The history of the thymus gland dates back more than 2,000 years. From this earliest time, the role of the thymus was a mystery. Fictitious disorders attributed to the thymus included thymic asthma and status thymicolymphaticus in the late 1800s. These two disorders are particularly notable due to the coincident discovery of x rays. Radiation provided a method to diagnose and treat an “enlarged” thymus in infants. The influence of pediatric radiology subspecialization contributed to the establishment of normal thymic variation and the eventual demise of thymic irradiation. However, there are contemporary challenges with thymic imaging that are fitting for the ancient thymic moniker “organ of mystery.”
The thymus gland has a colorful history. This is due not as much to an enlightened understanding as to the unfortunate misunderstanding of its form and function. In fact, throughout much of the 2,000 years since it was first acknowledged, the thymus gland has been predominantly a victim. The events underlying this perception reflect the social attitudes of the period, medicolegal trends, and important medical developments, including the discovery of x rays. This technology provided an unprecedented (and unfortunate) opportunity to visualize the thymus in children.
The intent of this article is to present the historic background of the thymus gland in children. The importance of this historical perspective for radiologists is twofold. First, thymic radiography and radiation therapy in the early 1900s were substantial issues in the evolving field of pediatric radiology (1). Second, the historical vantage provides a greater appreciation for the contemporary difficulties with thymic imaging. Despite the progress in elucidating the role of the thymus gland in immunology and the availability of new imaging modalities, the thymus remains an imaging enigma in many respects.
The name thymus comes from the Latin derivation of the Greek thymos, meaning “warty excrescence,” due to its resemblance to the flowers of the thyme plant. The homonym thymos also translates as soul or spirit, and it is for this reason that the thymus was misrepresented as the seat of the soul by the Greeks (2,3). The earliest known reference to the thymus is attributed to Rufus of Ephesus circa 100 ad (4). A Greek anatomist renowned for his investigations of the heart and eye, Rufus attributed the discovery of the thymus to the Egyptians. The most famous physician of antiquity, Galen of Pergamum (ca 130–200 ad), stated that the thymus played a role in the purification of the nervous system (5). He was also the first to note that the thymus was proportionally largest during infancy (5). Galen's most durable contribution to thymic history may be his reference to it as the “organ of mystery,” a moniker that remained fairly accurate for almost 2 millennia.
Like much of medicine, ideas with regard to thymic anatomy and physiology languished for centuries between the Fall of Rome and the 18th century. Signaling a renewed interest in the thymic gland, Vesalius wrote in the 1600s that the thymus was simply a protective thoracic cushion (6). In the 1700s, the predominant new theory was that the thymus somehow regulated fetal and neonatal pulmonary function. Hence, it became known as the “organ of vicarious respiration.” Others thought that the thymus simply filled the space that would later be occupied by the growing neonatal lungs. In 1777, William Hewson (7) published the first scientific treatise on the thymus. On the basis of findings of his investigations in dogs and calves, Hewson described the evolution of thymic size during fetal and infant life, thus verifying Galen's observation. He concluded that the thymus itself was some sort of modified lymph gland.
In 1832, Sir Astley Cooper published The Anatomy of the Thymus Gland (8). Keeping with the prevailing medical notion that anatomic study would reveal function, this work was largely the result of findings from animal dissections. Cooper (8) noted that there was wide variability in thymic size and morphology and reconfirmed Hewson's (and Galen's) observations with regard to fetal and infant growth. Cooper also poignantly disagreed with earlier opinions of fetal function, stating
That an important function must be performed by an organ . . . so large . . . and secreting abundantly, no one who duly considers the subject can for a moment hesitate to acknowledge; . . . I cannot subscribe to the opinion . . . [that] this Gland is designed merely to fill a space which the lungs . . . may be destined to occupy. (8)
Further elucidation of thymic function was still more than a century away. Of note, among 48 pages and many plates of elaborate illustration in the Cooper text, only three pages of text are devoted to diseases of the thymus, and these were largely a few case reports.
Twelve years after Cooper's book was published, John Simon (9) published what was to be considered a landmark essay on thymic structure and function, although in reality it offered no new observations and relied heavily on Cooper's work. The author concluded with the vague comment that the thymus is “the sinking fund in the service of respiration” (9). At about the same time, in 1846, Hassall and Vanarsdale (10) used recent improvements in compound microscope lens quality to study the thymus more thoroughly. Hassall's famous corpuscles were thus named. They (10) also described differences between the thymus and other lymphoid tissues.
Insight with regard to thymic function made little progress in the late 19th century. In fact, it became widely accepted that the thymus served no useful purpose. The disrespected organ, however, did become one of the biggest medical scapegoats of the century, and a great deal of pediatric disease was attributed to its enlargement. By 1904, there were enough publications dealing with thymic diseases to inspire the remark in the Reference Handbook of the Medical Sciences (11) that there had been “an overwhelming amount of attention in the literature concerning diseases of this organ.”
Most of the publications during the last half of the 1800s focused on two thymic conditions, thymic asthma and status thymicolymphaticus. Several social issues nourished the development of these fictitious diseases. These included increasing public concern with child health (and death), medicolegal trends, and the birth and explosive growth of both anesthesiology and radiology (12,13).
The last half of the 19th century saw proliferating public recognition of child welfare issues and the attendant increased awareness of child health and illness. In particular, there was growing concern over sudden infant death. Disorders (anatomic or constitutional) of the thymus that caused “suffocation” provided a convenient social absolution of mothers and nursemaids of negligence or murder in cases of unexplained infant death (later to become known as crib death and now known as sudden infant death syndrome). Medicolegal issues figured prominently in the perception of the thymus. A specific cause of death (as opposed to the previously accepted “visitation from God”) became mandatory for public records (12,13). These “nonscientific” forces perpetuated the belief in the two pediatric maladies, thymic asthma and status thymicolymphaticus, despite a lack of proof and often despite contradictory evidence.
The first known description of thymic asthma (also known as asthma thymicum, Kopp asthma, laryngismus stridulus, and laryngismus) is attributed to Kopp in 1830 (14). The existence of this disease, which became quickly and widely accepted, attributed sudden death in children to airway occlusion by an enlarged thymus. One early description is particularly striking: “ . . . the child was sitting on the floor amusing itself. . . . They saw the little thing stoop forward suddenly, as though to play. . . . As it remained in that position, however, they went to it, took it up, and found it dead. It had perished suddenly, no doubt in on the paroxysms of laryngismus” (15). It was not difficult to identify the so-called enlarged thymus in a previously healthy infant who died suddenly (Fig 1) when comparing him or her to those succumbing to prolonged illnesses. This idea of thymic compression as a cause of death persisted for at least a century. In the 1924 edition of Management of the Sick Infant (16) (in the colorfully named chapter “Internal Secretions”), the authors claimed that the clinical picture of thymic asthma was “so characteristic that once seen, it is unlikely to be mistaken.” This clinical “Aunt Minnie” is described in the same text as paroxysms of inspiratory and expiratory stridor, with resultant cyanosis or even death in extreme cases. These views persisted despite contrary evidence, some of which was cited in the same textbook. Investigators had noted that many children who died of other causes had an enlarged thymus, and in many deaths attributed to thymic asthma, the thymus actually was not large (17).
Although belief that the thymus could compress the airway (Fig 2) and result in sudden death persisted, contrary evidence gradually accumulated. Several researchers, using measurement of the gland, produced evidence that healthy infants had an enlarged thymus, an important finding given the lack of measurement of the allegedly lethal gland in prior series (17,18). It was also thought that the thymus was too pliable an organ to cause airway obstruction (19). The culmination of this trend was precociously summarized as early as 1858 by Friedleben (19), who aptly stated “There is no thymic asthma.” Despite these investigations, however, the prevailing attitude remained that the thymus must be a culprit for sudden death. Guntheroth (13) pointed out that the 1985 edition of Dorland's Medical Dictionary still contained a listing for Kopp asthma, concisely defined as “thymic asthma” (20). The implication is that this phrase should be as easily recognized or understood as, for example, the descriptor “congestive heart failure.”
In the late nineteenth century, many diseases were thought to have a “constitutional” origin, a throwback to the “humors” of antiquity. Medical philosophy was now moving on from its anatomic basis of disease. Thus, waning belief in thymic asthma comfortably yielded to the constitutional entity of status thymicolymphaticus.
In 1889, the Austrian physician Paltauf (21) filled the void of dwindling acceptance of thymic asthma with another (and more difficult to disprove) notion of the thymus gland as a cause of otherwise unexplained infant death. He described, in accordance with contemporary medical emphasis on constitutional disorders, status thymicolymphaticus (also known as constitutio-lymphatica, lymphatic constitution, lymphatic-chlorotic constitution, lymphatic diathesis, lymphatic dyscrasia, lymphatic habitus, lymphatism, status lymphaticus, status thymicus, and thymo-lymphaticus) (21). This disorder was thought to be due to an underlying process that caused all lymphoid tissue to be enlarged. One manifestation in the victims was an enlarged thymus (notably, no actual measurements were provided) (22). This concept differed from thymic asthma, because direct airway compression, an anatomic concept, was not a feature. One essential requirement was that there be no other potentially fatal disease or abnormality at autopsy.
This notion of a predisposition to sudden death, with the thymus again as culprit, was quickly seized upon by the medical profession. Those affected were nearly always infants or young children who tended to be “ . . .well fed, pale, pasty, flabby, and rather inert and effeminate, with large thymus and tonsils” (13) but otherwise usually healthy. Affliction (death) was sudden but was occasionally induced by mild stress. The disorder was a major focus of attention until the early 1930s. Status thymicolymphaticus provided an explanation for the death of infants and children who died during anesthesia. The need for such an explanation was fueled by developing legal concepts that physicians may be held responsible for pediatric deaths.
Radiology played a central role in the diagnosis of both thymic asthma and status thymicolymphaticus. For example, the 1924 edition of Management of the Sick Infant (16) states that a radiograph could be used to “distinguish an enlarged thymus and thus aid in differentiating it from laryngeal spasm or a papilloma.” This was the epitome of high pretest probability, because an enlarged thymus was considered as “the presence . . . of an increased triangular shadow . . . above the heart . . . with the base of the triangle about coincident with the upper border of the sternum” (16). After the advent of radiology, physicians often relied heavily on radiographs for the diagnosis of both thymic asthma and status thymicolymphaticus. After radiographic diagnosis, thymectomy (with a mortality rate that approached 33%) was often advocated (23). A less extreme recommendation for an enlarged thymus seen radiographically was a lifetime avoidance of general anesthesia (24).
Strict criteria were eventually accepted for considering the thymus large on a chest radiograph. One of the more popular estimations compared the width of the thymus to the width of the thoracic spine at the T2-T3 level. If the thymus was three or more times this width, it was considered large. Twice the width was considered borderline (25). Other authors, including Pancoast (26), advocated relying on the lateral image for evidence of tracheal displacement posteriorly. Findings of these same studies served as an impetus to obtain preoperative chest radiographs for all children, even before minor procedures.
Radiology was also prominent in the treatment of thymic asthma and status thymicolymphaticus. Had either disorder been considered undiagnosable in life and untreatable, perhaps they would have been more curiosities than tragic historic vignettes.
Before the advent of radiation therapy, the only treatment for thymic asthma and status thymicolymphaticus was surgical. Since the thymus was sensitive to radiation (27), this became a popular method of treating the disorders in children (Figs 3, 4). In 1907 in Cincinnati, Friedländer (29) reported on the first successful case treated (in 1905) with therapeutic irradiation (30). Thousands of children eventually received radiation to treat or prevent status thymicolymphaticus. There were those who even advocated prophylactic irradiation for all neonates (31).
The first patient was treated with a total of 96 minutes of x rays. The dose was progressively reduced over the next 2–3 decades to “half skin erythema dose” and eventually to a total of 75–200 rad (0.75–2.00 Gy) (28,32). Despite the obvious acute changes from treatment and the established connection between radiation and cancer, a request for thymic irradiation by an uninformed physician was made in the late 1960s (Taybi H, oral communication, 1997). The increased risk of thyroid malignancy in these patients was first recognized in 1949 (33). There is also evidence that other tumors occur at higher frequencies than expected, including breast cancer (34,35).
The beginnings of pediatric radiology as a subspecialty were forming in the earliest decades of the 20th century. In the 1924 text Management of the Sick Infant (16),the authors noted that, in children, “proper interpretation of the x-ray plate requires experience.” However, early in the history of status thymicolymphaticus there were essentially no pediatric radiologists. With the development of the specialization, pediatric radiologists were among the first to assert that a normal thymus could create a large shadow on chest radiographs (Fig 5). Indeed, in a taped interview in 1974, John Caffey, MD, stated that “destroying the thymus myth” was one of his field's most important contributions to medicine (videotape courtesy of C. A. Gooding). Caffey went on to say “ . . . most mistakes I've seen were not because one didn't know some disease, but because he didn't know he was looking at normal.” This sentiment succinctly summarizes the nearly three-quarters of a century of status thymicolymphaticus. In the first edition of his textbook in 1945 (36), Caffey proclaimed “ . . . a causal relationship between hyperplasia of the thymus and sudden unexplained death has been completely refuted. . . . Irradiation of the thymus . . . is an irrational procedure at all ages.” More detailed discussion on Caffey's involvement with this issue was provided in an editorial by Silverman (1).
There are more contemporary chapters in the controversy of the thymus. After the disappearance of status thymicolymphaticus, the thymus was found to “get in the way” of the cardiovascular structures. In the late 1940s, steroids were given to shrink the thymus in children for improved visualization of the heart and great vessels (37). This was not routinely advocated by all leaders in the then small group of dedicated pediatric radiologists at the time (Silverman FN, oral communication, 1997). A more controversial issue is the association of a cervical thymus with airway narrowing, as demonstrated with magnetic resonance imaging (38,39) and reminiscent of thymic asthma.
While the discussion of thymic asthma and status thymicolymphaticus is relegated to historical text and modern diagnostic methods (including imaging) minimize the promotion of specious disorders, definite thymic paradoxes continue. Delineation of thymic involvement by lymphoproliferative disorders in children continues to be challenging (40). Explanations for involvement of the thymus in some disease processes, such as the cystic change in patients with human immunodeficiency virus, or HIV, infection are presently elusive. The imaging features of the pediatric thymus as demonstrated at positron emission tomography are not yet well defined (41,42). Finally, there may be new demands on imaging of the thymus as procedures such as thymic transplantation for thymic aplasia (DiGeorge syndrome) emerge. Contemporary issues with thymic imaging have recently been reviewed (43).
Much like with the chest radiograph in the period of status thymicolymphaticus, radiologists must be aware of our limitations with imaging the thymus. The historical review of the thymus in children also reveals how social concepts influence scientific thoughts and the potential tragedy of preconception and misunderstanding (which can be robust) illustrated by thymic irradiation. It is ironic to note that the Greek word for the thyme plant, from which thymos is derived, means “to burn in sacrifice,” which is related to the ceremonial use of the plant (1,2). This derivation proved apropos some 2,000 years later with the ill-informed irradiation of the gland. In the end, it is no small consolation that this misunderstood organ provided a fundamental platform for the development of pediatric radiology. Finally, if we are to learn anything from the historical perspective of the thymus in childhood, it is that contemporary thought will also be history some day and under the scrutiny of individuals who will almost certainly be closer to the truth.
Figure 1. Illustration of a neonate at autopsy whose demise was attributed to “thymic death.” The caption drew attention to the ”enormous size of the thymus,” which is actually normal in appearance. (Reprinted, with permission, from reference 6.)
Figure 2. Thymic asthma. Sagittal illustration of tracheal narrowing (arrows) due to the enlarged thymus. In this case, tracheal narrowing is exaggerated with neck extension. Th = thymus. (Reprinted, with permission, from reference 6.)
Figure 3. Photograph illustrates the technique of thymic irradiation for either status thymicolymphaticus or thymic asthma. In the caption for the original illustration, note was made that a piece of lead rubber sheeting normally covered the restrained infant, except for a window over the thymus. In this photograph, the sheeting was not present to demonstrate the “relation of the cone to the chest.” (Reprinted, with permission, from reference 32.)
Figure 4a. Disappearance of the thymus after irradiation in an 8-week-old infant with “symptoms of thymic enlargement,” according to the original caption. (a) Arrows in an initial frontal radiograph point out “atelectasis” of the right lung and accompanying thymic enlargement, an appearance that today is recognized as a normal finding due to the thymus gland. (b) Radiograph obtained 5 weeks after thymic irradiation (dose not given) shows that the thymus is notably smaller; the original noted that the child “is now enjoying perfect health.” (Reprinted, with permission, from reference 28.)
Figure 4b. Disappearance of the thymus after irradiation in an 8-week-old infant with “symptoms of thymic enlargement,” according to the original caption. (a) Arrows in an initial frontal radiograph point out “atelectasis” of the right lung and accompanying thymic enlargement, an appearance that today is recognized as a normal finding due to the thymus gland. (b) Radiograph obtained 5 weeks after thymic irradiation (dose not given) shows that the thymus is notably smaller; the original noted that the child “is now enjoying perfect health.” (Reprinted, with permission, from reference 28.)
Figure 5. Normal variation in thymic appearance from the first edition (in 1945) of Pediatric X-Ray Diagnosis by Caffey. Original arrows demonstrate some of the variations in thymic size and configuration. Before Caffey emphasized this normal variation, thymic appearances on radiographs similar to these were implicated in cases of sudden infant death, particularly from status thymicolymphaticus. (Reprinted, with permission, from reference 36.)
Address reprint requests to D.P.F.
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