Early Concepts Of Cancer Causation

Because cancer was defined only by its clinical behavior, it was impossible for the clinician of the period seeing a lesion for the first time to recognize it as malignant. He could not even call a hard tumor a "scirrhus" if by that term he meant a definitely cancerous lesion. A suspicious growth could at best be considered only potentially malignant until its subsequent behavior could be ascertained.

Some form of humoral disease theory remained in vogue from the time of Galen until well into the 19th century. Since the 1500s, several powerful attacks on Galenist doctrine had been made, most notably by Paracelsus, "the Luther of medicine" (25), in the 16th century, and van Helmont in the 17th. In his 17th century work on fevers, Willis also explicitly rejected traditional Galenistic theory when he states, "We do not allow of the Opinion of the Ancients, That the Mass of Blood consists of the four Humours, viz Blood, Flegm, Choler, and Melancholy" (26).

"Iatrochemistry," a modified form of humoralism emphasizing hermetic chemical concepts rather than the traditional Galenic humors, increased in popularity over the course of the 17th century, so that by the century's end traditional Galenism was considered antiquated by the more progressive physicians (27).

Nevertheless, popular theory of tumor causation throughout most of the 17th century continued to embrace vital, humoral theory, in the form of the so-called "lymphatic humoralism" of Astruc and Peyrilhe (28). The lymphatic vessels had been discovered in 1628, and scirrhus was now considered to be the product of an abnormal accumulation of lymph, which could later degenerate into cancer (29).

Needless to say, the various humoral systems of disease failed to provide the physician the practical knowledge required to practice medicine effectively. In the words of William Osler, "What disease really was, where it was, how it was caused, had not even begun to be discussed intelligently" (30).

Practicing physicians were very aware of this shortcoming. In the 17th century, Sydenham's concentration on the clinical characteristics of disease (31), and in the 18th, Morgagni's emphasis on anatomical pathology (32), represented attempts at bringing medical theory closer to the bedside.

Unfortunately, however, these efforts had little immediate impact in the field of tumor medicine. As a matter of fact, the clinical antecedents of malignancy were understood little better in the first half of the 19th century than they had been in the 16th, as may be noted from a perusal of some representative writings of the period. For example, Buchan, writing in 1816, provided the following list of the common antecedents to tumor appearance:

This disease is often owing to suppressed evacuation; hence it proves so frequently fatal to women of a gross habit ... It may likewise be occasioned by excessive fear, grief, anger, religious melancholy, or any of the depressing passions ... It may also be occasioned by the long continued use of food that is too hard of digestion, of an acrid nature; by barrenness, celibacy, indolence, colds, blows, friction, pressure or the like ... Sometimes the disease is owing to an hereditary disposition. (33)

Buchan's list is very similar to that of Boerhaave's, written a century earlier, elements of which could, in turn, be traced to classical sources:

The cause of a Cancer is ... An alteration in the Circulation of Humors, from the Menstrua, Hemorroids or any other Hemorragy being suppress'd; Barrenness, abstinence from all Venereal Acts; the leaving off of Child-bearing from the Age of 45, to 50; An austere, sharp or hot Diet; the several and even contrary Affections of the Mind, whether Melancholy or Anger, and the like; Any external irritation of the Schirrus by it's Motion, Heat and Acrimony; or Medicines which ... will produce the same Effect, whether outwardly or inwardly applied. (34)

The mention of "melancholy" by both Buchan and Boerhaave is rooted in the Galenic concept of the melancholic (black) humors, an excess of which was thought to be the ultimate cause of cancer (35). Such thinking had not progressed noticeably from the attitude of the 16th century surgeon who considered malignancies to be caused by the "humors Melancholicke which come from all the partes of the bodie" (36).

The most important clinical observation of the period was Pott's recognition of the increased incidence of scrotal cancer in chimney sweeps, which he reported in 1775 and again in 1778 (37). Thomas, writing in the early 19th century, included this observation in his section on the subject (38). Otherwise, however, he merely recited the various causes listed by earlier authors. If anything, mid-19th century textbook authors had even less to say regarding the clinical antecedents of cancer than had their predecessors. The old concepts were noted to be fallacious, but nothing new replaced them.

From a pathologist's standpoint, knowledge of cancer likewise remained rudimentary. During the first four decades of the 19th century, one had to rely upon the naked eye, without the aid of significant magnification, to make tissue diagnoses. Little wonder then that there remained great difficulty in diagnosing malignancy by appearance alone. Authorities of the period tended to lump true cancers into the same category as other "tumors," including tubercle (at that time not considered to result from an infectious disease), melanosis, and encephaloid (39).

With the work of Bichat, published in the first years of the 19th century (40), patholo-gists began thinking more on the tissue level of disease. However, Bichat's studies were carried out without the aid of a microscope, and before the development of these instruments in the 1820s and 1830s, no real advances in tumor histology could be made.

The real breakthrough in pathology came with recognition of the cell as the ultimate structural component of the body. The first description of cancer cells, or "globular bodies," was made by Gluge in 1837 (41). Cell theory had actually begun with the botanists in the first quarter of the 19th century (42). Schwann broadened this concept to include animals in 1838. The same year, Müller recognized the true cellular nature of malignancies (43). With the aid of microscopes of improved accuracy, the new cell theory gradually came to replace the time-honored belief, derived ultimately from the writings of Aristotle, that the fiber constituted the ultimate structural component of life (44).

By the middle of the 19th century, through the pioneering work of Müller and others, a primitive classification system based upon the microscopic appearance of tumor tissue had been devised. Tumors were divided into three main groups: scirrhus, com posed predominantly of fibrous tissue, and therefore firm; colloid, made up of locula-tions containing a gelatinous substance termed "blastema;" and cephaloma or medullary, composed predominantly of recognizable cells (45,46). This last form of malignancy, said to resemble brain tissue, was also at times called "encephaloid" (47), a term probably first used by Bayle and Laennec (48).

One would think that once tumors were found to differ significantly in microscopic appearance, their true diversity would also come to be recognized. Surprisingly, however, such was not the case. All malignancies were still considered variants of a single disease, and different types of cancer, properly speaking, were not thought to exist. Watson offers a defense for this position:

You may ask upon what principle structures so dissimilar in their physical appearance have been assigned to the same genus? Why, for these reasons. They are all strictly destructive or malignant forms of disease. Although in any shape they are of somewhat rare occurrence, yet when they do occur, two, or all three of the species are often found to coexist in different organs of the same individual ... More than this: if a tumour consisting of one species be amputated, and a fresh growth springs (as too often it does) from the same spot, this secondary growth is frequently of another species ... (T) he facts I have just stated suggest the question, whether instead of being different species of the same genus, they ought not rather to be regarded as mere varieties of the same species. (49)

EARLY CONCEPTS OF INFECTIOUS DISEASE: CONTAGION AND MIASMA

While concepts of tumor morphology had changed markedly by the middle of the 19th century, infectious disease theory had not. Such changes were not to occur until several decades later. As a matter of fact, in the United States, owing to the conservatism and scientific backwardness of the American medical profession, theories of infectious disease remained more or less unchanged until the early 1880s (50).

Throughout the 18th and most of the 19th centuries, infectious diseases were considered to be of two major types, contagious and miasmal. The former, represented by such diseases as smallpox, were observed to be transmitted from one individual to another. The latter, the prime example of which was "intermittent fever," were not spread by contact, but rather were observed to affect numerous people in a community in a short period of time (51). Such diseases were therefore thought to be transmitted by a noxious "effluvia" exhaled by areas of rotting vegetation, such as marshes. The term "malaria" came to be used synonymously for this marsh miasm (52).

Regarding this latter form of disease spread, Gregory, in a well-known textbook of the period, stated, "It cannot be disputed that the miasmata of marshes are the most frequent and important exciting causes of intermittent fever" (53). Similarly, Rush considered yellow fever to be "produced by the exhalations from the gutters, and the stagnating ponds of water" (54).

Gallup, in his classic 1815 work on the epidemic diseases of Vermont, defined the two types of diseases in the following manner. Contagion is illness "eliminated from the diseased body in a subtle gas, or by contact, (producing) its likeness in a healthy body," while miasma "is the effect of animal and vegetable decomposition and corruption on the surface of the earth ... eliminating therefrom in the form of a subtle gas or effluvia" (55).

Gallup's description of contagion may have been influenced by the writings of Cullen. Already in the 18th century, the latter had recognized the somewhat arbitrary nature of the distinction between contagion and miasma, and argued that both types of disease spread involved emanations into the atmosphere, one of human (contagion), the other of nonhuman (miasmatal) origin (56). He went on to suggest the use of the terms "human" and "marsh" effluvia rather than the general terms "contagion" and "miasma" (57). Cullen's suggestion was not generally accepted, however, and this modification, considered somewhat trivial to modern readers, left the underlying traditional theory intact.

Understandably, the decision as to whether a particular disease was miasmal or contagious was sometimes not an easy one to make. Thus, in a footnote to the first page of Armstrong's 1829 work on typhus, his editor stated the following:

When Dr. Armstrong wrote this article he considered human contagion the primary source of the disease. Since then, however, he has abandoned this opinion, and now believes that marsh effluvium is the cause ... Some very eminent physicians in this country ... still believe in the contagious nature of this disease. (58)

Factions were formed, and debate ensued, sometimes heated, as to the mode of transmission of a particular disease. One example of such an exchange was the 1859 argument between contagionist and noncontagionist factions over the origin of yellow fever (59).

Still other authors, such as Stokes (60), expressed the opinion that no theory could satisfactorily explain all examples of infection. Despite the shortcomings of this dichotomous distinction, no one offered a clear alternative until the advent of the zymogen theory, to be discussed later.

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