Tumors, general data. Malignant cell features. Molecular fundamentals of carcinogenesis. Antitumor immunity. Non-malignant (benign) and malignant growth.
Tumors morphogenesis and hystogenesis.
Introduction to oncomorphology. Role of biopsy diagnosis in oncology.
Tumors etiology and pathogenesis. Modern theories of cancerogenesis. Tumor growth risk factors. Aging of human being. Geographic zones and environmental factors influence. Heredity: heredial tumor syndromes, family forms of neoplasia, syndrome of DNA reparation disorder. Tumor growth risk factors. Pretumor (precancerous) conditions and changes, their essence and morphology.
Molecular grounds of carcinogenesis. Cellular oncogenes, oncogenes’ protein products. Proto-oncogenes: range, characteristics, detection in human tumors. Growth factors, growth factor receptors, nucleus regulating proteins participating in signals transduction role in oncogenesis. Mechanisms of oncogenes activation. Mutations. Chromosome translocations. Genes amplification. Genes – oncosupressors. Molecular grounds of carcinogenesis. Stages of carcinogenesis. Changes of karyotype in tumors (translocations, deletions, telomeres shortening, DNA ploidy change).
Carcinogenous agents and their interaction with cells. The most important groups of chemical carcinogenes. Radiation carcinogenesis. Viral carcinogenesis. Mechanisms, clinicopathologic implications.
Antitumor immunity. Tumors antigenes. Immune supervision. Antitumor effector mechanisms (cellular and humoral).
Tumor growth biology. Tumors morphogenesis. Malignant cells growth kinetics. Tumor angiogenesis. Tumors progress and heterogeneity. Features of cell population in tumor focus. Invasive growth mechanisms. Metastais (dissemination of tumor): types, regularities, mechanisms. Metastatic cascade.
Tumors. Definition. Scope and principles of classification. Malignant and non-malignant growths: variety, comparative charactristics. Tumors histogenesis (cytogenesis) and differentiation. Basic features of tumor. Tumor structure peculiarities, tumor parenchyma and stroma. Types of tumor growth: expansive, infiltrating and apposition, exophytic and endophytic.
The most importamt clinicopathologic presentations of tumor growth. Neoplastic (tumor) process charactristics. Local influence of tumor. Organism homeostasis failure. Secondary changes in tumor. Metastases and systemic non-metastatic influences. Malignant cachexia, paraneoplastic syndromes.
Tumors etiology. Carcinogen agents and their interaction with cells. It is ascertained fact that tumors can be caused by physical, chemical and biological agents which are called cancirogens
Over 75% of human beings’ cancirous diseseas are caused by environmental factors, and in first turn – by chemical compounds. First experimental proofs of chemical compounds’ carcinogenicity, were Yamagiva’s and Ishikava’s researches (1915). They induced rabbit’s ear skin cancer by applying there coal-tar pitch for the period of 15 months.
Chemical cancirogens are wide-spreaded in invironment and the majority of them are of antropogenous origin. Same time we shouldn’t exaggerate their role in human being pathology as only about 100 compounds and manufacturing processes are acknowledged as carcinogenous for human beings.
By their chemical structure carcinogens are divided into several groups. The most important of them are as follows: a) polycyclic aromatic hydrocarbons; b) aromatic amine and amides; c) nitrosoamines and nitrosoamides.
First group consists of over than 200 substances with three and more benzene rings. Only one of them, namely 3,4-benzpyrene considered to be the one able to cause cancerous diseases of human being. The others cause tumors only in experimental animals. The biggest amount of this group of carcinogens is in tobacco fume, exhaust gases of automobiles, blast furnaces smoke, asphalt, waste of chemical plants, dried and overdone food.
Substance of polycyclic structure shows mostly local carcinogenous influence. In case during experiment they are applied on skin cancer occurs, in case they are applied under skin – sarcoma occurs. Polycyclic aromatic hydrocarbons are excreted by various organs of organism, so tumors of these organs occur – kidneys, skin, mammary glands.
The second group of carcinogens are mostly azo dyes, for which two or more azo groups presence is charactristic (mono-azobenzene, 2- naphthylamine, benzidine). These substances are used to color natural and synthetic fibers, in printing industry, cosmetics, color photography, to synthesize medicines, insecticides. Cancirogeneous action of amines and amides becomes apparent when they are introduced in digestive tract, subcutaneous or in case they are applied on skin. Tumors appears in organs far from the place of application, the most often in liver, urinal bladder, bowels, kidneys.
Nitrocompounds (nitrosoamines and nitrosoamides) are characterized with alkyl radical presence. They are utilized as antioxidants, pesticides, paints solvents, semi-products under paints, medicines and polymers synthesis. Their cancinogenity for human being is nor proved but experimental data causes oncologic alertness. Possibility of nitrocompounds synthesis of nitrites, nitrates, nitric oxide in human being’s intestinal tract is proved. Nitrites are widely used as conserved agents for foodstuff.
Practically all chemical substances are not carcinogenic as they are. They acquire these features after coming into organism and are subject to metabolic transformations. Here is the origing of idea of final carcinogens which are able to interact with cells macromolecules – DNA, RNA, proteins. Taking into consideration role of DNA in heredity information transfer the most attention is focused to carcinogens’ binding exactly with this acid. A number of products were found which made possible to decode fine mechanisms of final carcinogens interaction with DNA. They mostly methylate guanine and affect purine bases complementary character – instead of normal combination guanine - cytosine paramethylated guanine – hymine is created. So, carcinogens cause point mutations in certain DNA positions. In case these mutations refer to transforming genes, i.e. oncogenes a chain of events starts causing malignization.
Radiation carcinogenesis. Physical carcinogens includes ionizing radiation and to a lesser extend – ultraviolet rays. Ionizing radiation acts indirectly, through highly active free radicals distorting DNA structure. Ultraviolet rays prevent its reparation.
Viral carcinogenesis. There are various biologic agents able to cause malignant growth. The biggest group consists of viruses. Indisputable proofs were acquired regarding viral origin of many animal tumors – hens’ Rous sarcoma, rabbits’ Shope fibroma and papilloma, mice mammary glands cancer (virus is transferred through milk). The quantity of human beings’ tumors which are indoubtfully caused by viruses is not big – Burkitt's lymphoma, rhinopharyngitis cancer, carcinoma of uterine cervix.
Viruses causing tumors are called oncogeneous. They are divided into two groups depending of genome’s molecular structure - RNA-containing and DNA-containing. Major group consists of RNA oncogenous viruses, forming the group of retroviruses. Their mutual charactristics is the fact that their genom is of one chain RNA, and that they have ferment RNA-dependent DNA-polymerase (invertible transcriptase, revertase). The essence of virus inducted carcinogenesis adds up to the fact that oncogenous viruses introduce their own genome in infected cell, this genome contains transforming gene – viral oncogene. Its activity product (oncoprotein) starts cell transformation and keeps it in transformed condition.
Retroviruses are the major cause of human’s malignant growths, however they point the way to understand basic mechanism underlies this diseases. They became model system by means of which the most modern data was received of fine molecular distortions occuring under cellular transformations.
All above said allows to make major conclusion: tumor starts from DNA damage. This mechanism is obligatory for all tumors irrespectively what carcinogens caused them – chemical, physical or biological. All of them are carcinogens exectly because of the fact that they are able to cause genetic apparatus failures. Chemical agents cause mostly point mutations, ionizing radiation – mostly chromosome mutations and retroviruses introduce to DNA molecule additional genes and oncogenes are among them. In such a way DNA damages could be treated as molecular grounds of all further processes tranforming normal cell into transformed cell. In the other words DNA damage is common denominator to which the action of all known carcinogens is reduced.
Pathogenesis of tumors. Molecular grounds of cancerogenesis. The question arises: what kind of DNA damage is realized into tumor? The answer to that is not at all simple. Based on modern knowledge scientific theory was formulated which is known as oncogene consept. It combines all forms of carcinogenesis (chemical, physical and viral) into one universal mechanism. There are really many causes of cancer, but all of them similar to water through watering-can should pass through one critical channel – DNA and leave trace in it, meaning damage. This damage is specific. It will lead to normal cell transformation into malignant cell (tranformation phenomenon) only in case it localizes not at any random DNA portion, but exactly in the portion where genes controlling cells growth and differentiation are situated. These genes are called cellular oncogenes or proto-oncogenes. They are usual components of cellular genome and are absolutely necessary for cell’s vital activity. Cellular proliferation would be impossible without proto-oncogenes.
It is considered that under minor damages normal function of cellular oncogenes as auxesis could be keept in principle, but it stops to subordinate controlling influences of the cell itself. Normal controlled process of growth and maturing is lost and is interchanged with an endless process of cellular divisions under which cells do not have time to differentiate meaning to mature to condition when they are able to fulfill approprite specialized physiologic functions. It comes out that cell from its creation beginning hides the sprouts of its own death in the form of cellular oncogenes.
Right now nobody denies that normal cellular oncogenes under specific conditions could activate and cause malignant growth. Several ways of their activation are differentiated. One of them is viral transduction, in other words cellular oncogenes passage through viral genome. It is proved that retroviruses damage DNA by the way of introduction to it so called viral oncogenes. It was found that they are of cellular origin. They are proto-oncogenes which on the certain stage of evolution were deported from infected cell nucleus by viruses and included into self-genome. Starting from that moment they became viral oncogenes. Right now over 20 of them are known. All of them have cellular counteracts in various chromosomes.
Viral oncogens coming into cell for the second time behaves uncontrolled. The point is that they structurally differs of their cellular ancestry. Retroviruses, as a rule, capture cellular gene incomplete, without repressor genes, so similar viral oncogene keeps ability to stimulate cells growth and differentiation but loses regulator (operator) genes and becomes uncontrolled. It causes unlimited non-corresponding organism’s needs cells division. Cellular oncogene itself also is subject to structural changes at its capture by retrovirus. This makes difficult regulative influences on it by resprssor genes as well as by epigenome cellular regulators. Thus, viral transduction deprives cellular oncogenes their primary positive function of growth stimulators and simultaneously releases their hidden transformation abilities. Growth and proliferation genes starts to function as cancer genes.
Cellular oncogenes activation can occur in the result of chromosomal translocations. It was noted that under certain forms of tumors chromosome discontinuities take place exectly in those portions where cellular oncogenes are situated.
It was clarified that certain tumors, for example, Burkitt's lymphoma occurs when any foreign (viral) genetic material inserts into DNA molecule close to proto-oncogene, even if this material doesn’t include oncogene. Viral DNA built-in close to cellular oncogene activates it up to cancer level of expression. This mechanism is called insertion.
As a rule, cellular oncogenes are represented in DNA in one copy but it was proved that copies quantity can increase in the result of DNA replication abnormality. This phenomenon is called amplification (augmenting). Cellular oncogenes copies amount increase causes enhanced division of cells. This mechanism acts in human neuroblastoma and carcinoma of large intestine creation.
Anyway, point mutations independently of their cause are considered to be major mechanism of proto-oncogene transformation into active cancer oncogene. It is proved that that‘s enough to change in human urine bladder cancer only one base – guanine for the other one - thymine as inactive proto-oncogene becomes transfomating. Totality of scientific ideas of mutations’ decisive force in tumor etiology forms the grounds of mutation consept of cancerogenesis.
Epigenome concept adds up to the fact that the grounds of normal cell transformation into malignant one are not genetic apparatus’ structures changes, but persistent failures in genous activity regulation. The genes which should be repressed are disinhibited and those which should be active are clocked. Cell loses its specificity, becomes insensitive to regulative influences of the whole organism.
Stages of cancerogenesis. Tumors occurrence and progress is multistage process. There are three main stages – trasnformation (initiation), promotion and progression. Proto-oncogene activation finishes first stage – stage of initiation. Main feature acquired by the cell in the result of proto-oncogene transformation into oncogene is immortalization, meaning its potential ability to endless division, to immortality. However active oncogene presence is only potential possibilitity for expression. Cell with active oncogene could stay for years in latent (delitescence) state, doesn’t expressing itself in any way. Immortalized cell needs additional influences taking it out of latent state and give a stimulus to endless division.
Tumor growth risk factors. These provocative factors could be additional doses of chemical or physical cancerogenes, retroviral superinfection as well as various agents which do not cause tumors as they are, but are able to take immortalized cells out of latent state. Here starts old idea of super multicauses of tumor growth however in reality absolute majority of the factors attributed etiologic role should be considered among promotional conditions causing expression of latent, potentially cancerous, cells. Factors activating pre-cancerous cells are called promoters. Under their influence trasnformed cells go into new stage of development – promotion stage for which cellular oncogenes expresssion is charactristic.
Provided that the fact of oncogenes participation in oncogenesis is not under the doubt at the moment, mechanism of their action is still a mystery. It was ascertained that oncogenes code specific proteins (oncoproteins), most of them having tyrosinase activity. Further on it was found that oncoproteins which cause uncontrolled growth of malignant cells are similar to usual growth factors – thrombocyte growth factor, epidermal growth factor, insulin-like growth factors. Under the normal conditions growth factors comes into cell from outside providing cell dependability from organism. Malignant cells differs with the fact that they produce growth factors by themselves. A part of them is aimed to support their own proliferation (autocrine secretion), and the other one – for other type cells (paracrine secreation).
Progression is the final phase of tumor progress. Under this term persistent, irreversible qualitative changes of tumor to malignization are understood. For example hormone-dependent neoplasms became hormone-dependent, tumor reacted medicines stoped to react them. Progression is the last and the most long lasting stage of tumor progress lasting up to organism death.
The most important clinicopathologic implications of tumor growth. Interrelations between tumor and organism. Tumor negative influence on organism depends on its type (non-malignant or malignant), localization, speed of growth and directions of metastasis. Tumor directly injures organ in which it progresses disturbing its structure and functions. Surrounding organs are subject to atrophy and deformation, lumens of cavity organs narrows. Due to chronic intoxication with decay products and insufficient feeding cachesia develops. Hematosis depression, excessive hemolysis and chronic hemorrhage cause anemia.
In case tumor consists of hormone-active cells deseases occur connected with corresponding hormone hyperproduction or paraneoplastic syndromes of endocrinopathy, neurological aspects (dementia, neuropathy), skin implications, hematologic implications (hyper coagulability of blood, anemia, thrombocytopenia, polycythemia). Pheocromacytoma (cancer of adrenal glands cerebral layer, producing adrenalin) causes arterial hypertention progress, insulinoma (tumor of islet of Langerhans b-cells) causes hypoglycemia, gastrinoma (pancreatic tumor producing gastrin - gastric secretion stimulator) causes stomach ulcer.
Tumors structure. There are various tumors by their macro- and microscopic structure. Their appearance can remind mushroom, cauliflower, node or intumescence. In section tumors are mostly of white, grey and red color. The following is often found in them: hemorrhages, necrosis and cysts cavity of which is filled with mucus or bloody mass. Some tumors are of brown color, for example, melanoma.
Tumor size depends mostly of its origin, location and growth period. In some cases they can reach giant sizes (fibroid tumors) in the other cases they can be seen only through magnifying glass or microscope (microcarcinomas). Tumors localized close to vitally important centers as a rule are of rather small size.
Tumor consistency is defined first of all by the type of outgoing tissue and ratio between stroma and parenchyma. Tumors of bone (osseous) tissue, cartilage tissue and fiber conjunctive tissue are of dense consistence. Malignant growth of epithelium in which stroma is underdeveloped are flaccid and by their consistence they are similar to new-born child’s brain (cancer-brainer).
Stroma and parenchyma are seen microscopically in each tumor. Parenchyma is its specific part which is represented by malignant cells and determines tumor place in hystologic classification. Even in tumors originating from mesenchyma cells producing intercellular substances (collagen fibers, basic substance of cartilage or bone tissue) are also should be treated as parenchyma. Stroma is mechanical-trophic framework including conjunctive tissue, blood and lymph vessels and nerves.
Most of tumors look like organ by their structure, i.e. have parenchyma and completely represented stroma. Such tumors are called organoid. In undifferentiated tumors parenchyma prevails and stroma is underdeveloped. They are called histioid. Blood circulation insufficiency causing necrosis easily occurs in them. At the same time there are tumors poor with parenchymatous elements and rich with stromal, for example gastric fibrocarcinoma or sccirrhous. These tumors cause complications due to stroma’s corrugation. They deform organ or narrow its lumen.
Tumor corresponding structure of the organ it is localized in is called homologous, and the one which structure differs from this organ structure is defined as heterologous. In case tumor is developed from the cells of organ in which it occurred – this is homotopy tumor. In cases it occurs from the cells of embryonal displacement (heterotopia), it is called heterotopic, for example tumor of bone marrow in uterus.
Tumor (new growth, neoplasm, blastoma) is typical pathologic process in the form of excrescence of tissue subject to genetic apparatus change, characterized with potential infinity of its uncontrolled growth as well as structural elements’ atypicity.
Biology of tumor growth. Universal and mandatory feature of all the tumors – both non-malignant and malignant – is their ability to endless growth. This is fundamental feature of any tumor. Uncontrolled excessive proliferation of malignant cells doesn’t mean at all that they divide faster than homologous cells of healthy tissue. Vice versa, certain healthy tissues grow much more faster than the most malignant growth, for example, embryonal cells, regenerating liver. In such a way, malignant cells proliferation differs from normal cells proliferation not with cells division and growth speed, but in the character of division and growth.
Infinity of malignant cells growth is based on the fact that they are unable to exhaust division resource. It is found that genetic program limiting its divisions quantity is integrated into each cell. As a result of genetic somatic mutation malignant cell losses this restrictive program and starts to divide “endless”, escaping aging up to the death of host organism. In case these cells are carried from living organism to the other one of the same species, they will settle down and again will divide up to the death of recipient organism. In case these cells are carried to nutrient medium, there they will also divide endless times, in the other words they become independent of Heiflic’s rule. This ability of malignant cells to endless division is dominantly propagated to further cells generation.
Malignant cells life could be kept artificially. There are two methods to provide that: transplantation – tumor inoculation from one animal to the other one of the same species and explantation – malignant cells cultivation on nutrient medium. Tumor kept for a long time with transplantation or explantation method is called tumor strain. First transplantation strain was made in 1905 (Ehrlich's carcinoma in mice), first explantation - in 1950 (Hela’s cells – carcinoma of uterine cervix).
Malignant cell has one more feature – uncontrolled growth. On the level of the whole organism tumor growth is controlled with nervous and endocrine systems, and on the local level – with mitogens and keylones. Malignant cell gets out of this hand, that is shows autonomy, independence of growth. It’s clear that this autonomy is not absolute but in this or that way is characteristic for all tumors. In case tumor partially keeps ability to come under control influence of hormones, it is called hormone-dependent tumor and in case it completely loses this ability - hormone-independent tumor. Autonomy doesn’t mean that tumor lost any connection with organism. This connection changed. They can be characterized as relations between host organism and parasite tissue.
Third peculiar feature of malignant cells is anaplasia, which means their persistent dedifferentiation, loss of ability to form specific tissue structures or produce specific substances characteristic for normal cells. In the other words its return to embrional state, structural-chemical organisation simplification.
Tumor occurs from single parent cell subject to genous mutation. Malignant cells differs in several parameters from their common normal ancestor. This difference relates to cell’s and its organoids’ structure, metabolism, specific features and functions. Therefore morphologic, biochemical, physical-chemical, immunologic and functional anaplasia is differentiated.
The essence of morphological anaplasia comes to tissue, cellular and subcellular atypicity occurrence. Polymorphism is inherent to malignant cells – they acquire smaller as well as bigger size and shape which is not peculiar for normal cells. Interrelation between nucleus and cytoplasm is shifted in favor of nucleus due to its enlargement. Multinuclear cells, nucleus hyperchromatosis are observed caused by nucleic acids accumulation in them, nucleolus amount increase and their migration into cytoplasm, of subcellular structures mitochondrions are subject to most prominent changes. Their quantity and size are decreased, membranes became thinner, cristas also become thinner and disappear. At tissue level structures’ created by malignant cells size and shape changes are observed. This referes for example to glandular follicles in adenocarcinomas and focuses of ossification in osteosarcomas. Sometimes tumor completely losses morphologic features indicating its origin from the certain differentiated tissue.
Biochemical anaplasia is peculiar of malignant cells’ metabolism caused by theirs genetic apparatus change. Carcinogens are able not only to distort mitosis process and start endless division mechanisms, but also to supress or unbrake the other genes. As the result of that malignant cells enzymatic range changes. Intracellular enzyme insufficiency occurs - some enzymes are inhibited but the other ones activate or start to synthesize absolutely new substances which didn’t exist in normal cells.
It is found that all tumors, subject to progression start to look like each other by their enzymes set independently of what cells they come from. Unification of tumors izoenzymal range independently of their histogenesis is very characteristic manifestation of malignization.
It is known that every tissue synthesize enzymes specific for it, where every enzyme is represented with strictly specific set of isoenzymes. This specific feature is lost in tumors. So called monotonization or isoenzymic simplification is developed – amount of isoenzymes reduces and their set becomes approximately the same for tumor of any origin. Isoenzyme reconstruction goes in the direction of those enzymes increase which are peculiar for embrional tissues.
The most peculiar biochemical features of malignant cells relate to proteins and carbohydrates metabolism. Proteins synthesis prevails their decomposition. To build own proteins tumor captures aminoacides of the other organs (“tumor - trap for nitrogen”).
Carbohydrates metabolism and power of malignant cells significantly differ from the norm. In aerobic conditions normal cell provides itself with energy mostly at the expense of more advantageous glucose aplittance in Crabbs’ cycle, and in anaerobic conditions – it is forced to change to glycolysis. In case amount of oxygen is sufficient, glycolysis is opressed with breathing ( Paster’s effect).
Malignant cell also provides its demands in energy on account of glycolysis and breathing, but correlative meaning of these processes is different. Peculiarities of tumors power supply are as follows: a) activation of anaerobic glycolysis and enzymes providing it - pyruvatekinase, hexokinase, fructokinase; b) presence of aerobic glycolisis for which normal cells are not able (exceptions – leukocytes, spermatozoon, eye retina cells); c) breath opression with glycolisis (Crabtree effect), to say exact – with powerfult system of glycolytic enzymes, which intercept substrates – inorganic phosphorus, coenzymes.
Among physical-chemical features of malignant cells the following should be emphasized: acidosis in the result of lactic acid accumulation, intracellular aquation, potassium ions accumulation, electroconductivity increase, colloids density reduction, membrane negative change increase, their surface tension decrease.
Antitumor immunity. Under immune anaplasia changes of malignant cell’s antigene features is understood. These changes is the result of protein metabolism rebuilding. It is known that each tissue synthesize a set of antigenes specific for it. This set is changed in tumor. Tumor antigenes. Antigene simplification and antigene complication are differentiated. Antigene simplification is characterized with antigenes synthesized by malignant cell numerous times decrease.
Antigene complication is manifested with antigene divergence and antigene reversion. Antigene divergence means that malignant cells start to synthesize antigenes which are not characteristic for healthy cells, but these antigenes are usually synthesized by the other cells. For example hepatic tumor can synthesize antigenes of spleen or kidneys. Tumor’s synthesis of embrional antigenes is called antigene reversion. Renal carcinoma of human being synthesizes a- fetoprotein, which serves as the test for its diagnosis. In the course of tumor’s malignization it strats to synthesize antigenes characteristic for moire and more earlier stages of intrauterine evolution.
Organism is not defenseless towards carcinogenes and transformed (mutant) cells. It has strong defensive mechanisms providing prevention of tumors occurrence or slow down their progress. Here relates a system of carcinogenic compounds neutralization and their evacuation through kidneys, digestive tract and skin. Organism clears of mutant cells due to immune surveillance function, peculiar to Ò-lymphocytes. System of endonucleases exists providing damages oncogenes renewal and stopping synthesis of oncoproteins coded by them. Tumor growth is also influenced with hormones – insulin, adrenalin, tropic hormones of hypophysis, gormones of thyroid gland and sexual glands. This influence is ambiguous and depends on its combination with the other mechanisms of antineoplastic defense.
Functional anaplasia is manifested with loss or distortion of function fulfilled by cell. In thyroid gland malignant cells’ thyroid hormones synthesis can reduce or increase up to myxedema or thyrotoxicosis occurrence. Bilirubin conjugation is stopped in hepatoma (liver cell carcinoma). In some cases tumors start to synthesize the products not peculiar to them. For exmpale pulmonary and bronchi tumors can synthesis hormonoform substances.
Secondary changes in tumor. Secondary metabolism disorders can develop in tumors, like sliming, hyalinosis, adiposity, calcification. Blood circulation functional insufficiency is characteristic for malignant growth as parenchyma always grows faster than stroma. Besides that, blood vessels are often thrombosed causing progress of necrosis on background of which ulcers, hemorrages, perforations occur.
Non-malignant growth and malignant growth. Tumors are not equivalent from the clinical point of view. Depending on the stage of differentiation, speed and character of growth, inclination to metastasis and recurrence, secondary changes in tumors, their influence on organism, they are distributed into non-malignant, malignant and the ones with local destructive growth.
Non-malignant or mature tumors are built of cells from structure of which it is always could be determined from what tissue they grow. In case they do not locate near vital important centers they are manifested with local changes and their influence on organism is minor. But these tumors can transform into malignant ones – malignizate.
Malignant (immature) tumors are built of low-differentiated or nondifferentiated cells which lose structural similarity to cells they originate from. Apart from non-malignant tumors they give metastasis, recur, manifest themselves with local changes and influence on the whole organism non-transforming into differentiated forms.
Tumors with local destructive growth occupy intermediate position between non-malignant and malignant. They have the features of infiltrating growth, but do not metastasis. These are hemangioma, desmoid tumor.
Nomenclature of Neoplasia
Ø Based upon origin:
Ø Malignant neoplasms arising from tissue embryologically derived from ectoderm or endoderm are usually carcinomas. Examples include:
Ø Squamous cell carcinoma of cervix
Ø Adenocarcinoma of stomach
Ø Hepatocellular carcinoma
Ø Renal cell carcinoma
Ø Malignancies arising from mesoderm (connective tissues) are usually sarcomas. Examples include:
Neoplasms with more than one cell type but arising from only one germ layer are called "mixed tumors". The best example is the benign mixed tumor (also called pleomorphic adenoma) of salivary gland.
Neoplasms with more than one cell type and arising from more than one germ layer are called teratomas. Such neoplasms are common in the ovary.
Neoplasms ending in "-blastoma" resemble primitive embryonic tissues, which are often pediatric neoplasms. Examples include:
Not all malignant neoplasms have benign counterparts:
Hematopoietic and lymphoid cells (as in bone marrow and lymph node) give rise to leukemias and lymphomas. They have no benign counterpart.
Gliomas (astrocytomas, oligodengrogliomas, glioblastoma multiforme, etc) arise from glial cells in the CNS. They have no benign counterpart.
Arise from epithelial surfaces (in gastrointestinal tract, in respiratory tract, in urogenital tract, in biliary tract, in skin) and in organs with epithelial-lined ducts (breast, pancreas, salivary gland, liver). Endocrine glands, including testis and ovary, may also give rise to carcinomas. In general, carcinomas are composed of polygonal-shaped cells.
Carcinomas that form glandular configurations are called adenocarcinomas.
Carcinomas that form solid nests of cells with distinct borders, intercellular bridges, and pink keratinized cytoplasm are called squamous cell carcinomas.
Arise from soft tissues (connective tissues such as cartilage, bone, or fascia, smooth or skeletal muscle, blood vessels, lymph vessels, coverings of organs such as mesothelium). In general, sarcomas are composed of very pleomorphic spindle-shaped cells. Sarcomas are generally big and bad.
Causes of Neoplasia
The origin for many neoplasms is obscure. However, there are several theories of origin:
Chemicals: including those that are man-made (such as aniline dyes and bladder cancer), drugs (cigarette smoke and lung cancer), and natural compounds (aflatoxins and liver cancer) which are carcinogenic.
Oncogenic viruses: such as human papillomavirus (HPV) implicated in most squamous cell carcinomas of cervix and anogenital squamous papillomas, Epstein-Barr virus (EBV) implicated in African Burkitt's lymphoma, and hepatitis B virus (HBV) implicated in development of hepatocellular carcinomas.
Radiation: including ultraviolet light that induces pyrimidine dimers in DNA and promotes skin cancers. Ionizing radiation (such as gamma radiation) induces mutations in DNA and promotes malignancies such as leukemia, thyroid, lung, colon, and breast cancers.
There are two steps: initiation and promotion
An initiating carcinogenic agent irreversibly damages cell DNA (it is mutagenic) to start the process. Examples of carcinogenic initiators include: alkylating agents like cyclophosphamide, polycyclic aromatic hydrocarbons like epoxides found in smoked foods, aromatic amines or azo dyes used in food coloring, aflatoxins in moldy peanuts, nitrosamines in pickled foods.
A promoting agent (which may be the same as the carcinogen) then acts (reversibly) to cause proliferation of a neoplastic cell clone, but there appears to be a "dose-threshold" concentration of promoter below which neoplasia will not occur. Examples of promoters include: hormones such as estrogen, drugs such as diethylstilbesterol, and chemicals such as cyclamates used as sweeteners.
Chromosomes which have absent or defective anti-oncogenes that control growth (retinoblastoma results from defective chromosome 13)
Obscure defects: racial predilections (American women have breast cancer more often than Japanese women; Japanese men have stomach cancer far more often than American men).
Age: older persons have a greater propensity to develop neoplasms from lack of effective control mechanisms.
All of the above are probably mediated by the cause, whatever it is, producing a mutation in, or damage to, cell DNA
There can be mutations involving tumor suppressor genes (such as p53), which then fail to exert a controlling influence upon growth activation. The majority of human neoplasms probably arise via this mechanism.
In some cases these mutations are probably mediated by proto-oncogenes (genes which control cellular growth) that undergo mutation to oncogenes which give rise to neoplasia. Proto-oncogenes can be activated by point mutations, translocations, and by gene amplification.
An example of this is chronic myelogenous leukemia (CML) which is a neoplastic proliferation of white blood cells. All cases of CML have the "Philadelphia chromosome" which is a translocation between chromosomes 9 and 22. This translocation juxtaposes the proto-oncogene ABL with the breakpoint cluster region (BCR) on chromosome 22. The chimeric ABL-BCR gene leads to production of a mutant protein with enhanced tyrosine kinase activity. This protein may play a role in regulation of cell growth in CML.
About 15 to 20% of human cancers have been linked to oncogenic activity. The ras oncogene is the transforming gene found most frequently in human cancers.
Oncogenic viruses may bring oncogenes with them, so-called viral oncogenes (typical of RNA containing "retroviruses" such as human T-lymphotropic viruses (HTLV's).
DNA repair mechanisms may be affected. There are DNA excision repair genes that can be mutated, introducing genomic instability and a greater likelihood that mutations in other genes will occur to drive oncogenesis. Examples include:
DNA mismatch repair genes: defective nucleotide "spell checker" introducing "microsatellite instability" of tandem repeat sequences in DNA. Seen in hereditary non-polyposis colon cancer (HNPCC)
Nucleotide excision repair genes: defective function in xeroderma pigmentosa, allowing DNA damage from pyrimidine dimer formation induced by ultraviolet light
Growth factors such as epidermal growth factor (EGF), platelet-derived growth factor (PDGF) and colony-stimulating factor-1 (CSF-1) assist oncogene activity. Transforming growth factor (TGF-alpha) also promotes tumor growth.
Familial and Sporadic Neoplasia
Most human cancers are "sporadic" because there is no identifiable inherited gene involved, but the cancers developed as a result of environmental factors (carcinogens such as cigarette smoke) that randomly induced mutations in cells that led to uncontrolled growth. Such factors are encountered throughout life and act over a long period of time; hence, most sporadic cancers occur in adults. Most affected persons have one primary site, and that site is where you would expect most cancers to be (breast, lung, prostate, colon, etc.)
Familial cancers tend to occur at a younger age than sporadic cancers. There is a specific gene with a defined inheritance pattern. Thus, one is born with "one strike" and it is a matter of years before another event triggers the cancer growth. One form of classic familial cancer syndrome involves a tumor suppressor gene, with the "two hit" hypothesis. A person inherits a bad p53 gene, for example, (first hit), but still has another functional copy of this gene on the other chromosome. Sometime later, a mutation wipes out the good gene (second hit) and growth control is lost, allowing a clone of neoplastic cells to arise. Multiple organs can be affected. Thus, familial cancers often involve more than one organ, and affected individuals can have more than one cancer, and malignancies other than epithelial are more likely (soft tissue sarcomas, leukemias/lymphomas, nervous system tumors).
The rare Li Fraumeni Syndrome illustrates the difference between "familial" and "sporadic" cancers. In Li Fraumeni syndrome there is an inherited mutation in the p53 gene, and a variety of cancers arise in persons with this mutation. However, it should be noted that p53 mutations are the most common mutations in sporadic cancers, too.
The large fronds of endometrium seen in this uterus opened to reveal the endometrial cavity are a result of hyperplasia. This resulted from increased estrogen. With hyperplasia, there is an increase in cell numbers to produce an increase in tissue size. However, the cells are normal in appearance. Sometimes hyperplasias can be "atypical" and the cells not completely normal. Such conditions can be premalignant.
The first step toward neoplasia is cellular transformation. The chronic irritation from cigarette smoke has led to an exchanging of one type of epithelium (the normal respiratory epithelium at the right) for another (the more resilient squamous epithelium at the left). Thus, there is metaplasia of normal respiratory laryngeal epithelium to squamous epithelium in response to chronic irritation of smoking.
The two forms of cellular transformation that are potentially reversible, but may be steps toward a neoplasm, are:
Metaplasia: the exchange of normal epithelium for another type of epithelium. Metaplasia is reversible when the stimulus for it is taken away.
Dysplasia: a disordered growth and maturation of an epithelium, which is still reversible if the factors driving it are eliminated.
This biopsy of the lower esophagus in a patient with chronic gastroesophageal reflux disease (GERD) shows columnar metaplasia (Barrett's esophagus), and the goblet cells are typical of an intestinal type of epithelium. Squamous epithelium typical of the normal esophagus appears at the right.
Basic differential features of non-malignant and malignant growth
Characteristic of non-malignant and malignant growth
Have minor deviations from parent tissue
Expressed atypism: tissue and cellular
Reach big size
Rear rich big size
Rare are subject to ulceration
Often are subject to ulceration
Do not give metastasis
Recurrence is not characteristic
Minor influence on patient’s general condition
Have major influence on the whole organism subject to ulceration
Tumors’ growth and spread in organism. Depending on differentiation level the following forms of tumor growth are differentiated: expansive, opposition and infiltrative (invasive). First form is peculiar for non-malignant growth, and second and third – for malignant ones.
Tumor which grows expansively increases as a node, moving aside surrounding tissues. Cells surrounding it atrophy and stroma is subject to collapse causing pseudocapsule formation and sharpness of tumor boarder.
Opposition growth is intermediate between expansive and infiltrative. Tumor grows from multiple spots of growth – focal proliferates forming “tumor field”. Tumor transformation (malignization) is done consequentially from the center to peripheria and is finished with malignization focuses fusion into single node.
Infiltrative growth is characterized with tumor elements spreading into the least resistance directions and ingrown surrounding tissues destructing them. Tumor boarder in this case is indistinct, worn down.
In respect to organ’s cavity endophytic and exophytic growth are differentiated. Pre-invasive or intraepithelial neoplasia is observed as specific form. Hystologically epithelium displasia of epithelium, atypism are found, its normal distribution into layers disappears, but basal membrane is not injured.
Tumors which grow expansively do not spread out of organ’s boarder. In case infiltrative growth tumor spreads not only inside the organ but also out of it. Continuous contact tumor spread and metastasis are differentiated.
Continuous spread is tumor ingrowth into neighbour tissues. Under infiltrative growth malignant cells can reach serous tunic where reactive inflammation occurs and excudate organization is ended with commissure formation with neighbour organs. Through commissures tumor ingrow these organs (for example gastric carcinoma grows into liver or pancreas). In case cavity organs coalescence, fistulas formation is possible due to continuous spread and necrosis. Coloenteric fistula, for example, is observed in case gallbladder carcinoma.
Metastasis (dissimination) is malignant cells transfer from primary focus into distant parts with their further settle down and secondary focuses creation. Several ways of tumor dissemination exists: hematogenic, lymphogenic, perineural, implant, mixed.
This is the next step toward neoplasia. Here, there is normal cervical squamous epithelium at the left, but dysplastic squamous epithelium at the right. The dysplastic epithelial cells are darker, smaller, and more crowded, without an orderly process of maturation. Dysplasia is a disorderly growth of epithelium, but still confined to the epithelium. Dysplasia is still reversible.
Hematogenic metastases occur when malignant growth’s cells come into blood circulation system and moves by venous or arterial blood stream. Spreading through veins is the most often way of metastasis. In this case two possible directions exist: first is through vena cava system when malignant cells from primary focus (uterum, kidney, skeleton bones) are transferred into lungs, and the second one - through portal vein, when gastric, intestine carcinoma, tumor of pancreas metastasis in liver. Sometimes paradoxical and retrograde metastases are possible. Arterial way of metastasis relates, in the first turn, primary focus localized in lungs. At it metastasis into cerebrum, bone marrow, liver and other organs are possible. Hematogenic way of metastasis is most peculiar to sarcomas.
Lymphogenic metastasis is malignant cells transfer into regional, and further on – into distant lymph nodes. Later on malignant cells come into blood circulation system through thoracal lymphatic vessel.
Perineural metastases could be better characterized as an example of endless spread. Cells are disseminated through perineurium fissures.
Implantation metastasis is called tumor extension through serous cavities or natural channels. When serous tunic is invaded with malignant cells, they can come off and disseminate in serous cavity. In case conditions are favorable, they settle down and new focuses occur – implantation metastases. Macroscopically these metastases look like white plaques or humps. At that hemorrhagic inflammation occurs. Implantation metastases should be differentiated from lymphogenous metastases (carcinoma of pleura, peritoneum) when similar humps are formed downstream lymphatic vessels. Quite rare intracanalicular extension occurs. For example, malignant cells of bronchi, esophagus, pharynx oimplant into mucus tunic of little bronchi, ventricle, bowels and cause new tumors occurrence. Implantation metastases also include subinoculated metastasis (malignant cells transfer with surgeon’s hands and surgical tools) and contact metastasis (transfer from one organ to the other one, for example from labrum to labium).
Metastase cells have parent tumor structure and function. Intensity of metastasis depends on the stage of tumor differentiation and immunologic reactivity of organism. There is no correlation between tumor size and metastasis intensity. Malignant growth is able to metastasis from the moment of its occurrence. Metastases size often exceed parent tumor’s size. Most of cells die when transferred to the other place, so metastases could stay latent for a long time.
At high magnification, the normal cervical squamous epithelium at the left merges into the dysplastic squamous epithelium at the right in which the cells are more disorderly and have darker nuclei with more irregular outlines.
When an entire portion of epithelium is composed of abnormal cells and no normal epithelial cells remain, and the process is not potentially reversible, then the process has gone beyond dysplasia and is now neoplasia, which is loss of control of the cellular proliferative process. If the basement membrane is still intact, as shown here, then the process is called "carcinoma in situ" because the carcinoma is still confined to the epithelium. A neoplasm arising in epithelium is termed as a carcinoma.
Note the chronic inflammatory response in the submucosa. Dysplastic and neoplastic epithelia are abnormal and therefore not as protective as normal epithelia, so that irritants, infections, and trauma are more likely to damage the surface and initiate inflammation. It is also possible that the lymphocytes below the epithelium are part of an immune response, or "tumor immunity". Neoplastic cells may be altered or express antigens to elicit an immune response. This "immune surveillance" plays a role in stopping or slowing neoplastic processes, but can easily be overwhelmed when forces driving the neoplastic process persist.
Recurrent tumor is repeated occurrence of the same tumor by its features in the place of removed or treated tumor. Both non-malignant and malignant tumors recur, the latter - more often.
In clinical picture the following is differentiated: pretumor conditions (diseases at which the risk of tumor progress is increased) and precursors of cancer (histologic ‘;abnormalities” of tissues). They are classified in the following types: a) pathologic regeneration an example of which can be chronic bronchitis with epithelium metaplasia, mucus tunics’ leukoplakia, chronic atrophic gastritis, chronic stomach ulcer, subacute skin ulcer; b) chronic proliferative inflammation, first of all polyps of ventricle and large intestine; c) dishormonal diseases – proliferative mastopathy, glandular hyperplasia of endometrium, endocervicitis, prostatic hypertrophy; d) tissues development abnormalities – teratomas, nevus pigmentosis and birthmarks.
This is a neoplasm arising in the epithelium of the uterine cervix. Neoplasia is uncontrolled new growth. Neoplastic cells are no longer under complete physiologic control. Note the mass of abnormal tissue on the surface of this cervix. The term "tumor" is often used synonymously with neoplasm, but a "tumor" can mean any mass effect, whether it is inflammatory, hemodynamic, or neoplastic in origin. Once a neoplasm has started, it is not reversible.
This is the microscopic appearance of neoplasia, or uncontrolled new growth, in the uterine cervix. It is arising in the cervical squamous epithelium. Here, the neoplasm is infiltrating into the underlying cervical stroma. Of course, there can be carcinoma in situ in which a full-fledged neoplasm is present, but has not yet invaded below the basement membrane. Over time, neoplasms may acquire characteristics that make them more able to invade tissues, and this ability to invade distinguishes them as malignant.
This is a squamous cell carcinoma. Note the disorderly growth of the squamous epithelial cells in these large nests with pink keratin in the centers. Thus, these neoplastic cells retain the ability to make keratin, similar to normal squamous epithelial cells. Neoplasms may retain characteristics of their cell of origin. Benign neoplasms mimic the cell of origin very well, but malignant neoplasms less so.
Pretumor processes shouldn’t be connected with etiology. Pretumor changes presence do not mean at all that tumor will occur on their ground. So by cancer threat level they are distributed into optional (under which cancer develops rarely) and obligatory (under which cancer develops rather often).
At practical work it is necessary to know from what tissue tumor originates, in other words to make clear its histogenesis. In case tumor is built of differentiated cells keeping similarity to the parent one, its relatively easy to be done. In case undifferentiated cells prevail, histogenesis understanding faces with difficulties, sometimes it even becomes impossible.
Tumors classification. Terminology. Modern classification is built by histogenetic principle taking into consideration morphologic structure, localization, structure features in certain organs (organo-specificity), non-malignancy or malignancy. Tumor name ends with ‘oma” (mioma, fibroma). Malignant epithelium growth are called “cancer”, mesenchymal – “sarcoma”, tumors of embrional tissues – “blastoma”, of several embryonic leafs - “teratomas”. Some tumors are called with the name of the author described them – Kaposi's sarcoma (angiosarcoma), Wilms' tumor (nephroblastoma). International TNM system is used in respect to tumor process extention, where Ò(tumor) – tumor characteristic, N(nodus) – presence of metastases in lymph nodes, M(metastasis) – presence of distant hematogenous metastases. Seven groups of tumors were differentiated combining over 200 names:
a) epithelial tumors without specific localization (organo-nonspecific);
b) organospecific epithelial tumors;
c) mesenchymal tumors;
d) tumors of melanin creating tissue;
e) tumors of nervous system and cerebral membranes;
f) tumors of hematopoietic and lymphoid tissue;
g) teratomas .
Characteristics of Benign Neoplasms
A benign neoplasm looks a lot like the tissue with normal cells from which it originated, and has a slow growth rate. Benign neoplasms do not invade surrounding tissues and they do not metastasize. Thus, characteristics include:
Resemblance to tissue of origin (well differentiated)
Lack of invasion
Absence of metastases
Benign neoplasms usually arise in a solitary manner (e.g., lipoma of colon, meningioma of brain), but may be multiple (e.g., leiomyomata of uterus, intradermal nevi of skin). Though benign, they may cause problems through mass effect, particularly in tight quarters (pituitary adenoma in the sella turcica).
A hamartoma is a peculiar benign neoplasm which is a localized but haphazard growth of tissues normally found at a given site (pulmonary hamartoma has jumbled cartilage, bronchial epithelium, and connective tissue)
A choristoma is a benign neoplasm consisting of tissue that is not normal to the site of origin (e.g., salivary gland choristoma of the middle ear).
Nomenclature of tumors from tissues which take place from a mesenchyma. Morphological features of tumors from tissues which take place from a mesenchyma.
General characteristic of mesenchymal tumors. Non-malignant growths from mesenchyma: of conjunctive tissue (fibroma and dermatofibroma), of adipose tissue (lipoma, hibernoma), muscular tissue (leiomyoma, rhabdomyoma, granular cell tumor), clodd and lymph vessels (hemangioma, glomus-angioma, pericytoma, lymphangioma), synovial membrane (synovioma), mesothelial tissue (mesothelioma), osteous and cartilage tissue (osteoma, chondroma). Malignant growths from mesenchyma. Sarcoma, its types. Ways of sarcoma metastasis.
Neoplasms can be benign or malignant, though it is not always easy to tell how a neoplasm will act based upon gross or even microscopic appearances. Here is a benign lipoma on the serosal surface of the small intestine. It has the characteristics of a benign neoplasm: it is well circumscribed, slow growing, non-invasive, and closely resembles the tissue of origin (fat).
At low power magnification, a lipoma of the stomach is seen to be well demarcated from the mucosa at the lower center-right. This neoplasm is so well-differentiated that, except for its appearance as a localized mass, it is impossible to tell from normal adipose tissue. Benign neoplasms are always well differentiated.
Here is the lipoma at high magnification. This is a good example of how a benign neoplasm mimics the tissue of origin. These neoplastic adipocytes are indistinguishable from normal adipocytes.
Mesenchymal tumors are tumors growing from tissues derivative mesenchyma: conjunctive, adipose, muscular, vascular, osteous, cartilage tissues, synovial membranes and serous tunics. These tumors do not have organ specificity and are found not as often as epithelial tumors.
Benign neoplasms can be multiple, as is shown in this uterus opened anteriorly to reveal leiomyomas of varying size, but they are all benign and well-circumscribed firm white masses. Remember that the most common neoplasm is a benign nevus (pigmented mole) of the skin, and most people have several. As a general rule, without additional transforming influences, benign neoplasms do not give rise to malignant neoplasms.
Non-malignant (benign) tumors of conjunctive tissue: fibroma (hard, soft) – is found in skin, ovaries, extremities, grow slowly, expansively; fibrous histiocytoma or dermatofibroma – is found in skin, subcutaneous fat; fibromatosises (desmoid), which have local-destructive infiltrative growth, but do not metastasis, occurs downstream fascias, angioneurosises. Non-malignant growths of adipose tissue: lipoma (fibrolipoma, angiolipoma, myelolipoma), hibernoma – tumor of brown fat. Non-malignant growths of muscles: leiomyoma – tumor of smooth muscles, the most often occurs in uterus; rhabdomyoma – tumor of transversal striated muscles, occurs mostly among children; granular cell tumor or Abrikosov's tumor localizes in tongue, skin, esophagus.. Non-malignant tumors of vessels: hemangiomas, including capillary angioma, cavernous angioma, glomal angioma (Barre-Masson tumor) – occurs on toes and fingers, non-malignant hemangiopericytoma, lymphangiomas. Tumors of synovial membrane are represented with synoviomas, which most of the authors attribute to malignant independently of morphologic structure. Among mesothelial tissue tumors the most often fibrous mesothelioma is seen. Osteous tumors include osteoma spongiosum and compact osteoma. Cartilage tissue tumors – chondroma – could be of two types: ecchondromas and enchondromas, as well as non-malignant chondroblastomas. Mesenchymal origin tumors include also giant-cell tumor.
Malignant growths of mesenchymal origin are called sarcomas from Greek word sarcos – meat and are found rarely. On the section tumors are of whitish-grey color, look like fish meat, these tumors metastasis mostly in hematogenous way. Fibrosarcoma occurs of conjunctive tissue, which depending on cataplasia level could be differentiated and poorly differentiated, as well as malignant histiocytoma. Malignant tumors of adipose tissue – liposarcomas and malignant hibernomas grow rather slowly and do not metastasis for a long time. Among liposarcomas the following are recognized: high differentiated, myxoid, round cell polymorphonuclear sarcoma. From muscles malignant leiomyoma, malignant granular cell tumor and malignant rhabdomyoma occurs. Malignant growths from vessels – angiosarcomas develop from endothelium and pericytes – malignant hemangioendotelioma hemangiopericytoma, lymphangioendotelioma, Kaposi's sarcoma. In joints malignant synoviomas are found, in peritoneum, pleura, pericardium – malignant mesothelioma. In bones osteogenic and osteolytic sarcomas develop as well as Ewing's sarcoma, and in cartilage tissue - chondrosarcomas.
The microscopic appearance of this leiomyoma (a neoplasm arising from smooth muscle) indicates that the cells do not vary greatly in size and shape and closely resemble normal smooth muscle cells.
Multiple adenomatous polyps (tubulovillous adenomas) of the cecum are seen here in a case of a genetic syndrome in which an abnormal gene mutation leads to loss of control of cellular growth with development of multiple neoplasms in the colonic epithelium. The genetic abnormalities that are present in neoplasms can be either inherited or acquired.
This schwannoma was resected from a nerve. This neoplasm arises from the Schwann cells that myelinate peripheral nerve fibers. Note the circumscribed nature of this benign neoplasm. Though benign, this neoplasm could cause dysfunction of the nerve by mass effect. [Image contributed by Jeannette J. Townsend, University of Utah]
The schwannoma is seen microscopically to be composed of spindle cells (like most neoplasms of mesenchymal origin), but the cells are fairly uniform and there is plenty of pink cytoplasm. These are characteristics for a benign neoplasm.
Here is a small hepatic adenoma, an uncommon benign neoplasm, but one that shows how well-demarcated a benign neoplasm is. It also illustrates how function of the normal tissue can be maintained, because this adenoma is making bile pigment, giving it a green color with formalin fixation.
Nomenclature and morphological features of nervous tissue tumors. Features of CNS tumors Nomenclature of tumors derived from melanin-producing tissue. Morphological features of tumors derived from melanin-producing tissue.
Tumors of central nervous system: neuroectodermal (astrocytic, oligodendroglial, ependymal, tumors of choroid epithelium, neuronal, poorly differentiated and embrional), meningovascular. Clinical features and peculiarities of metastasis.
Tumors of vegetative nervous system. Tumors of peripheral nervous system.
Significance of pretumor changes. Nevuses, their variety. Melanoma, its clinicopathologic forms.
Tumors of neural tissue. Neural tissue tumors have a number of clinical peculiarities: referring to their course practically all of them are malignant independent of their morphological characteristic as they press neighbour portions of cerebrum, their extension goes on in the limits of neural tissue without distant hematogenous metastases. Nervous system tumors are distributed into neuroectodermal and meningovascular.
Neuroectodermal are divided into astrocytic, oligodendroglial, ependymal tumors of choroid epithelium, neuronal, poorly differentiated and embrional. Astrocytic tumors could be non-malignant (benign) – astrocytoma (fibrillar, protoplasmatic, fibrillar-protoplasmatic) and malignant – astroblastoma, and occur in any part of cerebrum. Oligodendroglial tumors are represented with oligodendrogliomas and oligodendroglioblastomas. Ependymal tumors include ependymomas, ependymoblastomas, chorioidpapillomas and chorioidcarcinomas. Among neuronal tumors the following is differentiated: ganglioneuroma or gangliocytoma, ganglioneuroblastoma, neuroblastoma. Poorly differentiated and embrional tumors include medullary blastoma (the most often is found in cerebellum and among children) and glioblastoma (occurs among adults in white substance, second by frequency, grows fast and causes death).
Meningovascular tumors develop from cerebral membranes and are represented with meningiomas and meningial sarcomas. Meningiomas could be arachnoidendotelial and fibrous. Meningial sarcoma by its histological picture looks like fibrosarcoma.
Tumors of peripheral nervous system, which develop in most cases from nerve sheathes are separated. They include neurinomas (Schwannomas), neurofibromas, neurofibromatosis (von Recklinghausen's disease) and neurogenic sarcomas.
Tumors of melanincreating tissue develop from cells of neuroectodermal origin – melanocytes, which are located in basal layer of epidermis, hair follicles, soft cerebrum membranes, eye retina and cornea. Melanocytes could be a source of tumor-like lesions – nevuses and malignant growthes – melanomas. Nevuses are found in skin of face, extremeties and other parts of the body in the form of dark protruding lesions. They could be of several types: epidermic-dermic (junction) nevus, intradermal nevus, complex (mixed) nevus, epithelioid or spindle-cell (juvenile), blue. Melanomas (melanoblastomas) mostly occur among females and are found on skin, pigment choroid, cerebral layer of adrenal glands, cerebral membranes. They grow in the form of a node or with surface extention. Melanoma, as a rule, looks like brown spot with red or black impregnations, bluish-black soft node or plaque. In cells cytoplasm melanin of yellow-brown color is found often, nevertheless sometimes pigmentless melanomas are found. Melanoma gives hematogenous and lymphogenous metastases early. Melanomas development is often connected with high
solar irradiation. Sometimes melanomas occur in the place of pigment formations, Lentigo maligna, dysontogenetic nevus, congenital giant nevus.
A malignant neoplasm is composed of cells that look less like the normal cell of origin. It has a higher rate of proliferation. It can potentially invade and metastasize. Malignant neoplasms derived from epithelial cells are called carcinomas. Those derived from mesenchymal (connective tissue) cells are called sarcomas. Malignant brain neoplasms and neoplasms of the immune system are special categories with complex nomenclature.
Thus, characteristics of malignant neoplasms include:
More rapid increase in size
Less differentiation (or lack of differentiation, called anaplasia)
Tendency to invade surrounding tissues
Ability to metastasize to distant tissues
Cytologic features of malignant neoplasms include:
Increased nuclear size (with increased nuclear/cytoplasmic ratio--N/C ratio).
Variation in nuclear or cell size (pleomorphism).
Lack of differentiation (anaplasia).
Increased nuclear DNA content with subsequent dark staining on H and E slides (hyperchromatism).
Prominent nucleoli or irregular chomatin distribution within nuclei.
Mitoses (especially irregular or bizarre mitoses).
All of these features are "atypical" microscopic findings. Atypia implies a change for the worse from normal.
Spread of Malignant Neoplasms
By direct extension (invasion) into surrounding tissues.
Through lymph channels to lymph nodes (lymphatic spread)--typical of carcinomas.
Via the bloodstream (hematogenous spread)--typical of carcinomas or sarcomas.
Within body cavities (seeding)--typical of neoplasms impinging upon body cavities, such as the peritoneal cavity.
In contrast, this hepatocellular carcinoma is not as well circumscribed (note the infiltration of tumor off to the lower right) nor as uniform in consistency. It is also arising in a cirrhotic (nodular) liver.
This renal cell carcinoma demonstrates distortion and displacement of the normal renal parenchyma by the tumor mass in the lower pole of this kidney. This malignant neoplasm has a variegated appearance on its cut surface, with yellow to white to red to brown areas.
This excision of skin demonstrates a malignant melanoma, which is much larger and more irregular than a benign nevus. From the history provided by the patient, we know that it grew quickly in size in 3 months. In contrast, a benign nevus hardly seems to change at all over many years.
Malignant neoplasms are also characterized by their tendency to invade surrounding tissues. Here, the tan tissue of a lung cancer is seen to be spreading along the bronchi into the surrounding lung. The dark round areas are lymph nodes also involved by the neoplasm.
This is a squamous cell carcinoma of the lung. It is a bulky mass that invades into surrounding lung parenchyma. This carcinoma involves large bronchi, which could produce signs and symptoms: cough, hemoptysis. Unfortunately, such signs and symptoms often occur when the cancer has reached a large size, making it more difficult to treat.
This infiltrating ductal carcinoma of the breast is definitely infiltrating the surrounding breast. The central white area is very hard and gritty, because the neoplasm is producing a desmoplastic reaction with lots of collagen. This is often called a "scirrhous" appearance. There may also be focal dystrophic calcification giving the cut surface a gritty texture.
Production of connective tissue stroma by a neoplasm is often what makes it appear firm on palpation. With invasion, this stroma may attach the cancer to surrounding structures so that it does not move freely with palpation.
Microscopically, this infiltrating ductal carcinoma of breast extends irregularly through the stroma as cords and nests of neoplastic cells with intervening collagen. There is a purplish microcalcification at the lower center right. Neoplastic cells are not as robust or as organized as normal cells and are more likely to undergo necrosis. Dystrophic calcification can occur in these areas.
At high magnification, this infiltrating ductal carcinoma of breast has pleomorphic cells forming small nests and irregular glandlike structures. The carcinonma cells infiltrate through the collagenous stroma. Note the abundant pink collagen bands from desmoplasia, which makes the tumor feel firmer than normal surrounding breast tissue on palpation.
Microscopically, invading adenocarcinoma can be seen here. Normal gastric epithelium at the left merges with the carcinoma at the right, and irregular neoplastic glands infiltrate downward into the submucosa. The surface of the carcinoma would appear grossly irregular and ulcerated, compared to the normal epithelium.
Branches of peripheral nerve are invaded by nests of malignant cells. This is termed perineural invasion. This is often the reason why there is pain associated with cancers and why that pain is unrelenting.
The concept of differentiation of neoplasms is demonstrated by this small benign adenomatous polyp (tubular adenoma) of the colon. Note the difference in staining quality between the epithelial cells of the adenoma at the top and the normal glandular epithelium of the colonic mucosa below. The neoplastic glands do not look exactly like the normal glands, but they are recognizable as glands, and would still be termed well differentiated.
In regard to differentiation, neoplasms range from well-differentiated to moderately differentiated to poorly differentiated. In general, less differentiation means that the neoplasm is more likely malignant and more likely to be aggressive. However, differentiation is just one of many variables that point to the potential biologic behavior of neoplasms.
At high magnification, the normal colonic epithelium at the left contrasts with the atypical epithelium of the benign adenomatous polyp (tubular adenoma) at the right. Nuclei are darker and more irregularly sized and closer together in the adenomatous polyp than in the normal mucosa. However, the overall difference between them is not great, so this benign neoplasm mimics the normal tissue quite well and this neoplasm is, therefore, well-differentiated. However, this lesion could serve as a precursor for adenocarcinoma with further growth.
The infiltrating glands of this colonic adenocarcinoma demonstrate less differentiation than the adenomatous polyp, although they still resemble glands. In general, less differentiation of a neoplasm means a greater likelihood of malignant behavior. This is the basis for histologic grading of malignant neoplasms. The less differentiated, the higher the grade, and the more aggressive the malignant neoplasm is likely to be. (Benign neoplasms aren't graded, since by definition they are well-differentiated.)
This gastric adenocarcinoma is positive for cytokeratin, with brown-red reaction product in the neoplastic cell cytoplasm, with immunohistochemical staining. This is a typical staining reaction for carcinomas and helps to distinguish carcinomas from sarcomas and lymphomas.
Immunohistochemical staining is helpful to determine the cell type of a neoplasm when the degree of differentiation, or morphology alone, does not allow an exact classification. Traditionally, the tumor cell morphology on light microscopy has been used to predict tumor behavior and prognosis. Further developments in molecular biology provide additional methods to determine tumor cell characteristics that can indicate how the tumor will act, how it can be treated, and what the prognosis for the patient may be.
The normal squamous epithelium at the left merges into the squamous cell carcinoma at the right, which is infiltrating downward. The neoplastic squamous cells are still similar to the normal squamous cells, but are less orderly. This is a well-differentiated squamous cell carcinoma, because the neoplastic cells still have many features of the squamous cell of origin.
Here is a moderately differentiated squamous cell carcinoma in which some, but not all, of the neoplastic cells in nests have pink cytoplasmic keratin. In general, neoplasms with less differentiation are more aggressive, growing more quickly, invading, or metastasizing.
At high magnification, this squamous cell carcinoma demonstrates enough differentiation to tell that the cells are of squamous origin. The cells are pink and polygonal in shape with intercellular bridges (seen as desmosomes or "tight junctions" by electron microscopy). However, the neoplastic cells show pleomorphism, with hyperchromatic nuclei. A mitotic figure is present near the center.
What is the significance of mitotic figures in a neoplasm? In general, their appearance suggests a higher rate of cellular proliferation. Mitoses certainly are present in normal tissues (surface epithelia are constantly regenerating, and hematopoiesis produces billions of new blood cells each day). However, the presence of mitoses, and particularly abnormal mitoses, in a mass lesion supports a diagnosis of neoplasia, and likely a malignant neoplasm.
This neoplasm is so poorly differentiated that it is difficult to tell what the cell of origin is. It is probably a carcinoma because of the polygonal nature of the cells. Note that nucleoli are numerous and large in this neoplasm. Neoplasms with no differentiation are said to be anaplastic.
Atherosclerosis and arteriosclerosis
Ischemic heart disease classification, clinical-morphological description. Myocardial infarction: causes, classification, dynamics of morpho-functional manifestations in myocardium.
Atherosclerosis is a chronic disease due to breach of fatty and albuminous substances exchange/metabolism. On determination of WHO, atherosclerosis is “various combinations of changes of internal membrane of arteries, which shows up as a focus laying of lipids, difficult connections of carbohydrates, elements of blood and circulatory in it matters, the formation of the connecting tissue and laying of calcium”. Atherosclerosis damages vessels of elastic and elastic-muscular types. According to prevalence, it occupies the first place in cardio-vascular pathology. Recent epideMyological data reveals a high occurrence in highly developed countries. It occurs mainly in people of mature age - after 30-35.
Etiology. It is a polyetiologic disease. There are a number of risk factors which are instrumental in the increase of the level of atherogenic lipoproteins in blood and their penetration into the walls of vessels: arterial hypertension, diabetes mellitus, obesity, hypodynamia, smoking, hyperlipidemia and dyslipoproteinemia, inherited inclination, age, sex (more frequently occurs in men), psychoemotional overstrain, etc.
There are some theories of the development of atherosclerosis : the infiltrative theory of Anichkov, the nervous metabolic theory of Myasnikov, the immunological theory of Klimov and Nagornev, the viral theory, the gerontology theory of Davidovskiy, the thrombogenic theory of Rokitansky.
Pathogenesis. The pathogenetic essence of atherosclerosis consists of the formation of lesions of atherogenic lipoproteins in the intimae of arteries of in response to the damage of the endothelium.
Lipoproteins are spherical particles which consist of a core and an external membrane. In the complement of core are triglycerides and esters of cholesterol, in the complement of external membrane are protein (apoproteins), phospholipids and unesterified cholesterol. Four classes of lipoproteins circulate in blood, which differ in sizes and maintenance of cholesterol and albumens - chylomicrons, lipoproteins of very low and high density. Atherogenic are considered to be lipoproteins of very low and low density, which contain the large supply of cholesterol (to 45%) and little apoprotein. Lipoproteins of high density in contrast, have much apoprotein (55%) and comparatively little cholesterol (16%). They execute an antiatherogenic function, that prevents the development of atherosclerosis.
Pathological anatomy. In the development of atherosclerosis four stages are distinguished –the prelipid stage, the stage of lipid spots, the stage of fibrous plaques(atheroma) and the stage of the complicated defeats (ulceration, calcinosis, thrombosis).
The prelipid stage is characterized by such processes, as the loss of glycocalix - protective polysaccharide layer of endotheliocytes, the expansion of intraendothelial cracks, the activation of endocytosis in endothelial cells. Intima swells up. In the subendothelial space, lipoproteins begin to penetrate from plasma of blood in increasing amounts.
The main transport form of cholesterol is lipoproteins of low density. They transport cholesterol from liver to the cells of organism. The mechanism by which cholesterol is transported into the cell, which is receptor-mediated, is called endocytosis. Parenchymatous cells and connective tissue types (fibroblasts, fibres of smooth muscles of arteries) capable of binding lipoproteins of low density have specific receptorson their surfaces(apo-v, Å-receptors). This co-operation takes place in the area of the special diaphragm structures, adopted by the coated pits. After co-operating with the particles of the lipoprotein the coated pits invaginate and fuse, forming bordered endocytic vesicle. They contact with lysosomes and fuse. The released cholesterol is utilized for the necessities of the cell, for example for the synthesis of membranes and hormones. Receptor-mediated endocytosis is regulated by the mechanism of feed-back. At the increase of cholesterol the quantity of Apo-v diminishes in a cell, Å-receptors on its membrane, and fusion of lipoproteins is limited. That is why there is no transport of cholesterol by receptormediated way to its accumulation in the cytoplasm.
It has been lately proved that in the genesis of atherosclerosis a leading role is played not by native lipoproteins of low density, but by their modified variants. Name such change of structure of Lipoprotein particle modification, when it stops to be recognized Apo-v, by the Å-receptors of fibroblasts and other cells and is not taken in by them. The modification of lipoproteins takes place in blood and vascular wall. To the major modified forms belong:
à) glycosylated lipoproteins , to which glucose was added;
b) peroxide-modified lipoproteins, which appeared under action of free radicals and products of peroxide oxidization of lipids;
c) autoimmune complexes of lipoproteins antibodies;
d) lipoproteins , that were partially degraded bt the action of proteolytic enzymes.
Modified lipoproteins, which entered the subendothelial space from blood or appeared in a vascular wall, carry with them macrophages. On the surface of these cells, next to typical Apo-B and E-receptors, are located receptors to the other type, adopted phagocytes -receptors. phagocytosis - absorption of modified lipoproteins greatly differs from endocytosis of native lipoproteins , mediated through Apo-B and E-receptors. This mechanism is not regulated by the principle of feed-back regulation that is why a high amount of lipoproteins of low density rich in cholesterol penetrates the Macrophages uncontrollably. The activity of lyzosomal enzymes becomes insufficient for the breaking up of the esters, and gradually the cytoplasm of macrophages becomes overfilled with lipid vacuoles with the accumulated esters of cholesterol. Under a microscope it looks like dots, that is why such cells are called foamy cells. The transformation of macrophaes to foamy cells is the irreversible stage of atherosclerotic process.
High density lipoproteins counteract the convertion of macrophages into foamy cells. They easily penetrate through the intimae, saturated cholesterol and likewise easily go back the into blood. Macrophages have on their surfaces, specific receptors for high density lipoproteins. The particles of lipoproteins after binding to the receptors are taken in, but are not broken by the enzymes of lysosomes. Enriched in cholesterol, they leave the macrophages by the mechanism of exocytosis and migrate to a blood-stream. Removal of cholesterol by this mechanism is important for those cells which take in modified lipoproteins through apo-B,E-receptors, that are uncontrolled. Purging them of surplus cholesterol, high density lipoproteinsslow development of atherosclerosis by such method.
Another characteristic morphological feature of atherogenesis is the proliferation of the cells of smooth muscles in the intimae of vessels. Myocytes migrate here from the middle layer of arteries (media) under action of factors of chemotaxis, and their reproduction depends on the growth factors - thrombocytic, fibroblastic, endothelial. The myocytes which migrated to the intima and began to propagate themselves transform from retractive cells into metabolically active ones. Without regard to the absence of scavenger -receptors, they acquire the property to take in modified lipoproteins and accumulate esters of cholesterol. Foamy cells also appear from them.
Lipid spots (strips) appear in different parts of the arterial system, but firstly, in the aorta. From cellular elements, foamy cells, T-lymphocytes and fibres of smooth muscles, prevail in them. In this stage, esters of cholesterol are mainly in cells. Around, there is insignificant excrescence of the connective tissue. Lipid spots do not hinder blood stream.
Foamy cells, overloaded with cholesterol, collapse in the course of time, and cholesterol is poured into the extracellular space. It irritates the surrounding tissues as an extraneous body and causes brief cellular proliferation at first, and afterwards - progresses to fibrosis. The accumulations of foamy cells and extra cellular lipids, embedded between elastic fibres, make light intima. Glycosaminglycans are replaced in it by γ-globulin and fibrin.
The fibres of smooth muscles which migrated into the intima from the media grow into secretory cells. They begin to increase the production of connective tissue proteins - elastin, collagen. Fibrotic tissue which surrounds lipid corpuscles like a capsule is formed from them. This structure is called the fibrous plaque. It is dense macroscopically, oval, white or whitish yellow color, and rises above the surface of the intimae. That part which bulges into the lumen of the vessel, is denser and that is why it obstructs the blood stream.
Fibrous plaques consist of amorphous mass, which tailings of elastic and collagen fibres, cholesterol, enter in the complement foamy cells are not blasted. If the processes of disintegration of plaques prevail over the formation of necrotic masses, then such plaques are called atheromatos. Foamy cells, lymphocytes, plasmocytes, newly formed vessels, accumulate on the periphery of the plaque. The lumen of the vessel is marked off *hyalinised* by the connective tissue (overlay of plaque). Complications begin on this stage.
Parietal blood clots often appear in the area of fibrous plaques. Their appearance is study theed by the ruptures of fibrous capsule of plaques, and also by the demage of the endothelium under them.
Ulceration of plaques - is also a frequent phenomenon. An ulcer has unequal edges, its bottom is formed by muscular layer or advevtitia. The defects of plaques are often covered by blood clots. If atheromatous masses get into the blood stream, they become the cause of brain embolism and embolism of other organs.
Another complication of fibrous plaques –is calcification (atherocalcinosis). This process is complete with atherosclerosis. Salts of lime are put aside in atheromatous masses, the fibrous tissue and intermediate matter between elastic fibres. Plaques attain stony consistency. The focus of calcinosis is localized mainly in abdominal aorta, coronary arteries and arteries of pelvis and thighs.
Rupture of aortic aneurysm
Depending on the localization of atherosclerosis, the following clinical-morphological forms can be distinguished: atherosclerosis of the aorta, atherosclerosis of the coronary vessels, atherosclerosis of arteries of the cerebrum, atherosclerosis of arteries of the kidneys, atherosclerosis of arteries of the intestine, atherosclerosis of arteries of the lower limbs.
Hypertensive disease (HI) or essential hypertension is a chronic disease with increase of arterial pressure. Symptomatic (Secondary) hypertension occurs at diseases of the nervous system, kidneys and vessels. Types of secondary hypertension also distinguished are: kidney (nephrogenic, renal vasculitis), endocrine (disease/syndrome of Icenko-Cushing, primary aldosteronism, to pheochromocytoma), neurogenic (trauma, tumor, abscess, hemorrhage in a cerebrum, defeat of hypothalamus and barrel of brain), vascular (coarctation of aorta, other anomalies of vessels, polycytemia).
Etiology and pathogenesis of hypertensive disease is not fully known.
That factor which needs to be considered as the starting one, as a result of
whose action arterial pressure begins to exceed critical border - 140 and
All factors which are able to increase the cardiac output or peripheral resistance or both simultaneously can be considered as the etiologic factors of hypertensive disease. To the majority of them belong: the increase of the volume of plasma, the increase of the cardiac output, the hyperactivity of the sympathetic nervous system, the breach of kidney functions.
Sympathetic hyperactivity -is one of the strongest factors of the development of the essential hypertension. This state affects the functions of some organs which can be considered as the targets of the sympathetic influencing. Except for the heart, arterioles, veins and kidneys belong here.
The pathological anatomy of hypertensive disease depends on its course which can be of high quality and malignant. In the first case there are three clinical-morphological stages – the preclinical or transient stage, the stage of widespread changes of arteries, or organic stage, and the stage of the second changes, or organ stage.
The transient (functional) stage clinically occurs as a periodic brief increase of arterial pressure, and morphologically - by the hypertrophy of muscular layer and hyperplasia of elastic structures of arteriole, the spasm of arteriole and moderate compensative hypertrophy of the left ventricle of heart.
The stage of widespread changes of arteries is characterized by constantly increased arterial pressure. Walls of small arteries and arterioles are in a state of proof reduction and hypoxia. Their permeability increases. Plasma enters the structures of vascular walls (plasmorrhagia), and the latter are destroyed. The elements of destruction, and also protein and lipids of plasma are removed through the wall by resorbtion, but as a rule, is incompleted, which results in the development of hyalinosis and arteriolosclerosis. The vascular wall becomes thickened, and the lumen of arteriole becomes narrower.
Atherosclerosis of the renal arteries
In large arteries, unlike the changes of arteriole mentioned above, elastofibrosis develops and atherosclerosis. Elastofibrosis is a compensative process for hypertension as hyperplasia and the ruptureing up of the internal elastic membrane of vascular wall. The development of atherosclerosis is related to the destruction of the vascular wall, accumulation of cholesterol and increased arterial pressure.
The typical clinical-morphological display of this stage is hypertrophy of the left ventricle of heart, and also dystrophy and necrosis of cardiomyocytes.
The stage of the secondary or organ changes is characterized by the destructive, atrophic and sclerotic changes of internal organs. There is diffuse smallfocus cardiosclerosis in the hypertrophied heart, in kidneys arterial sclerotic nephrosclerosis develops or initially wrinkled kidneys which are symmetrically diminished and have a dense consistency, with small tuberositas on the surface and the thickening of the cortical layer on section. Microscopically, the bulge of the afferent arteriole appears which expresses hyalinosis, sclerous and hyalinous, glomerular tubules are obsolete and the stroma is scleroused.
For the malignant clinical course of hypertensive disease such characteristic as frequent hypertensive crisis is present (it is a acute increase of arterial pressure, which occurs as a result of the spasm of arteriole). The morphological sign of crisis is goffering and the destruction of basal membrane, location in endothelium of paling, plasmarrhagia, fibrinoid necrosis of walls of arteriole and thrombosis. Myocardiac infarctions and hemorrhages develop in internal organs.
Cause of myocardial infarction.
Thrombosis of coronary artery, microscopic
Depending on the predominance of structural alteration of vessels in a certain pool and relation to its clinical-morphological changes, there are kidney, cerebral and cardiac clinical-morphological forms of hypertensive disease.
The kidney form of hypertensive disease is characterized by acute and chronic displays. Before acute displays, which removes the main malignant character of the disease, occurs myocardiac infarction, arterionecrosis and capillarnecrosis of the glomerules of kidneys. The latter can cause acute kidney insufficiency. Sometimes arteriole- and capillarnecrosis are transitory (malignant is chronic).
Chronic displays are expressed by the development of the initially wrinkled kidney. Thus the majority of nephrons due to insufficient blood supply become atrophied and scleroused, those are the small areas of microcavities macroscopically. Other nephrons are compensately hypertrophied and appear above the surface of kidneys as grey-red granules. Kidneys become dense, their surface is fine-grained, the cortical layer is thin, and its capsule is taken off with difficulty.
The cerebral form of hypertensive disease forms the basis of cerebro-vascular diseases, and cardiac - togester with the cardiac form of atherosclerosis - ischemic heart diseases.
The causes of death of hypertensive disease can be hemorrhages in the cerebrum, myocardiac infarctions, malignant nephrosclerosis and excavation of aorta.
Ischemic heart diseases name the breach of the heart functions, as a result of absolute or relative insufficiency of coronary blood supply. In connection with large social meaningfulness of this pathology it is selected IHO in independent nosology unit*. Ischemic heart disease is revealed in arrhythmias, ischemic dystrophy of myocardium, myocardial infarction , cardiosclerosis. It occurs mostly in men above 50 years and occupies the first place in invalidisation and death rate of patients with cardio-vascular pathology. Ischemic heart disease pathogenetically is related to atherosclerosis and hypertensive disease and is basically the cardiac form of these diseases having the same risk factors. Other defects of the coronary arteries, in particular at rheumatism, periarteritis nodosa can lead to ischemic heart disease.
Etiology and pathogenesis, risk factors. Direct causes of ischemia of heart are more frequently spasm, thrombosis or embolism of coronal arteries, and also functional overload of the myocardium in the conditions of sclerotic occlusions of these vessels. But these are only local factors of ischemia and necrosis of cardiac muscle. In the origin of ischemic disease as a cardiac form of atherosclerosis and hypertensive disease an important role is played by the following conditions hyperlipidemia, arterial hypertension, obesity,hypodynamia, smoking, diabetes mellitus and gout, chronic emotional overstrain, inherited inclination. At combination for the same person during 10 of such factors, as hyperlipidemia, arterial hypertension, smoking and surplus mass, there will be ischemic heart diseases in the half of cases.
Ischemic heart diseases has undulating motion. In the background there is chronic (relative) insufficiency of coronal blood circulation, there are flashes of acute (absolute) insufficiency. That is why we distinguish the acute and chronic forms of ischemic heart diseases. The acute form shows up ischemic dystrophy of myocardium of -stenocardia (Angina Pectoris) and myocardiac infarction (by necrosis) of myocardium, chronic - cardiosclerosis. The latter is diffuse small- and largfocus and postattack largfocus. Sometimes cardiosclerosis is complicated with chronic aneurysm of heart.
Subendocardial myocardial infarction
It is known that providing of myocardium blood for a healthy man is carried out the system functionally eventual arteries. The diameter of anastomoses between right, middle and left coronal arteries does not exceed 40 mkm, collaterals are not developed. At the time of physical training blood supply of myocardium is provided due to hyperemia of intraorganic branches of coronal vessels. Hyperemia is caused by metabolits that appear during activating of tissue exchange. In addition, metabolic expansion of coronal arteries is combined with the oppression of sensitiveness of a-adrenoreceptors to the vasoconstrictors influencing. Due to these mechanisms the increase of volume speed of coronal blood flowing always answers the growings requirements of myocardium in oxygen.
Patients with the stenous sclerosis of coronal arteries have the continuous piling up of vasoactive metabolits in the focus of ischemia that exists permanent dilatation vessels of microcirculatory river-bed, which diminishes their functional reserve. These vessels are not able to provide the increase of volume speed of coronal blood flowing the physical training. For patients with atherosclerosis even in the conditions of rest there is a deficit of blood supply of myocardium. Morphologically it reminds a mosaic, built of normal cardiomyocytes and cardiomyocytes with changed structure and function (dystrophy and necrosis - in one, hyperplasia - in other places). Clinically it shows up such characteristic as pains and electrocardiography changes, however enzymemia (increase of activity of transaminase, lactatdehydrogenase and other enzymes in blood), which testifies to the presence of myocardiac infarction is absent. This state is called stenocardia (Angina Pectoris). We distinguish its unstable and stable forms.
Morphologically stenocardia (Angina Pectoris) is characterized by ischemic dystrophy of myocardium. It is flabby, in the focus of ischemia, pale and filling out. Histologically we find out paresis of vessels, sometimes fresh blood clots, interstitial is swollen, red corpuscles stasis, the disappearance of transversal banding cardiomyocytes, diapedesis hemorrhages. Electronic - microscopic and histochemical changes are taken to diminish the amount of granules of glycogen, the swelling and destruction of chondriosome and tubules of sarcoplasmatic net. These changes are conditioned by the breach of the tissue breathing, the strengthening of anaerobic glycolysis, breaking up of breathing and oxidizing phosphorilation. In development of destructive changes of cellular organelles an important role is played by disengaged catecholamines and to the changed water-electrolyte exchange (loss of magnesium, potassium and phosphorus but piling up of sodium, calcium and water).
Long durated coronal spasm, thrombosis or occlusion of coronal vessels are causes of the transition of ischemic dystrophy of myocardium at the time of myocardiac infarction. Myocardial infarction is circulatory ischemic necrosis of cardiac muscle that is why, except for the changes of electrocardiogram, enzymemiya is typical for it. Morphologically it is ischemic myocardiac infarction with hemorrhagic crownom. It is classified by the time of origin, by localization, distribution and motion.
Complete necrosis of cardiomyocytes is formed within a day. At first myocardium in the pool of the damaged artery is flabby, unevenly vascularity. Histologically the accumulations of leucocytes appear in capillaries, emigration of them, diapedesis hemorrhages, relaxation of cardiomyocytes, the disappearance in the latter of glycogen and oxide restoration enzymes. During the following hours the outlines of fillings out cardiomyocytes become wrong, transversal banding disappears.
Macroscopically the area of a myocardiac infarction expressly appears only through 18-24 hours after the origin of disease. A necrotic area acquires grey-red color, it is limited by the ribbon of hemorrhage and something comes forward above the surface of section as a result of edema. The phenomenon of edema disappears in subsequent days, necrotic tissue falls back, becomes dense, yellow grey. On periphery a demarcation billow which consists of leucocytes is formed, fibroblasts and Macrophages. The latter take part in resorbtion of dead masses, lipids and tissue detritus accumulate in their cytoplasm. Fibroblasts take part in fibrinogenesis. The process of organization of myocardiac infarction lasts for 7-8 weeks. The connecting tissue germinates from the area of demarcation from the round of the stored tissue in the area of necrosis. Newformed connecting tissue at first is magnificent, as granulation, afterwards passes in rough fibrose. In it and round it islands of hypertrophied cardiomyocytes appear. Investigation of this process is the formation of a dense scar – the morphological basis of postattack largefocus cardiosclerosis.
The acute myocardial infarction has the most frequent complication as cardiogenic shock, fibrillation of ventricles, asystole, acute cardiac insufficiency, Myomalation, acute aneurysm and rupture of heart, parietal thrombosis and pericarditis.
There is melting of myocardium in the cases of predominance of autolisis of dead tissue - Myomalation. Myocardium in these cases is helpless to counteract interventricle pressure of blood. Wall of heart is thickeningand knobs outside, that results in formation of additional cavity - aneurysm of heart. Compensately parietaly blood clot appears in it. It covers the tears of endocardium and strengthens durability of wall. At insufficient thromboformation blood penetrates under endocardium and necrotic tissue what conduces hearts to the rupture. Blood is outpoured in the cavity of cardiac shirt (hemopericardium). Parietal blood clots arise up mainly at transmural and subendocardial myocardiac infarctions. They can be the source of embolism, for example, of kidney vessels.
At subepicardial and transmural myocardiac infarctions there is the reactive exudative inflammation - fibrinous pericarditis often enough
Cardiosclerosis makes the structural basis of chronic ischemic heart diseases. It can be atherosclerotic diffuse smallfocus or can be developed at hypertensive disease, and also postattack largfocus. The first form is related to hypoxia of myocardium. The connective tissue replaces the places of dystrophy, atrophy and dead cardiomyocytes, and also overgrows in perivascular spaces. Macroscopically such cardiosclerosis is presented as white perivascular layers and narrow ribbons in all layers of heart muscle.
The organization of myocardiac infarctions is completed by largefocus cardiosclerosis. Sometimes it is the vast fields of connecting tissue, which take all layer of wall of heart. In such cases it is thinned and knobs under pressure of blood - an aneurismatic sack appears.
At the time of chronic ischemic heart diseases constantly there are terms for development of the repeated myocardial infarction with all characteristic complications.
Cardiogenic shock, fibrillation of ventricles, asystole, acute cardiac insufficiency, come forward in the early period of myocardiac infarction direct causes of death. In the course of time the first place will be taken up by the rupture of heart and thromboembolia of vessels of cerebrum. At the time of chronic ischemic heart diseases death is caused by cardiac insufficiency, thromboembolic complications and rupture of wall of aneurysm.
Cardiomyopathy is an disease with the insufficient retractive function of cardiomyocytes as a result of dystrophic changes of myocardium, which are unconnected with coronal blood circulation or rheumatic defeats.
Classification. Cardiomyopathy is divided into primary (idiopathic): dillatation (congestive), hypertrophy (constrictive, obstructive), restrictive; but the second: intoxication (alcohol, salts of heavy metals, uremia)infectious, exchange inherited (amyloidosis, glycogenosis) and acquired (thireotoxicosis, gout, hyperparathireosis, avitaminosis), alimentary (malabsorption, cirrhosis of liver).