Etiology and pathogenesis of breast cancer. Breast cancer: classification, clinical picture, diagnosis, treatment. Growth and spread of breast cancer
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A malignant tumor that usually develops from the epithelium of the mammary ducts (80%) and gland lobules.
The incidence of breast cancer in women has been steadily increasing in recent decades and occupies one of the first places among malignant neoplasms.
Etiology. The reason contributing to the development of breast cancer is a combination of several risk factors:
1) presence of breast cancer in direct relatives;
2) early menarche;
3) late onset of menopause;
4) late first birth (after 30 years), women who have not given birth;
5) fibrocystic mastopathy in the presence of areas of atypical hyperplasia of the mammary epithelium;
6) history of intraductal or lobular cancer in situ (invasive or non-invasive);
7) mutation of the BRCA-1, BRCA-2 and BRCA-3 genes.
An increase in estrogenic activity, excessive synthesis of sex hormones or their introduction into the body for medical reasons stimulate the proliferation of the mammary gland epithelium and contribute to the development of its atypia. Chronic inflammatory processes in the female genital organs, postpartum mastitis leading to cessation of lactation, disorders of menstrual-ovarian function can also be considered as predisposing factors to the occurrence of breast cancer.
The state of estrogen receptors (ERC) is of great importance for the treatment of cancer, the course and outcome of the disease. Their presence in a tumor can radically change the course of the disease, which is why identifying ER C in the tissues of a removed tumor is so important. ER c-positive tumors are more often found in menopausal patients (in primary cancers 60-70% of cases). ER c-negative tumors are more often detected in premenopause. One third of patients with ER c-negative primary breast cancers subsequently develop relapses of ER c-positive tumors.
Pathological picture .
The right and left mammary glands are affected equally often. Bilateral damage to the mammary glands occurs in 13% of cases, and with lobular cancer - somewhat more often. The tumor of the second gland is often metastatic.
Macroscopically, nodular and diffuse forms of breast cancer are distinguished. The nodular form is mainly observed.
Clinical picture.
In diffuse cancer, the tumor node in the gland is not palpable in most cases. The tumor is detected as an infiltrate without clear boundaries, which can occupy a significant part of the mammary gland. The diffuse form is observed in edematous-infiltrative, inflammatory (mastitis-like or erysipelas-like) and armored cancer. Diffuse forms of cancer are characterized by rapid growth and early metastasis. The prognosis is unfavorable.
Metastasis of breast cancer occurs mainly through lymphogenous and hematogenous routes, most often to the bones, lungs, and pleura.
When determining the stage of the disease, the size of the tumor and the extent of the process (T - tumor), metastases to regional lymph nodes (N-nodus) and the presence of distant metastases (M - metastasis) are taken into account.
In the preclinical stage, tumor detection is possible with a specially organized clinical examination, including ultrasound and mammography. In this case, tumors or accumulation of microcalcifications with a diameter of up to 0.5 cm are detected, which cannot be detected by palpation.
Usually a woman herself discovers a tumor in the mammary gland, which forces her to see a doctor. Sometimes this happens unexpectedly for the patient during a routine examination or visiting a doctor about another disease. During this period, the tumor usually already has a diameter of 2-5 cm.
Surgical treatment of breast cancer is the leading method.
IN Depending on the stage of tumor development, the following operations are performed:
- radical mastectomy according to Halsted - which involves removing the mammary gland en bloc along with the pectoralis major and minor muscles, and removing the axillary lymph nodes.
- modified radical mastectomy according to Patey - two semi-oval transverse incisions are made, bordering the gland from the parasternal to the mid-axillary line. The gland is removed from this incision along with the fascia of the pectoralis major muscle, and the muscle itself is left in place.
3. simple mastectomy without removal of axillary lymph nodes;
- quadrantectomy - the quadrant (one fourth) of the breast containing the tumor is removed.
- lumpectomy - removal of a stage I-II tumor with a surrounding rim of healthy gland tissue up to 2 cm in size from the edge of the palpable tumor
Breast cancer ranks first in incidence among all “female” cancers worldwide (excluding skin cancer). There are several etiological factors involved in the pathogenesis of the disease. These include: age, heredity, nutrition, alcohol, obesity, lifestyle, lack of physical activity, as well as endocrine factors (endogenous and exogenous).
Lumps in the breast detected during mammography and previous benign diseases of the mammary gland are also considered as one of the causes of the disease. However, it is still quite difficult to find out a clear relationship and cause-and-effect relationships in the pathogenesis of breast cancer.
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Epidemiology
The incidence is higher in Western countries compared to countries in Africa, South America and Asia. It is estimated that one in ten English women will develop the condition in their lifetime. It accounts for a quarter of all “female” crayfish in England and the USA.
General pathophysiology (pathogenesis) of cancer
The human body consists of several trillion cells. The cell cycle—the growth, maturation, division, and death of these cells—is tightly controlled. In a child's body, cell division is accelerated, which allows it to grow. In adulthood, they divide to replace worn out or damaged cells. Cell division and growth are controlled by DNA (deoxyribonucleic acid), or more precisely, by genes, which are located in the nucleus of the cell.
Cancer occurs when cells in a specific area of the body begin to divide uncontrollably. All types of cancer, regardless of their origin, arise as a result of disruption of cell division, which leads to the appearance of tumors.
In addition, cancer cells acquire some “cheating” properties:
- Their lifespan increases, and instead of dying, they continue to grow and divide, causing new abnormal cells to appear.
- They acquire the ability to penetrate other tissues—something that healthy cells do not do. This property is called metastasis.
- They require a new network of blood vessels to meet their nutritional needs. The process of formation of new blood vessels is called angiogenesis, which is unique to cancer.
What causes a normal cell to become cancerous?
A normal cell can become cancerous if its DNA becomes damaged due to some influence. Since DNA regulates the cell cycle (cell growth, function and death), any damage to it will lead to changes in this cycle.
Most normal cells, if they develop DNA damage, either repair it or die. In cancer cells, DNA damage is not repaired, but is transferred to new abnormal cells that appear as a result of division, which are initially born as cancer cells.
Pathophysiology of breast cancer
A cancerous tumor arises from normal cells of this organ. There are many reasons (etiological factors) that increase the risk of developing the disease. DNA damage resulting from exposure to estrogen and leading to the development of cancer of this organ has been proven experimentally. Some people inherit defects in DNA (the BRCA1, BRCA2 and P53 genes) that have been linked to cancer.
The human immune system tracks down cancer cells (with damaged DNA) and destroys them. If it loses its ability to identify a cancer cell and perform its protective function, this leads to the formation of a tumor.
The etiology of breast cancer is multifactorial: several causes are simultaneously involved in the process, which can act independently of each other or interact with each other. Below are the etiological (causal) factors that are associated with the occurrence of breast cancer.
Etiological factors
Geography
Western countries account for more than half of breast cancer cases: 200 thousand cases in the USA and 320 thousand in Europe. This cancer accounts for 3–5% of all deaths in the Western world, 1–3% in developing countries. In Japan, the incidence is one of the lowest. According to the latest data, the mortality rate in the United States is 2.3% and is constantly decreasing, which is associated with improved methods (measures aimed at early detection of cancer), as well as the emergence of new treatment options.
Age
Breast cancer rarely occurs before the age of 25. With age, the incidence gradually increases. There are less than 10 new cases per 100 thousand women under the age of 25, and by the age of 45 this figure increases 100 times. This confirms the fact that female sex hormones are involved in the pathogenesis of cancer. Other malignant diseases do not have such a clear correlation with the female reproductive period.
Genetic factors
A large number of studies have shown that 12% of women diagnosed with breast cancer have a close relative suffering from this disease, and 1% of patients may have several.
Although the vast majority of breast cancer is not inherited, there are genes in which mutations increase the likelihood of developing the disease. These include the BRCA1 and BRCA2 genes, mutations in which can be passed from parents to child. There are other genes that have been linked to breast cancer (P53, P65 and ATM). For women who have two or more close relatives (mother and sister, mother and daughter) diagnosed with breast cancer, genetic screening is indicated to detect mutations in these genes before the disease develops. If these specific mutations are identified, the woman is recommended to either undergo regular preventive surveillance or bilateral preventive surveillance (with some mutations, the probability of developing cancer by the age of 40 is close to 80%).
Diet and alcohol
Diet and alcohol are believed to play a role in the etiology and pathogenesis of breast cancer. There is a clear connection between phytoestrogens, as well as alcohol abuse, and this disease. According to the latest data, the risk of getting sick increases progressively with the dose of alcohol consumed, as well as the strength of the drink. Thus, every 10 g increase in daily alcohol consumption increases the risk by 9%.
Diets high in animal fats contribute to cancer. This is because they are rich in cholesterol, which is a precursor in the synthesis of estrogens and other steroid hormones that stimulate the development of cancer.
Fiber has been shown to interfere with the intestinal absorption of estrogen. This is probably why breast cancer is less common in developing countries (Africa, Asia and South America) than in the Western world. Soybeans and vitamins are also considered as dietary factors that reduce the incidence of this disease.
Obesity, lifestyle and physical activity
Along with diet, exercise can reduce plasma hormone levels. It has been noted that these two factors, individually or in combination, affecting body weight in menopausal women, can reduce the risk of developing cancer. Every 5 kg of excess weight increases the risk of developing the disease by 8%. This is because adipose tissue is an important source of estrogen, which is synthesized from cholesterol.
Endocrine factors
Endogenous
Breast cancer is more common in nulliparous women and in those who did not breastfeed. Early full-term pregnancy, especially when combined with late menarche and early menopause, which reduce the duration of estrogen exposure, has been found to reduce the risk of developing this cancer. A woman with three or more children has half the risk of a woman who is childless. This is associated with low estrogen levels during pregnancy; accordingly, in women with many children, the effect of estrogen on the gland is less than in nulliparous women.
Exogenous factors
Hormone replacement therapy (HRT) is considered to increase the risk of cancer, especially among women using estrogen and progesterone for 5 years or longer. However, HRT has many benefits, such as:
- relief from vaginal dryness,
- reduction in headache intensity,
- reduction of mood swings and depression,
- reducing the risk of developing osteoporosis and pathological fractures.
Therefore, there is a debate among doctors about what should prevail in the decision-making process when prescribing HRT - the above benefits or its role in breast cancer.
The same can be said for oral contraceptives. They are associated with a slight increase in the risk of breast cancer. The risk is believed to be greater in those who started contraception before age 20.
Similar to HRT, it is important to note the clear benefits of oral contraceptives in preventing unwanted and mistimed pregnancies as a method of family planning, which outweigh the slight increase in the risk of breast cancer.
Increasing fabric density
It is a well-documented risk factor observed in women both during and after their reproductive years. Studies have shown that women with >75% increased breast density detected on mammography have a 5-fold increased risk compared with those with< 5%.
Benign diseases
A woman's history of benign breast diseases such as fibrocystic disease (fibroadenomatosis) and fibroadenoma increases the risk of developing cancer. Fibroadenomatosis with severe dysplasia is considered a precancer, although it does not always develop into cancer. Therefore, women with these diseases need careful monitoring and screening (a set of measures that make it possible to diagnose breast cancer in the early stages). This allows for improved treatment results.
Current trends in increasing incidence rates put breast cancer (BC) in first place in the structure of cancer incidence in women.
The social significance of breast cancer is so great that scientific research to solve this problem occupies one of the leading places in modern oncology. As a result, over the last decade, ideas about the biological characteristics of breast cancer have changed significantly; it was possible to identify a number of genomic disorders that determine the tumor process, its degree of malignancy, metastatic potential, and possible markers of drug sensitivity. Many scientific achievements have been introduced into clinical practice, which has made it possible to move to more conservative treatment methods and significantly improve the quality of life of patients with breast cancer.
Breast cancer accounts for 23% of all neoplasms in women. Epidemiological studies demonstrate a heterogeneous distribution of breast cancer incidence in different regions of the planet.
In 2002, 1,150,000 new cases of breast cancer were registered on the planet, of which 360,000 were in Europe, 260,000 in North America, and 46,000 cases in Russia.
A high incidence rate was noted among the female population of British Columbia, Hawaii, and California and averaged 80-90 cases per 100,000 women.
The lowest level of breast cancer - 12-15 cases per 100,000 women - is registered in Japan. Every year in the United States, 18,000 women are diagnosed with breast cancer for the first time. The incidence curve of breast cancer continues with a steadily low level of registration of this type of malignant tumors (India, Vietnam, Korea, Thailand, China and Gambia). If this epidemiological situation continues, the risk of breast cancer will be real for every tenth woman. At the same time, in most Western countries there is a clear trend towards a decrease in mortality from breast cancer. This fact is associated with the widespread use of mammographic screening and, as a consequence, early diagnosis of the tumor process, as well as the improvement of treatment methods.
For Eastern European countries, the incidence rate of breast cancer ranges from 40-60 cases per 100,000 female population.
In the Republic of Belarus, over the past ten years, there has been an increase in the incidence rate of breast cancer from 45.8 to 57.2 per 100,000 female population. The increase in incidence was 21%. The absolute number of newly diagnosed breast cancer cases in 1993 was 2508, in 2002 - 3043. In the structure of cancer incidence among the female population of Belarus, breast cancer ranks first and the share of this pathology is 17.5%, and in the structure of the general morbidity - 5th place.
The study of geographic variability and trends in the incidence of breast cancer on the planet, taking into account the migration of groups of women from countries with low rates of breast cancer to countries with high rates of breast cancer, allows us to identify some external factors influencing the pathogenesis of this disease. It has been established that low fertility, late age at first birth, early onset of menstruation and late menopause are important factors that are associated with an increased risk of developing breast cancer. But the most significant and general risk factor for the occurrence of breast cancer in the female population of the planet is the increasing age of the woman.
Overall, for women aged 20-24 years, the incidence of breast cancer is 1.3 cases per 100,000 women, and for women aged 75-79 years, it is 483.3 cases per 100,000 women. For women aged 70 years, the annual risk of breast cancer is 3 times higher than for women aged 40 years, and the annual risk of death from breast cancer is 5 times higher than for women aged 40 years.
One of the most important features of breast cancer is its biological heterogeneity (heterogeneity), which is due to the polyclonality of the cellular composition of the primary tumor. The simultaneous coexistence in the tumor of biologically different subpopulations of cells with unequal growth (reproduction) rates, different karyotypes, immunogenic characteristics, hormonal receptors, sensitivity to chemotherapy and many other not fully known parameters determines the extreme variability of the clinical course of the disease from aggressive, rapidly progressing to slow with a late-onset process of metastasis.
Breast cancer factors
Factors determining individual characteristics of the clinical course of the tumor process and response options to various therapeutic interventions are divided into prognostic and predictive.
Prognostic factors
Prognostic factors for breast cancer are constantly being updated as information accumulates, but the main ones remain the number of axillary lymph nodes with the presence of metastases, the size of the primary tumor, the age of patients and the state of menstrual function, and the presence of tumor cells at the edges of the surgical wound.
Prognostic factors suggest the clinical outcome of the disease, i.e. long-term survival rate and the likelihood of early relapse of the disease in the absence of additional treatment. In clinical practice, this usually means the result of radical surgical treatment without adjuvant (additional) therapy.
Predictive factors
Predictive factors are clinical, pathological and biological features of the tumor process that are used to assess the body's response to specific adjuvant (additional) therapy.
Pathogenesis of breast cancer
Much attention is paid to the development of laboratory tests that allow identifying groups of breast cancer patients with a high risk of early relapse of the disease after radical surgical treatment, who require the correct selection of adjuvant treatment.
For patients with metastatic breast cancer It is relevant to determine tests of hormonal and chemotherapeutic sensitivity of the tumor process. To address these issues, the determination of molecular biological tissue markers in the tumor is used.
The first molecular factors Characterizing the degree of hormonal sensitivity of breast cancer, estrogen receptors (ER) were identified; somewhat later, in addition to them, progesterone receptors (RP) in the tumor began to be determined. Using molecular biology methods, the structure and functions of steroid receptors, as well as their exact localization, were elucidated. It has now been established that receptors for steroid hormones are located in cell nuclei, and monoclonal technology has made it possible to more accurately localize receptors in target cells.
Human estradiol receptor(ER) was cloned from breast cancer cells in 1987. The estradiol receptor is a protein belonging to a family of hormone-activating transcription factors that initiate or enhance gene transcription. The human estradiol receptor consists of 595 amino acids and its molecular weight is 66 kDa. The first ER was named ER-α. In the mid-90s of the XX century. A second type of estradiol receptor, ER-β, was discovered. The gene for the first kDa receptor is localized on chromosome 6, and the gene for the second is located on chromosome 12. ER-β contains 485 amino acids and its molecular weight is 54.2 kDa. As a result of the interaction of estrogens, receptors and DNA, a large number of tumor cell proliferation regulators are stimulated: proto-oncogenes - myc, jun, fos, cyclins, cyclin-dependent kinases, autocrine and paracrine growth factors with their receptors.
Determination of estradiol and progestin receptors in the primary tumor is a reliable criterion for the sensitivity of breast cancer to therapeutic effects. The presence of both types of steroid hormone receptors in tumor tissue indicates a favorable prognosis for the course of the disease and high sensitivity of the tumor process to endocrine treatment. For clinical practice, not only the very fact of the presence of steroid receptors is important, but also their quantitative content. Throughout the years after the discovery of steroid receptors, the lower limit of positive ER was considered to be 10 fmol. In recent years, there has been an active tendency to increase this limit to the level of 30 fmol.
As a result of a large number of observations (Rhodes A., 2000 - 4056 observations), it was found that in 54-58% of cases the primary breast cancer tumor is ER +; and RP + positive; in 15-26% - RE - negative and RP - negative, in 16-23% - RE + positive and RP - negative, and in 3-5% of breast cancer is RE - negative and RP + positive. Tumors with an ER content below 10 fmol are considered estrogen-negative. Tumors with a high content of steroid hormone receptors, as a rule, have high differentiation, low proliferative activity and a less aggressive course. The phenomenon of the presence or absence of steroid receptors in the primary tumor, along with the fact of metastatic lesions of the axillary lymph nodes, is prognostic for women with operable breast cancer. In clinical practice, combinations of these two factors make it possible to identify groups of breast cancer patients with varying degrees of increase in unfavorable outcomes of the disease.
Traditionally, much attention is paid to the study and identification of new markers of the proliferative activity of tumor cells. The proliferative activity of breast cancer is directly proportional to the degree of histological malignancy, tumor size, and the presence of metastases in the axillary lymph nodes and is inversely related to estrogen and progesterone receptors. The proliferation index is determined by a test with bromine-2-deoxyuridine, which is included in DNA during replication and makes it possible to determine the number of cells in the phase of DNA synthesis. The proliferation index in breast cancer is an independent prognostic factor that determines the likelihood of early relapse of the disease. A very promising marker of proliferation is the Ki-67 antigen, which is expressed in all phases of the cell cycle and characterizes the size of the proliferative pool. Low values of the Ki-67 antigen (less than 20%) coincide with high ten-year survival rates for patients with breast cancer.
According to modern ideas about carcinogenesis, the basis of malignant cell transformation is the activation of single or multiple cellular oncogenes or suppressor genes. Of particular interest in breast cancer are the c-erb (HER2/neu) oncogene and the bcl-2 oncogene. The expression of the p185 protein encoded by the HER2/neu oncogene is determined immunohistochemically in 15-30% of breast cancer cases. In 2004, evidence was obtained that overexpression of HER2/neu in breast cancer cells with positive ER + and negative ER - is combined with tumor resistance to antiestrogens (tamoxifen). The combination of increased expression of the HER2/neu oncogene with negative estrogen and progesterone receptors indicates an unfavorable prognosis of the disease.
The bcl-2 oncogene determines the mechanism of cell death by suppressing apoptosis. Expression of bcl-2 is associated with a favorable prognosis for the clinical course of breast cancer.
The predictive value of the p53 suppressor gene is evidenced by the data that p53 status may be decisive in determining the sensitivity of breast cancer to radiation and drug treatment.
The study of the molecular pathogenesis of breast cancer has made it possible to establish the presence of a whole spectrum of genetic disorders in sporadic breast cancer and in the so-called hereditary variant of breast cancer, which occurs in “cancer families” as hereditary syndromes. Hereditary breast cancer can manifest itself in consanguinity as various combinations of tumors (the so-called integral specific hereditary breast cancer syndrome).
Today it is known that hereditary mutations in genes DNA repair systems and suppressor genes involved in the development of malignant breast tumors (BRCA1; BRCA2; p53; etc.) determine the predisposition to the development of hereditary breast cancer. In this case, initial mutations occur in germ cells with subsequent genetic events in target epithelial cells of the mammary gland.
The fact of familial accumulation of breast cancer in three or more close relatives, the young age (mainly up to 40-44 years) at detection of the disease, and the high frequency of bilateral breast cancer are cardinal signs of a hereditary variant of breast cancer.
There are several levels of etiological and genetic heterogeneity of breast cancer associated with the patterns of accumulation in families of tumors of other locations in combination with breast cancer.
For example:
- families with accumulation of cancer of one localization (organ-specific breast cancer or ovarian cancer (OC));
- families with accumulation of tumors of different locations in the reproductive system - breast cancer syndrome - ovarian cancer - endometrial cancer;
- families with the accumulation of malignant tumors of the female reproductive system and gastrointestinal tract (Lynch syndrome II).
Of these, families with the accumulation of malignant tumors in the reproductive system of different locations are of particular interest.
Genetic analysis of pedigrees in these families showed a high coefficient of genetic correlation between OC and breast cancer (r = 0.72), i.e. 72% of common genes form a predisposition to these two different types of malignant tumors.
Currently, more than 300 mutations have been identified, localized in various loci of the BRCA1 gene, mapped on the long arm of chromosome 17, which give a very high risk of developing a hereditary variant of OC and (or) breast cancer. In addition, mutations in the p53 and estrogen receptor gene (ESR) genes can be inherited, which also sharply increases the likelihood of developing breast cancer and (or) ovarian cancer. Changes associated with mutations of the p53 gene in germ cells most often lead to the development of Li-Fraumeni syndrome (breast cancer - brain tumor - bone and soft tissue tumors).
Unlike the hereditary variant of breast cancer, in sporadic breast cancer, which occurs outside of “cancer families,” mutations of the BRCA1 gene in somatic cells are quite rare and do not play a major role in the carcinogenesis of malignant breast tumors in these cases.
In addition to Li-Fraumeni syndrome, there are a number of hereditary diseases and syndromes against which breast cancer and ovarian cancer develop. These are Gardner, Peutz-Jeghers, Cowden syndromes, SBLA syndrome (breast cancer and adrenal cortical carcinoma), as well as an immunodeficiency condition such as Louis-Bar syndrome.
Along with BRCA1, there is another suppressor gene that is more specific for breast cancer. This is the BRCA2 gene, associated with the proximal region of chromosome 13. It is assumed that the BRCA2 gene plays an important role in the formation of familial cases of breast cancer in both men and women.
Fundamental discoveries of mutations in the BRCA gene family have established that BRCA1-associated breast cancer is characterized by the presence of steroid receptors, high expression of cyclin E, low expression of cyclin D, severity of p53 mutations, and negative HER2-neu. Breast cancer associated with the BRCA2 gene is characterized by the presence of a high level of receptors for estrogen and progesterone, as well as a low degree of tumor malignancy.
The use of the above-mentioned molecular genetic and protein markers (with the exception of steroid hormone receptors) to assess the prognosis is still within the framework of experimental studies and requires refinement of the methodology for their determination.
Growth and spread of breast cancer
Breast cancer occurs in that part of the organ structure that is represented by lobules and ducts that penetrate the lobules towards the nipple. If tumor growth begins in the epithelium of the ducts and does not extend beyond the basement membrane, then the process is designated as intraductal carcinoma in situ. This is the intraepithelial phase of the development of true breast cancer, which in morphological terms is a pool of malignant cells limited only to the epithelium without involving the basement membrane, incapable of metastasis, but potentially capable of invasion. Lobular carcinoma in situ involves both the acini of the lobules and the terminal parts of the ducts. Therefore, during histological examination it can be difficult to distinguish this variant of breast cancer in situ from intraductal carcinoma in situ or from atypical lobular hyperplasia.
All other forms of breast cancer are invasive or infiltrating.
It is logical to assume that for breast cancer, the in situ stage is mandatory in the natural biological history of the tumor process, regardless of how it initially appears: monoclonal or immediately polyclonal. However, the point of view that an epithelial breast tumor inevitably progresses from atypia to carcinoma in situ and further to invasive cancer and subsequent metastasis is not supported by all researchers. Molecular genetic studies of ductal carcinoma in situ and atypical ductal hyperplasia have demonstrated similar genetic lesions, suggesting a clonal origin for these pathological conditions. In addition, it has been shown that non-invasive (in situ) and invasive morphological changes in breast cancer have identical molecular genetic disorders, i.e. are steps of one pathogenetic mechanism.
The period of time from the hypothetical “first” cancer cell to the moment of death The patient, as a result of the tumor reaching a “critical” mass, was called the “natural history” of breast cancer. Its duration depends on the growth rate of the primary tumor and metastases, as well as on the time of onset of the metastasis process. By palpation, a tumor in the breast tissue can be determined when the size exceeds 1 cm, when the number of cells in the tumor is 10 9 .
Using special calculations it was established that the average duration of the preclinical stage for primary breast cancer is 8.4 years. The process of breast cancer metastasis depends on the intensity of tumor vascularization. The formation of blood vessels in the tumor (angiogenesis) begins when the number of cells is 100-200 with the obligatory synthesis of angiogenic factors by them. From this moment, tumor cells can penetrate into the vascular bed. Radioisotope methods have shown that no more than 0.1% of cells circulating in vessels with blood and lymph survive. Thus, the process of metastasis is not random; it is based on the selection of clones, due to which some of the tumor stem cells remain viable.
With the help of modern experimental and clinical studies it has been proven that the microenvironment of each organ can have a positive or negative impact on the process of implantation, invasion, survival and growth of metastatic tumor cells. Apparently, this determines the specificity of metastatic damage to certain organs during the progression of the tumor process.
For some patients with breast cancer it is typical the presence of occult regional and distant micrometastases, the exact localization of which cannot be determined by modern instrumental methods, but which ensure early progression of the tumor process after radical surgical treatment. This fact was fundamental in creating the hypothesis of the systemic development of breast cancer, formulated by V. Fisher (1965). He was able to experimentally prove that hematogenous and lymphogenous dissemination of breast cancer occur simultaneously due to the presence of a large number of lymphovenous shunts. Therefore, the presence of metastases in regional axillary lymph nodes can be considered as an indicator of the systemic spread of the tumor process. The exception is rare cases where the tumor has not yet acquired a metastatic phenotype and remains a localized disease.
Primary tumor size(T) in the mammary gland gives an idea of the timeliness of diagnosis of the disease and is therefore an important prognostic criterion that determines the likelihood of regional metastasis. According to various data, the frequency of regional metastases even with minimal tumors (less than 1 cm) ranges from 10 to 24%. This means that the threat of regional metastasis is real with clinically non-palpable lymph nodes (N0). That is why a number of methods for more accurate preoperative and suboperative determination of the condition of regional lymph nodes are currently being developed.
The location of the tumor in the mammary gland affects choice of treatment tactics, volume of surgery and direction of skin incision. Tumors located in the internal parts of the mammary gland tend to metastasize to the parasternal lymph nodes (in approximately 1/3 of cases), and this lymphatic collector may be the only one with signs of metastatic lesions. Tumors localized in the center of the mammary gland (areolar zone) have the highest incidence of regional metastasis. Tumors located in the area of the submammary fold metastasize not only to the parasternal lymph nodes, but also through the lymphatic vessels of the abdominal wall and coronary ligament to the liver, retroperitoneal and inguinal lymph nodes.
The type of tumor growth determines the clinical form of the disease.
Highlight
- knotty and
- diffuse forms of breast cancer.
Knotty forms, in turn, are divided into delimitation and locally infiltrative growing. Nodular delimitation of growing forms of breast cancer is characterized by a slow course of the disease and a less pronounced intensity of metastasis than infiltrative ones.
Tumors of the infiltrative type are more common in premenopausal women and have a very unfavorable prognosis.
Diffuse forms. Depending on the predominance of certain symptoms, diffuse forms of breast cancer are divided into edematous, diffuse-infiltrative and lymphangitic forms. Separately, there are inflammatory forms of breast cancer (mastitis- and erysipelas-like cancers) and the so-called “armored” cancer, which is characterized by a very fast, sometimes lightning-fast course and high resistance to therapeutic effects. It should be noted that swelling of the mammary gland can be caused not only by compression of the main lymphatic collectors (axillary, subclavian) by metastatic lymph nodes, but also by the presence of tumor emboli in the lymphatic vessels and plexuses of breast tissue. With the appearance of edema and (or) hyperemia of the skin of the breast, breast cancer should be considered as a systemic disease. Swelling of the arm on the affected side indicates a significant spread of the tumor process and the inappropriateness of surgical treatment.
Thus, the condition of the lymph nodes is the most important factor that determines not only the degree of spread of the tumor process, clinical prognosis, but also treatment tactics. The presence of metastases in 4 or more axillary lymph nodes or a single lesion of the subclavian, parasternal lymph nodes correlates with a poor prognosis of the disease, and metastatic lesions of the supraclavicular lymph nodes are almost always associated with generalization of the tumor process.
Classification of breast cancer
The anatomical and biological characteristics of the tumor are of fundamental importance for the creation of modern classifications of breast cancer. The presence of a unified classification of tumors, agreed upon internationally and equally acceptable to specialists in various fields, allows everyone who works on the problem of breast cancer to compare diagnostic data and treatment results according to a single standard.
Histopathological classification
breast tumors
Currently, it is customary to use the WHO histological classification (1984).
A. Non-invasive cancer (in situ):
- intraductal (intracanalicular) carcinoma in situ,
- lobular (lobular) cancer in situ. B. Invasive cancer (infiltrating carcinoma):
- ductal;
- lobular;
- mucous (mucinous);
- medullary (brain-like);
- tubular;
- apocrine;
- other forms (papillary, squamous, juvenile, spindle cell, pseudosarcomatous, etc.).
C. Special (anatomical and clinical) forms:
- Paget's cancer;
- inflammatory cancer.
The most favorable in terms of course and prognosis include tubular, mucosal, medullary and adenoid cystic cancer. Breast cancer with metaplasia and Paget's cancer have a less favorable prognosis. These forms make up no more than 10-15% of all breast cancer. The majority of breast cancer accounts for ductal infiltrating cancer and cancer with a predominance of the intraductal component (about 60%), as well as lobular infiltrating cancer (about 25%), which tends to be multicentric and bilaterally affecting the mammary glands.
ΤΝΜ-classification
Currently, the International Classification of Tumors according to the ΤΝΜ system (1997) is used. The stage of cancer is established during the initial examination of the patient, and then clarified after surgery (ρΤΝΜ).
T - primary tumor
- TX - insufficient data to evaluate the primary tumor.
- TO - the tumor in the mammary gland is not detected.
- Tis - preinvasive carcinoma (carcinoma in situ), non-infiltrating intraductal or lobular carcinoma, or Paget's disease of the nipple without detectable tumor.
Note. The combination of Paget's disease with a defined tumor is classified according to the size of the latter.
T1 - tumor no more than 2 cm in greatest dimension.
T1mic - microinvasion up to 0.1 cm in greatest dimension.
Note. Microinvasion is considered to be the spread of cancer cells beyond the basement membrane with foci less than 0.1 cm. If there are multiple foci of microinvasion, the largest foci are classified (the sizes of microfoci cannot be summed up). The presence of multiple foci of microinvasion should be noted additionally.
- T1a - tumor from 0.1 cm to 0.5 cm in greatest dimension.
- T1b - tumor 0.6 cm to 1 cm in greatest dimension.
- T1c - tumor 1.1 cm to 2 cm in greatest dimension.
- T2 - tumor from 2.1 cm to 5 cm in greatest dimension.
- T3 - tumor more than 5 cm in greatest dimension.
- T4 - a tumor of any size with direct spread to the chest wall or skin.
Note. The chest wall includes the ribs, intercostal muscles, and serratus anterior, but no pectoral muscles.
- T4a - spread to the chest wall.
- T4b - swelling (including lemon peel sign), or ulceration of the skin of the breast, or satellites in the skin of the breast.
- T4c - signs listed in 4a and 4b together.
- T4d is an inflammatory form of breast cancer.
Note. The inflammatory form of breast cancer is characterized by diffuse thickening of the skin with firm margins, usually without an underlying palpable mass. If the skin biopsy is negative and there is no localized tumor mass, the rTX category is used for pathological classification and the T4d category for clinical classification. Skin retraction, nipple retraction, or other skin changes other than those associated with T4b and T4d may be graded as T1, T2, or T3.
N - regional lymph nodes
- NX - there is not enough data to assess the condition of regional lymph nodes.
- N0 - there are no signs of metastatic damage to regional lymph nodes.
- N1 - metastases in the displaced axillary lymph nodes (node) on the affected side.
- N2 - metastases in the axillary lymph nodes (node) on the affected side, fixed to each other or to other structures.
- N3 - metastases in the parasternal lymph nodes on the affected side.
M - distant metastases
- MX - insufficient data to assess the presence of distant metastases.
- M0 - no signs of distant metastases.
- M1 - there are distant metastases, including skin lesions outside the gland, in the supraclavicular lymph nodes.
G - degree of malignancy of the tumor
by Bloom-Richardson
- G1 is a tumor with a high degree of differentiation.
- G2 - a tumor with an average degree of differentiation.
- G3 is a tumor with a low degree of differentiation and undifferentiated.
The degree of malignancy is an important prognostic factor for the development of local recurrence of breast cancer. In women with tumor grade I or II, local recurrence occurs in only 5% of patients during the first five years after radical treatment. With grade III malignancy of breast tumors, the frequency of local relapse in this period reaches 10%.
Grouping by stages |
|||
Stage 0 | N0 | M0 | |
Stage 1 | T0 | N0 | M0 |
Stage 2A | T0 | N1 | M0 |
T1 | N1 | M0 | |
T2 | N0 | M0 | |
Stage 2B | T2 | N1 | M0 |
TK | N0 | M0 | |
Stage FOR | T0 | N2 | M0 |
T1 | N2 | M0 | |
T2 | N2 | M0 | |
T3 | N1 | M0 | |
T3 | N2 | M0 | |
Stage 3 | T4 | N0 | M0 |
N1 | M0 | ||
N2 | M0 | ||
ST stage | Any T | N3 | M0 |
Stage 4 | Any T | Any N | With M1 |
International Classification of Diseases (ICD-10).
C50 Malignant neoplasm of the breast
- C50.0 Nipple and areola
- C50.1 Central part of the mammary gland
- C50.2 Upper inner quadrant of the breast
- C50.3 Lower inner quadrant of the breast
- C50.4 Upper outer quadrant of the breast
- C50.5 Lower outer quadrant of the breast
- C50.6 Axillary posterior part of the mammary gland
- C50.8 Lesion of the mammary gland extending beyond one or more of the above localizations
- C50.9 Mammary gland, unspecified part
D50 Iron deficiency anemia
- D50.0 Iron deficiency anemia secondary to blood loss (chronic)
- D50.1 Sideropenic dysphagia
- D50.8 Other iron deficiency anemias
- D50.9 Iron deficiency anemia, unspecified
1 State Budgetary Educational Institution of Higher Professional Education “Saratov State Medical University named after V.I. Razumovsky Ministry of Health and Social Development of Russia", Saratov
The article analyzes literature data on the etiology and pathogenesis of breast cancer, as well as the results of the authors’ own research on the nature and mechanisms of development of paraneoplastic disorders in this pathology based on a comprehensive examination of patients with nodular and edematous-infiltrative forms of breast cancer. The authors come to the conclusion that in the mechanisms of tumor progression in this pathology, an important role should be given not only to the initiating mechanisms of oncogenic cell transformation, but also to the features of systemic paraneoplastic disorders that affect the intensity of elimination of tumor cells and contribute to the development of tumor progression.
mammary cancer
carcinogenesis
paraneoplastic disorders
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Carcinogenesis is a multi-stage process of accumulation of changes in the genome of cells, leading to the appearance of asocial cells characterized by morphological, functional, biochemical atypia, autonomous growth, and “escape” of cells from humoral and nervous influences.
Ideas about the molecular cellular mechanisms of oncogenic cell transformation have undergone significant evolution over the past few decades.
As is known, the initiating factors of malignancy of cells of various morphofunctional organizations are carcinogens of a chemical, physical, biological nature, various in nature, including viruses, hormones and genotoxic products of their metabolism.
Naturally, given the extreme heterogeneity of the etiological factors for the development of neoplasia, the dominant concept of the pathogenesis of oncogenic transformation of cells: their activation or promotion, with subsequent tumor progression, could not be formed quickly enough.
In early studies on carcinogenesis, emphasis was placed on the epigenomic mechanisms of the development of neoplasia, and, of course, a number of provisions in this direction are not only historical in nature, but can be to a certain extent associated with modern viral-genetic and oncogenic theories of carcinogenesis. To date, one of the leading concepts of carcinogenesis is the mutation theory, according to which all carcinogens have mutagenic activity, although not all mutagens are carcinogens.
In the mechanisms of induction of carcinogenesis, an important role is played by oncogenic DNA and RNA containing viruses, capable of incorporating their DNA or a DNA copy into the host genome, followed by possible oncogenic transformation of the cell in the case of expression of proto-oncogenes. As is known, the viral-genetic theory of L.A. Zilber was the basis for the formation of the modern theory of carcinogenesis - the theory of oncogenes, proto-oncogenes and antioncogenes.
It has been established that the following categories of genes are fundamentally involved in the tumor transformation of cells that occurs under the influence of various inducers of carcinogenesis:
Oncogenes are function stimulators.
Cell growth and proliferation genes (Myc, Ras, Los, ABL and others).
Antioncogenes (loss of function).
Genes responsible for programmed cell death (apoptosis):
Abolishing programmed death: Bcl-2 (stimulation of functions);
Cell death genes - p53 (loss of function).
Oncogenes, as specific chemical material encoding information about a specific chemical product, were first identified as part of retroviruses. The genome of a typical non-transforming retrovirus consists of two single-stranded RNA molecules. The main genes of the virus belong to three regions: gag encodes the structural proteins of the virion particle, env - virion envelope proteins, the pol gene - carries information about reverse transcription. The latter ensures the formation of a DNA copy on the RNA virus matrix.
Currently, the following mechanisms of activation of proto-oncogenes are obvious:
Amplification of proto-oncogenes, resulting in a sharp increase in their overall activity, which can lead to malignancy of the cell;
Mutations of proto-oncogenes leading to their activation and inhibition of antiproto-oncogenes;
Translocation of proto-oncogenes into a locus with a functioning promoter;
Adduction of a promoter near a proto-oncogene. DNA copies of certain sections of oncornaviruses, as well as mobile genetic structures that can move and integrate into various parts of the genome, can act as promoters.
The human genome is expected to contain about 100 proto-oncogenes that perform the following functions:
Coding of growth factors, their receptors and post-receptor transmitters;
Coding of blockers of programmed cell death, contact inhibition of proliferation.
Transformation of proto-oncogenes into oncogenes leads to their expression and synthesis of oncoproteins. In this case, oncoproteins are produced permanently in increased quantities or in a qualitatively changed state. Along with the above generally accepted principles of carcinogenesis, the features of the molecular cellular mechanisms of oncogenic transformation of cells and the formation of their atypism in certain nosological forms of cancer have now been formulated.
This article makes an attempt to systematize information concerning the etiological factors, risk factors and molecular cellular mechanisms of breast cancer development, in particular the role of systemic paraneoplastic disorders in the pathogenesis of tumor progression in this pathology.
Breast cancer (BC) is one of the most common cancers in women. The incidence of breast cancer in Russia, as in most developed countries of the world, tends to steadily increase, occupying first place among malignant neoplasms in women since 1985. Thus, in 2009, the incidence of breast cancer was 68.8 per 100 thousand female population, which is 15% higher than in 2005. The incidence rate in 2009 in the Saratov region increased and amounted to 77.8 per 100 thousand female population.
The modern theory of carcinogenesis of proto-oncogenes-oncogenes-antioncogenes finds real confirmation in the mechanisms of breast cancer development, as evidenced by the expression on the membranes of malignant cells of oncoproteins, in particular, receptor proteins for estrogens, progesterone, somatostatin, epidermal and insulin-like growth factors, cytokines and other compounds of varying functional significance. It has now been established that breast cancer occurs with excessive expression of oncoproteins-cell cycle switches in the case of transformation of the PRADI proto-oncogene into an oncogene, as well as a number of other oncogenes: erb B, myc, myb, H-ras, N-ras, K-ras .
It was found that the number of oncogenes of the Ras family in MCF-7 breast cancer cells increased 20 times. When the cloned human oncogene c-Ha-ras-1 was introduced into normal epithelial cells of mice, the development of invasive mammary cancer occurred in nude mice.
It is known that in cases of development of aggressive breast tumors that do not contain steroid receptors, with a prognostically unfavorable outcome, amplification and increased expression of a number of oncogenes are detected. Thus, an estrogen receptor-negative breast cancer cell has a large number of receptors for epidermal growth factor on its surface. In primary breast tumors, mutations and expression of three oncogenes Her2/neu, C-mys, Int-2 most often occur, as well as suppressor genes - the P53 gene and the retinoblastoma RB gene.
The Her2 or c-erB/2 oncogene, the human analogue of the neu gene, is homologous to the epidermal growth factor receptor gene (c-erB/1). The protein product of the Her2/neu/c-erbB/2-p185neu gene has tyrosine kinase activity and is a transmembrane receptor similar to the epidermal growth factor receptor. An assessment of the expression and/or amplification of the Her2/neu gene in tumors of 11,408 breast cancer patients did not reveal any significant differences between the frequency of amplification and overexpression of this gene. However, there is no consensus regarding the importance of the Her2/neu gene for relapse-free survival of patients, as well as predicting the response to endocrine and chemotherapy. However, our studies found that the presence of the Her2/neu surface receptor was detected in 20-30% of breast cancer patients with a particularly poor prognosis.
According to a number of authors, it has been established that another oncogene, c-mys, is expressed in 17.1% of cases of primary breast cancer and in 33% in the group of patients with subsequent development of metastases. Tumors expressing c-mys oncogene in patients with metastatic breast cancer respond less well to chemotherapy rather than endocrine therapy than tumors with normal c-mys copy numbers.
A major role in the mechanisms of proliferation induction in neoplasia is assigned to oncoproteins - homologs of growth stimulator receptors, as well as multireceptor transmitters that control the cell cycle. In the latter case, the objects of action of oncoproteins can be tyrosine protein kinases, GTP-binding proteins, and nuclear transcription factors. The interaction of growth factors with membrane receptors leads to a cascade of intracellular metabolic reactions - activation of phospholipase C, which initiates the production of inositol phosphates and diacyl glycerol, followed by the release of calcium into the cytosol and stimulation of calmodulin-dependent protein kinases (PIP2 pathway).
Under the influence of growth factors (hormones, cytokines), activation of GTP-binding proteins is possible - G proteins, ras proteins, RafI binding protein, which stimulate phosphorylation of mitogen-activated protein kinases.
The final stages of the phosphorylation process are controlled in the G phase by cyclin proteins E and D, which form a complex with the products of cell division genes (cdc) - the protein kinase cdc2, which triggers DNA replication. In the G2 phase, the synthesis of cyclins B, which binds protein kinase, is induced; cdc2, activate it and trigger mitosis. After completion of mitosis, cyclins are destroyed. The work of cyclins is stimulated by the C-proto-oncogene bcl and disrupted by the antiproto-oncogene p53, anticyclin antibodies.
Normal breast growth and development are regulated by a complex interaction of many hormones and growth factors. Breast cells themselves secrete some of them and thus perform autocrine functions. In addition, malignant breast cells express receptors for many polypeptide factors and hormones.
The exact biological processes that occur in the mammary gland and then induce carcinogenesis are still unknown. The key to understanding these processes lies in studying the life activity of normal cells. The mentioned hormones and growth factors play an important role in cell division and development of the mammary gland, lactation, and, if necessary, in the involutional processes in it after the cessation of functions.
Currently, one of the leading concepts of breast cancer is the point of view about the important role of enhanced hormonal stimulation of proliferative processes in the development of neoplasia.
A detailed study of the nature of hormonal imbalances, in particular the level of estrogen, progesterone, and thyroid hormones in the pathogenesis of breast cancer, was undertaken by us in the process of a comprehensive examination of 154 patients who were hospitalized in the oncology department of the National Health Institution "Road Clinical Hospital at Saratov-II Station" of JSC "Russian Railways" in the period from 2009 to 2011, in the dynamics of the spread of neoplasia in the nodular form of breast cancer. The results of a study of the level of estrogen in the blood of patients with nodular breast cancer revealed that at the initial stages of the tumor process (in patients without metastases), the level of estradiol in the blood did not change relative to those of the control group, at the same time there was a sharp decrease in the content of free estriol and increase in progesterone levels.
In the dynamics of tumor progression in patients with nodular breast cancer, but the presence of regional metastases, there was a sharp increase in estradiol content relative to the control group and patients with the initial stages of the disease. The level of free estriol in patients in this group remained consistently low. The level of progesterone decreased in relation to estradiol. The study revealed pronounced disorders in the metabolism of sex hormones, manifested by an increase in the blood level of estradiol - a highly active fraction of estrogens, as well as a decrease in the level of estriol - a less active hormone - a metabolite of estradiol. As it turned out, one of the manifestations of hormonal imbalance in the tumor process is a natural decrease in the blood level of progesterone, a competitive inhibitor of the biological effects of estrogens, which correlates with the stage of neoplasia spread. These changes in hormonal balance were observed in different age groups of patients with breast cancer, reaching maximum changes in the pre- and menopausal periods.
Regarding the significance of the imbalance of estrogen and progesterone in the initiation of the oncological process, it should be noted that these hormones play the role of a promoter in the induction of carcinogenesis in breast cancer. The results of the interaction of estrogen receptors, EREs and transcription genes are stimulation of transforming growth factor alpha (TGF-alfa), suppression of transforming growth factor beta (TGF-beta) and stimulation of insulin-like growth factor (IGF).
Estrogens allow microfoci to enlarge and replicate the ER to support growth. The role of estrogen hyperproduction in the genesis of breast cancer is also confirmed by the following fact: women who underwent oophorectomy before the age of 30 for non-tumor reasons develop breast cancer 2 times less often than those who have not had such operations.
Estrogen-induced proteins are known to regulate cell proliferation. Under the influence of estrogen control, the cells themselves synthesize and secrete growth factors that have stimulating autocrine and paracrine effects on the stroma.
According to our data, a hormonal imbalance in the hypothalamic-pituitary-gonadal system in breast cancer is combined with hormonal imbalances in the hypothalamic-pituitary-thyroid system in the form of an increase in the level of thyroxine and triiodothyronine in the blood with a simultaneous decrease in the content of thyroid-stimulating hormone in the early and metastatic stages of cancer mammary gland. Moreover, the hyperproduction of thyroxine and triiodothyronine in the dynamics of the spread of neoplasia in breast cancer, suppressing the production of thyroid-stimulating hormone by the pituitary gland, indicates the preservation of the principle of “feedback” between the content of thyroid hormones in the blood and the nature of centrogenic regulatory influences on the thyroid gland, not only in the early stages, but also at metastatic stages of the tumor process.
The above analysis of the literature on the problems of etiology and pathogenesis of the tumor process indicates that the efforts of domestic and foreign researchers are aimed at establishing the molecular cellular mechanisms of cell transformation, development of the promotion stage and tumor progression. However, as is known, malignancy of a cell does not yet mean the development of a tumor process, much less an oncological disease. Under normal conditions, tumor cells are eliminated due to nonspecific resistance mechanisms and specific immunological defense mechanisms.
However, our studies indicate the development of an immunodeficiency state in breast cancer and, accordingly, the insufficiency of the mechanisms for eliminating malignant cells from the body. Thus, the study of the functional activity of the T- and B-lymphocyte system in the dynamics of the spread of the tumor process in nodular and edematous-infiltrative forms of breast cancer made it possible to establish that a characteristic feature of these diseases is the formation of insufficiency of the cellular and humoral immunity, which correlates with the degree of spread of the tumor process. Thus, in the nodular form of breast cancer in the early stages of the disease (stages I-IIA), there is a lack of CD3-T-lymphocytes, CD4-T-lymphocytes in the blood, an increase in the level of CD8-T-lymphocytes, a decrease in the CD4/CD8-T-lymphocyte ratio. lymphocytes. The antibody-producing ability of B-lymphocytes undergoes certain changes, as evidenced by a decrease in the level of immunoglobulins of all classes in the blood: IgG, IgA, IgM.
As the tumor metastasizes in patients with nodular breast cancer (stage IIB), a progression of the immunodeficiency state is noted - the formation of more pronounced immunosuppression in the B- and T-lymphocyte systems occurs: the levels of CD3 and CD4 T-lymphocytes, the level of IgG, IgA, IgM decreases, and at the same time the number of NK cells drops sharply.
The development of the primary edematous-infiltrative form of breast cancer also occurs against the background of immunodeficiency in the B- and T-lymphocyte systems, the level of NK cells, which is more pronounced compared to the nodal form of the disease.
Thus, the studies conducted convincingly indicate the important role of immunosuppression in impaired elimination of tumor cells, the development of the promotion stage and metastasis in breast cancer.
In recent years, an important role in the mechanisms of oncogenic transformation of cells of various morphofunctional organizations, as well as stages of promotion and tumor progression, has been assigned to chemical carcinogens of exogenous and endogenous nature, in particular free radicals.
A detailed study of the role of activation of free radical oxidation in the mechanisms of induction of breast cancer and tumor progression in this pathology was carried out by a number of researchers in Saratov. The development of breast cancer is naturally combined with paraneoplastic disorders in the form of activation of lipid peroxidation processes, insufficiency of antiradical cell protection, and the occurrence of cytolysis and autointoxication syndromes. Moreover, minimal changes in the form of a slight increase in the content of lipid peroxidation intermediate products - MDA, DC - in the blood and in the neoplasia zone, as well as SOD deficiency, a decrease in the level of vitamin E, peroxide resistance of erythrocytes, and an increase in the activity of serum transaminases occur already at the initial stages of the development of nodular breast cancer. (I-IIA stages of the disease). As the tumor metastasizes (stage IIB), lipid peroxidation products and MSM levels progressively increase in the blood and in the neoplasia zone, and the insufficiency of antiradical cell protection and the development of cytolysis syndrome worsen. The primary edematous-infiltrative form of breast cancer (T4bN0M0) is also characterized by a pronounced accumulation of MDA and DC in the area of neoplasia and in the blood, suppression of immunological surveillance of the internal environment and antiradical protection of cells, a sharp increase in autointoxication and cytolysis, compared with the nodular form of breast cancer, and an increase in the percentage of expression oncoreceptor HER2/neu on malignant cells.
Thus, in the zone of neoplasia, regardless of the clinical form of breast cancer (nodular or edematous infiltrative), activation of lipid peroxidation processes and insufficiency of antiradical cell protection occur, progressing as the tumor metastasizes. Excessive accumulation of lipid peroxidation products in the neoplasia zone induces epigenomic mechanisms of disruption of intercellular interaction, caused by the destruction of lipid components of biological membranes. As has been established, further in the dynamics of adequate complex therapy for nodular and primary edematous-infiltrative forms of breast cancer, it is necessary to monitor the levels of lipid peroxidation products in the blood, especially after radiation and polychemotherapy, which ensures not only the eradication of tumor cells, but also the development of cytolysis syndrome due to free radical disorganization biomembranes. Moreover, the most sensitive indicators of insufficiency of antiradical cell protection are suppression of SOD activity, a decrease in the level of vitamin E in the blood and peroxide resistance of erythrocytes; suppression of SOD activity, decrease in the level of vitamin E and sulfhydryl groups in tumor tissue, correlating with the nature and degree of metastasis of neoplasia and aggravated by polychemo- and radiation therapy.
Paraneoplastic disorders in various clinical forms of breast cancer include changes that occur in the cellular composition of peripheral blood, characterized by the development of leukopenia, anemia, lymphopenia, thrombocytopenia, progressing against the background of polychemo- and radiation therapy.
Changes in the cellular composition of peripheral blood are naturally combined with disorders of the coagulation potential of the blood, activation of the fibrinolysis system, and proteolytic systems of the blood in particular.
Summarizing the above, it should be concluded that the induction of a tumor process does not arise as a consequence of a simple one-time mutational event. Carcinogenesis is “multi-step” in nature. For the formation of a malignant tumor, at least two or more mutations are required in cells of the same clone - the progenitor and the daughter. At the same time, it is obvious that the development of oncogenic transformation does not yet mean the formation of a tumor process, much less a disease. In the pathogenesis of breast cancer, as well as neoplasia of other localizations, an important role should be given to the nature of paraneoplastic disorders that contribute to tumor progression. However, the establishment of patterns of development of systemic paraneoplastic disorders in breast cancer requires further resolution in order to provide a pathogenetic substantiation of new principles of cancer therapy aimed at eliminating systemic proto-oncogenic metabolic and functional changes that occur with neoplasia.
Reviewers:
Konopatskova O.M., Doctor of Medical Sciences, Professor of the Department of Faculty Surgery and Oncology of the Saratov State Medical University named after V.I. Razumovsky" Ministry of Health Development of the Russian Federation, Saratov.
Morrison V.V., Doctor of Medical Sciences, Professor, Head. Department of Pathological Physiology, State Educational Institution of Higher Professional Education “Saratov State Medical University named after V.I. Razumovsky" Ministry of Health and Social Development of the Russian Federation, Saratov.
The work was received by the editor on 02/06/2012.
Bibliographic link
Chesnokova N.P., Barsukov V.Yu., Zlobnova O.A. BREAST CANCER: PROBLEMS OF PATHOGENESIS // Fundamental Research. – 2012. – No. 4-1. – P. 146-151;URL: http://fundamental-research.ru/ru/article/view?id=29733 (access date: 12/12/2019). We bring to your attention magazines published by the publishing house "Academy of Natural Sciences"
The development of mammary gland cancer in animals is also observed as a result of impaired ovarian function during unilateral castration, resection and irradiation of the ovaries, etc. As a result of these effects, follicular cysts develop in the ovaries, causing hyperestrogenization, and later changes occur in the mammary glands (fibroadenoma, mastopathy , cancer and tumors of the ovaries) and endometrium.
The opinion about dishormonal influences and, first of all, about an increase in estrogenic activity as one of the main reasons for the development of mastopathy and breast cancer is shared by many scientists. It has been established that endocrine influences that have a stimulating effect on the processes of epithelial proliferation in the mammary glands depend on the complex interaction of ovarian hormones (follicular and luteal), hormones of the adrenal cortex and gonadotropic hormones of the pituitary gland, primarily on follicle-stimulating hormone (FSH). The correlative production of these hormones is carried out due to influences coming from the hypothalamic
areas and cerebral cortex. With various dishormonal disorders, the function of not only the ovaries, but also the adrenal glands, pituitary gland or hypothalamus (due to general diseases such as intoxications) may be primarily affected. It is impossible to take into account all these harmful effects that occurred in the past in patients with mastopathy and breast cancer in each case. The ovaries are the most vulnerable and susceptible to various harsh external influences (chronic and acute inflammatory processes); Apparently, their dysfunction is most often the basis of the pathogenesis of pretumor diseases and breast cancer in women.
According to M. N. Zhaktaev and O. V. Svyatukhina (1972), based on a study of ovarian-menstrual function and the condition of the genital organs in 500 patients with mastopathy, 500 patients with breast cancer and 1000 healthy women (see p. 617), It was revealed that various menstrual dysfunctions were found in 81.3, respectively; 73 and 15.2%, and a history of gynecological diseases in 52.2, 58.6 p 34.4 "/o (at the time of examination, gynecological diseases were found in 33.4, 36.8 and 5.5%, respectively) .
These data indicate a more frequent and longer period of pathological conditions, and therefore pathogenetic influences from the ovaries on the mammary glands of women suffering from mastopathy and breast cancer. In my opinion, timely complete recovery from inflammatory processes of the appendages and uterus can protect against the development of pathological conditions in the mammary glands.
The viral nature of human breast cancer has not been proven. Only in mice of pure lines was a milk factor identified, called the Bitner virus. However, the origin of this virus has not yet been clarified. Some authors consider the Bittner virus to be exogenous, while others consider it to be an endogenous factor that develops due to changes in endogenous proteins (L. L. Zplber, 1946; L. M. Shabad, 1947; Bittner, 1939, etc.). There are studies indicating the presence of a large amount of milk factor in males, but mammary gland cancer does not occur in them. If estrogens are administered to males, then they develop mammary gland cancer (E. E. Pogosyants; Shimkin, etc.). However, the presence of milk factor is not enough to cause breast cancer. Only with changes in endocrine status can the incidence of tumor development in experimental animals be increased or sharply decreased. The milk factor in other animal species and in humans has not yet been established.
The significance of the hereditary factor for the development of breast cancer has not been sufficiently studied. There are reports that among close relatives of patients this type of malignant tumors is more common than others. According to S. A. Holdin (1962), E. B. Polevoy (1975), Winder, McMahon (1962) and others, breast cancer sometimes occurs in several sisters, mother and daughters, etc. The causes of these factors are unknown . E. B. Polevaya reports that the daughters of women. Breast cancer (BC) is a malignant lesion of breast tissue, usually its ducts and lobules.
Epidemiology.
Benign breast tumors are the most common cancer after skin cancer and account for 16% of all cancers among the female population. Over the past 25 years in Russia there has been a significant increase in this pathology, in different regions - from 150 to 200% and higher, from the indicators before 1985. Breast cancer also occurs in men, but not in comparable numbers than in women. Women over 50 are at greatest risk of developing breast cancer, accounting for 80% of all cases of this disease.
Etiology and pathogenesis.
Despite the fact that the reasons for the development of breast tumors are not fully known, there is an opinion in scientific circles that this type of cancer can occur due to the combined effect of several risk factors, including:
Age. The risk of cancer in one or both breasts increases with age. The disease very rarely occurs in women under 35 years of age, and 8 out of 10 cases occur in women aged 50 years or older.
The patient has a history of cancer and some other breast pathologies. The risk of developing breast cancer increases 3-4 times if a woman has had one of the following diseases, disorders and conditions in the past:
Precancer of the breast, including ductal carcinoma (DCIS);
Local carcinoma (LCIS);
Atypical ductal hyperplasia;
Treatment with radiation therapy for Hodgkin's lymphoma at a young age;
Dense breast tissue (when the breasts are composed primarily of glandular and connective tissue with very little fatty tissue).
Hormonal factors. The risk of breast cancer increases if you:
Are over 50 and have been taking estrogen- or progesterone-based hormone replacement therapy for more than 10 years;
Do not have children or gave birth after 30 years;
Did not breastfeed at all or breastfed for less than a year after the birth of the child;
Have menarche before 12 years or late menopause (after 50);
Are you taking birth control pills?
Lifestyle factors.
Alcohol abuse. Long-term use of alcohol-containing products usually leads to liver damage. This directly increases the risk of developing a malignant breast tumor, since the liver helps control estrogen levels. Excess weight. After menopause, body fat is the main source of estrogen. If a woman is overweight, the level of these hormones in the body can increase significantly, which, in turn, increases the risk of breast cancer. Smoking. Genetic factors (familial anemia). Only 5-10% of breast cancers are associated with the inherited oncogene BRCA1 or BRCA2. Provided that several blood relatives have cancer of the female genital area or breast, inheritance of a genetic defect can be suspected. Classification: Breast cancer is described according to four classification schemes, each of which considers different criteria and serves different purposes: - histological description; - degree of differentiation (low, high and middle classes); - status of proteins and gene expression; - tumor stage according to TNM grading. Currently, breast cancer must be classified primarily by histological type.
1.1 Locally advanced (non-invasive) types of tumor (precancer).
Ductal carcinoma in situ; - lobular carcinoma in situ. 1.2 Invasive types (cancer itself). - ductal invasive tumor (occurs in 80% of cases); - lobular invasive tumor (in 10%). 1.3 Rare types of breast cancer. - inflammatory; - triple negative. 1.4 Extremely rare types of breast cancer. - Paget's cancer (affects the areola and nipple); - tubular; - mucinous; - medullary.
Clinic and symptoms.
There are practically no subjective symptoms in the initial stages of breast cancer; most often, the tumor is discovered by chance by the woman herself or her partner in the form of an atypical lump. It is precisely because of the absence of obvious signs of the disease that women after menopause are recommended to undergo routine mammography once a year. Any of the following signs may indicate the presence of a malignant tumor: - swelling of the entire breast or some part of it; - skin rashes on the mammary gland, similar to irritation; - soreness of the nipple or change in its position from normal to retracted; - redness, peeling or roughening of the breast/nipple skin; - nipple discharge not associated with lactation; - an unexplained change in the shape of the mammary gland (deformation); - a dense, inactive compaction in the form of a lump in the armpit area. These symptoms can also be signs of less serious diseases, such as a cyst or infection, but, in any case, if abnormalities appear in the mammary glands, you should immediately seek medical help.
Diagnosis.
One of the important preventive measures for breast cancer is early diagnosis. Methods of early diagnosis, depending on age:
Women over 20 years of age should conduct self-examinations once a month, 3-5 days after the end of the regimen. Each mammary gland and armpit should be examined and carefully palpated; if any changes are found, you should visit a gynecologist. If there are no changes, you must undergo a medical examination every 3 years.
Women over 40 should visit a gynecologist for a checkup once a year and also have a screening mammogram once a year.
When visiting a specialist, the patient is interviewed and examined. If necessary, a referral is given for mammography or ultrasound examination of the mammary glands, depending on the results of which a biopsy may be prescribed. The collected material is examined for the presence of atypical cells; if they are found, their histological features are assessed. Also, to determine the characteristics of the tumor (its location, extent, size), clarifying diagnostic methods are prescribed - ultrasound, magnetic resonance or computed tomography.
Treatment.
Depending on the characteristics of the tumor, as well as the general condition of the patient, one of the main treatment methods or a combination of them is selected: - surgery - radiotherapy - chemotherapy - hormonal therapy - biological therapy (targeted). Surgery. Most patients with breast cancer undergo surgery to remove the tumor. In the early stages of some types of cancer, it is possible to perform surgery to remove only the cancer focus and preserve the breast (organ-preserving surgery):
Lumpectomy: the tumor itself and part of the healthy tissue around it are removed at the same time;
Partial (segmental) mastectomy: an operation to remove part of the gland, tumor and some normal tissue around the lesion. For more serious indications, a simple mastectomy is performed - surgical removal of the entire mammary gland and part of the lymph nodes from the armpit area. Modified radical mastectomy - removal of the entire gland, more axillary lymph nodes and part of the chest muscles. If necessary, neoadjuvant therapy is indicated - chemotherapy treatment before surgery to reduce the size of the tumor. To reduce the risk of relapse and kill those cancer cells that could remain in the body, adjuvant therapy (radiation, hormonal or chemotherapy) is prescribed after surgery. Radiation therapy. This method uses high-energy X-rays or other types of radiation to destroy cancer cells or stop their growth. External and internal (sealed needles, catheters, etc.) radiation sources are used. Chemotherapy.
The tumor is treated with cytostatics. The advantage of this method is that it acts systemically and destroys atypical cells anywhere in the body. The above listed treatment methods are locally targeted. Hormonal therapy. Allows you to block certain hormones that have a positive effect on the development of tumors. For certain types of breast cancer (early stages, metastatic), tamoxifen is prescribed. A side effect of this drug is the growth of the endometrium, so the patient is recommended to undergo an ultrasound of the uterus once a year and, in case of atypical bleeding, immediately consult a doctor. For the treatment of early stages of breast cancer, some aromatose inhibitors can be used as adjuvant therapy instead of tamoxifen or as a replacement after 2 years of taking it. To treat metastatic cancer, it is chosen which of the two drugs is more effective in a particular case. Targeted therapy. Unlike chemotherapy drugs, biological drugs (Lapatinib, Trastuzumab) act not on the atypical cells themselves, but on proteins (HER2) that promote tumor growth. They can be used either independently or in combination with other types of treatment.
Prevention.
It is obvious that the risk of developing breast cancer is directly related to a woman’s reproductive behavior and her lifestyle. As preventive measures, regular physical activity is recommended (it will reduce the risk by 15-25%), giving up bad habits and returning to previous norms associated with the birth and feeding of children.
Mammary cancer. Epidemiology. Etiology. Pathogenesis. Clinic. Breast cancer is a malignant neoplasm that develops from epithelial cells of the ducts and/or lobules of the gland parenchyma.
Epid-i. Breast cancer ranks 1st in the structure of cancer incidence in women. Ranked 2nd in the world. In 5th place in Bel. The highest rates are in the USA. The lowest incidence is recorded in African countries. The incidence of breast cancer increases with age, starting at 40 and reaching a peak in early adulthood. For women aged 70 years, the annual risk of breast cancer is 3 times higher than for women aged 40 years, and the annual risk of death from breast cancer is 5 times higher than for women aged 40 years.
Etiol-i. A hereditary predisposition to breast cancer has been proven. Based on this, we distinguish:
Sporadic cancer (about 68%); no cases of breast cancer in both parents in 2 generations;
Familial breast cancer (about 23%). Cases of breast cancer in one or more blood relatives;
Genetic predisposition to cancer as a result of the presence of mutations in the BRCA1/BRCA2 genes (about 9%). There are cases of breast cancer in blood relatives, as well as associated cancer (primary multiplicity - damage to the ovaries, colon).
Risk groups for breast cancer depend on the following etiological factors:
1. Hormonal factors:
a) endogenous - hyperestrogenemia as a result of:
Features of the menstrual cycle (early menarche before 12 years; late menopause after 55 years)
Childbearing function (nulliparous women, first birth after 30 years of age; abortions before 18 years of age and after 30 years of age)
Features of lactation (hypo- and agalactia)
Features of sexual life (its absence, late onset, frigidity, mechanical methods of contraception)
Hormone replacement therapy in pre- and postmenopausal women for more than 5 years.
Long-term use of combined oral contraceptives: more than 4 years before the first birth, more than 15 years at any age.
2. Lifestyle and environmental factors
- geographical location and nutrition (high-calorie diet, excess consumption of animal fats, low physical activity)
Alcohol abuse (increases risk by 30%)
Smoking (under 16 years of age – doubles the risk)
Radiation (exposure) and breast injuries
3. endocrine and metabolic disorders. obesity, atherosclerosis, adrenal and thyroid diseases
4. individual history:
Age over 40
Previous history of breast or ovarian cancer
5. Pre-existing breast diseases
- atypical mammary hyperplasia
6. Family history: genetic factors:
- close relatives have breast cancer, ovarian cancer, colorectal cancer
Association with hereditary syndromes (Cowden, BLOOM)
- BRCA-1 gene mutations; BRCA-2
Pathogenesis. Due to the influence of factors - activation of proliferative processes, increase in FSH production. follicle - enlarged estrogens - proliferation of the uterine mucosa, epithelium of the gland ducts. Protective factors: early pregnancy, first child is a boy, debt. feeding. Clinical manifestations of breast cancer.
1) a painless dense formation of various sizes, round or irregular in shape, with a lumpy surface, slight limitation of mobility (if it does not grow into the chest wall). The mammary gland is often deformed (enlarged or reduced, has local bulging, cut contour).
2) skin symptoms. a) symptom of wrinkling - the skin over the tumor is gathered into a wide fold with the index and thumb, the wrinkles that appear are normally located parallel; with cancer, the parallelism of wrinkles is disrupted, they converge to one area (a positive symptom of “wrinkling”)
b) platform symptom - when administered in a manner similar to the previous one, a flattened area of fixed skin appears
c) symptom of retraction (umbilication) – when taking the same method as the previous one, a slight retraction appears
d) lemon peel symptom – lymphatic edema of the skin, visible visually
e) thickened fold of the areola (Krause's sign)
f) change in skin color over the tumor
g) cancerous ulcer - not deep, denser than the surrounding tissues, has undermined edges protruding above the surface of the skin and an uneven bottom covered with a dirty coating
3) nipple symptoms. changes in the shape and position of the nipple, retraction of the nipple and limitation of its mobility up to complete fixation (Pribram's symptom - displacement of the tumor along with the nipple - the result of tumor germination of the excretory ducts of the gland), hemorrhagic discharge from the nipple
4) Enlarged axillary lymph nodes.
5) Isolated edema.
Secondary symptoms. ulceration of the skin, bleeding, secondary infection, metastases to the bones (spine, pelvis, hip, ribs), metastases to the liver, lungs, pleura.
Physical examination: asymmetry, increase in volume, different levels of nipples, nipple discharge, skin changes, palpation while standing and lying down, symptoms see above.
Inspection. Examination of the mammary glands should be carried out in sufficient lighting, at some distance from the patient, standing first with her hands down, and then with her hands raised up.
Examination reveals local or total hyperemia of the skin of the mammary gland; hyperemia can spread to the skin of the chest or abdominal wall, upper limb. In most cases, it is combined with local or total swelling of the mammary gland, which is referred to as the “lemon peel” symptom. The presence of skin ulcerations, nodular seals, crusts, fistulas, and tissue decay are also inherent in the tumor process. During palpation the following is examined:
1) dimensions (diameter) - it is customary to mark up to 1 cm, up to 2 cm, from 2 to 5 cm, over 5 cm; measurements are usually made using a ruler or compass;
2) anatomical form - nodular, locally widespread, or locally infiltrative, diffusely infiltrative (occupying either most or the entire mammary gland);
3) consistency - dense, densely elastic, lumpy;
4) localization - central, external quadrants (upper and lower), internal quadrants (upper and lower).
When palpating regional l. u. in the axillary, subclavian and supraclavicular areas it is important to establish:
a) absence of compacted and enlarged l.u.;
b) the presence of enlarged or compacted l.u.;
c) location of enlarged l.u. in the form of a chain or conglomerate of nodes welded together;
d) the presence or absence of edema of the upper limb.
The combination of anamnestic information, examination and palpation data is a condition for determining the clinical form of breast cancer: nodular, local infiltrative, diffuse infiltrative or complicated (infiltrative-edematous, infiltrative-lymphangitic, ulcerative).
The so-called “occult” form of breast cancer, which is characterized by a combination of a microscopic primary tumor with large metastatic lesions of regional lymph nodes, most often axillary, is considered separately.
Of particular interest is Paget's cancer, a unique form of breast cancer that affects the nipple and areola. Based on the predominance of certain clinical symptoms in Paget's cancer, they distinguish between eczema-like (nodular, weeping rashes on the skin of the areola), psoriasis-like (the presence of scales and plaques in the area of the nipple and areola), ulcerative (crater-like ulcer with dense edges) and tumor (the presence of tumor-like formations in subareolar zone or in the nipple area) shape.