Structure and Origin of Uterine and Extragenital l=ibroids Induced Experimentally in the Guinea Pig by Prolonged Administration of Estrogens* Alexander Lipschotz, M.D., and Louis Vargas, Jr., M.D. (From Department o/ Experimental Medicine, National Health Service o/the Republic o/Chile, Santiago, Chile) (Received for publication December 13, x94o) The purpose of this communication is to present the These experimentally induced abdominal tumors findings of a detailed microscopical study of the sites present a smooth surface formed of a capsule com- of origin and stages of development of the subserous posed of flattened superficial cells (Plate 2, Figs. 2-A fibroid tumors induced in guinea pigs by prolonged and 2-B). The cells beneath the capsule resemble administration of estrogens. Details of treatment of fibroblasts. These cells have definite boundaries or the animals are given in the explanations of Plates I- 5. they are separated from each other by collagenous Subserous uterine tumors which can be induced in fibers (Plate 4, Fig. ix-C). guinea pigs by prolonged administration of estrogens, The masses of fibroid tumors arising from the apex as described by Nelson (26, 27), were found to be of the uterine horn may enclose the tubes or large fibroids. Lipschiitz, Iglesias, and Vargas (i3, 18, 22) tubal cysts. The demarcation between the muscular have shown that extragenital tumors in the abdominal coat of the tube and the tumor is not always sharp. cavity, induced by estrogens, also were fibroids. The In some instances, especially when the apical fibroid localization of these tumo~:s at various sites on the is small, the tumor is in close contact with an abun- uterus, pancreas, kidney, spleen, etc., have been de- dance of smooth muscle and adipose tissue (Plate 2, scribed by Iglesias (5), Vargas and Lipschiitz (32), Fig. 2-B), whereas the fibroid itself, to whose area the Bellolio (1), Murillo (25), Rodrlguez (3 o), and Lip- muscle tissue belongs, is covered with a capsule (Plate schlitz, Iglesias, and Vargas (15). Several examples of 2, Fig. 2-A). In some places fibrous tissue may also be uterine and extragenital fibroid tumors, induced in in direct contact with adipose tissue (Plate 4, Fig. guinea pigs treated with estradiol monobenzoate, are I I-A). Small epithelial tubes, probably belonging to shown in Plate i. We have demonstrated that similar the Wolffian body (Plate 2, Fig. 2-B) may be found fibroids at these sites can be induced by administra- surrounded by muscle tissue or connective tissue, as tion of all natural estrogens (estradiol, estrone, estriol) previously described by Lipschiitz (io). These fea- free or esterified (dipropionate, caprylate, benzoate- tures indicate that the apical fibroid is a tumor of the butyrate). Similar results were obtained by the ad- mesosalpinx. In the untreated normal animal patches ministration of such artificial estrogens as stilbestrol, in of compact smooth muscle may also be found near the the free form, by Lipschiitz and Vargas (I9), or esteri- tube. These masses of muscle probably hypertrophy fled, by Lipschiitz, Vargas, and Bruzzone (2i) or by under the influence of the estrogen, and are found hexestrol, by Lipschiitz and Egana (I2). subsequently in contact with, or incorporated in, the growing fibroid. GENERAL CHARACTERISTICS OF FIBROIDS Apical uterine fibroids occurred only in castrated The central portion of a typical large apical uterine females treated with estrogens. On the other hand fibroid is composed predominantly of fibrous tissue fibroids occurred at other sites in the abdominal cavity with few cells scattered between the bundles of fibers. in both normal and castrated guinea pigs. In some areas bundles of smooth muscles may be Abdominal fibroids can be induced experimentally found; in others the loose fibrous tissue may be edema- by estrogens both in noncastrated and castrated males. tous. These characteristics are shown in Plate 2, Figs. But larger quantities of estrogens administered over I-A, I-B, and I-C. longer periods of time are required to bring about * This investigation was aided by grants from The Ella Sachs these tumors in males than in females. The histologi- Plotz Foundation for the Advancement of Scientific Investigation, cal structure of the fibroids is the same in the males from The Jane Coffin Childs Memorial Fund for Medical Re- as in the females. Nevertheless, there is a pronounced search, from Mr. Adolfo Eastman (Limache, Chile), and by sex specificity in the collagenous tumoral reaction, as special Government funds for research work, by courtesy of the Minister of Health of the Republic of Chile. described by Koref, Lipschiitz, and Vargas (7), Jed- 236 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 1941 American Association for Cancer Research. Fibroid Tumors Induced in Guinea Pigs 237 licky, Lipschiitz, and Vargas (6), Chaume (i7), tumoral proliferation of the mesothelium of the serosa Szab6 (3i), and Palma (28). and of the endothelium of vascular and lymphatic In the castrated male a fibroid tumor is formed also spaces, or of the cells of the mesenchyme which are at the site of ligature of the spermatic cord. These in immediate contact with the endothelium. inguinal tumors, like the apical uterine tumors, may be In i938 LipscMitz, Vargas, and Iglesias (22) de- rich in smooth muscle. scribed an example of apparent proliferation of the As Lipschiitz (ii) has pointed out the structure of endothelium of vascular or lymphatic spaces in a fibroid the experimentally induced fibroid tumor of the male of the abdominal wall. In the past i8 months many or female guinea pig differs considerably from the additional observations have been made. Typical ex- spontaneous fibromyoma in women. In the experi- amples are shown in a series of sections of small mental fibromyoma there is much less order, particu- intramural fibroids of the uterus of a guinea pig larly in the arrangement of the fibrous tissue. The treated for 3 months with estrone (Plate 3, Figs. io-A compact myomatous tissue shows an orderly arrange- to Io-F). The cleft in the muscular septum between ment in both types of tumor. Another important dif- the uterine horns (Fig. Io-A) is lined with endo- ference is the abundance of fibroblasts near the capsule thelium and may be a lymphatic or vascular space. in the experimentally induced tumor (Plate 2, Fig. 2-A; A fibroid is in process of formation in the myometrium Plate 4, Figs. I I-B and r I-C). In addition numerous (Fig. Io-B). Neoformation of tumoral tissue here ap- cells of other types, some with pyknotic nuclei, may pears to be intimately related to the underlying cells be found in these fibroids (Plate 2, Fig. 3). of the mesenchyme and not with the endothelium. Small nodules or excrescences, called "tumoral seed" The club of tumoral tissue consists at its base of dense (Plate 2, Figs. 4-A and 4-B) deserve special attention. fibrous tissue and at its periphery of spindle cells, These have been found by Vargas and Lipschiitz (32) easily distinguishable from the muscle fibers of the on the inner abdominal wall, the surface of the stom- myometrium in which the fibroid is growing (Fig. ach, the spleen, and elsewhere. Their structure is io-C). The cells of the small nodule shown in Figs. similar to, though not always identical with, the typi- i o-D and i o-E are different from the spindle cells of cal experimental fibroid. Cells rich in cytoplasm may Fig. i o-C. These cells have the appearance of under- predominate in these small nodules (Plate 2, Fig. 5) going necrosis. In Fig. io-F definite evidence of necro- and an intimate relation with the mesothelial cells of sis is shown. the serosa is often evident. The structure of some of Another aspect of cellular proliferation is shown in these small nodules is the same as that of the large Plate 4, Fig. x I-A, from a splenic tumor. At the top fibroids. The cells at the periphery have the shape of the tumor is infiltrating the pancreas. But the contact fibroblasts and there is an abundance of fibrous tissue of the tumor with the pancreas is incomplete, so that in the center. In general these small excrescences seem a cleft remains between the two. There is abundant to have a strong tendency to undergo sclerotization, cellular proliferation in this cleft. These cells may be as shown in Plate 3, Figs. 6-A and 6-B. Although it is mistaken for proliferating endothelium; more prob- probable that the small excrescences may develop into ably they are the cells of the peripheral layer of the large fibroids it is not likely that every small nodule tumor, as shown also in Plate 4, Figs. I2-A and 14. or tumor seed of this type is potentially a large fibroid. One may find also an accumulation of cells sur- Apparently their development into large tumors is rounded by adipose tissue, as in Plate 4, Fig. i3, from often interrupted by sclerotization. a tumor of the hilum of the spleen. These accumula- tions are rich in blood vessels, as shown in Plate 4, ABUNDANCE OF CELLS Fig. I2-B, from an apical tumor. The processes re- sponsible for this accumulation of cells appear to be In our experimental animals there was often a re- intimately related to the blood vessels. One may as- markable augmentation of the mesothelium of the sume that the accumulation of cells around the blood serosa, as shown in Hate 3, Figs 7-A and 7-B. Al- vessels is due to proliferation of mesenchyme cells though the dii~erence between the serosal cells of underlying the endothelium, but the question is far normal guinea pigs and guinea pigs under treatment from being settled.