In the first lecture we saw that cancer was an alteration of the normal cells of the body, whereby they take on a malignant action and continue to do so, destroying contiguous tissues and leading to a lowered vitality, with an apparent poisoning of the system, which finally causes death. As the cells of various organs furnish different secretions, which in health contribute to proper metabolism, resulting in growth or maintenance of the tissues, so these disordered cells are believed to secrete a toxic substance, or malignant hormone, which has a prejudicial action on the body, and hæmolytic action on the blood, as has been brought out pretty clearly by Troisier and others.
We saw that as yet the definite cause had not been determined, why at some period certain cells take on the action which we call cancer, nor why they persist in their destructive course. Long continued and abundant laboratory and clinical research have about decided certain questions negatively in regard to its etiology, so that in a measure the field is cleared for the study of some of the possible basic causes of the disease in question. Thus, all are pretty well agreed that cancer is not contagious or infectious, that it is not caused by a micro-organism or parasite, that it is not wholly due to local injury, that it does not appertain to any particular occupation, that it is not hereditary to any great degree, that it does not especially belong to or affect any particular sex, race or class of persons, nor is it confined to any location or section of the earth, and that it is not wholly a disease of older age.
We saw further that there appeared to be good evidence that certain misplaced “embryonal rests” were the original starting points of diseased cell action, but as these are now known to exist in every one from birth, this offers no real explanation of the occurrence of the disease at different times in life. It is, of course, quite possible that local injury of one kind or another may be the exciting cause which determines that a cell or group of cells shall revert to its original reproductive activity, as Williams contends that the process is one of agamogenesis, dependent upon excessive and faulty nutrition. The question as to the relation of uricacidæmia, or lithæmia, to cancer has never been fully studied, and it is worth considering whether, as in gout and rheumatism, to which cancer is often associated and perhaps closely allied, the exciting cause may not be the lodgment somewhere of uratic deposit, which is further excited and fed by effete or imperfectly oxidized nitrogenous elements; for later we shall see that perverted metabolism, largely of proteid elements, is closely associated with cancer.
We noted also that some attributed cancer to independent cell action, relating to the polarity of cells, etc.; but it is inconceivable that a cell or cells can idiopathically start out on a rampant course and pursue it with increasing severity, even until death results, without, at least, some definite pre-disposing cause, even though diligent and earnest work has not as yet determined just what that cause may be. The error has been, we believe, in searching too exclusively by the microscope and by certain laboratory methods, and not sufficiently along clinical and bio-chemical lines. For it must be recognized that all the cells of the body are continually bathed in the vitalizing fluid of the blood, whence they derive their nutriment, and into which, with the lymphatics, they return the products of their vital action, by anabolism and catabolism.
By exclusion, therefore, we are reduced to seek the etiology of cancer along other lines, and about all that is left is metabolism, as influenced by advancing, so-called civilization, which relates very largely to diet and mode of life. This we will take up later, but will first examine some of the scientific findings in regard to the blood in cancer, and data relating to the various secretions and excretions of the body bearing upon metabolism in this disease.
That the blood shows great changes in advanced cancer is recognized by all, as is clinically manifested by the intense cachexia and anæmia commonly present and always strongly marked toward the end, of which the cytology has been very fully studied and presented by Türk. When then examined there is found to be a marked reduction of red cells, low hæmoglobin index, and distinct leucocytosis, with greatly diminished alkalescence.
The reported changes in the blood have also varied with the location of the malignant disease, according as it may interfere mechanically or otherwise with the function of certain organs, which fact naturally obscures the question of the true relationship of the blood to cancer. Thus, it is stated that in cancer of the liver and pancreas there is always leucocytosis and glycogen, and that “cancer appears to interfere greatly with the function of the liver as a destroyer of intestinal toxins, they pass into the general circulation, probably cause the glycogen reaction, and at least part of the leucocytosis, and very often give rise to fever.” There are also other microscopical alterations in the blood in late cancer. Thus, degenerative change in the leucocytes are common, with derangement in the normal proportion of their different forms, as also changes in the erythrocytes, with nucleated red cells and megalocytes in severest cases.
Price Jones in a study of the blood in 30 cases of cancer (9 of the breast) found the red blood cells diminished on an average of 6 per cent., the white blood cells increased 38 per cent., lymphocytes increased by 10 per cent., large mononuclear cells increased 164 per cent. and polynuclears 42 per cent. Burnham states that in the severe grades of anæmia with malignant disease, poikilocytosis is marked, and nucleated cells of both normoblastic and megaloblastic type may be present. The red corpuscles may be reduced to 2,500,000, and exceptionally to 1,000,000. Cohnreich in a very technical study of blood from cancer subjects, observed very great increase in the resisting power of the red blood cells to osmotic tension, that is, in regard to their hæmoglobin, which he believed to be of diagnostic value in doubtful cases.
Unfortunately, there have been relatively few studies of the plasma of the blood in this or other diseases; and yet the condition of this fluid must be of the utmost importance, as from it are derived the nutrient principles not only of the solid constituents of the blood, but also those of the entire system, about 8 per cent. of it being serum albumen and serum globulin. It also holds in solution the phosphates, carbonates, sulphates, and chlorides, the latter often varying greatly, and being chiefly responsible for the isotonic relation of cells and serum. In cancerous cachexia a diminution of carbonic acid, a constantly diminished alkalinity, and an increase of acid principles of the blood have been fully demonstrated, pointing in all probability to the existence of an acid intoxication. The formation of the corpuscular elements of the blood must be greatly interfered with when metastases occur in the blood making organs, the lymphatic tissue, bone, marrow, and spleen, which probably occur more frequently than is generally recognized. It seems that the toxic secretion from a cancerous mass has a distinct action upon the blood, for after complete removal there is often observed an increase of hæmoglobin, as I have witnessed, and a high leucocytosis has disappeared after the removal of schirrus of the breast, only to return again with the recurrence of the tumor. Abderhalden states that in from two to three weeks after the operative removal of cancer, certain defensive ferments can no longer be found in the serum.
Many laboratory studies have been made upon the chemistry of cancer tissue, seeking to determine the nature of the toxin produced, and its experimental effect on animals, but thus far no great results have been obtained. It has been observed, however, by Gruner that when cancer juice is injected intra-venously a marked lymphocytosis arises, which is followed by the appearance of large mast cell myelocytes in the blood. This cancer juice is supposed to be autotoxic in cancer patients, and to comprise toxic albuminoids, which being in quantities too great to be quickly neutralized poison the system, especially the blood and the hæmatopoietic organs.
In regard to the real bio-chemistry of cancer, we are still greatly in the dark. Vast numbers of studies and researches have been made to determine the real character and nature of the bio-chemical changes which occur in cancerous tissue, and the mere recounting of the reported findings and theories elaborated from them would occupy far more time than can be profitably given in these lectures. Some have claimed very positive findings which account in a measure, at least, for the pathological conditions, while others, as Beebe, state that “the chemical study of tumors is in its infancy. We have scarcely proceeded far enough to know where the medical problems are, nor have methods now available been perfected to such an extent as to enable a decisive experiment to be made.” “No phase of metabolism,” says he, “has been described in cancer which does not have a counterpart in non-cancerous conditions. This applies to such questions as the nutritive relations between the cancer cells and the normal body tissue, to the nitrogenous balance, retention, elimination of sodium chloride, excretion of acetone, the relation of ammonia excretion, and a possible acidosis.” He adds, however, “Diet doubtless forms an important part in the growth of cancer, possibly even in the origin of the disease.” It is encouraging, therefore, to find that this able and careful laboratory investigator recognizes, in a measure, the basic cause of diet, toward which all evidence points so strongly, although the definite connection may not yet have been established by laboratory methods.
In all our study in regard to the relation of diet to cancer it must be remembered that there are divers elements and agencies which combine to produce the many and various disordered conditions of the body, to which we give the names of different diseases, and that cancer is no exception to this general rule. For instance, in old-fashioned gout the patient may have consumed an excess of Port and Madeira wine for years before the system finally rebelled and acute gout resulted; and among the causes for the systemic reaction we know that frequently it is great mental strain or shock which has so disturbed metabolism that the wine was no longer tolerated. Much the same is true in regard to cancer and nitrogenous diet. And we will see later that mental disturbance and nerve strain or shock often seem to be causative elements; also that constipation, or intestinal stasis, is so common in cancer subjects that it must be looked upon as one of the contributing causes among others, to be mentioned later.
Although it is quite possible that many of the reported bio-chemical changes found in primary cancerous tissue and metastases may not be of etiological importance, it may be interesting to briefly refer to some of them as indicating the vital alteration in tissues connected with what we recognize as malignancy; even as in acute and chronic gout the affected tissues exhibit abnormal conditions in regard to uratic deposit.
Many writers, some of them dating back many years, agree that albuminous constituents predominate in cancer tissue, and, as in actively growing structures in general, sugar forming substances abound. Wolter states that cancer of the breast contains 20 per cent. more nucleo-proteids than the normal breast. Casein is also present in breast cancers, and the abundance of fatty matters, contained in the cells of such neoplasms, is well known. In regard to the proteids, Wolff, after many studies, concludes that their character is identical with that of normal tissues, and it is only the quantitative distribution of these that differentiates the tumor from the physiological tissue. Wells agrees with others that there is no very distinctive character in the bio-chemistry of malignant tumors, but by reason of their excessive chemical component, as compared with benign tumors, they naturally show a high content of nuclear proteins; they, therefore, contain a high proportion of phosphorus and iron.
Interesting observations have also been made on other characteristics of cancerous tissues, such as the great abundance of enzymes of great variety which are actively autolytic, also in regard to certain relations of cholesterin, in regard to which Ewing has recently said, “There appears to be something in the chemical or mechanical nature of the irritation of cholesterin which is peculiarly effective in producing atypical proliferation of epithelium”; this has been found to be no less than 65 per cent. greater in quantity in fatty deposits, as in the mesentery, in subjects of cancer than in healthy persons, etc., etc. It would weary you to no purpose to attempt to refer further to the bewildering mass of research studies in connection with the bio-chemistry of cancer which are found in special literature: much of it is fragmentary and some of it contradictory, but all has its value as contributory to our knowledge of the actual conditions developed in connection with cancer growth; but up to the present time it cannot be claimed that any very practical results have been thus attained which will aid us in treating the disease.
As all cell life and proliferation of tissue depends on the activity of the cell nuclei, much attention has been paid to the changes found in them and the behavior of the centrosomes and chromosomes, all of which is too technical for us to consider here: suffice to say, however, that several observers have demonstrated heterotypic mitosis in malignant tumors, and that histologic examination confirms what other judgment has indicated, namely, that the cancer cell differs from a normal tissue cell mainly in its aberrant action under some stimulus, probably derived from the animal fluids by which it is surrounded. Thus we come back to our original proposition, for these fluids are, of course, but a reflection of the nutrition of the body or diet, as modified by the action of the various organs, including the internal secretions; all this is influenced again by the action of the nervous system.
It is difficult to produce definite proof in regard to the influence of nervous and mental strain and shock in the production of cancer, but careful observers have long claimed that there is such an influence, and from what I have seen I am firmly convinced that in some way these conditions often do so disturb the metabolism, or otherwise operate, in such a manner that cancer results. The influence of the mind upon the body is unquestionable, as has been so fully illustrated by Tuke, and from what I have observed I cannot doubt but that the mental depression common in those with the beginning of a process which they fear might result in active cancer, has much to do with accelerating its growth; whereas, on the other hand, the hopefulness which can arise with the attempt to change the diseased process by diet and proper medication, has much to do with the favorable results which may follow in suitable cases. In the same way the constant fear of recurrence after operative removal can have its share in inducing and perpetuating the metabolic error which excites the tissues to renewed cancerous action. I know that some of you will think that this is fanciful theorizing, but many a scientific fact, in many branches of science, has been worked out from a theory which at first has seemed fanciful.
We will now consider some of the data which have been recorded in regard to the relation of the secretions and excretions of the body to cancer, including the internal secretions.
Much labor has been expended, by very many observers, upon the analysis of the urine in connection with cancer, as that might be expected to reveal the metabolic changes connected with this disease. While many departures from the normal have been reported, and while under complete volumetric analysis the urine of a subject of cancer is rarely if ever that of health, it cannot be said that any definite and specific changes have been established which may not be found in those without cancer; although there have been several who have so claimed even diagnostic signs from the urine. But minute, volumetric analysis is often of great service in guiding the nutrition and medication of these patients, and gross errors are continually met with, which have the greatest bearing on the case in hand, as indicating very great metabolic disturbance: and constantly the urinary excretion will be found to be extremely deficient, both as to its quantity and its total solid elimination. In one very interesting case of cancer of the breast, in a stout, flabby lady, near 55, in private practice, the total daily quantity of the urine, measured for weeks, is always very far below the normal amount; and in spite of active medication it seems almost impossible to raise the total daily solids excreted in the urine, to more than one-half of that called for by the weight of the patient. We may now briefly consider some salient points reported in connection with the urine in cancer.
As remarked in regard to other elements in the study of the disease, it would be very desirable to have a knowledge of the urine in pre-cancerous stages of health, or ill health, and also in very early cancer, likewise after surgical operations, that we might better understand the metabolic changes which lead up to malignant disease; but unfortunately these are exceedingly few and unsatisfactory, and almost all the studies have been made in advanced cancer, and often when the disease has affected vital organs, or when by its own poison it has disturbed the workings of the economy.
Many observers agree that there is a disturbance of proteid metabolism in cancer, and dependent upon this many deviations from normal are found in the urine, some of which in turn are related to the inanition which occurs. The urea is almost invariably diminished, often very greatly, as I have verified time and again in many cases.
A number of studies have been made upon the nitrogen partition in cancer by Einhorn, Kahn, and Rosenblum, also by De Bloeme, Swart, and Terwen, and others, showing an increase in colloid nitrogen, to more than double the normal amount, increased elimination of xanthin, oxyproteic acid, and urinary ammonia, together with many other changes which show that disintegration of the protein elements is very imperfect and often excessive. An interesting statement is made by Blumenthal that the oxyproteic acids are increased even in very early cancer, and independently of the size of the tumor and degree of cachexia, seemingly showing them to have some specificity for cancer, because they have not been found in other forms of malignancy. He also states that urobilin is increased in a large proportion of cases of cancer, especially when cachexia is setting in, and is a grave symptom.
Reid, who has confirmed many of these matters reported by others, says: “I have found an increase of amino-acid nitrogen in practically every case of cancer I have examined”; ... “Hence we can only infer that in cancer, the liver, while not involved in the disease, is still unable, for some reason, to perform its functions in synthetizing urea. The organ is functionally injured, no lesions having been found to explain its insufficiency”; or possibly ... “cancerous subjects form proteids which the liver is unable to deal with, so that they are excreted unchanged, or nearly so.” Degrez has made confirmatory studies along these lines, and found the nitrogen disintegration very imperfect, with increase of the ammonia fraction of nitrogen, and increased elimination of xanthin bases. He states that “the toxicity of the urine is increased apparently as the result of the presence of substances which have not been fully oxidized.”
Notable changes have also been recorded concerning the sulphur elements in the urine, with a great increase in neutral (unoxidized) sulphur and a considerable excess of sulpho-cyanic acid, together with an increase in sulphates and indican showing the results of intestinal fermentation of protein elements, which also I have constantly observed.
The chlorides, on the other hand, are, as a rule, diminished in cancer, especially in its late stages, when there is inanition or kidney insufficiency; and probably any change in them has only a relation to the nutrition of the patients, for the chlorides come from the food and are commonly an index of the amount of nutriment absorbed. Robin finds some relation between the excretion of chlorine and nitrogen, according to the stage or degree in which the system is affected by cancer.
The phosphates are known to be increased in the urine of cancer subjects, although irregularly and in an inverse ratio to the chlorides; as inanition increases there is greater autolysis of cellular structure, and the nuclei yield an excess of phosphates, which are excreted in the urine. A more or less general demineralization of the system through the urine has been observed by several, and has been recognized as a significant matter, and is of special importance when we consider what an important part minerals take in the nourishment of cell life.
While the changes which have been observed in the urine in connection with cancer are not wholly pathognomonic, but occur in connection with other diseased states of the system, so that none of them can be accepted as diagnostic of malignant disease, they all have a certain significance as indicating the metabolic changes which accompany and, as we believe, have much to do with the etiology of cancer; and, as stated before, a careful, systematic, and frequently repeated volumetrical analysis of the urine certainly assists greatly in the proper management of these cases, that is when the departures from normal are carefully studied and correctly interpreted.
The saliva, and its action, constitutes a very important part in the process of digestion, and consequently of metabolism and the genesis of cancer; far too little attention, however, has been paid to it practically, in ordinary life or disease, although there have been many laboratory studies and writings on the physiological action of this secretion; but I have not been able to find in literature any investigations relating to its condition in cancer. And yet the experience and writings of Mr. Fletcher and others have demonstrated wonderful results from perfect mastication and thorough insalivation, and a careful consideration of digestion must convince every one of the importance of this secretion in connection with nutrition, both in health and disease.
Our time does not permit of more than a brief allusion to the subject, but in cancer patients I have so constantly found the salivary secretion acid, and often strongly so, instead of the normal alkaline or neutral, that I cannot but believe that this condition has some bearing upon the subject which we are studying; the saliva also is apt to be acid in diabetes, which is closely allied to cancer. It is to be remembered that the saliva, which amounts in health to between one and two quarts daily, varying somewhat with the food, is not wholly for the purpose of lubricating the mouth and facilitating deglutition, but its enzymes, ptyalin and maltase, effect radical and important changes in the starchy matters consumed. It is also to be remembered that the latter cannot be acted upon by the stomach secretions, but must be passed on to the influence of the pancreatic fluid in the small intestine, in case the action of the saliva has not been effective; hence there follows delayed and imperfect digestion, faulty metabolism, deranged nutrition, and possibly tumor growth. The importance, therefore, of very slow eating, thorough mastication, and perfect insalivation cannot be too strongly insisted on, both as an element of importance in the prevention of cancer, and also as a curative measure in patients in whom the diseased process has already manifested itself.
The so-called internal secretions have also been the subject of much research and speculation of late years, in regard to their influence on metabolism and the life processes of the economy, and many studies have been made concerning their connection with cancer, which cannot be long dwelt upon now; but there seems to be little doubt but that the secretions of the ductless glands in common have much to do with regulating the metabolism of the cells. We know, for instance, that disease of the pituitary body produces bone disorder, resulting in gigantism, that thyroid derangement results in myxœdema, and that disease of the supra-renal capsules gives rise to Addison’s disease, or bronzed skin; and it is not at all impossible that the derangement of secretion of one or more of these and other organs may be an element in the disordered action of certain epithelial cells, resulting in cancer. Harrower calls attention to the fact that cancer is essentially a disease of that period of life when certain of the ductless glands lose their normal function, this loss entailing related changes in the whole chain of interrelated functions of the ductless glands.
The supra-renal glands by their secretion have, as we know, great vaso-constrictor influence, and their complete removal is followed by death; it is more than possible that some failure in this secretion allows the exuberant blood to supply cancerous growths. Sajous says: “Certain growths, particularly the more malignant forms of sarcoma and carcinoma, seem closely connected with adrenal insufficiency and its normal consequences,” and there have been some clinical and research data confirming such a conclusion. Sajous further says, “The adrenals, as supporters of the thyroid apparatus in the defensive process, and in sustaining oxidation, metabolism, and nutrition, seem to offer a new clew to the pathogenesis and treatment of cancer that is worthy of further inquiry.”
The pancreas has been thought to have some influence in a perverted metabolism leading to cancer, Kahle stating that there is a retention of silica in that organ in cancer patients, to even double the normal amount. A treatment of cancer introduced by Beard, also strongly presented by Saleeby, by trypsin and amylopsin, the enzymes of the pancreatic fluid, excited some attention a while ago; but unfortunately no satisfactory results have thus far been obtained from this line of medication, as was fully demonstrated by Bainbridge at the New York Skin and Cancer Hospital, in one hundred cases.
The pituitary gland by its secretion has undoubtedly some coordinating power, with the adrenals and thyroid, over the processes of metabolism, and a number of observers have regarded it as of importance in connection with the genesis of cancer. Little has recently reported some cases of cancer in which pituitary extract with that of the pancreas has produced remarkable results.
The thyroid is now recognized as playing an important part in assisting metabolism, and, like the adrenals and pituitary, its complete removal, with the parathyroids, in animals is followed by death. While the study of the hormones is still in its infancy, there seems to be no question but that the endocrinous glands act conjointly, the one influencing the other, and that together they exert a very great influence in the life processes of the body and on the behavior of its component cells. The thyroid has been shown to be one of the main factors in the management of calcium within the body, which is believed to be an element in cancer, and enhances the catabolism of toxic wastes, which are etiologic elements in this disease. Many have reported favorably on the effect of thyroid feeding in cancer, and after an experience with it in many cases I am convinced that it has been one of the means which contributed to the good results obtained. On the other hand it has been claimed by Stuart-Low that the surgical removal of the thyroid, or part of it, or ligation of the thyroid blood vessels has arrested cancer, in several cases.
Thymus gland feeding has also been reported on favorably by a number of observers (Rohdenburg, Bullock, and Johnson, also Gwyer), they reporting relief of pain and improved general conditions, notably gain in weight and increased hæmoglobin in all but one of sixteen cases, though some of them died. On the other hand Ross reports most unfavorably on the administration of thymus, which he gave to some inoperable and hopeless cancer cases, in which he said that in two or three weeks the tumors had quadrupled in size and the condition of the patients was very much worse; the same occurred also when some cancer patients were given calcium salts freely. Ross makes some interesting suggestions in regard to the thymus, and its relation to calcium and magnesium; these latter are freely utilized in the growth of bone up to the age of twenty-five years, by which time the thymus gland has quite disappeared; but after this time these salts tend to have pathological relations in various tissues, and also cancer becomes frequent.
The internal secretions of the testicles and ovaries are also thought to have some share in metabolic processes, and observations have been made in regard to their influence in cancer. Thus Cahen reported that Beatson’s operation of castration for cancer, done first in 1896, had been repeated by many, so that Lott had reported 99 cases including his own. Of these in 23.2 per cent. the operation caused a distinct improvement in the cancer. In 15 cases the improvement persisted for a year, in 4 cases for 4½ years and in one case for over 5 years. Cahen operated on seven women with remarkable results; in two cases life was prolonged 4 and 6 years respectively. Others, however, have shown by statistics, that damage to the ovaries by disease, or their removal by operation, greatly increases the proclivity to cancer. Several writers have connected cancer with the waning of the sexual powers, and the suggestion is made by Sherrington and Copeman that in the period which antedates the cancer age, the reproductive glands, by means of internal secretions, are able to inhibit the growth of cancer.
In looking back over what has been observed in regard to the secretions, including those of ductless glands, we see that very strong evidence has accumulated to show that they have a very intimate connection with the development of cancer, as was to be expected, since they are very important factors in connection with metabolism.
We have also seen that while there has not been demonstrated any very definite and specific change in the bio-chemistry of tumors, and no specific enzymes or poison secreted by cancer cells which can communicate the disease, there is evidence that the disordered cells secrete a something which deranges the blood and ultimately tends to end life; for the blood in advancing cancer undergoes very radical, degenerative changes, some of which improve decidedly when a cancerous mass is removed surgically, but return with the regrowth of the tumor.
We have also seen that the urine manifests alterations which show a disturbed metabolism, and that the saliva has an abnormal acidity leading to disturbed amylaceous digestion.
We have further seen that there is evidence that the internal secretions of many organs, probably, through their influence on metabolism, are factors of importance in connection with the genesis and cure of cancer. Little well says, “Cancer is a disease of disordered nutrition, as a result of which cells revert to a primitive stage, which permits reproduction. The disordered nutrition is due to relative hypofunction of the ductless glands.” In later lectures we shall consider the basic causes of this deranged nutrition, which, as has been already intimated, has much to do with diet and the various elements of life which tend to induce functional and other derangements of the system, many of which are included in and influenced by what we term the advance of civilization.