spread of tumor cells from the primary tumor to other organs through lymphatic and blood vessels, perineurally, and implantation, which became the basis for distinguishing types of metastasis.

The process of metastasis is explained by the theory of the metastatic cascade, according to which a tumor cell undergoes a chain (cascade) of rearrangements that ensure spread to distant organs.

During the process of metastasis, a tumor cell must have certain qualities:

• penetrate into adjacent tissues and lumens of blood vessels (small veins and lymphatic vessels);
• separate from the tumor layer into the blood (lymph) stream in the form of individual cells or small groups of them;
• maintain viability after contact in the blood (lymph) flow with specific and nonspecific immune defense factors;
• migrate to venules (lymphatic vessels) and attach to their endothelium in certain organs;
• invade microvessels and grow in a new place in a new environment.

The metastatic cascade can be roughly divided into four stages:

1. formation of a metastatic tumor subclone; invasion into the lumen of the vessel;
2. circulation of the tumor embolus in the bloodstream (lymph flow);
3. settling in a new place with the formation of a secondary tumor.

The process of metastasis begins with the emergence of a metastatic subclone of tumor cells with an altered plasmalemma, as a result of which intercellular contacts are lost and the ability to move appears.

Then the tumor cells migrate through the extracellular matrix, attaching with integrin receptors to laminin, fibronectin, collagen molecules of the basement membrane of the vessel, and carry out its proteolysis due to the release of collagenases, cathepsin, elastase, glycosaminohydrolase, plasmin, etc.

This allows tumor cells to invade the basement membrane of the vessel, attach to its endothelium, and then, changing their adhesive properties (suppression of adhesive molecules of the cell adhesive molecules - CAM family), separate from both the tumor layer and the vascular endothelium.

At the next stage, tumor emboli are formed, which can consist only of tumor cells or in combination with platelets and lymphocytes. The fibrin coating of such emboli can protect tumor cells from elimination by cells of the immune system and the action of nonspecific protective factors.

At the final stage, the interaction of tumor cells with the endothelium of venules occurs due to β-receptors and CD44 molecules, attachment and proteolysis of the basement membrane, invasion of perivascular tissue and growth of a secondary tumor.

As the tumor progresses, it may clonal evolution(Nowell P., 1988), that is, new clones of tumor cells may appear, arising as a result of secondary mutations, which leads to the polyclonality of the tumor and the dominance of the most aggressive clones as a result of clonal selection.

Benign tumors are characterized by the dominance of tumor cells of one clone throughout their existence, while in malignant tumors polyclonality constantly progresses, especially in low-differentiated, highly malignant variants.

The theory of clonal evolution can help explain not only the progression of a malignant tumor and metastasis, but also provide answers to the following questions:

• why the phenomenon of metaplasia (changes in cell differentiation in certain areas) can occur in tumors;
• how the malignancy of a tumor may increase over time or especially after antitumor therapy;
• why tumors resistant to antitumor effects arise spontaneously and after therapeutic effects (the phenomenon of multidrug resistance of the tumor).

The role of tumor stroma and angiogenesis processes in its autonomous growth and progression

An important structural component of a tumor is its stroma. The stroma in a tumor, like the stroma in normal tissue, mainly performs trophic, modulating and supporting functions.

The stromal elements of the tumor are represented by cells and extracellular matrix of connective tissue, vessels and nerve endings. The extracellular matrix of tumors is represented by two structural components: basement membranes and interstitial connective tissue matrix.

The composition of the basal membranes includes collagens IV, VI and VII types, glycoproteins (laminin, fibronectin, vitronectin), proteoglycans (heparan sulfate, etc.). The interstitial connective tissue matrix contains collagen types I and III, fibronectin, proteoglycans and glycosaminoglycans.

Origin of tumor stroma. Convincing experimental data have been obtained on the emergence of cellular elements of the tumor stroma from pre-existing normal connective tissue precursors of the tissue surrounding the tumor. In 1971

J. Folkman showed that malignant tumor cells produce a certain factor that stimulates the proliferation of elements of the vascular wall and the growth of blood vessels. This complex protein substance is called the Volkmann factor.

As was subsequently established, Volkmann factor is a group of fibroblast growth factors, of which more than 11 are already known. Volkmann was the first to convincingly show that stroma formation in a tumor is the result of complex interactions between the tumor cell and connective tissue cells.

An important role in stroma formation in the neoplasm is played by connective tissue cells of both local, histiogenic, and hematogenous origin. Stromal cells produce a variety of growth factors that stimulate the proliferation of cells of mesenchymal origin (fibroblast growth factors, platelet growth factor, tumor necrosis factor a, fibronectin, insulin-like growth factors, etc.), some oncoproteins (c-sis, c-myc).

At the same time, they express receptors that bind growth factors and oncoproteins, which makes it possible to stimulate their proliferation along both autocrine and paracrine pathways.

In addition, the stromal cells themselves are capable of secreting a variety of proteolytic enzymes, leading to the degradation of the extracellular matrix.

Tumor cells actively participate in the formation of stroma.

Firstly, transformed cells stimulate the proliferation of connective tissue cells through a paracrine regulatory mechanism, producing growth factors and oncoproteins.

Secondly, they are able to stimulate the synthesis and secretion of extracellular matrix components by connective tissue cells.

Third, tumor cells themselves are capable of secreting certain components of the extracellular matrix. Moreover, the type of such components has a characteristic composition in some tumors, which can be used in their differential diagnosis.

Fourth, tumor cells produce enzymes (collagenases, etc.), their inhibitors and activators, which promote or, on the contrary, prevent the filtering and invasive growth of malignant tumors. The dynamic balance between collagenase activators and their inhibitors ensures a stable tumor state and prevents growth into adjacent tissues. During growth, tumor cells actively synthesize collagenases, elastases and their inhibitors.

Malignant tumors often form a stroma in which the collagen type of the stroma of the corresponding organ predominates at the stage of embryonic development. For example, in the stroma of lung cancer, the predominant type of collagen is collagen III, characteristic of the embryonic lung.

Different tumors may differ in the composition of stromal collagens. In carcinomas, as a rule, type III collagens (lung cancer), type IV (renal cell carcinoma and nephroblastomas) predominate; in sarcomas, interstitial collagens predominate, but in chondrosarcomas, collagen II predominates. Synovial sarcoma contains a lot of collagen IV.

The described differences in stromal composition are especially important to consider in the differential diagnosis of sarcomas.

Angiogenesis in tumor. The growth of tumors depends on the degree of development of the vascular network in them. In neoplasms with a diameter of less than 1-2 mm, nutrients and oxygen come from the tissue fluid of the surrounding tissues by diffusion. To nourish larger neoplasms, vascularization of their tissue is necessary.

Angiogenesis in a tumor is ensured by a group of angiogenic growth factors, some of which can also be generated by activated epithelial cells in areas of chronic inflammation and regeneration. The group of tumor angiogenic factors includes growth factors of fibroblasts, endothelium, glioma vessels, keratinocytes, epidermoid growth factor, angiogenin, some bone marrow colony-stimulating factors, etc.

Along with growth factors, the composition of the extracellular matrix of the tumor stroma is of great importance in angiogenesis. Favorable is the content of basement membrane components - laminin, fibronectin and type IV collagen.

The formation of blood vessels in tumors occurs against the background of perverted mitogenetic stimulation and an altered extracellular matrix. This leads to the development of defective vessels, predominantly of the capillary type, often having a discontinuous basement membrane and a damaged endothelial lining. The endothelium can be replaced by tumor cells, and sometimes completely absent.

The role of the stroma for a tumor is not limited to trophic and support functions. The stroma has a modifying effect on the behavior of tumor cells, that is, it has a regulatory effect on the proliferation, differentiation of tumor cells, the possibility of invasive growth and metastasis.

The modifying effect of the stroma on the tumor is due to the presence on the cell membranes of tumor cells of integrin receptors and adhesive molecules that are capable of transmitting signals to the elements of the cytoskeleton and further into the nucleus of the tumor cell.

Integrin receptors- a class of glycoproteins located transmembrane, the inner ends of which are associated with cytoskeletal elements, and the outer, extracellular, is capable of interacting with the substrate tripeptide Arg-Gly-Asp.

Each receptor consists of two subunits a and b, which come in many varieties. Different combinations of subunits provide the diversity and specificity of integrin receptors.

In tumors, integrin receptors are divided into intercellular and integrin receptors between tumor cells and components of the extracellular matrix - laminin, fibronectin, vitronectin, to various types of collagens, to adhesion molecules of the CD44 family.

Integrin receptors mediate intercellular interactions between tumor cells, as well as with cells and the extracellular matrix of the stroma. Ultimately, they determine the tumor's ability to grow invasively and metastasize.

Adhesive molecules CAM are another important component of the cell membranes of tumor cells, ensuring their interaction with each other and with stromal components. They are represented by the NCAM, LCAM, N-cadherin, and CD44 families.

During tumor transformation, the structure and expression of adhesive molecules that make up cell membranes change, as a result of which the relationships between tumor cells are disrupted, and consequently, invasive growth and metastasis begin.

Depending on the development of the stroma, tumors are divided into organoid and histioid.

IN organoid tumors there is parenchyma and developed stroma. An example of organoid tumors are various epithelial tumors. The degree of development of the stroma can also vary from narrow sparse fibrous layers and capillary-type vessels in medullary cancer to powerful fields of fibrous tissue, in which epithelial tumor chains are barely distinguishable, in fibrous cancer or scirra.

IN histioid tumors parenchyma dominates, stroma is practically absent, as it is represented only by thin-walled capillary-type vessels necessary for nutrition. Tumors of the histioid type are constructed from their own connective tissue and some other neoplasms.

So, we can conclude that the formation of stroma in a tumor is a complex multi-stage process, the main steps of which can be considered:

1. secretion of mitogenic cytokines by tumor cells - various growth factors and oncoproteins that stimulate the proliferation of connective tissue cells, primarily endothelium, fibroblasts, myofibroblasts and smooth muscle cells;
2. synthesis by tumor cells of some components of the extracellular matrix - collagens, laminin, fibronectin, etc.;
3. proliferation and differentiation of precursor cells of connective tissue origin, their secretion of components of the extracellular matrix and the formation of thin-walled capillary-type vessels, which together is the tumor stroma;
4. migration of cells of hematogenous origin into the tumor stroma - monocytes, plasma cells, lymphoid elements, mast cells, etc.

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Fibrous tissue - causes of development and treatment of fibrosis in women

• early puberty;
• late pregnancy;
• allergic reactions;
• bad habits;
• obesity;
• stressful situations.

Periductal perivascular fibrosis involves areas around the milk ducts, lymphatics and blood vessels. Excessive growth (proliferation) of interlobular connective and intraductal tissues is called linear (interlobular) fibrosis. When palpating the breast, dense cords are felt, the contours of which are clearly visible on the mammographic image.

To diagnose breast fibrosis, consultation with a mammologist and gynecologist is necessary. During the conversation, the specialist finds out the presence of a genetic predisposition to this pathology and chronic diseases, the date and nature of the last menstruation, whether hormonal medications are being taken, including for the purpose of contraception. Afterwards, the breasts are palpated and additional examinations are prescribed:

• general blood analysis;

Prevention

drlady.ru

Breast fibrosis - what is fibrous formation and its types: local, diffuse, focal

Throughout life, a woman’s mammary glands undergo many external and internal changes. One of these changes is the involution of the mammary glands, which occurs as the period of menopause approaches.

During this period, the glandular tissue of the breast is replaced by fatty tissue. But in addition to these two types, the mammary gland contains connective tissue cells - stroma. And there are often cases when, in addition to adipose tissue, excessive growth of connective tissue begins. This process is called fibrosis.

What is breast fibrosis? Another common name for this problem is mastopathy. These are pathological compactions or formations, which mainly consist of connective tissue made of collagen and elastin. Such a pathological process can form in any tissue of the body. It is benign in nature.

Causes

It should be noted that every year this disease affects an increasing number of women.

The reason for the uncontrolled growth of fibrous tissue in the mammary gland is mainly a hormonal imbalance, and all other factors are provoking:

• hormonal changes that occur during menopause, pregnancy and lactation;
• surgical interventions in the breast area;
• radiation therapy;
• the use of foreign bodies, for example, implants for breast augmentation;
• prolonged state of stress and overwork;
• diseases of the thyroid or pancreas;
• gynecological diseases, abortions, refusal to breastfeed, etc.;
• heredity.

Symptoms

At the initial stage of compaction formation, symptoms show little. Most often, this disease can be suspected by independently detecting one or several small ball-shaped seals under the skin.

In the area of ​​these formations there may be a slight change in skin color. Depending on the size of the compaction, a woman may experience a feeling of discomfort, heaviness and bloating. You may experience slight pain - nagging or aching, which can radiate, for example, to the shoulder. With obvious fibrosis, lymph nodes may become enlarged.

This pathology is often distinguished from other diseases by the absence of nipple discharge.

Kinds

There are several types of fibrosis depending on the location or method of location, as well as the cells involved in the proliferation process.

Local (focal)

This type of fibrosis is very common. And many women are interested in what “local fibrosis” is and is it dangerous? This type is characterized by the concentration of compaction at one point. Most often, such lumps appear in the upper parts of the chest. Local fibrosis of the mammary gland is what the onset of breast disease usually looks like. If you miss this moment, then more serious violations may develop. The downside is that a small seal is extremely difficult to detect. Usually it can only be felt when it reaches a certain size.

The detected focal fibrosis of the mammary gland is benign. But, nevertheless, focal fibrosis of the mammary gland requires treatment without fail. Inaction is fraught with uncontrolled growth of connective tissue, which in the future will lead to diffuse fibrosis.

Diffuse

Diffuse fibrosis of the mammary gland differs from focal fibrosis in that the spread of connective tissue does not affect a single gland, but the entire breast tissue. The formations can be large and it is quite difficult to cure this form.

It is accompanied by various unpleasant symptoms: pain, swelling, discharge from the nipples, etc. If treatment is not started in a timely manner, this will lead to surgery.

Stromal fibrosis

The stroma is part of the connective tissue of the mammary gland. The peculiarity of fibrosis of the mammary gland stroma is that as it grows, voids are formed that are filled with fluid.

Breast stromal fibrosis is quite harmless, but has unpleasant symptoms that can affect a woman’s general well-being. Treatment of focal stromal fibrosis is prescribed individually, after additional examination.

Periductal

Another obscure diagnosis that raises questions: periductal fibrosis of the mammary gland - what is it? It is also called plasmacytic, as it is characterized by the appearance of collagen fibers, which is part of the connective tissue, around the milk ducts.

Most often, this form is observed in women during menopause.

Linear

Linear fibrosis of the mammary gland has the additional names “interlobular” or “stranded” fibrosis. This is the result of proliferation of interlobular connective and intraductal tissue, which is often accompanied by the formation of cysts. This process is clearly visible in the photographs and is felt upon palpation by a specialist.

Diagnostics

One of the first forms of diagnosing breast fibrosis is an independent examination of the breast by palpation. If suspicious symptoms appear, you should immediately contact a specialist. He will conduct an initial examination and analysis of complaints. If necessary, some types of additional studies may be prescribed.

First of all, the following is carried out:

• Ultrasound and mammography;
• blood test for hormones and general clinical analysis.

To determine the nature of the formations and clarify the diagnosis, the following can be used:

• CT scan;
• Doppler sonography – assessment of blood circulation;
• biopsy;
• chropoductography - X-ray with contrast of the ducts of the mammary glands.

Treatment

The chosen type of treatment for breast fibrosis directly depends on the detected form, the degree of neglect of the disease, as well as the individual characteristics of the body, for example: age, previous gynecological diseases, etc.

Conservative

Preference is given to conservative treatment methods. It is suitable for almost all forms of breast fibrosis that are in the initial stages of their development. First of all, the hormonal background is examined, and treatment with hormonal drugs is prescribed.

In addition, homeopathic remedies are used, for example, to treat diffuse fibrous formation in the mammary gland.

Surgical

Surgical intervention is prescribed as a last resort, and only in cases where nodular fibrosis of the mammary gland or large cystic formations are detected.

Forecast

Almost 30% of women who are diagnosed with lumps of various kinds are diagnosed with breast fibrosis. This disease is not a pathology leading to oncology. But it is necessary to undergo constant examinations and treatment, since the likelihood of developing a serious illness is much higher than in women with healthy breasts.

A diagnosis such as breast fibrosis is not very scary and is diagnosed in many women. But it obliges you to monitor the condition of the mammary glands even more carefully than before.

Video

You will learn about the symptoms, causes and treatment of mastopathy from our video.

Home » Diseases » Other » What is breast fibrosis: types, symptoms, treatment methods

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Fibrosis of the breast and mammary glands in women and how to treat them

Fibrosis of the mammary glands (breasts) is an inflammatory pathology. It is as a result of fibrosis of the mammary glands that cysts and nodes develop. For a long time, mammologists have been urging women not to ignore the symptoms of fibrosis, as this disease can lead to dangerous consequences for health and life. Every woman should have an idea of ​​what this disease is, know its symptoms, complications and methods of treatment.

At its core, fibrosis, both in the mammary gland and in other tissues, is an increased proliferation of elastin and collagen fibers, as well as fibroblasts, fibrocytes and other cells. As a result of this pathological process, various changes occur in the tissues, which are similar to scarring, and this, naturally, affects the functioning of the organ.

Reasons for development

In the female breast, two components predominate - stromal and glandular. The first is a kind of frame, and the function of the second is to produce milk during the lactation period. Fibrosis of the mammary glands is a violation of the ratio of these two components; the stromal component becomes larger. This leads to tissue compaction, that is, fibrosclerosis develops.

Why does fibrosis develop? Pathological processes in the mammary gland are triggered as a result of an imbalance of sex hormones. This mainly concerns progesterone and estrogen. Since these two hormones can lead to hormonal imbalance. Many women experience this phenomenon during natural monthly bleeding. The balance of these hormones is of great importance during pregnancy, menopause, and after abortion. It is always difficult to balance these hormones, so it is necessary to closely monitor their levels and take appropriate measures if there are deviations.

The following factors can provoke breast fibrosis:

1. Prolonged stress and overwork, especially if these conditions turn into depression.
2. Various pathological processes in the functioning of the endocrine glands and pancreas - hypothyroidism or diabetes mellitus.
3. Toxic poisoning of the body by certain substances.
4. Inflammatory processes in the reproductive organs that are ignored and not treated in a timely manner.

Breast fibrosis can occur with a hereditary predisposition to this disease; this phenomenon is usually observed in women after 40 years of age. However, if provoking factors occur, the disease can begin at an earlier age.

There is another reason why fibrosis can develop (in the mammary gland) - radiation, for example, during radiotherapy. But solariums can also provoke violations, so women are contraindicated to sunbathe topless.

If fibrosis occurs due to radiation exposure, then mammologists classify it as radiation fibrosis; treatment of this type of disease is carried out according to a special scheme. Women should understand that the radiation form of fibrosis can give impetus to the onset of pathological fibrotic processes in other tissues that are not related to the mammary gland.

Types of pathology

Changes in the tissues of the mammary gland can develop in several directions; this is explained by the unequal sensitivity of areas of the mammary gland to the effects of hormones. Therefore, there are different forms of fibrosis:

• Focal fibrosis develops when connective tissue begins to grow pathologically somewhere in one place. That is, there is a focus of pathology, as a rule, it is located in the upper region of the mammary gland and looks like a dense nodular formation. The size of this formation can be from one to several centimeters.
• Nodular fibrosis develops in the same way as focal fibrosis.
• Cystic fibrosis (CF) is characterized by the appearance of cavities (cysts) that are filled with liquid contents. This pathology is called fibrous cyst of the mammary gland.
• Periductal fibrosis is the growth of collagen fibers directly around the glandular ducts. This process is often observed in patients who have entered menopause.
• Linear fibrosis. Connective tissue looks like a large number of strands.
• Stromal fibrosis. From the name it is clear that in this case the pathological process affected the stromal component of the organ.

Diffuse FAM and fibrous adenoma of the mammary gland are distinguished by mammologists separately, since in these pathologies fibroadenomas are formed - a large number of benign tumors. Fibroadenoma is diagnosed and examined not only by mammologists, but also by oncologists.

Clinical picture

While the change in the mammary gland is mild, the woman may not experience any symptoms, but as the disease progresses, the following signs appear:

1. The mammary glands become engorged and increase in size (mastodynia).
2. In the middle of the menstrual cycle or just before menstruation, discomfort appears in the chest.
3. On palpation, increased sensitivity and soreness of the mammary gland is noted.
4. Pain (mastalgia) can be temporary (premenstrual) or permanent.
5. The skin on the breasts may change color, and there may also be discharge from the nipples.
6. A woman can feel the lumps themselves a few days before the start of her period.

All of these symptoms are a reason to consult a mammologist, especially since the symptoms of fibrosis are quite similar to other pathologies of the mammary gland.

Diagnostic measures

It is impossible to diagnose fibrosis on your own. This can only be done by a mammologist, and only after a diagnostic examination. Therefore, you should not start looking for drugs to treat breast fibrosis, much less take them, until the doctor makes an accurate diagnosis.

It is not possible to determine the problem by symptoms alone; as mentioned above, the symptoms of fibrosis are quite similar to the signs and manifestations of other breast ailments. Therefore, the doctor, after a conversation with the patient (during which symptoms and complaints, heredity, background diseases, etc. are clarified), palpates and refers her to the following diagnostics:

• mammography;
• general blood analysis;
• blood test for hormones;
• Ultrasound, CT;
• study of the nature of blood flow in the chest and determination of the condition of blood vessels - dopper sonography;
• X-ray examination of the mammary gland ducts using a contrast agent - chromoductography;
• biopsy and histology of the obtained material.

Treatment of fibrosis

If the diagnosis of fibrosis is confirmed, therapy should begin as soon as possible; timely treatment of this disease is very important, since if you delay, you may encounter more serious diseases.

Don't think that your doctor will immediately prescribe a mastectomy for you. No, with fibrosis, the breast is not removed in all cases; most often, only nodes and cystic formations are removed. It is also worth saying that surgical intervention is prescribed only in difficult situations and in acute cases of the disease. In all other cases, fibrosis is treated with conservative methods.

Drug treatment of fibrosis is based on an integrated approach, which includes eliminating the cause of the disease. As a rule, doctors prescribe medications to eliminate premenstrual syndrome, hormone therapy, and dietary nutrition.

The regimen and tactics of therapy are determined by the doctor based on the form of the disease and the reasons that provoked it. In addition, the patient’s age, the presence of underlying diseases and other points must be taken into account.

If focal fibrosis is diagnosed, the patient is prescribed Duphaston, a hormonal drug containing progesterone (prescribed only if this hormone is insufficient). This will neutralize the effect of estrogen.

Cytophene or Zitazonium also reduces estrogen levels. These drugs block the receptors that are responsible for their quantity.

They also use an external remedy - Progestogel, which relieves breast swelling well and also contains progesterone.

In rare cases, Abergin is prescribed, however, it cannot be used for benign tumors, or if a woman has premenstrual syndrome. For diffuse fibrosis, Mastadion is prescribed. This is a homeopathic remedy that has a herbal composition.

If a woman has hypothyroidism, she is prescribed Iodomarin and other iodine-containing drugs. And if there are liver problems, then it is mandatory to take hepatoprotectors - Karsil, Essentiale. If breast swelling is severe, herbal diuretics may be required. Vitamin complexes and sedatives are also prescribed.

It is very important to maintain normal functioning of the gastrointestinal tract during therapy; the fact is that estrogens are excreted by the liver during treatment, and if there is constipation, they are very quickly reabsorbed from the intestines into the blood. Therefore, you need to eat more vegetables and fruits to ensure regular bowel movements.

As for traditional medicine, in this case it cannot cope with the disease. The only way traditional medicine can help with fibrosis is to normalize stools and relieve pain. Therefore, it is not worth wasting time on herbal treatment.

In severe and complicated cases (fibroadenomatosis, cyst), surgical intervention is possible.

Predictions and prevention

As for the prognosis, it is favorable; doctors are confident that this pathology, with proper and timely treatment, cannot cause oncological processes.

There is currently no specific prevention of the disease. The only thing that can be recommended is regular breast self-examination for early detection of the disease.

The risk of developing the described disease is lower in women who gave birth to a child before the age of 30, who did not terminate the pregnancy, were not addicted to hormonal contraceptives, and breastfed the child for up to a year. In addition, it is recommended to give up bad habits and visit a mammologist once a year for preventive purposes.

Fibrocystic mastopathy, causes. Breast treatment – ​​Jozef Krinicki CHEST PAIN! MASTOPATHY! The best remedy for chest pain and mastopathy! Biopsy of breast tumors under ultrasound control. Mastopathy (fibrous, diffuse, cystic). Treatment of the mammary gland - Jozef Krinitsky Benign tumors of the mammary gland Fibroadenoma of the mammary gland - symptoms and treatment Breast cyst. Breast cyst - treatment without surgery or medication. Nikolay Peychev. Breast fibroadenoma: don’t miss the threat! How to treat fibrous mastopathy of the mammary glands How to treat fibrous mastopathy of the mammary glands? Menopause in women, symptoms and treatment Elena Malysheva. Fibrocystic mastopathy Elena Malysheva. Fibrocystic mastopathy Symptoms of fibrocystic mastopathy Complications after mammoplasty. Capsular fibrosis. — Vasily Khrapach

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What is fibrous tissue?

Fibrous tissue is a type of connective tissue consisting of collagen and elastic fibers that provide relatively high tensile strength. Mechanical injuries and inflammatory processes occurring in the body contribute to its growth and activation of collagen production, which leads to the formation of nodes and tissue compaction (fibrosis). In women, this pathology mainly develops in the mammary glands.

Mechanism and causes of fibrosis development in women

With the development of an inflammatory process or mechanical damage, fibroblasts are activated to isolate healthy membranes from infection or hemorrhage. They accelerate the production of collagen, elastin and glycoprotein cells, which are the basis of connective tissue. This process can occur in all internal organs of a person.

More often, stromal fibrosis develops in women of childbearing and menopausal age in the mammary glands and uterus (myometrium). As a result of the pathological proliferation of connective tissue, the formation of compactions and scars, an inevitable disruption of the organ’s functioning occurs. Thus, fibrosis of the myometrial stroma is the cause of missed abortion and infertility.

The main reason for the development of fibrosis is a change in the level of hormones in the blood during pregnancy, lactation, menopause and as a result of natural or artificial abortion.

General factors leading to the replacement of organ cells with connective tissue include:

• genetic predisposition;
• diseases of the thyroid and pancreas;
• use of hormonal contraceptives (pills, intrauterine device);
• inflammatory processes in the uterus and ovaries;
• completing a training course (radiotherapy), hormonal therapy;
• early puberty;
• late pregnancy;
• mechanical damage to tissues;
• allergic reactions;
• bad habits;
• obesity;
• unfavorable environmental conditions;
• stressful situations.

In addition to the above reasons, breast fibrosis can occur due to refusal of breastfeeding.

The proliferation of connective tissue in the breast often provokes endometrial fibrosis, which develops as a result of infection entering the uterine cavity. This can occur due to violation of personal hygiene rules (improper use of tampons during menstruation), tissue ruptures during natural delivery, after surgical interventions (cesarean section).

Breast fibrosis: forms and symptoms

The breast is composed of fatty, glandular and fibrous tissue. With age, as reproductive function declines, fat cells are replaced by glandular ones. The main function of the stroma is to support their location, form the walls of the milk ducts and septa between the lobules of the parenchyma.

With the development of mastopathy, the stroma grows and displaces glandular cells, which transform into cavities (cysts). If connective tissue predominates in the breast, fibrosis develops, the nature of which depends on the form of the pathology.

At the initial stage of the disease, local fibrosis appears. This type is characterized by the formation of mobile (not fused to the skin) nodes (cysts) with clear contours and a smooth surface. They have a round shape and range in size from 0.2 cm to 3 cm. The lesions are easy to detect by palpation.

If left untreated, connective tissue grows, displacing parenchyma and fat cells. Complete damage to the mammary gland is called extensive (diffuse) fibrosis. It does not have clear boundaries when palpated.

Women of menopausal age often develop periductal fibrosis (plasmacytic). It is characterized by the growth of stroma around the milk ducts.

In ductal fibrosis, excessive formation of connective tissue occurs inside the milk ducts, while adjacent tissues are not affected. It is a type of periductal form.

Periductal perivascular fibrosis involves areas around the milk ducts, lymphatics and blood vessels. Excessive growth (proliferation) of interlobular connective and intraductal tissues is called linear (interlobular) fibrosis. When palpating the breast, dense cords are felt, the contours of which are clearly visible on the mammographic image.

Symptoms of breast fibrosis:

• the presence of moving nodes or compacted areas of different localization that do not cause pain upon palpation;
• change in skin pigmentation over the site of the gland lesion (not always found);
• liquid discharge from the nipple mixed with blood or clear;
• discomfort in the chest (pain, heaviness, pressure from inside);
• severe nagging pain during menstruation, radiating to the armpit and shoulder;
• swelling and engorgement of the mammary glands in the premenstrual period.

If cysts form during the growth of fibrous tissue, then when they are palpated, a feeling of pain appears; before the onset of menstruation, the lymph nodes may enlarge. As the disease progresses, the size of the nodes increases.

Depending on the strength of the manifestation of characteristic symptoms, fibrosis of the mammary glands can be moderate or severe.

Diagnosis of breast fibrosis

To diagnose breast fibrosis, consultation with a mammologist and gynecologist is necessary. During the conversation, the specialist finds out the presence of a genetic predisposition to this pathology and chronic diseases, the date and nature of the last menstruation, and whether hormonal medications are being taken, including for the purpose of contraception. After palpation of the chest, additional examinations are prescribed:

• general blood analysis;
• mammography (image of the mammary glands);
• blood test for hormone levels;
• Ultrasound of the mammary glands and pelvic organs;
• Doppler sonography - study of the blood vessels located in the mammary glands and the movement of blood through them;
• X-ray of ducts using a contrast agent (chromoductography);
• taking a puncture from neoplasms and its cytological examination;
• computed tomography and MRI.

If the presence of neoplasms is confirmed, then consultation with an oncologist is necessary, since women with fibrous changes in the mammary glands are at risk of developing breast cancer.

Treatment of breast fibrosis

Once fibrosis is diagnosed, treatment should not be delayed. Depending on the severity of the pathology, surgical or conservative methods are used for treatment. In the initial stages, the disease responds well to drug treatment.

When choosing tactics, the reasons for the development of fibrosis, the patient’s age, the presence of inflammatory processes, chronic diseases, disorders in the functioning of endocrine organs and the central nervous system are taken into account.

• Focal stromal fibrosis and other forms of pathology require hormonal therapy. Proliferation of connective tissue is stimulated by estrogen. The activity of this process can be blocked by progesterone. Progesterone deficiency in the body is accompanied by the appearance of swelling of the mammary glands and hypertrophy of intralobular fibrous tissue, which leads to the formation of cysts. To normalize the balance, drugs containing progesterone (Duphaston) and tamoxifen (Cytofen), which neutralize the effect of estrogen, are prescribed.
• For local treatment of fibrosis of the mammary glands, progesterone-containing gel Progestogel is used. It has an analgesic effect and relieves swelling.
• Mastopathy can develop against the background of increased levels of prolactin in the blood. In this case, drugs are prescribed that reduce the production of the hormone (Ronalin, Bromocriptine).
• Extensive breast fibrosis is treated using the homeopathic remedy Mastodinon.
• If there are problems with the thyroid gland, medications containing iodine are prescribed.
• In case of severe swelling, it is necessary to take herbal diuretics.
• Fibrosis cannot be treated without the use of vitamin-mineral complexes and sedatives.

If conservative treatment is ineffective, as well as in the later stages of fibrosis development, surgical intervention is necessary. To remove formed nodes and cysts, sectoral resection or enucleation is performed (husking out benign neoplasms without removing adjacent healthy tissue). In rare cases, the breast must be completely amputated.

Prevention

It is impossible to completely exclude the possibility of developing fibrosis, but there are a number of recommendations, the implementation of which will reduce the risk of the appearance and recurrence of the pathology.

• During treatment for fibrosis, it is necessary to follow a special diet to maintain normal bowel function. It involves limiting the diet of animal fats and consuming large amounts of fiber found in vegetables, fruits and cereals.
• The use of hormonal drugs and contraception should be under the supervision of a physician and in compliance with the prescribed dosage.
• After the baby is born, it is advisable to breastfeed until milk is produced (at least 6 months).

Fibrosis is a protective reaction of the body in which connective tissue displaces fat and glandular cells in order to isolate the source of inflammation or hemorrhage. At the initial stage of development, the pathology practically does not manifest itself. Neoplasms (nodules, cysts) formed as a result of stromal hyperplasia are benign in nature, but there are cases of their degeneration into a malignant tumor. To prevent the development of severe complications, it is necessary to be regularly examined by a mammologist and gynecologist.

Reasons for appearance

The main causes of fibrotic changes are inflammatory processes and chronic diseases. The disease also occurs after injury, radiation exposure and allergic reactions, infections and due to weakened immunity.

Different organs may have specific causes for the development of the disease. For example, in the liver this disease develops as a result of:

• hereditary diseases;
• immune system disorders;
• inflammation of the biliary tract;
• viral and toxic hepatitis;
• portal hypertension.

Pulmonary fibrosis develops as a result of the following factors:

• pneumonia;
• inhalation of dust microparticles for a long time;
• chemotherapy procedures;
• irradiation of the chest area;
• granulomatous diseases;
• tuberculosis;
• smoking;
• long-term use of antibiotics;
• living in an environmentally polluted area.

Fibrosis in the prostate gland develops due to:

• hormonal imbalances;
• irregular sex life or lack thereof;
• chronic prostatitis;
• vascular atherosclerosis affecting potency.

Fibrous changes in the mammary gland are caused by fibrocystic mastopathy and hormonal imbalance. Uterine fibrosis develops with chronic endometritis. Age-related changes in the myocardium or infarction can lead to cardiac fibrosis. Connective tissue scarring is a complication of diabetes, rheumatoid arthritis, and obesity.

Types of disease

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The classification of fibrosis varies among specific organs. In the liver, the type of disease depends on the location of the scars in its lobules:

• focal;
• perihepatocellular;
• zonal;
• multibular;
• bridge-like;
• periductular;
• perivenular.

Pulmonary fibrosis can be local or diffuse. Fibrosis of the prostate gland can be focal and with nodose hyperplasia, with cyst transformation and parenchymal atrophy. Sometimes a congenital form occurs.

Local and focal fibrosis is the initial stage of the disease, when isolated areas of tissue are damaged. With a diffuse disease, the damage covers most of the organ. Cystic fibrosis is characterized by damage to the exocrine gland, the ducts become blocked and cysts form. This leads to the development of disorders in the respiratory organs and gastrointestinal tract.

Among the sensory organs, epiretinal fibrosis of the eye occurs, when changes of varying degrees occur in the structures of the vitreous body and retina. Men may develop cavernous fibrosis of the penis. Women in some clinical situations may develop linear breast fibrosis.

Symptoms of the disease

Fibrosis develops slowly and at first the patient does not have any complaints. In rare cases, people experience health problems and consult a doctor. There may be regular fatigue. Then disturbances in the functioning of organs appear, in some cases blood flow worsens.

With liver fibrosis, general malaise is initially observed. After a slight blow, bruises appear on the skin. Liver destruction lasts six to eight years, after which critical symptoms occur. Liver function is significantly impaired as scar tissue cells grow and close together. Further, the spleen increases in size. Other complications include varicose veins of the esophagus and bleeding from them. Then either anemia, thrombocytopenia or leukopenia develops.

At the first stage of development, clinical tests show that fibrotic changes in the liver are insignificant. The disease can be determined by the fact that splenic and portal pressure has increased. Ascites may sometimes appear and disappear. There is also a feeling of heaviness in the right hypochondrium and problems with digestion. Sometimes itching and rashes occur on the skin.

Pulmonary fibrosis can be signaled by shortness of breath, which worsens over time and is accompanied by a dry cough. Then chest pain and rapid shallow breathing occur. Cyanosis is noted on the skin. Frequent bronchitis and heart failure may indicate the progressive development of the disease.

Women may develop focal fibrosis of the mammary gland during hormonal changes. It can be felt by palpation only when the compaction reaches a size of 2–3 millimeters or more. The skin over the affected area will change color. Over time, discomfort in the chest occurs, and then the pain increases. As the disease progresses, there may be a clear or pale discharge from the nipple. There is a feeling of fullness in the chest and heaviness in it. Then the pain intensifies, becomes aching and constant, radiating to the armpit and shoulder.

The danger of uterine fibrosis is that fibroids can be a complication. Pain in the lower abdomen and prolonged menstruation, as well as discomfort during sexual intercourse, may signal the development of the disease.

Symptoms of pancreatic fibrosis are decreased appetite and decreased body weight, diarrhea and vomiting, pain in the hypochondrium on the left side and flatulence.

Cardiac fibrosis is characterized by changes in blood pressure and shortness of breath, as well as disturbances in the rhythm of the heart. Initially, aortic valve fibrosis does not show any symptoms. Over time, pain in the heart and dizziness occur, and then the heartbeat quickens, shortness of breath occurs and the patient may lose consciousness.

In men, pain in the perineum and lower abdomen, discomfort during intimacy and urination may indicate prostate fibrosis. Then erection problems arise and libido decreases. Complications may include pyelonephritis, renal failure and hydronephrosis.

Fibrous changes can occur in different parts of the eye - in the lens, retina or vitreous body. Symptoms are a decrease in the field of vision, a decrease in its acuity and painful sensations.

What is Fibrosis

Fibrosis is the development (new formation) of connective tissue in the portal field, in the periportal zone (around hepatocytes and proliferating ductules), in the center of the lobule (around the hepatic vein) and intermedullary (around hepatocytes).

What Causes Fibrosis?

Fibroblasts play an important role in the development of fibrosis, while the collapse of the reticulistroma in foci of hepatocyte necrosis, previously considered the main mechanism for the development of fibrosis, is of secondary importance. Silent fibrogenesis in the liver is observed with damage to hepatocytes, inflammation, proliferation of ductules (especially in chronic hepatitis and cirrhosis). Fibrosis-inducing factors can be peptides, macromolecular substances or fragments of cytoplasmic organelles (lysosomes), released when hepatocytes are damaged. In the process of fibrogenesis, a certain role belongs to the sinusoidal surface of the damaged hepatocyte with the reduction of microvilli, the basement membrane, and iron-containing macrophages. With continued damage in the space of Disse, a basement membrane forms between the proliferating sinusoidal cells and hepatocytes. Subsequently, a vicious circle arises: damage to hepatocytes stimulates fibrogenesis, and fibrogenesis aggravates damage to hepatocytes due to malnutrition. As is known, the basement membrane surrounds proliferating small bile ducts. Its fibrous part consists of compressed connective tissue argyrophilic fibers, and the homogeneous, SIK-positive part is formed by epithelial components - ductular cells.

Pathogenesis (what happens?) during Fibrosis

The degree of fibrosis is determined by the ratio of collagen synthesis and breakdown. The reversibility of the process (disappearance of connective tissue) depends on the state of macrophages resorbing collagen and the chemical nature of the main substance.

In foci of fibrosis, active and passive connective tissue septa are distinguished. Active septa are rich in cellular elements and are formed in foci of active fibrogenesis as a result of the formation of connective tissue by fibroblasts. Passive septa result from the collapse of the reticulin stroma in areas of parenchymal necrosis and contain few cells.

Connective tissue fibers with a large number of cellular elements undergo reverse development better than fibers containing few cells. Connective tissue septa growing into the lobule from the portal fields or from zones of collapse divide the parenchyma into separate sections - pseudo-lobules, which leads to a restructuring of the microarchitecture of the liver, and subsequently to the formation of cirrhosis of the liver. Active formation of septa is of great importance, especially in the cirrhotic stage. Along the septa there are blood vessels that are anastomoses between the branches of the portal vein and hepatic artery and the branches of the hepatic veins, which leads to intrahepatic shunt blood flow and, as a result, there is a decrease in the amount of blood washing the liver parenchyma. Poor circulation leads to insufficient supply of oxygen and nutrients to hepatocytes and loss of liver function, increasing pressure in the portal vein system. In alcoholic liver damage, excessive formation of connective tissue occurs in the center of the lobule, around the hepatic vein, which also contributes to disruption of hemodynamic processes during passive blood stagnation, prolonged cholestasis, and some intoxications accompanied by the death of parenchyma in the center of the hepatic lobule. In areas of parenchymal necrosis, connective tissue collapses. In these cases, the formation of excess connective tissue determines active fibrogenesis, prevailing over collapse.

Based on its localization in the liver lobules. There are focal, perihepatocellular, zonal (centrilobular, portal, periportal), multilobular, bridge-like, as well as periductular, perivenular fibrosis.

Focal fibrosis is characterized by the presence of introlobular small scars at the site of the granuloma, which may indicate previous liver damage.

Perihepatic fibrosis is characterized by the formation of a basement membrane at the sinusoidal surface of hepatocytes. If the process involves all the liver lobules or most of them, fibrosis is designated as diffuse. Perihepatocellular fibrosis can occur with alcoholic lesions, hypervitaminosis A, syphilis and a number of other conditions,

Zonal central fibrosis can lead to the formation of connective tissue septa extending from the central veins towards the portal tracts. At the same time, with zonal portal fibrosis, a cylindrical expansion of the portal fields is observed.

Sclerosis of the portal tracts with the spread of the process beyond them due to necrosis of adjacent hepatocytes is a characteristic sign of zonal periportal fibrosis.

Multilobular fibrosis occurs as a result of massive necrosis of the liver parenchyma, covering the territory of several lobules. Against their background, the intact part of the liver tissue can retain its normal structure.

Bridging fibrosis is characterized by the formation of connective tissue septa between the vessels of the liver. In addition to complete septa, there are incomplete septa that blindly end in the liver lobule. Complete septa can be porto-portal, porto-central, or centro-central.

The central veins contain anastomoses through which blood flows bypassing the parenchyma. The consequence of the formation of full-fledged septa is a violation of the architectonics of the lobules, up to the formation of false lobules.

In periductular and periductal fibrosis, collagen is deposited under the thickened basement membrane of the corresponding bile ducts, but the fibers never penetrate between the epithelial cells of these formations. Periductal fibrosis reaches its greatest severity in sclerosing cholangitis.

Perivenular fibrosis is more common with alcoholic liver damage, as well as in drug addicts. From the subsinusoidal spaces, fibrosis can spread to the central vein, and this leads to thickening of its walls.

A unique form of liver disease is congenital fibrosis. In this case, pronounced portal fibrosis, hypoplasia of the intrahepatic branches of the portal vein and hepatic artery, and a sharp dilation of the bile ducts are observed. There are clear boundaries between the sclerotic portal tracts and the parenchyma, and there is no inflammatory infiltration. Adjacent portal tracts can be connected by septa. A characteristic feature of congenital fibrosis is the absence of false lobules.

In the liver, the processes of fibrogenesis are primarily controlled by a complex of interacting cells of the sinusoids and parenchyma. A fibrous scar not only causes deformation of the liver, but is also the main cause of impaired liver function, clinical manifestations, and a number of complications. Excessive development of connective tissue in the liver can be observed in the portal tracts, in the periportal zone (around hepatocytes and proliferating ductules), in the center of the lobule (around the central vein), intramedianly, around hepatocytes. With fibrosis, a special variant of interaction between sinusoid cells and hepatocytes is formed. The formation of fibrosis (fibrogenesis) is a universal process caused by excessive deposition of extracellular matrix (ECM) proteins in tissues. In addition to collagen, the extracellular matrix includes glycoproteins, glycosaminoglycans (GAGs) and proteoglycans. There are 5 types of collagen in a normal liver: I, III, IV, V, VI. In fibrosis, one type of collagen predominates, which contributes to their disproportion.

Proteoglycans are complex macromolecules consisting of a core protein covalently linked to a series of polyanionic sulfated carbon polymers, or GAGs. Depending on the carbon chain of GAGs, heparan sulfate, dermatan sulfate, and chondroitin-4,6-sulfate are distinguished. ECM fibers are firmly associated with structural glycoproteins (lamin, fibronectin, nido-gene/entactin, undulin, tenascin), which envelop collagen fibers and thus separate the liver stroma from the parenchyma. Liver damage is accompanied by an increase in the production of all types of collagen. The main sources of ECM protein formation are hepatic stellate cells (HSCs) and Ito cells. When activated, their transformation into myofibroblasts, loss of vitamin A, the appearance of oc-actin fibers, an increase in the rough endoplasmic reticulum, the content of messenger RNA of collagen types I, C. IV, and the number of receptors for cytokines stimulating proliferation and fibrogenesis are observed. With fibrosis, one or another type of collagen begins to predominate. Fibrous tissue contains a lot of helical collagen types I and III, while type IV collagen predominates in the basement membranes.

Myofibroblasts take part in collagen synthesis and the formation of fibrosis. Activation of the PGC of sinusoids begins with their paracrine stimulation, which promotes gene expression by Kupffer cells, endothelial cells, hepatocytes, and platelets. This enables Ito cells to respond to the effects of cytokines and other mediators, such as transforming growth factor -pi (TGF-(3i), platelet-derived epidermal growth factor, tumor necrosis factor-(TCR-os), thrombin. This stimulates proliferation processes , contractility, release of leukocyte chemoattractants, cytokines, excess production of ECM components, type I collagen.

The formation of fibrosis is largely due to the activity of tissue metalloproteinases (MPs), which destroy ECM proteins. Tissue MPs are synthesized by Kupffer and Ito cells. Their activity is regulated by tissue inhibitors, in particular TIMP, as well as plasmin and ag-macroglobulin. TIMPs are produced by various cells, including Ito cells (Fig. 5).

3 types of MP are described:

• interstitial collagenases (destroy collagen types I and III);
• gelatinases (destroy collagen types IV and V, fibronectin, elastin, denatured collagens);
• stromelysins (destroy fibronectin, laminin, collagen types III, IV, V, peptides, procollagen).

Depression of macrophages takes the system of Ito cells out of control, which gain the opportunity to realize their fibrogenic functions. At this stage of the disease, macrophages actively produce antifibrogenic cytokines (IFN-a/R), as well as metalloproteinases (collagenases, prostaglandins Ei/Er).

In acute liver damage, there is a certain balance between the synthesis and destruction of ECM components. At the same time, during the chronic process, there is a predominance of ECM synthesis over its destruction, which leads to excessive activation of the fibrosis process. Thus, enhanced hepatic fibrogenesis is characterized by an increase in collagen production, a decrease in the secretion and activity of tissue MPs, and an increase in the concentration of tissue inhibitors of metalloproteinases, most often TIMP-1.

Triggers of hepatic fibrogenesis are often alcohol, hepatotropic viruses hepatitis B, C, D, viral co-infection, autoimmune process, drug-induced liver damage, excessive accumulation of copper and iron in the liver tissue, carbohydrate and lipid metabolism disorders, biliary obstruction at all levels, etc.

Changes in collagen synthesis by activated PGCs begin with increased expression of their genes. Messenger RNA serves as a carrier of information from the gene to the protein-synthesizing system of cells and acts as a matrix for protein synthesis. The main mechanism of collagen mRNA stability is determined by the interaction of the a-CP2 protein complex with the nucleotide sequence. Proteins of this complex are able to interact with collagen mRNA only in activated PGCs. Collagen is synthesized as an intracellular precursor molecule. The early precursor of collagen is preprocollagen, which contains a signal sequence at the N-terminus, which is cleaved off in the endoplasmic reticulum and turns into procollagen. After a series of specific transformations, collagen molecules in the ECM form fibrils. When exposed to damaging agents, fibrosis forms over several months or years. The timing of fibrosis formation can be altered by additional risk factors (alcohol, chronic infection, male gender, etc.). With biliary obstruction, fibrosis can develop within a period of 2.5 to 18 months.

The formation of fibrosis in the liver also depends on the nature and severity of the inflammatory process. Liver cirrhosis with manifestations of arterial hypertension is considered an irreversible condition; however, at the precirrhotic stage there is a possibility of further development of the process. We observed cases of reverse development of fibrosis in a patient with biliary cirrhosis of the liver when the bile flow through the extrahepatic bile ducts was normalized. The longer fibrosis exists, the fewer opportunities there are for its correction. Currently, much attention is paid to methods that allow not only to detect fibrosis, but also to determine the activity of fibrogenesis in the liver, its tendency to stabilization, involution or progress. The degree of fibrosis in the liver is assessed using morphological methods. Conventional histological methods using standard dyes make it possible to give a qualitative assessment of the content of collagen and glycoproteins. Spectrophotometric analysis quantifies collagen based on the concentration of collagen-specific dyes. In addition, semi-quantitative systems for assessing the degree of fibrosis are widely used. For this purpose, inflammatory markers are determined in the blood - endothelial adhesive proteins from the E-selectin class (ICAM-1, VCAM-1), IL-8, which determine inflammatory infiltration in the liver. The destruction of the ECM and the activity of fibrogenesis can be judged by the content of hyaluronate, laminin, and other structural glycoproteins in the blood.

Symptoms of Fibrosis

In the early stages of fibrosis, the liver works relatively well, so only a small number of people notice that something is wrong. They may feel constantly tired and notice that after the slightest blow, bruises appear on the skin. Few people associate this with liver disease. However, as liver destruction continues, scar tissue grows and adheres to existing scars, and liver function is impaired. Eventually the liver becomes so scarred that it impedes the flow of blood through it and significantly reduces its function.

The disease progresses slowly. It is believed that clinical symptoms occur 6-8 years after the onset of liver fibrosis. Clinical symptoms usually develop in the following sequence:

• significant enlargement of the spleen (splenomegaly);
• manifestations of portal hypertension (varicose veins of the esophagus and bleeding from them);
• the occurrence of hypersplenism (anemia, leukopenia, thrombocytopenia). In this case, there are no symptoms of liver cirrhosis and liver function tests are not changed or changed slightly. Despite the absence of morphological changes, significantly increased portal and splenic pressure is noted. There may be periodic appearance of small ascites, which then spontaneously disappears.

Diagnosis of Fibrosis

The early stage of fibrosis is difficult to detect, as it often occurs without any symptoms. To diagnose the disease, blood and urine tests are taken, and an ultrasound examination of the liver is performed. Currently, the best method for determining the stage of the disease is a liver biopsy. A small sample of liver tissue is removed with a special needle, mixed with a special dye, and examined under a microscope. In order to monitor the development of the disease and respond to changes in a timely manner, it is recommended to repeat the biopsy every 3-5 years.

Fibrosis Treatment

Clinicians have very few effective options for treating liver fibrosis. Currently, correction of hepatic fibrogenesis can be carried out in several directions:

• treatment of the underlying disease in order to eliminate the causative factor of fibrosis;
• “inhibition of activation” of the PSC;
• reducing the activity of the inflammatory process in the liver;
• activation of fibrolysis mechanisms to destroy excess ECM proteins.

Elimination of the etiological factor of the pathological process in the liver is an important component of therapy aimed at reducing fibrosis processes. These therapeutic measures include etiotropic therapy of viral lesions (interferons, interferon inducers, chemotherapy drugs), avoidance of alcohol, narcotic and hepatotropic drugs, elimination of excess iron and copper, decompression for bile duct obstruction, etc.

By “inhibiting” the activation of PGCs we mean blocking the processes of transformation of stellate cells into active myofibroblasts, the triggers of which can be oxidative stress, endotoxemia, lipid metabolism disorders, etc. In order to inhibit the activation of stellate cells, antioxidants (a-tocopherol, vitamin C) can be used, under the action of which accumulates glutathione in the liver, which is part of glutathione peroxidase, which destroys reactive oxygen species. In addition, phosphatidylcholine, cholestyramine, antibacterial drugs, etc. can be used

In order to inhibit the activation of PZK, drugs with anti-inflammatory activity can be used - glucocorticoids, interferons (a, P), D-penicillamine, etc.

Fibrolysis mechanisms can be activated by enhancing the degradation of ECM proteins. Substances that have a similar effect include alkaloids such as cytochalasin B or colchicine, prostaglandins of group E. The toxicity of these alkaloids prevents their widespread use in clinical practice. It must be remembered that exogenous PGEs are quickly destroyed in the body without having time to affect the connective tissue of the liver. Currently, research is being conducted on the use of cytokines and their receptor antagonists as drugs. In liver fibrosis, Ito cells have increased sensitivity to growth cytokines (TGF-bb). However, their sensitivity decreases under the influence of factors that stimulate hepatocyte regeneration, which confirms the promise of using growth factors in preventing the development of fibrosis.

Which doctors should you contact if you have Fibrosis?

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The development of the disease is influenced by many factors: refusal of childbearing and breastfeeding, poor lifestyle, early puberty, late menopause.

These factors lead to an increase in the production of estrogen; in addition, they provoke the body’s excessive sensitivity to the slightest fluctuations in hormonal balance.

Breast fibrosis varies depending on the type of course:

• Focal (local) fibrosis of the mammary gland. This form of pathology is characterized by the appearance of pathological foci in which cysts and nodes develop. In addition, in medicine this form is considered the initial stage of fibrosis. At this period of development, the disease is easy to diagnose through a routine examination;
• Diffuse (extensive) fibrosis of the mammary gland. In this case, we are talking about the progression of the disease, when the pathological process affects absolutely the entire gland. Characterized by complete destruction of the glandular tissue of the breast.

• Availability of seals;
• Change in skin color;
• Nipple discharge;
• Feeling of heaviness, fullness, pain.

In this case, we are talking about the pathological growth of one’s own fibrous tissue – the stroma, which supports and connects adipose tissue and parenchyma.

Also, through the fatty tissues of the breast, there are peculiar partitions of fibrous tissue that connect the skin with the glandular capsule.

This form of the disease is characterized by the formation of collagen fibers around the milk ducts. This type is mainly found in menopausal women.

A type of pathology is dictal fibrosis - damage to the ducts that does not affect other breast tissues. The periductal perivascular appearance is characterized by excessive growth of connective tissue around ducts, lymphatics and blood vessels.

This form of pathology occurs as a result of proliferation of interlobular connective and intraductal tissue. Cysts often form in this case. On palpation, dense cords are detected in the chest. Linear fibrosis with cords is clearly visible on mammography.

• Palpation (palpation) of the chest, regional lymph nodes;
• Mammography – radiography of the mammary glands;
• General blood test, as well as a study of hormone levels;
• Doppler sonography – study of the state of blood vessels and blood flow;
• Chromoductography - x-ray of ducts with the introduction of contrasts;
• Biopsy and further histological examination of the obtained biological materials.

After confirmation of the diagnosis, therapy begins immediately, without delay. Timely contact with a specialist plays an important role. You should consult a doctor if the slightest alarming signs appear. Otherwise, complications will arise that are more serious than fibrosis itself.

The doctor must conduct a comprehensive diagnosis in order to accurately establish the diagnosis and identify the cause of the pathology, and obtain a complete clinical picture. Treatment can be conservative or surgical, depending on the severity of the disease.

Female breasts in the presence of this pathology are not always subject to removal; surgical intervention involves excision of only cysts and nodes. It is worth noting that surgery is used extremely rarely, in very complex cases with an acute course. As a rule, the disease is well treated with conservative methods.

As for the latter, a complex effect is implied, including eliminating the cause of the disease. Typically, therapy includes diet, treatment of premenstrual syndrome and various hormonal medications.

Treatment tactics are determined by the form of the detected disease and its etiology. The patient’s age, the presence of pelvic inflammation, and endocrine disorders are taken into account.

Focal fibrosis, however, like other forms of the disease, requires the use of hormonal drugs. For example, a doctor may prescribe progesterone (Duphaston) if it is deficient. Such a remedy will neutralize the effect of estrogens. As a rule, they drink it one tablet per day for 2 weeks in each menstrual cycle.

An anti-estrogenic drug is tamoxifen (“Cytofen”, “Zitazonium”), which blocks endogenous estrogen receptors. It is prescribed for menopause, cancer of the endometrium, breast, and infertility due to unripe eggs.

Progestogel is often prescribed for external use. This product contains progesterone and relieves swelling. Sold in gel form and applied to the skin twice a day.

Sometimes the doctor prescribes bromocriptine (Parlodel, Abergin) - a drug that limits the synthesis of somatropin and prolactin, but it is contraindicated for use in benign neoplasms and premenstrual syndrome.

Diffuse fibrosis is often treated with the drug Mastodinon. The remedy is classified as homeopathic and is an alcohol tincture of several plants (iris, tiger lily, cyclamen, emetic). Take it 30 drops twice a day for 3 months.

If hypothyroidism and iodine deficiency are detected, potassium iodide (Iodomarin, etc.) is prescribed. If there are problems with the liver, it is necessary to supplement therapy with hepatoprotectors (Essentiale, Karsil, etc.). The treatment complex includes vitamin therapy (B vitamins, as well as A, E and C).

With severe swelling, there is a need for herbal diuretics. Typically, treatment is not complete without taking sedative (calming) drugs.

During therapy, it is necessary to maintain normal bowel function so that estrogens are not absorbed back into the blood, since at this time they are carefully eliminated by the liver. For these purposes, it is recommended to exclude animal fats from the menu and introduce more plant fiber (fruits, vegetables). It is worth noting that various folk remedies are useless in this case. Alkaloids, phytoncides and flavonoids will not be able to cope with such a disease.

Chapter 2. Clinical and morphological classification of prostate cancer

In 70% of cases, prostate cancer develops in the peripheral zone, only in 10-15% of cases the tumor appears in the central zone, in the rest - in the transition zone. As noted above, the disease, with rare exceptions, begins after 50 years. However, histological examinations of prostate autopsies in young men aged 30 to 40 years revealed microscopic foci of latent cancer in 20% of cases. Since such microscopic tumors grow extremely slowly, the disease does not manifest itself clinically. Over time, the foci of latent cancer gradually increase in size and begin to lose their characteristic features of differentiation. It is generally accepted that when a tumor reaches a volume of 0.5 cm 3, it becomes clinically significant and requires appropriate treatment. Morphologically, malignant prostate tumors are divided into epithelial and non-epithelial. In turn, epithelial tumors are divided into adenocarcinoma, transitional cell carcinoma and squamous cell carcinoma. The last two forms of tumor are quite rare. The most common epithelial tumor is adenocarcinoma. It should be noted that microscopically adenocarcinoma is heterogeneous in its structure. The following types of adenocarcinoma are distinguished:
1) small acinar,
5) solid trabecular cancer,
2) large acinar,
6) endometrioid,
3) cribriform cancer,
7) glandular-cystic,
4) papillary adenocarcioma,
8) mucus-forming cancer.

The main diagnostic criteria for prostate cancer are structural atypia: compact arrangement of tumor acini, their chaotic growth with infiltration of the organ stroma. In the stroma of the tumor, the death of elastic fibers occurs, infiltration of the adjacent tissue by the tumor, and invasion into the perineural and perivascular lymphatic spaces are noted.

Currently, the histological Gleason classification is most widely used, since it largely meets the clinical requirements when choosing treatment tactics and prognosis of the disease (Fig. 1).

Rice. 1. Histological Gleason classification of prostate cancer

Gleason classification is based on the degree of differentiation of the glandular structures of the tumor. A tumor with a Gleason score of 1 forms almost normal glands, the structure of which is lost as the Gleason score increases, and with a score of 5 the tumor is characterized by undifferentiated cells. The more tissue differentiation is lost, the worse the prognosis for a given patient.

According to the Gleason classification, the degree of tumor differentiation is divided into five gradations:

• gradation 1: the tumor consists of small homogeneous glands with minimal nuclear changes;
• grade 2: the tumor consists of clusters of glands, still separated by stroma, but located closer to each other;
• gradation 3: the tumor consists of glands of various sizes and structures and, as a rule, infiltrates the stroma and surrounding tissues;
• grade 4: the tumor consists of clearly atypical cells and infiltrates the surrounding tissues;
• gradation 5: the tumor consists of layers of undifferentiated atypical cells.

An analysis of the outcomes of expectant management in the treatment of prostate cancer showed that in patients with a Gleason score of less than 4, the tumor metastasized in 2.1% of cases per year, in patients with a Gleason score of 5 to 7 - in 5.4% of cases, and in patients with a Gleason score of more than 7 - in 13.5% of cases.

Table 9. Gleason grading.

Unfortunately, it is currently impossible to predict which tumor will be asymptomatic throughout the patient’s subsequent life and which will progress to a stage with clinical manifestation. To evaluate the merits of the classification proposed by Gleason, let us compare it with the system of the World Health Organization, used mainly in Europe. It provides for a 3-gradation division of cells (G1 - G2 - G3) into highly, moderately and poorly differentiated, and the conclusion is given according to the lowest differentiation of cells. The Gleason system is based on the analysis of gland differentiation at a relatively low microscope magnification. And cytological examination of cells does not play a role here. When comparing these two classifications, their incomplete compatibility appears. For example, a Gleason score of 2 to 4 may be considered a high-grade tumor, and a Gleason score of 8 to 10 may be considered a low-grade tumor, but a Gleason score of 5 to 7 cannot be compared with an intermediate-grade tumor. Tumors with a Gleason score of 7 have been found to be significantly more aggressive than cancers with a Gleason score of 5 to 6. Some tumors with a Gleason score of 5 and 6 may remain under observation, while a Gleason score of 7 will most urologists most definitely treat sick. Of course, in each individual case there may be differences between individual grades, but the differences between 6 and 5 or up to 4 are not critical, since the prognosis and treatment of these tumors are the same. Errors in tumor grading occur in cases where the number of tumor pieces is limited.

A comparison of the Gleason score of the submitted biopsy and the results obtained after radical prostatectomy is necessary to know how accurate our preoperative diagnosis is. According to Epstein I (1997), based on 499 biopsies, agreement within the same Gleason score occurs in 74% to 94% of cases (see Table 10).

Table 10. Correlation of Gleason score between biopsy and radical prostatectomy.

The author believes that errors made in tumor grading according to biopsy and radical prostatectomy are associated with poor sampling, borderline cases of tumor differentiation and the subjectivity of its assessment. So, in 55% of biopsies that were graded in other institutions and given a Gleason score of 2-4, the tumor had either invasion into the capsule and seminal vesicles, or metastases to the lymph nodes. To increase the accuracy of morphological examination, the author recommends introducing an additional parameter - the extent of cancer during needle biopsy, and also taking into account the PSA indicator simultaneously with the data of histological examination.

The main value of any classification is its significance for the treatment and prognosis of prostate disease. When studied, Gleason data for 2911 patients showed a fairly high correlation between the Gleason score and the prognosis of the disease. “In our data, an increase in Gleason score in the case of radical prostatectomy is associated with a deterioration in all prognostic parameters,” notes Epstein I. (1997).

As the author points out, Gleason score is also the most powerful predictor of progression after radical prostatectomy. Tumors with a Gleason score of 8 to 10 have a dismal prognosis. If regional metastases are detected, then there is no point in prostatectomy, although it is technically feasible. All of the above is illustrated in Table 11. As can be seen from the table, with a Gleason score of 8-10, all prognostic factors worsen several times.

Table 11. Correlation of Gleason score with detected pathology after radical prostatectomy.

International classification of prostate cancer according to the TNM system (1997).

Stage T1, as noted in the classification, means a disease detected incidentally after transurethral resection of the prostate or determination of PSA levels, which is not detected by palpation and ultrasound. Despite the above, this stage is divided into 3 options. The point is that the prognosis for each varies significantly. For example, for stage T1b the median time period before progression is 4.75 years, and for stage T1a it is 13.5 years, i.e. In older adults with stage T1a disease, watchful waiting is often warranted, while those with stage T1b disease require aggressive therapy aimed at curing the disease.

International classification of prostate cancer using the TNM system

Tumor
T1 - Incidentally detected (not palpable and not detected by ultrasound)
T1a - Well-differentiated cancer detected after transurethral resection of the prostate gland, occupying less than 5% of the resected tissue
T1b - Any tumor detected after transurethral resection of the prostate, of lower grade or occupying more than 5% of the resected tissue
T1c - Non-palpable prostate cancer detected by transrectal ultrasound-guided biopsy; indications for biopsy - elevated PSA levels

Rice. 2. Incidentally diagnosed prostate cancer is a tumor discovered after transurethral resection of the prostate gland. Stage T1a cancer is a small, well-differentiated tumor occupying less than 5% of the resected tissue. Stage T1b prostate cancer is a larger tumor, occupying more than 5% of the resection tissue, and is less differentiated.

T2 - Tumor limited to prostate gland
T2a - Tumor affects one lobe
T2b - The tumor will affect 2 lobes
T3 - Tumor grows beyond the prostate capsule
T3a - Extracapsular tumor spread
T3b - Tumor extends to seminal vesicles
T4 - The tumor grows into neighboring organs

Fig.3. According to the TNM system, four stages of local tumor spread are distinguished - from T1 (incidental finding) to T4 (spreading into neighboring organs).

N - Regional lymph nodes
NX - Metastases to regional lymph nodes not identified
NO - No metastases to regional lymph nodes
N1 - Metastases to regional lymph nodes

M - Distant metastases
MX - Distant metastases not identified
M0 - No distant metastases
M1 - Distant metastases
M1a - Metastases to lymph nodes other than regional ones
M1b - Bone metastases
M1c - Metastases to other organs (rectum, seminal vesicles)