there is undoubted tumor-growth. No sharp demarcation can be established. In the substance of the organs adenomata occur as nodular tumors, usually singly and well circumscribed, and not rarely surrounded by a fibrous capsule. They are moderately firm, and on section whitish or pink in color. Sometimes cystic change occurs as the result of dilatation of the glandular acini or in consequence of degenerative softening; in these cases the consistence is correspondingly altered.

Seats. Among the situations in which adenoma is frequent may be mentioned the mucous membranes, the skin, and certain organs, notably the mammary gland, liver, kidney, suprarenal bodies, thyroid gland, and ovaries. Clinically important seats are the pylorus, the duodenal papilla, the rectum, and the uterus. In these situations adenomata spring from the epithelial tubules or mucous glands. In the skin the points of origin are the sebaceous and sweat-glands.

Structure. The definition in general indicates the structure of these tumors. They are more or less typical; that is to say, there are acini of normal appearance presenting a single layer of columnar epithelium, with perhaps in places a tendency to heaping up the several rows of epithelial cells. These acini are well inclosed by a surrounding connective-tissue reticulum, and the appearance of normal gland-tissue is thus produced. Unlike normal glands, there are no excretory ducts, or at most imperfectly developed ducts.

Two varieties of adenoma are sometimes distinguished, the tubular and the racemose or alveolar. In the former the glandular system is simple and consists of tubular formations lined with columnar epithelial cells; in the latter the appearance is that of more complicated glands with closely aggregated acini of circular outline containing columnar and often cubical or polyhedral cells. The number of varieties may be carried further, however, for in the liver the adenomata resemble the normal liver-structure rather than the ordinary glandular formation above described, while in the suprarenal capsules and kidney the appearance is that of slightly atypical suprarenal structure, or in other cases that of embryonal renal tubules.

With the further growth of adenomata the appearance may be little changed. In other cases considerable variations occur, and there is a tendency, more marked in some situations than in others, to active proliferation of the epithelium, which may cause a considerable alteration in the appearance of the tumor, and eventually transformation into definite carcinoma. In other cases the structure from the beginning is so atypical and the epithelial proliferation so irregularly active that the term adenocarcinoma is applicable.

The connective-tissue stroma of adenomata may be moderate in quantity or may be considerable. In some adenomatous

proliferations of the mucous membranes the number of glandacini or tubules may be relatively small, while the interglandular connective tissue shows active round-cell infiltration to a very considerable degree. Sometimes the interglandular tissue is distinctly sarcomatous (adenosarcoma). In other instances the bulk of the tumor may consist of connective tissue of fibrous character in which are embedded a relatively small number of glandular alveoli. In all of these cases it is difficult to determine whether the connective-tissue process was primary and the epithelial secondary, or the reverse.

Secondary changes are common, the adenomata of the stomach and uterus being particularly prone to change their character to that of carcinoma. In these cases there may be noted active proliferation of the epithelial cells, so that the acini or alveoli become completely filled, or that the ends of the tubular structures become blocked up. There is a tendency to extension of epithelial infiltration beyond the limits of the acini, cancerous outgrowths being the result. In other cases the malignancy is manifested by the excessive epithelial proliferation in the form of new acini of irregular character (Fig. 63). This form is known

५

FIG. 63.-Destructive adenoma (Beyea).

as destructive adenoma, adenoma destruens, or adenocarcinoma. Eventually the tumor may become purely carcinomatous; in other cases, however, it continues to increase in size, always retaining its adenocarcinomatous appearance, but never becoming typically carcinomatous.

Degenerative changes may be met with as in other tumors. Hyaline transformation or production may give the tumor an

appearance justifying the term "cylindroma" or "cylindro-adenoma." Such cases are rare. Myxomatous and even calcareous change may sometimes be observed. The connective-tissue stroma may proliferate actively and assume sarcomatous appearancesadenosarcoma. Cystic change may result from gradual dilatation of the glandular acini or from distention of normal ducts or alveoli of the gland in which the tumor occurs. In these cases the term cystic adenoma or cyst-adenoma is applicable (Fig. 64).

Nature.-Adenomata are benign tumors. In some cases, however, a pure adenoma may give rise to metastasis. Those of the liver, for example, not rarely cause secondary deposits in the spleen and less frequently elsewhere. The adenomata of the thyroid gland similarly cause metastasis, though it is less certain that these are to be considered as pure adenomata. Destructive adenomata or adenocarcinomata are malignant in proportion to the amount of carcinomatous transformation.

The effect of adenomata on the general health is variable. They do not contribute to the organic metabolism as far as is known, though occasionally biliary pigmentation of the adenomata of the liver and the secretion of milk-like fluid in mammary adenomata evidence the partial preservation of function by the cells. The general health may be unfavorably influenced by

adenomata of the mucous surfaces in consequence of their interference with normal functions or in consequence of secondary ulceration and hemorrhage.

CARCINOMA.

Definition. The term carcinoma or cancer may be applied to tumors in which epithelial proliferations in the form of solid blocks or columns, or in the form of atypical acini, separated by more or less connective tissue, present themselves, the epithelial proliferation showing a tendency to extend beyond normal anatomic limits. It is extremely difficult to construct a definition that will be universally applicable. Some have regarded the tendency of the epithelial proliferation to break through the normal limits and extend beyond the confines of the epithelial structures from which it rises, as the important fundamental element of carcinoma. Others have held that there is a peculiar atypical character in the epithelial cells themselves, shown by irregular cell-division, hyperchromatosis, and other features. The older authors believed that polymorphism and certain irregularities of cell-contour suffice to distinguish carcinoma-cells from normal cells or those of other tumors; but this polymorphism is now recognized to be the result entirely of compression in the growth of the tumor, and to be therefore accidental. Some have believed that the term carcinoma should include all epithelial tumors giving rise to metastasis, but this necessarily restricts the term too greatly on the one hand, and, on the other hand, includes certain tumors probably purely adenomatous. I prefer to regard as carcinoma any epithelial growth atypically reproducing certain glandular or other structures and showing a manifest tendency to irregular

extension.

Etiology. The causes and nature of carcinoma are still obscure. A number of theories have been offered. These may be considered under different headings.

(a) Congenital Theory. The theory of Cohnheim regarding the etiology of tumors in general is less applicable to cancer than to certain other growths. There are a few examples, however, which would seem to prove that misplaced epithelial cells undergo carcinomatous proliferation; for example, there are cases of apparently primary carcinoma springing from bones which would seem to require this explanation. It is not always certain, however, that such cases are actually primary. They may represent metastases from small primary growths which have escaped notice. The rarity of carcinomata in early life would seem to negative the congenital theory, and at all events would show that other influences of importance are requisite. Of late, a number of hypotheses that in a measure contain the idea of congenital

origin have been put forward to explain the formation of carcinoma. In these there are assumed some form of peculiar irregularity in cell-multiplication, and a tendency to independent proliferation supposed to originate in faulty development. These hypotheses are vague and uncertain.

(b) Traumatic Theory.-Clinicians are inclined to give great weight to this. A single traumatism probably has little importance, though women frequently state that they recall distinct injuries from which carcinoma of the breast has seemed to originate. It must be recalled that such injuries are sustained by practically every woman, and the presence of carcinoma would readily be attributed to a preceding hurt. In cases of epitheliomata of the lip in pipe-smokers, in the carcinomata of the scrotum and limbs in chimney-sweeps and paraffin-workers, and in cases of uterine carcinomata following laceration of the cervix, the effect of chronic irritation would seem to be important.

(e) Parasitic Theory. The peculiar growth of cancer, its destructiveness of the general health, and its metastasis readily suggest an infective origin. Bacteriologists sought to isolate micro-organisms without success; later investigators have turned their attention to low forms of animal life, protozoa. (For further discussion, see Animal Parasites.) A few successful experiments have been made at implantation from man to animals, or from one animal to another; but as Hanau, one of the few successful experimenters in this work, himself states, these experiments do not prove infectiousness. The secondary growths in the second animal may be simply of the nature of metastasis, due to implantation of the cancer-cells and subsequent proliferation. Occasionally an endemic occurrence of carcinoma has been claimed, and some authors have even referred to houses in which carcinoma frequently

arose.

(d) Tumor-dyscrasia. This indefinite term is supposed to indicate a tendency to cancer-growth probably due to peculiarities of the liquids of the body. No proof of the existence of any definite dyscrasia has ever been furnished, though it is apparent on study that some form of disposition to this growth acts as the predisposing cause, even if traumatism, infection, or other factors are the immediate cause.

Age plays an important part in the formation of carcinoma, as this tumor is essentially one of advanced years. Among 275 cases collected by Lubarsch, 55.6 per cent. occurred between the ages of forty-five and sixty-five. There were a few instances in childhood and early life. Between fourteen and nineteen there were 1.46 per cent.; between twenty and twenty-five, 1.8 per cent.; between twenty-six and twenty-nine, 1.1 per cent. The frequency in later life was formerly ascribed to some alteration in