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Popular Science Monthly/Volume 84/January 1914/The Present Status of Cancer Research

THE PRESENT STATUS OF CANCER RESEARCH
By Dr. LEO LOEB

BARNARD FREE SKIN AND CANCER HOSPITAL, ST. LOUIS, MO.

IT is well known that all organisms, plants as well as animals, are composed of small units—the so-called cells—in which a nucleus is surrounded by protoplasm and certain special structures. Each part of the animal body is formed by aggregations of different kinds of cells. The skin and the cavities within the body as well as the glands are composed of epithelial cells, the bones and muscles are produced by special bone and muscle cells. Uniting the various special structures and cell layers in the body, we find the so-called connective tissue consisting of special cells (connective tissue cells) and their product, the connective tissue fibers.

In the normal adult organism some kinds of cells are entirely or almost at a standstill as far as their growth (increase in number and size of cells) is concerned, while other kinds of cells are continually propagating. However, as for each newly formed cell an old one is cast off, no actual increase in the number of cells takes place during adult life under normal conditions. If, however, a small part of the body, e. g., the skin, is removed, the neighboring cells begin to proliferate, and soon fill out the defect. We call this kind of growth regenerative. Very energetic cell proliferation of course is necessary for the transformation of an ovum into the fully developed young organism. This growth, which ceases as soon as the definite organism has been formed and the various organs have been differentiated, we call embryonic growth. A very interesting rapid cell proliferation takes place also in the uterus after the insertion of the ovum, leading to the formation of the maternal placenta.

In the normal adult organism, a definite equilibrium exists between the different kinds of cell aggregations which we call tissues. Each kind of cell respects the territory of the neighboring cells. Not rarely it happens however that suddenly in a young or adult organism cells in a certain part of the body begin to proliferate in an unusual manner; they multiply more or less rapidly. This growth can not be called regenerative, because there was no primary defect to be filled out, and if there had been such a defect the proliferation does not limit itself to wound healing. This multiplication of cells leads to a definite swelling in a-certain part of the body. We call it a tumor. The aggregation of newly formed cells may form a well-defined mass which simply pushes aside the neighboring parts of the body. After some time the growth may entirely cease or it proceeds usually slowly. In this case we speak of a "benign" tumor. In many other cases, however, the newly formed cells not only multiply, but they also invade the neighboring tissues either as isolated cells or in clusters of cells. Each cell which migrates in the neighboring territory becomes again the center for the formation of a new tumor inasmuch as it has the power for indefinite propagation. Other cells even invade the lymph or blood channels of the body, and are carried with the "lymph or blood stream to different parts of the body. At certain places they can not pass the narrow passages, they remain attached to the vessel wall, begin again to multiply, to break through the vessel wall into the neighboring tissue and produce at various places, often distant from the original site of the tumor, secondary tumors which are called metastases. This infiltrating, metastatizing tumor we call a malignant growth or a cancer. According to the kind of cells which form the cancer and according to the proliferative and infiltrative energy of the cells composing the growth we distinguish many varieties of cancer. There are morphological as well as physiological differences between different varieties of cancer. Eoughly we may however classify the various cancers in those derived from epithelial tissue (for instance of the skin, stomach, uterus, the various glands) which we call carcinomata and those derived from proliferating connective tissue cells. Connective tissue in any part of the body may give rise to cancer. These connective tissue cancers are called sarcoma. The growth of a cancer exerts injurious influences on the organism as a whole. Through pressure on neighboring organs it often interferes with important functions of the digestive, respiratory, excretory organs, and leads to serious disturbances of metabolism. It often breaks through the epithelial membranes of the skin or of the inner cavities of the body; under those conditions parts of the tumor die, break down, and are cast off; an ulcerative surface is thus produced which serves as a place where certain bacteria find a favorable culture medium; putrefaction takes place and the absorption of the putrid material further weakens the organism. But even without the formation of an ulcer, parts of the tumor which are under unfavorable conditions of nourishment constantly die (become "necrotic"), while neighboring parts continue to grow. The absorption of the necrotic material may also exert an unfavorable influence on the metabolism. It is furthermore very probable that the living tumor cells give off certain substances which differ quantitatively or qualitatively from the substances produced in the normal organism, but whether these latter substances exert a toxic influence on the organism it is impossible to state at the present time. Cancer almost invariably progresses continuously and it is doubtful whether it ever disappears spontaneously. It is therefore a disease which leads without special interference to the death of the patient, sometimes very soon, sometimes many years after the first symptoms appear, according to the rapidity of the growth of the cancer. The characteristic feature of cancer as a disease may therefore be stated as follows: Cancer consists in an abnormal multiplication of cells at a certain, at first, usually well-defined place of the body. All the deleterious results are primarily produced through this continuous growth which spreads into different parts of the body. This growth as such through the pressure it exerts on neighboring organs or through its infiltration into and destruction of vital parts of the body leads to the death of the affected individual, secondarily toxic influences may be added to the primary results of the growth; but these toxic influences are as far as we know not of a specific character. It is different in the so-called infectious diseases. There the disease consists primarily in an intoxication by products given off by the invading organisms and a proliferation of the body cells plays only a subordinate role in the disease process.

While we can thus, in a rough way, define and differentiate cancer from certain other diseases, we must be well aware of the fact that a complete and satisfactory definition of a process can be given only after the completion of its scientific analysis. Usually, however, definitions are given in the beginning of the study of a certain process; and they have therefore only a provisional value. Certain apparent, often superficial features are at first used for characterization. During the progress of scientific investigation new relationships to neighboring fields are discovered, differences which at first appeared to be of a qualitative are gradually to be found to be merely of a quantitative character. Thus we must prepare for the eventuality that the sharp differentiation between cancer and infectious or toxic diseases may not be upheld through future investigations. In fact already at the present time we know of conditions which seem to be intermediate between the two sets of phenomena and it is probable that we will gradually have to add certain subdivisions defining conditions which have factors in common both with cancer and the so-called infectious diseases. At present it is of comparatively little importance to discuss whether certain intermediate phenomena are to be classed as cancer or infectious disease, while it is of the greatest importance to describe and analyze the character of these intermediate phenomena. In a similar manner, it is of relatively slight importance to justify or deny the admissibility of calling certain processes in animals and plants cancer—the definition of cancer necessarily being a provisional one—while it is of the greatest importance to discover similarities between certain tumor-like conditions in man, animals and plants.

We have various methods for approaching the cancer problem. We can observe the frequency with which human cancer appears, its symptoms, and conditions which precede it. We can study the finer structure and mode of development of cancer with the microscope on pieces of tumor which have been excised. We can study cancer from a comparative point of view, its occurrence in animals and plants. The comparative study leads to the experimental investigation of cancer in animals.

 

1. Frequency, Distribution, Varieties of Human Cancer

Cancer among man is found in all countries where a closer search for it has been instituted. The frequency with which it occurs differs, however, very much among people living under the ordinary conditions of present civilization in Europe and America and among races or nations living under more primitive conditions, especially in Africa and Asia.

If we consider first the former category we find that approximately 3.1-5 per cent, of all human beings die from cancer. We are struck by the relative uniformity in the percentage of deaths from cancer, which indicates that within certain limits the conditions causing cancer are relatively constant and uniformly distributed over the civilized world. In this respect cancer resembles certain diseases which are caused by organisms evenly distributed over wide areas and to diseases primarily due to internal factors and not or only secondarily to parasitic agencies, while it differs from such diseases as smallpox, bubonic plague and poliomyelitis which are very irregular in their appearance.

If we compare the death rate from cancer in various countries we find the following figures: In a population of 10,000 die from cancer each year: in Switzerland 13.2, Norway 10, Holland 10.1, England 9.1, Austria 7.8, France 7.6, Prussia 7.1, Italy 6.1, Spain 4.8, Algiers (European inhabitants) 3.2. The death rate is also relatively low in Russia, Hungary, Servia, Jamaica and Ceylon. In Kyoto (Japan) it is approximately like Austria 7.9 per 10,000 inhabitants. On the whole the death rate from cancer is low in the countries around the Mediterranean.

In the United States in an area comprising one half of the population, the death rate per 10,000 inhabitants was (according to a report by the Health Commissioner of Pennsylvania (Dr. S. C. Dixon), 7.31 in 1907; the death rate in the United States is therefore very similar to that of Germany and Austria. Approximately 75,000 people die from cancer in one year in the United States and about half a million in the civilized world (F. L. Hoffman). If we consider only persons over 45 years old, considerably more people in the registered area of the United States die from cancer than from tuberculosis. Between the age of 45 and 60 years almost 7 per cent, of the male and 16 per cent, of the female population die in this country from cancer.

If we compare the death rate from cancer in the last 40 or 50 years we notice a universal increase in all civilized countries. The increase has taken place rather steadily and not by leaps. According to W. J. Whitney there was in Massachusetts from 1850-1910 during each 5 years an average but not quite uniform increase of 1.20 in the death rate for 10,000 persons over 30 years of age every five years. According to Dr. S. C. Dixon in an area comprising one half of the United States in population the death rate increased from 4.79 (1890)-7.31 (1907). In New York City there has been an increase from 5.4, which was the death rate during the 4 years ending 1882 to 8.1 during 1908-1912. A similar increase we notice in Germany, Norway, Amsterdam and everywhere else, where statistics are available.

While there can therefore be no doubt as to the actual increase in the death rate from cancer, the interpretation of this phenomenon is not quite clear. While some authors believe in a real increase, others believe it to be only apparent, due to improvements in diagnosis and to better registration. It is pointed out by some authors (especially by Bashford) that the increase in the death rate is found mainly in internal cancers which are difficult to diagnose. The increase concerns to a great extent cancer in the alimentary tract. This increase is found especially in persons over 60 years of age. Now in children cancer not rarely attacks internal organs, and still no noteworthy increase is reported in those cases. Furthermore errors in diagnosis would equally prevent physicians from diagnosing as cancer cases which are not cancer as well as from attributing to other causes deaths really due to cancer.

Furthermore the same increase has been noted in the well-conducted autopsies in the Charité Hospital in Berlin, where the diagnostic methods have not to any considerable extent changed within the last thirty-five years. According to Professor Orth, in autopsies on persons over 20 years of age cancer was found from 1875-1885 in 4 per cent., in 1904 in 10.7, 1909 in 19, 1911 in 20.8 of all the cases. It is, therefore, probable that a certain factor which is potent in the production of cancer has been gradually changed within the last fifty years causing a general increase in the cancer rate, while at the same time there has been a marked decrease in the death rate from tuberculosis in the corresponding period.

We will now consider the relative frequency of the different varieties of human cancer. Here we find again a similar distribution of the various kinds of cancer in all civilized countries in Europe, America and as far as we can judge at the present time also in Japan. The most frequent seat of cancer is the gastro-intestinal tract, especially the stomach, and in the second place the female generative organs, especially the cervix of the uterus and the female breast. Cancer of the stomach is approximately equally frequent in man and woman; in some countries it is slightly more prevalent among men. On the average 35-45 per cent, of all cancer affects the stomach and about 22 per cent, of all cancers develop in the female generative organs and breast. About 20-35 per cent, of all women who die from cancer have cancer of the uterus. Cancer occurs also relatively frequently at the lip, tongue, rectum and skin, especially of the face. Sarcoma is much less frequent than carcinoma. The relative frequency of the different varieties of cancer in the most populous areas of the United States is (according to S. C. Dixon) as follows: mouth 3.2 per cent., stomach and liver 38 per cent., intestines 11.7 per cent., female generative organs 14.3 per cent., breast 8.5 per cent., skin 3.7 per cent.

There occur, however, some notable deviations from the average rate of the different varieties in some countries. In Norway cancer of the uterus is relatively rare; only 6.3 per cent, of cancer develop in the uterus and 3.8 per cent, in the breast. In some parts of Norway cancer of the uterus is almost unknown. Cancer of the gastro-intestinal tract preponderates therefore considerably in Norway. In Sweden on the other hand cancer of the uterus is only slightly less frequent than elsewhere. In Switzerland also cancer of the stomach preponderates somewhat more than in the majority of other countries. A very peculiar deviation we find furthermore in Portugal, where cancer of the lip is very much more frequent than elsewhere (29 per cent, in men). While, on the whole, carcinoma of the male generative organs is rare (0.4 per cent, of all kinds in man), it is very frequent in the Cape Verde Islands. The proportion of cancer of the respiratory and excretory organs (kidney, ureter, bladder) is everywhere relatively low.

If we compare the incidence of cancer in the two sexes we find in most countries women somewhat more frequently affected than men. In Prussia the proportion is 3 men to 4 women. The relative incidence in women is even somewhat greater in the United States. The difference depends upon the difference with which various kinds of cancer affect the two sexes, and mainly upon the frequency of cancer in the female generative organs and breast; cancer of the gall-bladder, intestines, especially rectum, is also more frequent in women than in men, while cancer of the lip, tongue, skin, is more frequent in men. Cancer of the stomach is either equally frequent in both sexes or somewhat more frequent in men. In countries where cancer of the stomach prevails, and where a larger proportion of men than women are affected by this kind of cancer, the cancer death rate is higher in men, as in Switzerland, Norway and Kyoto (Japan).

There is no marked difference between married and single persons; the majority of statistical studies, however, indicate that married women are more frequently affected by cancer of the uterus and breast than unmarried women.

Sometimes we find the statement made that cancer is more frequent among the well to do than among the poor. It is doubtful whether this statement is correct. Some recent statistics point rather to the reverse. Again there seems to be in this respect some difference in the various kinds of cancer. Cancer of the cervix of the uterus appears to be more frequent among the poor, while mammary cancer is perhaps more frequent among the well to do.

There exists no marked difference in the incidence of cancer in country and city. On the whole, we are apt to find a somewhat greater incidence of cancer in the cities, especially in parts of the world where the number of physicians per unit of population is considerably smaller in the country and where therefore in all probability the number of unrecognized cases of cancer is greater in the country. The difference is therefore probably rather apparent than real.

There have been noted in various countries certain areas where cancer appeared to be more frequent than in others. Some observers believed especially damp-wooded country to be favorable to the development of cancer. Some physicians recognized certain houses or streets in villages or small towns, where the incidence of cancer was especially great. Behla for instance reported such an occurrence in the small Pommeranian town Luckau. These observers declared cancer to be "endemic" in certain localities and were often inclined to attribute this localized increased frequency to unknown infectious agencies. Although it is very difficult to interpret these observations, it does at present not appear probable that they ought to be referred to infection. Such cancer houses have been found only rarely: the number of cancers that occurred in these houses were relatively few, and furthermore cancer occurred also in the neighboring districts. Neither can we exclude the possibility that hereditary factors played a part in some of these cases. There is, however, no doubt that in certain parts of various countries cancer is more frequent than in others.

So far we have considered the incidence of cancer mainly among the white population of Europe and America. The incidence of cancer among certain races living under more primitive conditions is quite different. Among the negroes of Africa cancer is much rarer than among the whites of Europe and America. Although according to von Hansemann the same varieties of cancer occur there as in civilized countries, the proportion of the various kinds of cancers differs markedly. We find among the African negroes relatively frequently benign tumors of the connective tissue group as for instance lipomata (fat tumors). Sarcomata are correspondingly much more frequent than among the Europeans and it is furthermore very probable that the relative frequency of the various kinds of carcinomata is different. Also among the Arabs of Algiers sarcoma is more common than carcinoma. Among the male Arabs nine tenths of all cases of carcinoma occur in the face, which is especially exposed to the rays of the sun, and in the women carcinoma is more frequent in the vagina than in the uterus. Carcinoma of the gastro-intestinal tract is relatively rare. Also among the inhabitants of East India and Ceylon and among the Chinese we find a lower cancer rate than in Europe. In Japan however cancer seems to be relatively frequent as far as the available statistics indicate.

Also among the Indians in the reservation of the "United States cancer is considerably rarer than among the white population (J. Levin). Differences in climate can therefore not be held responsible for these great differences in the cancer incidence. But is it due to inheritable race characteristics or differences in mode of living, preceding infection with other diseases? This question we can not answer definitely at the present time. Some facts however are of interest in this connection. W. Renne found that among the natives of Sierra Leone cancer is very rare; but since a more intimate intercourse between the natives and immigrated whites has taken place, cancer has increased in Sierra Leone. But even in this case we are unable to decide whether this increase is due to changes in the conditions in life or to the intermarriage between whites and natives. In the United States we also find that within the last fifty years there has been a considerable increase in the cancer incidence among the colored population. Cancer of the uterus, which was formerly rare among colored women, is now more frequent among the colored population than among the white. Here again we can not be sure how much of this increase is due to changes in the mode of living, to increase in the inflammatory conditions of the uterus, and how much to intermarriage.

In the case of the relative rarity of uterine cancer among Norwegian women, we again do not know whether it is due to the relative infrequency of preceding infections of the uterus or whether it is a question of race. Interesting problems thus present themselves as to the relative importance of race and of external conditions in the origin of cancer. More definite knowledge could be gained if in statistics a distinction were made between negroes and mulattoes; it would also be of interest to establish the frequency of uterine cancer in the first and second generation of Norwegian women in this country, especially distinguishing between those interspersed among the rest of the population and those living in close rural communities in which the original customs are preserved.

We mentioned already that on the whole carcinoma occurs especially in old age. In the United States the average of death from carcinoma is 60 years for males and 58 years for females. Between 45 and 64 years 7 per cent, of all deaths in the male and 16 per cent, of all deaths in the female sex are due to cancer (Hoffman). From the thirty-fifth year on the death rate from cancer increases rapidly. There seems to be an optimal age for the appearance of certain cancers which differs somewhat in various kinds of cancer. Whether the death rate from cancer as a whole increases with advancing age or whether there occurs a maximal death rate at a certain age after which there is again a decrease observed does not appear to be certain.

While the typical cancers which we have considered so far occur in the large majority of cases in older people, some cancers of the same type may appear in young people; thus carcinoma of the stomach, tongue, esophagus, appeared in very rare cases in children. But there are special kinds of cancer which appear typically in younger persons. This applies for instance to the "carcinoid" tumor of the appendix and to similar often multiple carcinomata of the small intestines, which are found in relatively young adults (Bunting). These tumors are much more benign than the typical carcinomata—they grow very slowly and make ordinarily no metastases. But certain tumors are quite typical for young children. While in adults carcinomata are considerably more frequent than sarcomata, in children sarcomata are much more numerous than carcinomata. The most frequent seats of cancer in children are neither the gastro-intestinal tract nor the female generative organs, but kidney and adrenal, next the eye, brain, skin, cranium and liver. And while the few carcinomata of the stomach and intestines in childhood are observed in 12-14 year old children, the tumors of the kidney appear often in infants.

Besides the sarcomata we find in young children frequently so-called mixed tumors, consisting of several kinds of tissue; in the kidney tumors for instance we may find side by side proliferating epithelial gland tissue, round cells resembling sarcoma, muscle and even bonelike tissue. In other organs also we find not rarely such mixed tumors to prevail among the cancers in children. Cancer of the female generative organs occurs in children not mainly in the uterus, as is the case in adults, but in the ovaries and in the vagina. In the eye and brain we find besides sarcomata which originate from connective tissue cells certain special kinds of structures, the so-called glia cells—which are related to nerve cells—to give origin to malignant tumors. Even in the abdominal organs there may appear in young persons tumor-like proliferations of cells derived from the sympathetic nervous system (Neuroblastoma of J. H. Wright).

There is still another class of tumors which occur especially in children and in young adults, but may occasionally be observed even in older people and which are of great interest, the so-called teratomata or embryomata. They have certain seats of predilection, as for instance in the pelvis in front of the sacral bone, or in the anterior mediastinum, even in the buccal cavity; however most frequently they are found in the ovaries and testicles. In these tumors are observed a great variety not only of ordinary tissues but of incompletely developed organs, as brain, eye, lungs, gut. These structures represent evidently malformed embryos. At first they grow usually slowly—in contradistinction to the typical mixed kidney tumors of children—but not infrequently somewhat later in life one or several of their constituent parts begin to assume a malignant growth, and even produce metastases.

Now the large majority of these tumors which appear in early childhood are in all probability congenital, they were preformed before the child was born; they are, however, usually noticed only at a time when they begin to grow somewhat more rapidly, and this may take place many years after birth; thus the sacral embryomata are often noticed first somewhere between the fifteenth and twenty-fifth years, when they begin to enlarge a little, and certain kidney tumors developing in all probability from misplaced embryonal adrenal tissue may even not become apparent until later in life. We may furthermore conclude that these congenital tumors of childhood and young adult life are in part due to localized aberrations during embryonic development, their composition of a mixture of tissues suggesting similar combinations of tissues which existed at such places some time during embryonic development. At that period certain tissues did not differentiate normally, did not become a functionating part of the organism restricted in its growth—but somehow preserved a part of the proliferative power which not fully differentiated embryonic cells usually possess and they exerted a destructive influence on the otherwise normally developed organism. The famous pathologist Cohnheim especially emphasized this origin of tumors; but he and still more so some of his pupils and followers extended the significance of their observations too far, explaining on this basis the origin of tumors in general, while their conclusion applies in all probability only to that class of tumors which appear in childhood and early adult life and perhaps to certain other related tumors. Recent investigations of Robert Meyer and others have indeed shown that certain minor embryonic malformations, especially in the region of the kidneys, the thyroid, thymus and eye are quite frequent; but that in the large majority of cases they certainly do not lead to tumor formation.

Other more or less benign tumors, which are often multiple, occurring simultaneously at different places are also frequently congenital, as for instance, growths consisting of lymph or blood vessels, cartilage, muscle tissue developing around small blood vessels, and fibrous tissue growths around nerves in certain areas of the body, furthermore pigmented moles.

However, not all the tumors found in the first half of life develop on the basis of embryonic malformations. It is very probable that many embryomata especially those of the ovaries and testicles owe their origin to the parthenogenetic development (development without previous fertilization) of a germ cell, a suggestion made more probable through the discovery of Jacques Loeb that in various classes oi invertebrates ova can be induced by artificial means to develop without previous fertilization. And yet the majority of pathologists believe with Bonnet and Marchand that such embryomata just as other mixed tumors of childhood are due to embryonic aberrations, to a separation of early cells which are formed in the course of the early division of the previously fertilized ovum or to the abnormal fertilization of a little cell separated normally from the egg previous to the entrance of the spermatozoon.

However, this hypothesis can not be easily reconciled with the fact that the majority of embryomata appear in the germinal.glands (ovaries and testicles), an observation which can be readily explained, if we assume that these embryomata are due to the parthenogenetic development of ova in the ovarian follicles. This is the more probable as I found that in about 10 per cent, of the ovaries of young guinea-pigs formations occur which can not very well otherwise be explained than as embryonal structures, placental[1] as well as embryonic in the stricter sense, developing abnormally from ova in the ovarian follicles and gradually being destroyed by the surrounding tissues. A previous fertilization could be excluded in these cases.

Moreover in the ovaries of various mammals one can not rarely observe ova in athretic (degenerating) follicles which show the first, somewhat irregular segmentations, and in the armadillo as many as eight cells may, according to H. H. Newman, be seen.[2]

While these observations explain satisfactorily the relatively frequent occurrence of embryomata in the germinal glands, they may also explain the embryomata found at other places, inasmuch as it is known that the germ cells migrate in various directions in the developing embryo, before they reach the germinal gland. In some cases however blastomeres (cells formed in the course of the early segmentation of the egg) may form the matrix of the tumors, inasmuch as it has been shown in certain classes of animals that a detached blastomere may reproduce the whole organism.

We have still to consider one very interesting kind of tumor, namely, the so-called chorionepithelioma malignum, which also owes its origin to irregularities in the activity of certain embryonic cells but which in some respects differs markedly from the other tumors considered so far. When the segmenting egg attaches itself to the uterine wall it does not only produce the embryo proper, but it gives also rise to certain cells which attach themselves to the uterine wall of the mother, and are mainly concerned in transferring food from the mother to the embryo, thus forming the embryonal placenta, the outer layer of which is called the chorionic. These chorionic cells, which are therefore of embryonic origin, migrate already under normal conditions deeply into the uterine wall; they may even penetrate into maternal blood vessels and be carried to other parts of the body of the mother. Usually these chorionic wander cells perish after some time in the mother, but occasionally they give rise to very malignant tumors which destroy the uterine wall, and form metastases (L. Fraenkel, Marchand).

Just as these chorionepitheliomata may be produced from the fertilized egg cell developing in the uterine wall, so they may occasionally owe their origin to egg cells which develop into embryomata in the germinal glands and especially in the testicle. Here likewise chorionepitheliomata may develop. In the structures which I found in the ovaries of guinea-pigs the greater part of the dividing egg cells formed in contact with and probably under the influence of the ovarian tissue of the mother placental tissue and especially migrating cells which penetrated occasionally even into the walls of the neighboring blood vessels.

We have now analyzed some of the factors concerned in the origin of tumors found in childhood and early adult life. We recognized that they are caused partly by abnormalities of embryonic development, partly by parthenogenetic development of germ cells. At least these are two of the factors concerned in their origin—whatever additional factors may be found in the future. However, the greater number of all tumors, especially the large majority of the typical cancers found in later life, owe their origin to different causes. We can appreciate these causes best, if we consider certain special kinds of cancer which are somehow associated with certain kinds of occupation.

In general the character of the occupation does not seem to have a marked influence on the incidence of cancer, although it seems that cancer in certain callings (agricultural and forest workers, textile and wood workers, domestic servants) is somewhat more frequent than in others (miners, soldiers, factory workers in general). There are however certain occupations in which a direct connection exists between the character of the work and the development of cancer. For instance in Röntgen ray technicians, especially in those who began their work, in the first years following the discovery of the rays, when the dangers connected with this occupation, the various precautions used at the present time were as yet unknown, gradually, often after many years of work, a painful condition of the skin arose, mainly on the hands and arms which were exposed to the rays, it became thickened, cracked, ulcers formed. The epithelium grew further down into the deeper tissues and slowly a carcinoma developed which later made metastases.[3] Approximately 70 cases are known where cancer thus developed, and in some cases it developed a considerable time after the exposure to the Röntgen rays had ceased.

Chimney sweeps develop relatively frequently cancer of the skin, especially of the scrotum, and it is interesting that this cancer may be found in young people. It has for instance been observed in a boy eight years old. The cause of this cancer is the irritation produced by soot. Those who are employed in the distillation of tar (especially of gas work tar) in the manufacturing of grease and briquettes are liable to develop cancer of the skin. Certain organic substances contained in tar and pitch cause the development of warts on the skin, which later break down and become transformed into cancers. In men employed in the manufacturing of aniline dyes, and certain other benzol derivatives, wartlike excrescences of the skin may appear; but especially interesting is the frequent appearance of cancers of the bladder in such cases. Each of the affected men had been in the dye works for 20 years or more. Evidently substances excreted through the kidneys exert in such cases an irritating action on the epithelium of the bladder.

There are some other occupations in which certain substances are the direct or indirect cause of the development of cancer. Just as Röntgen rays and certain chemicals, so may also light rays under certain conditions be the cause of cancer, especially in sailors, in whom sometimes the skin of that part of the body which is exposed to the light shows certain changes which lead gradually to the development of cancer. We notice also occasionally in old people and in rare cases even in young men in the face and on the hands, in parts therefore exposed to the action of the light rays, the development of multiple lesions, which in the course of time become transformed into carcinoma. There occurs furthermore in children a congenital skin disease, xeroderma pigmentosum, which develops usually into a carcinoma at places exposed to the light rays.

Very instructive is the cancer which is not rarely found in Kashmir among the carriers of the kangri, a little stove, which burns the skin on which it rests. Gradually cancers develop in the scars; the downgrowth of the epithelium is at first slow, but later metastases form in the lymph glands and a typical malignant carcinoma is now present (E. T. Nere).

Eelated processes—namely the gradual transformation of epithelium into cancerous growth—have been observed in cases of chronic ulceration of various kinds with incomplete healing of the epithelial surface as for instance in the case of the chronic ulcer of the leg, in the case of lupus, a tuberculous skin affection and in other similar conditions. Another class of cancers is produced directly or indirectly through the action of certain parasites, especially of certain worms (nematodes and trematodes). Thus in Egypt infection with bilharzia (Distoma haematobium) is relatively common. This trematod lives in the veins of the abdomen and lays its eggs in the mucosa of the bladder; they cause inflammation in the bladder, mostly in older persons, and later cancer develops in about 31/2—5 per cent, of patients infected with bilharzia. In Bosnia, after bites of sandvipers, chronic ulcers without a tendency to heal may develop, and they may become carcinomatous. Also in other cancers a causal connection between a metazoan parasite and the tumor has been suggested in man, but this connection can not yet be considered as proven. Thus Askanazy found in a case of primary carcinoma of the liver Opistorchis felineus, while in Japan in similar cases a Distoma has been observed. In cases of chronic trichinosis carcinoma was found in organs which were situated in the neighborhood of the infected muscles. The presence of certain mites were noticed by Borrel in the case of mammary cancers and considered as its cause. It appears however that these latter parasites are just as frequently found in the non-cancerous breast as in cases of mammary cancer. The importance of nematodes as the cause of certain cancers in animals has been recently demonstrated, as we shall later explain more in detail. Of especial interest is the fact that while in the large majority of cancers caused by external irritation carcinoma developed, a few sarcomata have been observed in the skin under the influence of Röntgen rays, in the bladder in aniline dye workers and in persons infected with hilharzia.

We see then that under the influence of a considerable variety of agencies, cancer can develop in the human body and that in many cases cancer is preceded by the formation of warty or papillomatous excrescences and in other cases by long-continued ulceration, which in itself seems to be able to lead to the formation of cancer. At present we leave out of consideration the mechanism through which these agencies produce cancer, especially the question whether their action consists in a direct specific stimulation of the epithelial cells by the light and Rontgen rays, chemical substances and parasites or whether all these agencies act indirectly causing primarily ulceration, which later is followed by the development of cancer. We know indeed that chronic ulceration due to various causes may in itself lead to the development of cancer. Later we shall have occasion to return to this question.

We mentioned already that certain pathological conditions prepare the soil for the subsequent development of cancer, such as for instance lupus, chronic ulceration of the leg. But there are numerous other morbid conditions which stand in a certain causal relation to the growth of cancer. Gastric carcinoma originates in a considerable number of cases at the site of a previous ulcer of the stomach. Long-continued suppuration in the middle ear, fistules of various parts of the body may be followed by the development of cancer; so may certain affections, in which either certain parts of the skin or the mucosa are covered by plaques of horn, so-called (leukoplakia of the tongue and vulva, psoriasis). In the mammary gland chronic inflammation may lead to the subsequent development of cancer. Carcinoma may be preceded in the thyroid by goitre, in the liver, by chronic inflammation leading to an increase in fibrous tissue (cirrhosis), in the prostate by hypertrophy which is relatively common in old men. Inasmuch as certain conditions predisposing to cancer may be caused by syphilis, also syphilitic infection is indirectly one of the causes of cancer.

We mentioned previously that xeroderma pigmentosum, a congenital lesion of the skin, becomes usually cancerous. We furthermore know that certain at first benign tumors may later be transformed into cancers. Thus papillomata (polypus or cauliflower-like outgrowths) very often precede cancer of the small and large intestines or of the bladder. These papillomata are in the intestines frequently caused by preceding long-continued irritation; in certain cases however they are congenital. Pigmented moles of the skin if constantly irritated may be transformed into a pigmented cancer which is often very virulent.

At first benign tumor-like proliferations of the epithelium of the liver, mammary gland, ovaries, uterus, and especially glandular tumors (so-called adenomata) may later become transformed into carcinoma. As we have already mentioned, certain parts of teratomata at various places of the body are not rarely changed into carcinoma or sarcoma. The usually benign muscle tumors of the uterus (myomata) are in 6-10 per cent, of all the cases transformed into tumors resembling sarcomata, a change which does usually not take place before the patient has reached the fortieth year. In other cases, however, such myomata of the uterus are only the indirect cause of the development of cancer, the mucosa in their neighborhood becoming converted into carcinoma. Possibly the constant irritation caused through the pressure of the muscle tumors upon the epithelial lining of the organ may be responsible for this transformation. Furthermore, fat tumors (lipomata) may occasionally assume a malignant growth and become sarcomatous or soft, mucus-producing tumors (myxomata) which may be malignant and may metastasize.

Long-continued irritation is not always necessary but in certain cases one single traumatism may undoubtedly cause the development of cancer. While, however, long-continued irritation usually leads to the formation of carcinoma, one single traumatism causes more frequently the development of sarcoma. Thus cases are known in which two months after a blow on the eye a sarcoma began to grow at the place of injury; in a child sixteen months old a sarcoma of the ciliary body of the eye developed after a blow; a sarcoma of the arm followed a stab wound at the site of injury. There are also cases on record in which a bone sarcoma developed after a fracture of the bone and after an extraction of a tooth the development of a cancer has been observed in the jaw. Also other than connective tissues may assume a rapid cancerous growth after an injury, as for instance the glia cells of the brain which are of the same origin as the nerve cells. Also carcinomata of the jaw originated subsequent to an extraction of a tooth. A carcinoma of the testis followed six weeks after an injury received from a horse.

In all these cases we have to distinguish between two possible results of the traumatism; the latter may either actually cause the new formation of a cancer or it may merely increase the rate of growth of a tumor that existed previous to the injury, which however only became apparent after the injury had increased the rapidity of the tumor growth. The latter condition existed for instance in the case of an embryoma of the testis which assumed a rapid growth after an injury, taking on the characteristic of a malignant tumor with subsequent formation of metastases.

We have now learned to know several sets of conditions which are either alone or in combination with other factors responsible for the occurrence of cancer, namely: (1) Irregularities of embryonic development. (2) Parthenogenetic development of ova. (3) The long-continued action of external stimuli, as for instance Röntgen and light rays, various substances acting chemically, long-continued ulceration and certain parasites. (4) Traumatism.

In certain of these cases we can state definitely that a combination of several factors had to come into play before carcinoma developed, for instance, in those cancers which follow xeroderma pigmentosum. Here a congenital lesion becomes converted under the influence of an external agency—namely, the light rays—into cancer. A pigmented mole is the result of some irregularity of embryonic development; it is present at the time of birth, and therefore a congenital lesion; mechanical stimuli cause its transformation into cancer.

We recognized that the majority of cancers of childhood differ in a definite way from the typical cancers of old age. We found reason to believe that certain embryonic irregularities are in part at least responsible for many cancers of childhood and early adult life. In the light of the data which we gave concerning the significance of external stimuli in cancer, let us now briefly survey the typical cancers of old age. Such a review will demonstrate that for the production of the majority of all cancers the long-continued action of external stimuli is of the greatest importance. We stated that in civilized countries the large majority of human cancers occur in the alimentary and female generative organs, while the respiratory tract and kidney and ureter and the nervous system are much more rarely affected. The alimentary tract is the one through which the solid substances pass and which is therefore most easily exposed to constant irritation and possibly the action of certain parasites while through the respiratory and excretory tract (kidney, ureter) only gaseous substances or liquids pass; there is here therefore much less opportunity for long-continued irritation, and consequently less cancer. In the alimentary tract, those parts in which mainly fluid material is present, namely the small intestines, are least affected, while those in which especially solid material stagnates as in the stomach and rectum, cancer is most frequent. Cancer of the lip is frequently caused through the irritation of a pipe, cancer of the tongue and cheek is sometimes the result of constant irritation on the part of a defective tooth or prothesis. In the esophagus those places are the favorite seats where there is the greatest opportunity for irritation; in the stomach cancer is frequently found at the same site where gastric ulcer occurs most frequently and where the foodstuffs are apt to press against the pylorus in entering the small intestines. Certain chronic digestive disturbances characterized by a decrease or lack of digestive substances secreted by the stomach (achylia gastrica), in which there is therefore more irritation as a result of insufficient liquefaction of the intaken food, may also be followed by cancer. Irritation caused by the consumption of alcoholic beverages seems, in certain countries in which cancer of the stomach is more frequent in men than in women, to be one of the causes of gastric carcinoma. In the intestines cancer is frequently preceded by the formation of papillomata which again are in most cases the result of chronic irritation and inflammatory processes. Cancer of the gallbladder is more common in women, because women more than men are, as a result of certain habits, prone to suffer from gallstones, and gallstones cause a condition of constant irritation in the gallbladder. Carcinoma in the bile ducts has been observed to originate at a place where a gallstone was most likely to find obstruction in its passage into the intestines.

In the female generative organs cancer is most frequent in the cervix of the uterus, where, as the result of preceding labors, and of infection, tears and chronic inflammatory conditions are found to occur. In the mammary gland also cancer stands often in causal relation to preceding inflammatory conditions. In the ureter cancer has been found in connection with an incarcerated stone. In the respiratory tract cancer in the nose may follow a disease, ozæna, while in the larynx cancer originates most frequently in the vocal chords which, through their situation and function, are most exposed to various external injurious influences.

This may suffice to prove the great significance of the continuous action of external stimuli in the production of the majority of the typical cancers of more advanced age.

While in general we can very well determine the dividing lines between the fields of the typical tumors caused through the action of external stimuli and those due to embryonic disturbances, there may in individual cases be some doubt. A number of pathologists extended it seems unduly the field of the tumors belonging to the latter class. They believed that microscopic studies of early tumors frequently demonstrated that they took their origin not from cells attached in a normal manner to the rest of the organs but from detached small fragments of organs. There would have been good reason to interpret the existence of islands of disconnected cells as an indication of imperfect embryonic development. Careful microscopic investigations show however that in the typical cancers of the stomach and intestines (Hauser, Versé)—with the possible exception of certain atypical so-called carcinoid tumors of the small intestines—and even in the multiple tumors of the skin (Janeway, Loeb and Sweek) the cancers originate through a direct downgrowth of the surface epithelium into the deeper tissues. Conditions preceding the development of carcinoma cause primarily an increased proliferative power of the epithelium which, as the result of this change, in the large majority of cases grows down into the deeper tissues and destroys them, but in some cases the resistance of the deeper tissues is so great that it successfully counteracts the invasion or dissolving power of the epithelium and the latter may instead of growing downwards be forced to grow towards the outside of the skin, as we could observe in a case of multiple carcinoma of the skin. This increased proliferative and infiltrative power of the epithelium is therefore the principal characteristic of cancer.

This change in the proliferative power of the epithelium may be accompanied by a change in the structure of the affected cells, which appear often less differentiated. This loss in the complexity of proliferating cancerous cells has been called anaplasia. In other cases, however, this morphological change in the proliferating cells may be entirely absent, as for instance in some beginning Röntgen ray cancers.

Still furthergoing structural modifications of the proliferating cells may take place in the secondary (metastatic) growths, although on the whole metastases repeat more or less the structure of the primary tumor. Thus we may in the case of a primary carcinoma of the liver find metastases in which the tumor cells continue to produce bile just as the normal liver cells do, and especially primary as well as metastatic tumors of the thyroid may be hardly distinguishable from the normal tissue from which they are derived.

Microscopic studies of early stages of cancers showed furthermore that in many cases the growth starts at one well-defined rather limited area of the affected tissue; and that all the tumor masses developing subsequently are derived from the relatively few cells which were originally seen to proliferate. In other cases, however, the tumor growth originates at several neighboring places simultaneously. And in still other cases a certain tissue may, over a wide area of the body and even at distant places, give rise to cancer formation simultaneously or successively. In such cases we may assume that some change predisposing to the development of cancer has taken place in the affected tissue, and that relatively slight external stimuli, as for instance an injury, effect of light, are sufficient to call forth the actual cancerous proliferation.

Usually the proliferating cancer cells do not infect neighboring cells with which they may come in contact during their proliferation. While as a rule the neighboring normal cells do not become cancerous in contact with cancer cells, this does not hold good generally; and as we shall see later the study of animal cancer has shown that such transformations may take place under certain conditions.

The careful microscopic studies of many pathologists (among American investigators we might cite among many others: Councilman, Mallory, Ewing, LeCount, Warthin, Wilson and MacCallum) have contributed many important and interesting facts concerning the structure of various tumors, their resemblance to and deviations from the structure of normal organs from which they are derived and such studies formed the basis of a more detailed classification of tumors (von Hansemann, Adami). We have learned that each organ or tissue gives rise to specific tumors which not only differ in structure and metabolism, but also in their proliferative and metastasizing energy. It will, however, not be necessary to discuss these differences more in detail on this occasion.

Before leaving the problem of human cancer we will briefly consider what part heredity and microorganisms play as the cause of tumors in man.

Heredity is undoubtedly a factor in those cancers which develop occasionally in cases of xeroderma pigmentosum or from pigmented moles. We know that here the conditions preceding cancer are hereditary and therefore cancer itself is indirectly hereditary. We furthermore know that a certain class of cancers originates on the basis of embryonic malformations, and inasmuch as these are under certain—as yet not well defined—conditions hereditary, we may assume that certain cancers belonging to this class are also hereditary. There is indeed some evidence which points to this conclusion. There is for instance a case known in which both the mother and her one and one fourth years old child became affected by glioma of the retina (a tumor originating in modified nerve cells of the eye). In another case a twenty-one-year-old man had 17 osteomata (tumors consisting of bone tissue) symmetrically arranged and his father had similar tumors. It is furthermore known that in certain cases polyps of the intestines are congenital and occur in several members of the same family. On the basis of such polyps cancer not infrequently develops. We have therefore reason to believe that heredity plays a role in a certain number of that type of cancers in which flaws in embryonic development are a factor.

In the case of the typical cancers of later life in the causation of which as we stated external stimuli play such a prominent part, it is very much more difficult to determine the significance of heredity. We know that the frequency of cancer varies very much in different races; but we have also seen that we can as yet not be certain how much this difference is due to factors inherent in the race (heredity) and how much it is due to variations in the mode of living and to preceding inflammatory conditions in the affected parts of the body. The ordinary methods of vital statistics which almost exclusively have so far been applied in cancer seem to show that in about 14—18 per cent, of persons affected with cancer other cases of cancer occurred in the family. Now it is doubtful whether this incidence is greater than should be expected according to the law of probabilities. Even extensive statistical studies of this character can evidently not solve the problem. We must rather turn to intensive studies of the incidence of cancer in various families for a solution. There are indeed already some data available which seem to indicate the existence of a hereditary factor also in the causation of the typical cancers of more advanced age. In certain families, as for instance one reported by Broca, the incidence of cancer has been extraordinarily high. A. C. Garmann found that in a certain district of Norway, the population could approximately be divided into 20 distinct families, and 72.8 per cent, of all cases of cancer occurred in a single one of these 20 families. J. Levin has begun to use the statistical material collected at the Eugenics Eecord Office of the Carnegie Institution in Cold Spring Harbor for such intensive statistical studies. In one family on which he has reported recently he found, that a fraternity in which one or more members suffer from cancer, usually shows in a previous generation a cancerous member either on the paternal or maternal side or on both sides. It may be expected that a continuation of such studies will decide definitely the problem as to the significance of heredity in human cancer. As we shall see later, in the case of animal cancer the great importance of heredity has recently been established.

Especially since the discoveries of various microorganisms as the cause of certain diseases, the possibility was always in the minds of investigators, that also in cancer besides the conditions enumerated microorganisms might be responsible for the cancerous cell proliferation. We must of course remember that our present knowledge of the factors underlying cancer was only gradually acquired; furthermore that certain experiences concerning animal cancer which we shall discuss later, suggested microorganisms as the direct stimulating agencies while the other factors which we analyzed so far would represent merely indirect causes, making the infection with microorganisms more easy. We know indeed that to a certain extent microorganisms can call forth cell proliferation. Thus the tubercle bacillus may cause a limited growth of connective tissue and as especially Borrel has pointed out the organisms causing smallpox and vaccinia may even produce a slight proliferation of the infected epithelium. But in all those cases the proliferation soon ceases and toxic substances produced by bacteria lead usually soon to the death of a great part of the newly-formed cells.

Based on such considerations many attempts have been made to prove the constant presence of certain parasitic microorganisms in human cancer. Under the microscope it is possible to recognize in cancer cells certain inclusions which are usually absent in normal tissues and a number of investigators claimed such included bodies definitely as protozoa (among others, Thoma, Sjoebring, Leyden, Gaylordand Eisen). Even the life cycle of these protozoa was apparently determined by some of these authors. It could, however, be shown that similar cell inclusions may originate otherwise and did in all probability therefore not represent protozoa. Also bacteria (Doyon), mucor (Schmidt), chytridiaceæ (Behla) and other microorganisms were held responsible. Others (Sanfelice, Leopold) believed yeast-like organisms to be frequently demonstrable in human cancer; they cultivated some yeasts in culture media and by injecting the organisms into animals believed to have reproduced the disease. Careful studies by many investigators, however, could not confirm these interpretations. In the case of yeasts it has for instance been shown that although they occasionally occur in cancers, they are on the whole rare and do not reproduce the disease if injected into animals (Busse, Nichols, Loeb, Moore and Fleisher). They act in the body in a similar manner as inert foreign bodies, and we found a yeast which we isolated from a sarcoma to lead, after intravenous injections, to the death of the animal through occlusion of the kidney tubules, without ever producing cancer.

These persistent claims of the discovery of a microorganism as the cause of cancer which could in no case be substantiated led in the case of many pathologists, especially of those mainly interested in the careful study of the structure of pathological tissues, to a reaction which induced them to deny the possible importance of microorganisms in the causation of cancer; they were inclined to hold on the whole the factors already established as sufficient to explain the origin of cancer. On the other hand, a number, especially of experimental investigators, without being able to accept as valid any of the claims as to the discovery of a microorganism as the cause of human cancer, always pointed out the possibility that microorganisms might at least in a certain number, perhaps even in a majority of cases, be a factor in the production of cancer and tried to find new experimental means to approach these problems; accordingly on various occasions we pointed out the possibility that ultra-microscopic, perhaps intracellular, microorganisms might induce body cells, under certain conditions, to proliferate in such a manner that cancer resulted. However, in no case of human cancer has the causative significance of a microorganism so far been proven. We shall see later on that in a certain kind of animal cancer this proof has recently been supplied by Peyton Rous.

  1. The placenta is an organ of partly embryonic, partly maternal origin which is attached to the uterine wall and which transmits nourishment to the embryo.
  2. The first cleavages of ova in athretic follicles of mammalian ovaries previously described by various investigators and also by myself can not all be explained as maturation divisions which precede the segmentation; we may see occasionally ova which have divided into a number of segments, several or the majority of which may contain nuclei and at the same time observe in two segments mitotic figures or their remnants, the position and character of these segments making it extremely improbable that they represent polar bodies (Leo Loeb, Archiv f. milcroscop. Anatomie, Bd. 65, 1905).
  3. Cf., the careful microscopical studies of S. B. Wolbach.