Metastasis

Metastasis (from Greek metastasis - rearrangement, transfer), a term used to denote the transfer of a certain pathological material from one place in the organism to another. The term M. equally applies to the focus of the pathological process that has formed as a result of such a transfer. The concept of M. has much in common with the concept of embolism; one can in particular say that those M. that are based on the transfer of material by the current of blood or lymph are subject to the same laws as embolism. The difference between embolism and M. consists mainly in that embolism represents the transfer of particles that occlude arterial branches or capillaries, which has purely mechanical significance, whereas in M. the transferred particles in most cases are so small that they have no mechanical significance and do not cause occlusion of vessels; at the same time, in M. the quality of the transferred material is often such that a pathological change of tissue develops at the place of its detention. The closeness between embolism and M. is also manifested in the possibility of combining what is characteristic of embolism with consequences belonging to M.; thus, it happens that an embolus causes occlusion of an artery and corresponding mechanical consequences (e.g., formation of an infarct), and subsequently in connection with the qualitative features of the embolus in this place a pathological process develops that belongs to M.-The material transferred in M. can represent something living, which, being brought to a new place, causes in it a pathological process analogous to the process that exists in the place, primary for M. On the other hand, in M. non-living material can be transported in the form of dense particles or even dissolved substances. The metastasis of living material concerns the transfer of 1) microorganisms and 2) tumor cells. 1. Of microorganisms, M. most often concerns bacteria, and usually it is a matter of the presence in the organism of a pathological focus from which bacteria are transported by the current of blood or lymph to new places. Such pathological foci, which are the primary sites for bacterial M., can be various abscesses, phlegmons, purulent inflammations of cavity organs, pneumonias, endocarditis, appendicitis, septic postpartum endometritis, purulent otitis, gonorrheal inflammation of the sexual organs, anginas, tuberculous lesions of organs, and many others. M. from such foci occurs because the corresponding bacteria, the causative agents of this process, in the area of the pathological focus penetrate into the current of blood or lymph; this can happen by the direct introduction of individual bacteria, free or enclosed in phagocytes, into small veins or into lymphatic spaces, or by the destruction of the wall of the corresponding vessel by the pathological process, or finally by the involvement of the vessel wall in the pathological process and thrombosis of its lumen (thrombophlebitis and thrombolymphangitis); in the latter type of cases, thrombotic masses containing bacteria undergo softening and disintegrate or are washed away by the current of blood, whereby a very large number of bacteria may appear in the blood or more often in the lymph. The M. themselves are formed as a result of the detention on the inner surface of a vessel or in a capillary of the new place or in the sinuses of lymph, glands of individual bacteria or the carrying of a group, colony of microorganisms in the form of a bacterial, mycotic embolus; if such bacteria that have become stuck in the new place do not perish but multiply, then a reaction of the surrounding tissue arises, expressed in an inflammatory process, in character in most cases corresponding to the inflammation that exists in the pathological focus that was the source of M. There are exceptions to this rule, e.g., in the form of the appearance of purulent inflammation in M. in the case of fibrinous inflammation in the main pathological focus. In thrombophlebitis, the transfer of a considerable portion of thrombus containing bacteria often occurs; then an infarct can first arise, which subsequently turns into a focus of corresponding inflammation (purulent, tuberculous). In some cases, in the place of M. bacteria cause a change in the vessel leading to the formation of an acute aneurysm (e.g., mycotic aneurysms in sepsis lenta). Under all the above-mentioned conditions, the transfer of bacteria is the basis for the formation of new foci of the inflammatory process, which are called foci of metastatic inflammation. The character and type of these foci can be different. In some cases, limited metastatic foci are formed; this includes the formation of metastatic abscesses, which are either miliary or larger foci of suppuration caused by the transfer of pyogenic bacteria, as well as the formation of tuberculous tubercles in M. of tuberculous bacilli. In other cases, M. of bacteria gives inflammation spreading over a larger territory of an organ, e.g., metastatic pneumonias in septic diseases. Finally, in M. of bacteria into the walls of serous cavities, inflammation can arise that involves the entire given serous cavity; this includes inflammations of joints that arise as M. in gonorrhea and in sepses, purulent meningitis observed as metastatic inflammation e.g. in pneumonia, tuberculous meningitis, which is most often M. from the primary tuberculous complex in the lungs and in the lymphatic glands, peritonitis in angina, etc.-Besides bacterial M. that form from the main pathological focus, inflammatory foci of the M. type can also occur in the absence of such a focus; in such cases one can assume the introduction of bacteria into the blood through unnoticed damage to the skin and mucous membranes; however, in many of such cases it is more correct to think of the latent presence of microorganisms in some place of the organism (e.g. in the spleen) with subsequent metastasis to other organs. It must still be added that the entry of bacteria into the blood or lymph does not necessarily lead to the formation of metastatic foci. One must remember that the basis of the mechanism of formation of bacterial M. consists of four phases: a) entry of bacteria into the blood or lymph, b) settling of bacteria in one organ or another, c) multiplication of bacteria in the place of settling, d) reaction of the surrounding tissues giving the pathological process. The first of these phases does not always lead to the second, third, etc. Thus, bacteria that have entered the current of blood can perish there or circulate in the blood without being detained in any organs; microorganisms that have settled in an organ may not multiply and perish; finally, the settling and multiplication of bacteria in an organ may not be accompanied by an inflammatory reaction due to the peculiarities of the reactive properties of the organism. The fact is that the formation of M. is connected not only with the peculiarities of the main pathological focus but to a considerable degree depends on the general condition of the organism, on its specific immunity to these bacteria and the non-specific ability to reactive manifestations. A good example of the difference in the tendency of a process to give M. depending on the difference in the general immunobiological state of the organism is tuberculosis; in the primary period for the tuberculous process the formation of M. along the lymphatic and blood routes is even characteristic, whereas in secondary pulmonary phthisis in adults in connection with the relative immunity of the organism to tuberculosis M. of the process are rare. Bacterial M. can be single, but more often they are multiple; sometimes (in hematogenous metastasis) their number is extremely large; M. of this type give generalization of the pathological process. In those cases when bacterial M. arise from time to time giving an outbreak of the pathological process here and there, this can give the impression as if the disease is wandering through the organism; some forms of so-called migration of pathological processes are explained by such impulse-like M. of bacteria. Regarding the terminology of bacterial M., it must be said that besides terms with the adjective 'metastatic' (metastatic abscess, meningitis, arthritis, metastatic pneumonia) it is very common to use the term 'metastasis' with the addition of an adjective characterizing the etiology of M., e.g. gonorrheal M. (arthritis and abscesses caused by the transfer of Neisser's gonococci), tuberculous M. (tuberculous foci caused by the transfer of tuberculous bacilli), streptococcal M.; in other cases the corresponding adjective characterizes the patho-anatomical essence of M. (purulent M., putrefactive M.). If in the organism there is a primary focus of the infectious process and foci formed by the path of M., then the first is called the primary focus, primary infect, and the second-secondary, metastatic foci.-The metastasis of living causative agents of diseases can also concern animal parasites; this includes the transfer of trichinae, sporocysts (cysticerci), tapeworms, - bladders of the one-chambered and many-chambered echinococcus. In these cases around the transferred parasites a banal delimiting inflammatory reaction develops. The term M. is little used here. 2. M. of tumor cells represents the transfer of cellular elements of malignant neoplasms possessing infiltrating and destructive growth, mainly of cancer and sarcoma.

However, occasionally it happens that tumors, in structure corresponding to benign neoplasms (colloid goiters, chondromas, angiomas), also give rise to metastases. The basis of tumor metastasis is the penetration of cells or groups of cells that have separated from the main primary tumor nodule into the blood or lymphatic vessels, followed by their movement by the current of blood or lymph, or the implantation of tumor cells on a contacting surface or on the wall of any cavity (so-called implantation, see below). Where the displaced tumor cells stop, they may multiply, which gives rise to the formation of a tumor nodule at the new site, similar in character and structure to the primary tumor nodule. Such new tumor nodules formed as a result of metastases are called metastatic, secondary, or daughter tumor nodules. In general, the tendency of tumors to form metastases is associated with a large number of various conditions. The histological type of the neoplasm and its growth are of very significant importance; tumors of the medullary type, which grow rapidly, are more likely to give rise to metastases. Various local influences on the tumor can sometimes promote metastasis, for example, injuries, biopsy operations, X-rays; the general condition of the body is important both for the process of separation of cells from the tumor and for the further fate of these cells. In relation to the formation of metastases of tumors, it is necessary to emphasize the essential difference between them and bacterial and infectious metastases: this difference lies in the fact that in bacterial metastases, the development of the metastatic focus is based on the reaction of tissues to the introduced infectious agents, whereas in tumor metastases, the metastatic focus is formed only due to the multiplication of the introduced tumor cells and does not include the multiplication of local cells or any reactive changes from the local tissue elements (for more details on metastases of tumors, see Tumors). Speaking of metastases of tumor cells, it can be recalled that some attribute to normal epithelium the ability to take root and multiply in a new place when carried by the lymphatic current. Such benign metastases of epithelium, which form glandular cavities and passages at the site of transfer, can occasionally be observed in the mesenteric lymph glands in ulcerative processes in the intestine, in the pelvic and inguinal glands in diseases of the uterus; at present, however, many researchers consider this change not to be metastases, but a local change of the endothelium of the lymphatic pathways. Metastases of non-living material refer to the transfer by the current of blood or lymph of small dense particles or dissolved substances that precipitate in the tissues. 3. Dense particles transferred as metastases can be of endogenous and exogenous origin. The former include, for example, small grains of lime and fat decay washed out by the blood from atheromatous ulcers in arteries, products of disintegration of red blood cells, hemosiderin, malarial pigment; all these substances very rarely cause embolic occlusion of vessels; in most cases, circulating in the blood, they are gradually retained in the spleen, liver, bone marrow by elements of the reticulo-endothelium; these same materials, when transferred by the lymphatic current, are retained by the endothelium of the sinuses of the lymph glands. Of exogenous particles, metastases occur to particles of coal that have entered the lymphatic current, and subsequently the blood current, as well as other dusty materials (see Anthracosis, Pneumoconioses). All these substances are carried either free or enclosed in phagocytes. 4. Of the dissolved substances that are carried by the current of blood or lymph and precipitate out of solution in certain parts of the body and are deposited in the tissue, lime is of the greatest importance. With various disorders of calcium metabolism that result in an increase in the concentration of lime in the body fluids or a change in its solubility, lime begins to precipitate out of solution, which is called calcium metastases (see Calcium deposits, metastases). Of exogenous substances, colloidal silver (resulting from medicinal administration of silver salts) can circulate in the body in dissolved form, and it is deposited in the tissue as metastases in the form of the smallest grains of reduced silver (see Argiria). In all those cases where the transferred and deposited substance has the character of a pigment, it is customary to speak of pigment metastases. The deposition in the tissue of the above-mentioned non-living particles, if they belong to material that is chemically and physically indifferent, and the amount of deposited material is not large, may not be accompanied by any special reactive changes. If the deposition is significant or concerns material that is not indifferent, then reactive proliferation of connective tissue occurs in the sites of metastases. The pathways of metastases are of three kinds: 1) movement by the current of blood, 2) movement by lymph, 3) implantation. 1. Metastases moving by the current of blood through the blood vessels, i.e., hematogenous metastases, can refer to microorganisms, tumors, and non-living particles. The movement proceeds in the direction of the blood current, and the metastasizing material is usually retained where, along the course of the blood current, the vessel breaks up into a capillary network; more rarely, the material stops on the inner surface of a larger vessel. If the metastasizing material (bacteria, tumor cells) penetrates into the lumen of an arterial vessel, then metastatic foci are formed in the area of branching of this artery; an example of this can be local miliary tuberculosis in the lung. If bacteria and tumor cells in the area of the primary focus of the process penetrate, as is most often the case, into the veins of the systemic circulation, then they are carried into the right atrium, right ventricle, and through the pulmonary artery into the lungs, where the metastatic foci of the infectious process or metastatic tumor nodules are formed; thus, for example, metastatic abscesses in the lungs occur in purulent otitis, septic endometritis, phlegmon, etc., as well as metastases of many tumors, especially sarcomas. In those cases where the metastasizing material penetrates into the venous vessels that are the roots of the portal vein, it is carried and retained in the liver, where metastatic foci arise: these include metastatic abscesses of the liver in appendicitis, dysentery, metastatic nodes of cancer in the liver in cancer of the stomach, intestines. In the presence of a pathological focus in the left heart (endocarditis of the left heart valves), metastases occur along the arterial system of the systemic circulation; for example, in ulcerative endocarditis of the aortic or mitral valves, small metastatic abscesses can be found in the brain, kidneys, walls of the intestines, skin, etc. Metastases along the arterial system of the systemic circulation can be observed in the presence of a pathological focus in the lungs or mediastinum and penetration of the corresponding material into the pulmonary veins, from where it enters the left heart; thus, for example, it happens in the development of general miliary tuberculosis from a tuberculous focus in the lung or in a mediastinal lymph gland. In general, it should be noted that the most abundant formation of metastases, often spread throughout the body, is usually based on the penetration of pathological material into the pulmonary veins, the left heart, and the main trunks of the arterial system of the systemic circulation. It should also be borne in mind that in metastasis along the veins to the lungs and liver, not all the material is necessarily retained in these organs; not only bacteria but also tumor cells can pass through the capillaries of the lungs and liver; this explains those cases where on the path between the source of metastases and the arterial system of the systemic circulation lie the lungs or liver, and at the same time we see metastases in the organs of the systemic circulation. The same thing, however, can be observed in the form of so-called paradoxical metastases, analogous to paradoxical embolism; this name is applied to cases when material from the veins of the systemic circulation is transferred to its arterial system through an opening existing in the septum between the ventricles or atria of the heart (most often in the form of an unforgotten oval foramen), bypassing the lungs. An exception to the rule of transfer of hematogenous metastases in the direction of the blood current are retrograde metastases, which are based on the movement of material against the blood current, which occurs when the blood flow is weakened, especially in veins, in which the movement of blood has a direction from bottom to top (carrying of an embolus from the right heart into the hepatic or renal veins, from the inferior vena cava into the veins of the lower extremity). 2. Metastases moving by the current of lymph through the lymphatic vessels, i.e., lymphogenous metastases, concern exactly the same microorganisms, tumor cells, and non-living particles. Usually, the pathological material, having entered the area of the primary focus of the pathological process in the lymphatic vessels, is carried in the direction of the lymph current to the regional lymph glands, where it is retained in the sinuses. If it is a matter of non-living particles, then they are phagocytized by the cells of the sinus endothelium and in this form are deposited for one period or another in the gland; part of the material may pass through the first regional gland and be retained in the next gland, etc. With a significant accumulation in the gland, for example, of particles of coal pigment, induration of the gland tissue and obliteration of its sinuses occur.

If M. [metastasis] in a lymph gland involves pathological material, it becomes a source for the development of a pathological process in the gland; bacteria cause metastatic lymphadenitis of one character or another (suppurative, gonorrheal, tuberculous); when tumor cells are carried into the lymph glands, they begin to multiply in the sinuses and displace the elements of the gland, as a result of which a metastatic tumor node forms in the gland. Such M. [metastases] in the first regional lymph glands are called regional metastases. From the first regional glands, the pathological material passes to the following glands and so on, and the spread of the material through the lymphatic system can reach the great lymphatic duct (ductus thoracicus major); in such cases, as a result of the involvement of the walls of the thoracic duct (as occurs in tbc) or without it, the material enters the venous blood of the systemic circulation, and metastasis takes on a hematogenous character. In M. [metastases] in the lymphatic vessels, the possibility of retrograde M. [metastases], i.e., those that spread in the direction opposite to the normal flow of lymph, undoubtedly has great importance (much greater than in veins). Such M. [metastases] are observed mainly in cases when the lymph glands are affected by tumor M. [metastases]; this creates a stagnation of lymph, dilation of the lymphatic pathways, and consequently a disruption of their valve apparatus in the area from which these glands receive lymph; all this results not only in the cessation of the continuous movement of lymph but also in impulses of its reverse flow, which is the basis of retrograde M. [metastases]. This explanation applies to the small M. [metastases] of cancer scattered throughout the lymphatic pathways of both lungs (the so-called "cancerous lymphangitis of the lungs"), in cancerous metastatic involvement of the lymph glands of the lung hilus, as well as M. [metastases] of cancer in the ovary in cancer of the stomach (resulting from metastatic involvement of the retroperitoneal glands by cancer and retrograde M. [metastases] from them into the ovaries). However, retrograde M. [metastases] should not be confused with cases that are based on the continuous growth of a tumor along the lymphatic pathways (the so-called progressive cancerous thrombosis of lymphatic vessels), often going in the direction opposite to the normal flow of lymph. -As to the question under what conditions metastasis occurs hematogenously and under what conditions lymphogenously, it should be said that foci of infectious processes localized outside contact with large vessels, in the beginning of their development, give lymphogenous M. [metastases]; only with further development of the process do hematogenous M. [metastases] join. This is observed in various abscesses and phlegmons of the extremities, as well as in tbc of the lungs, which is even characterized by the fact that with primary infection, a focus appears in the lung and a very rapidly developing metastatic involvement of the regional lymph gland (the so-called primary tuberculous complex), and only then can hematogenous M. [metastases] follow. As for M. [metastases] of tumors, it is undoubtedly that carcinomas more often give their first M. [metastases] along the lymphatic pathways to the regional lymph glands, while sarcomas often metastasize along the blood vessels from the very beginning. M. [metastases] of non-living materials can occur hematogenously and lymphogenously - depending on the way they penetrate the body. 3. Metastasis by implantation implies the direct transplantation, or rather, inoculation, of pathological material from one place to another. - Operative implantation M. [metastases] are the result of the inoculation of particles of the tumor (German "Impfmetastasen") during one or another surgical intervention; this can occur during a puncture biopsy of a neoplasm, when particles of the tumor can be carried by the instrument into the normal tissues located above the tumor, as well as during the removal of soft, disintegrating tumors, when their particles during the operation of extirpation fall, for example, into the abdominal cavity, into the surgical wound, etc. The fate of M. [metastases] is largely connected with the nature of the pathological process that arose in the places of transfer of pathological material, and, naturally, with the nature of the transferred material itself. M. [metastases] caused by microorganisms can have very different fates; first of all, it should be noted that M. [metastases] in abundant metastasis of an infectious process, giving its generalization, may remain in the initial stage of development due to the rapid onset of death of the body. In those cases where separate M. [metastases] form, they usually undergo one or another course, in general analogous to the course of the main pathological process. Metastases of tumors - in the form of secondary nodes of neoplasms - usually possess the same properties as the main tumor in the primary node. Metastases of non-living material usually give slight reactive changes, acquiring the character of persistent fibrosis of the tissue; the deposited material can remain in its places of deposition for one or another time without any changes and only gradually undergo resorption. It should be added that the state of the body has not only minor importance for the formation of M. [metastases] (see above), but also for their fate; the development of pathological changes in each individual metastatic focus of an infectious process, as well as the growth of a tumor in its daughter nodes, can represent one or another variant depending on the state of nutrition of the body and its reactive abilities. There are known cases when the growth of a tumor in M. [metastases] intensified after large blood losses, and, on the other hand, there are observations that with improvement of the general condition associated with the removal of the primary node of a malignant tumor (for example, chorioepithelioma), its metastatic nodes underwent reverse development. The significance of M. [metastases] is very great. In general, the formation of M. [metastases] always aggravates the course of the pathological process. When the formation of multiple M. [metastases] of an infectious process occurs, giving a generalization of the disease in the form of, for example, pyemia or general miliary tbc, this usually leads to rapid death. The significance of individual M. [metastases] is different, and the localization of M. [metastases] plays an important role in this respect. It is self-evident that the formation of M. [metastases] in the brain has more serious consequences than M. [metastases] in the skin. The formation of M. [metastases] in the case of one or another tumor has very serious significance, as it represents a significant worsening of the course of the pathological process and in addition often makes almost hopeless any therapeutic (operative and radiation) measures.

A. Abrikosov