Part 1. The Thymus Gland and Its Unfortunate Location
We have made a choice concerning which data we shall use for a detailed illustration of the "nuts and bolts" features of our handling of the actual procedures of processing the breast-dose data. And we make this choice for many reasons. Some of the very best clinically-available data needed for the study are those of breast irradiation in female infants under 6 months of age, with breast irradiation occurring both in the diagnosis and the therapy of "Enlarged Thymus," the thymus being a gland lying under the sternum (breast-plate). Moreover, the results are strikingly important in this entire picture, as will be seen. Analysis of this evidence represents a fascinating, exciting, useful effort for humanity's health in the future, if we take heed of its message. But it is also a tragic recounting of how high the price can be for a message, with many, many thousands of women paying the price via breast-cancer.
We shall present the story of the "Enlarged Thymus" problem first in this book. No reader will have any difficulty with this account from history. However, when we come to Chapter 8, there will be some numbers and calculations. None are foreboding. Nevertheless some readers may prefer to leave those calculations for later in-depth examination, if they choose to do so. They can choose to "accept" our numbers on their first time through the book.
How Did the Thymus Gland Get Embroiled in All This, Anyhow?
We are seeking out the extent to which ionizing radiation is a major cause of breast-cancer in our country. Why "pick" on the thymus? It happened that an organ, the thymus, became known as an organ needing diagnosis and needing therapy with ionizing radiation in some cases. But it was a pure accident of fate that the anatomic locations of the thymus and the breasts were such that if the thymus were going to get thoroughly irradiated by x-rays or gamma-rays from radium (and both were used), it was nearly impossible to avoid partial irradiation of the breasts. Undoubtedly there were some private offices and institutions that gave much lower, others, much higher breast-doses than the average in the course of their management of alleged thymus disease.
If the thymus had been located on the thigh, and if we were concerned about breast irradiation, the thymus problem would not have anything to do with the problem of breast irradiation. It is necessary to have the reader understand this, for otherwise the impression could be left that thymus disorders and breast-cancers have some special intimate relationship which we are investigating.Part 2. The "Enlarged Thymus" Story
This is the story of a set of symptoms and signs which captivated the medical profession for essentially a half-century. A careful reading of the medical literature of that half-century reveals the absolute certainty of numerous experts on opposite sides of the question of the meaning and ultimate effect of these symptoms and signs. Many physician-experts in the field reported 90 to 100% cure with ionizing radiation for the variants of the "enlarged thymus" problem, in series involving hundreds of cases. Others reported that the disease being treated did not really exist and had never existed before. All of this went on for a half-century, often with white-hot debate.
Of one thing we can be certain: It was an inevitability that female breasts in infancy --- even in the first month after birth --- received a great deal of radiation in the course of this long-ongoing giant medical debate over the questions about existence of "enlarged thymus," its appropriate diagnosis, and its appropriate treatment.
After examining the literature of the multi-decade convulsion in the medical-radiological-pediatric-surgical community, it is clear to us that it would be impossible to understand the magnitude of the x-ray dose to female breasts in the 1920-1960 period, without intensive investigation of the "enlarged thymus" story. Friedlander (1907) is widely credited with having reported the first case of a child with enlargement of the thymus treated "successfully" with x-ray. Sidney Lange (1911) brought this to the attention of roentgenologists with a report, quickly noted as important, of successful treatment of four cases of enlarged thymus with x-rays.Part 3. Dr. Sidney Lange
Puts the Enlarged Thymus Problem "On the Map"
This beginning in 1911 came when Dr. Lange, of Cincinnati, published his paper, "X-Ray Therapy of Enlarged Thymus" (in the American Quarterly of Roentgenology, Vol.III, April 1911, 1-22). We quote directly from his paper (p.1):
"It is the purpose of this paper to report four cases of enlarged thymus treated by X-rays, to make a plea for the consideration of enlarged thymus as a separate entity, apart from the so-called status lymphaticus of Paltauf [which we will consider later], and by experiments upon young rabbits to demonstrate the action of the X-ray upon the thymus." And:
- "Case 1, E.L., male, aged 7 weeks, was referred for X-ray treatment because of cyanosis [blueness of the skin] and inspiratory stridor [ stridor is often described as any noise apparently coming from the trachea during breathing, often characterized as" "crowing" in nature]. The diagnosis of enlarged thymus was based upon the presence of an abnormal area of dullness over the upper part of the sternum [medically, dullness in the" chest means apparent solid or liquid beneath the percussing finger where there should be air-filled tissue]." And:
"The family history strongly supported this diagnosis. A previous child which was normally delivered at full term developed, a few days after birth, a marked cyanosis which persisted without remission. At the age of three months it began to have attacks of suspended respiration, with extreme cyanosis, which attacks were relieved by raising and lowering arms above the head. The child died suddenly in one of these attacks at the age of four months." And (p.2):
"The present baby was delivered normally at full term, weight at birth, 6 1/2 lbs. It was breast-fed. From birth it was noticed that the child's color was not good, appearing dusky and blue at times. When about two weeks old, he began to snuffle in respiration as though there were an obstruction in the nose. The respirations became wheezing in character and at times noisy. After crying, very rapid crowing inspirations would occur, and cyanosis [was] very marked." And:
"When presented for treatment child was seven weeks old, and weighed 8 1/4 lbs. Color was dusky, and at times decidedly blue, especially marked after crying. Mucous membranes were pale, hands and feet cold. The child was very restless, arms and legs jerking, and head and body constantly moving." And:
"The respirations were accelerated and noisy. There was a snuffling in nose and wheezing in chest, alae nasi flared slightly in inspiration, and there was retraction of the jugulum and intercostal spaces."
And, after several intervening paragraphs,
"The skiagram [x-ray picture] which was made with difficulty because of the great restlessness of the child, showed a broadening of the upper mediastinal shadow [the region in which the thymus gland resides]."
Dr. Lange elected to treat this child for enlarged thymus, giving x-ray exposures twice a week, the treatment extending over a period of two months, during which time fifteen exposures of the child to x-rays were made.
We again quote Dr. Lange (p.2):
"The response was prompt. The dyspnoea and cyanosis rapidly improved, appearing at only infrequent intervals after crying and occasionally in morning on awakening. The restlessness disappeared, the child became quiet and playful." And (p.3):
"Two and a half months after beginning treatment, child appeared normal, except after a severe crying-spell when slight duskiness would appear. The skiagram showed a decrease in the breadth of upper mediastinal shadow..."
The child was discharged from treatment.
- A second child was described thusly (p.3): "Stridor so constant and severe that the child could not take food. Attacks of parxysmal cough and cyanosis coming on at short intervals threatened his life."
The child was immediately treated with x-rays over the upper mediastinum, with exposures made over front and back (age 9 1/2 months at this time).
"Within 48 hours after the first treatment there was slight improvement. This improvement continued uninterruptedly over six weeks, during which 13 treatments were given." And (p.4):
"Cough and stridor had practically disappeared, and the thymic dullness in chest decreased to normal bounds." And (p.4):
"... at intervals of about three months thereafter, the child had three slight attacks" of cough and dyspnoea. Each time he was brought to Cincinnati promptly, and given one" or two X-ray treatments which at once dissipated the symptoms. One year after beginning the treatment the father reported that child seemed perfectly well."
- A third child had shown a crowing respiration a few weeks after birth. Dr. Lange relates that at 3 1/2 months the child was in such desperate condition that when the child was brought into the waiting room, the crowing inspiration could be heard in the next room, although the door between the two rooms was closed. "Ten treatments were given over a period of eight weeks. The improvement was prompt. The crowing subsided and nursing became less difficult."
The child did well, although the mother reported that some wheezing could be heard at times, especially during sleep. Dr. Lange suggests the child should have had a few more x-ray treatments.
- A fourth child also presented with noisy breathing. Inspiration was audible at all times. An x-ray plate showed a broadening of the upper mediastinal shadow, especially to the left. At page 6:
"Seven X-ray treatments were given which improved the child so much that the mother considered the child cured and although further treatment was advised failed to bring the child in."
Lange wrote the following at page 7 of his 1911 paper:
"Furthermore, it is well-known that the thymus may enlarge in any chronic infection, and that it is regularly enlarged in Addison's disease, and in exopthalmic goiter. Enlargement of the thymus, therefore, may be considered as a separate entity apart from the status lymphaticus of Palthauf, although it is the usual accompaniment of the latter, and the profound influence of the X-ray upon thymic enlargement of whatever origin should be borne in mind. The action of the X-ray upon the thymus is analogous to its action upon the spermatogenic epithelium of the testicles, or if we accept the lymphatic origin of the thymus, it is comparable to the destruction of lymphocytes in lymphatic enlargements or in leukemia."Part 4. Were There Any Ideas of Mechanisms at Work in This Therapy?
Lange wrote further at page 8 in his 1911 paper:
"In all four cases reported the symptoms were those of actual pressure upon air passages and blood vessels. This question of actual mechanical pressure by an enlarged thymus has been much discussed and doubted by some, notably Paltauf, because of the fact that in many cases of `thymus deaths,' the thymus while enlarged did not at autopsy seem to be compressing the trachea or veins." And (p.8):
"Drawing my conclusions from the cases reported in the literature, thymus deaths may be grouped under three headings. The first group includes those cases in which there are actual pressure symptoms appearing sometime before death and the post-mortem reveals evidence of pressure upon the mediastinal contents. In the second group, the thymus while enlarged does not produce any prodromal pressure symptoms during life, and the post-mortem shows enlargement but no actual signs of pressure. The fatal issue in these cases is explained by a sudden swelling of the thymus, due to some exertion, as in crying, or due to some interference with the circulation as produced by certain positions of the patient, or as would occur in giving an anesthetic. In these cases, a vicious circle is established. In addition to the swollen thymus, the mediastinal veins become distended and the heart dilated which again react on the swollen thymus, the combination producing death." And (p.9):
"In the third group, the deaths are extremely sudden without evidence of mediastinal pressure of any kind. Upon autopsy the thymus may or may not be enlarged. This group includes the true status lymphaticus of Paltauf, and the cause of death, according to Svehla's theory and experiments, is `Hyperthymization.'" And:
"However, the post-mortem state of the gland is not a criterion of its volume and relations during life, for vascular turgescence of the gland during life alters these relations. The swollen thymus presses upon veins which in turn become turgid and react upon the thymus, thus greatly increasing the mediastinal pressure..." And (p.9):
"Jackson [JAMA, 1907] by bronchoscopy demonstrated actual pressure upon the trachea in a case of enlarged thymus without any accompanying signs of status lymphaticus."
Lange's recommendations at p.12:
"Upon considering the tendency to recurrence after X-ray treatment in each case and noting the experiments of Rudberg showing rapid regeneration following irradiation, it would seem that the X-ray exposures were given too conservatively in these cases. The vague fears of the mother as to the possible harmful effects of the ray, which fears are not infrequently shared by the physician, often cause the X-ray operator to err on the side of conservatism and to treat too lightly and discontinue the treatment too soon." And:
"Therefore, in view of the difficulty often encountered in the diagnosis of thymic enlargements, and in view of the prompt action and the harmlessness of a few X-ray exposures, Roentgen therapy may be rationally employed as a therapeutic test in obscure cases."
The literature decades later was still suggesting x-ray therapy as a therapeutic test "in obscure cases." We might add that mother's intuition may have been written off fifty years too soon, with respect to "possible harmful effects" of this therapy.Part 5. The Mixed Reception
of Dr. Lange's Therapy for Enlarged Thymus
What followed the presentation of Lange's paper became a major war among physicians over the next half-century! Dr. Lange did not suffer from an absence of powerful, prestigious physician following. And on the other hand, the opposition hardly was silent during the fifty-year period following his paper.
At the presentation itself, Professor Henry Pancoast, a "dean" among radiologists and organizer of the University of Pennsylvania department of roentgenology, said (p.16):
"The Society should feel grateful to Dr. Lange for this report on something new. This is a treatment which is undoubtedly of great value."
And in closing his remarks, Dr. Pancoast said (p.17):
"If all we have heard is true, we have here a new and interesting field for X-ray work, especially if the effect of the ray on lymph tissue is what I believe it to be."
And Dr. A.M. Cole, of Indianapolis, said (p.18):
"This excellent paper of Dr. Lange's does demonstrate that the Ray will cause a partial atrophy of the Thymus gland and thereby will cure the train of symptoms associated with its enlargement. I consider this paper one of the most valuable contributions to Roentgen Therapy."
Fond references to "the Ray" are commonly seen in early radiological writings.
The boiling controversy gained momentum from this date forward.
In a 1924 paper, Dr. George Pfahler, widely labeled "the dean" of American roentgenologists, wrote on the subject (and thus lent a whole lot of prestige to the ideas), some 13 years after Lange's plea for more attention to this disorder and its treatment. We quote Dr. Pfahler (at p.39):
"Thymic enlargement is receiving more and more attention throughout the country. I am sure, however, that many cases go unrecognized and, as a result the symptoms are unduly prolonged from lack of treatment. The roentgen ray is undoubtedly the most reliable means of diagnosis, and radiation by x-ray or radium is a specific in treatment. So general is the response to treatment, that if the symptoms do not show definite improvement after a few x-ray treatments or one radium treatment, the diagnosis is almost certainly incorrect, or the symptoms are influenced by some associated pathological condition." And (p.39):
" ... On the other hand, thymic symptoms may develop, we believe, even when no enlargement is shown by the x-ray. For by the x-ray we can only show lateral enlargement, and yet it is the anteroposterior pressure which causes the symptoms." And: "For this reason, Dr. [James] McKee frequently sends children for examination and treatment, with instructions that the child shall be treated even if I find no enlargement of the thymus. I believe that this therapeutic test is even more reliable than the x-ray diagnosis. In nearly all such cases the symptoms are relieved by the radiation."
What symptoms? Let Dr. Pfahler answer (1924, p.40):
"Symptomatology. The classical symptoms are dyspnea, cyanosis, and an inspiratory stridor, but if one depends only on this trio of symptoms many cases will go undiagnosed." Dr. Pfahler refers (p.40) to a letter from Dr. Lange saying that he sees at least three new cases each week and often three new cases in one day, and gives me [Pfahler] by letter the recommendation of x-ray examination for any of the following symptoms: "Inability to cry loudly, crowing respirations when crying, noisy respirations or wheezing, noisy respirations during sleep, difficulty in nursing, vomiting or regurgitation, feeble respiration, grunting as though the child wants to have a stool, slow or retarded development..."
Dr. Pfahler cites G.W. Grier recommending the x-ray examination in all premature babies, and cites Lange saying, "Premature infants and infants with enfeebled respiration are stimulated and often tided over by x-ray exposure to the thymus." Much argument ensued in the literature during those early years as to whether there was, or was not, a direct pressure problem accounting for many of the signs and symptoms.
"Uniformly Brilliant Results"
Dr. Pfahler concluded (1924, p.44):
"There is probably nothing in radiotherapy that gives such uniformly brilliant results. The younger the child, the more prompt are the results."
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Note: Journals vary. Some write "X-ray" and others write "x-ray" --- some write "the Ray" and others, "the ray." And in Lange 1911, variation occurs within a single article.